european heart rhythm association (ehra) endorsed by...

European Heart Rhythm Association (EHRA)

position paper on arrhythmia management and

device therapies in endocrine disorders

endorsed by Asia Pacific Heart Rhythm Society

(APHRS) and Latin American Heart Rhythm

Society (LAHRS)

Bulent Gorenek (Chair)1 Giuseppe Boriani2 Gheorge-Andrei Dan3

Laurent Fauchier4 Guilherme Fenelon5 He Huang6 Gulmira Kudaiberdieva78

Gregory YH Lip910 Rajiv Mahajan11 Tatjana Potpara12 Juan David Ramirez13

Marc A Vos14 and Francisco Marin (Co-Chair)15

ESC Scientific Document Group Carina Blomstrom-Lundqvist16 Aldo Rinaldi17

Maria Grazia Bongiorni18 Elena Sciaraffia19 Jens Cosedis Nielsen20

Thorsten Lewalter21 Shu Zhang22 Oswaldo Gutierrez23 Abdel Fuenmayor24

1Eskisehir Osmangazi University Eskisehir Turkey 2Cardiology Division Department of Diagnostics Clinical and Public Health Medicine University of Modena and ReggioEmilia Policlinico di Modena Modena Italy 3University of Medicine and Pharmacy ldquoCarol Davilardquo Colentina University Hospital Bucharest Romania 4Centre HospitalierUniversitaire Trousseau et Universite Francois Rabelais Tours France 5Hospital Israelita Albert Einstein S~ao Paulo Brazil 6Renmin Hospital of Wuhan University WuhanChina 7Adana Turkey 8Center for Postgraduate Education and Research Bishkek Kyrgyzstan 9Institute of Cardiovascular Sciences University of Birmingham Birmingham UK10Aalborg Thrombosis Research Unit Department of Clinical Medicine Aalborg University Aalborg Denmark 11The University of Adelaide Lyell McEwin Hospital RoyalAdelaide Hospital and SAHMRI Adelaide Australia 12School of Medicine Belgrade University Cardiology Clinic Clinical Centre of Serbia Belgrade Serbia 13ClinicaCardioVid Medellın Antioquia Colombia 14Umc Utrecht Utrecht Netherlands 15HU Virgen de la Arrixaca Murcia Spain 16Department of Medical Science andCardiology Uppsala University Uppsala Sweden 17St Thomasrsquo Hospital London UK 18Santa Chiara University Hospital of Pisa Pisa Italy 19Uppsala University HospitalUppsala Sweden 20Aarhus University Hospital Aarhus Denmark 21Peter Osypka Heart Center Munich Germany 22Beijing Fuwai Hospital Beijing China 23HospitalClinica Bblica San Jose Costa Rica and 24Electrophysiology and Arrhythmia Section Cardiovascular Research Institute University Hospital of The Andes Avenida 16 deSeptiembre Merida 5101 Venezuela

Received 19 February 2018 editorial decision 22 February 2018 accepted 25 February 2018

Endocrine disorders are associated with various tachyarrhythmias including atrial fibrillation (AF) ventricular tachy-cardia (VT) ventricular fibrillation (VF) and bradyarrhythmias Along with underlying arrhythmia substrate electro-lyte disturbances glucose and hormone levels accompanying endocrine disorders contribute to development ofarrhythmia Arrhythmias may be life-threatening facilitate cardiogenic shock development and increase mortalityThe knowledge on the incidence of tachy- and bradyarrhythmias clinical and prognostic significance as well as theirmanagement is limited it is represented in observational studies and mostly in case reports on management ofchallenging cases It should be also emphasized that the topic is not covered in detail in current guidelinesTherefore cardiologists and multidisciplinary teams participating in care of such patients do need the evidence-based or in case of limited evidence expert-opinion based recommendations how to treat arrhythmias using con-temporary approaches prevent their complications and recurrence in patients with endocrine disorders In recog-nizing this close relationship between endocrine disorders and arrhythmias the European Heart RhythmAssociation (EHRA) convened a Task Force with representation from Asia-Pacific Heart Rhythm Society (APHRS)

Corresponding author Tel thorn905424312483 E-mail address bulentgorenekcom

Published on behalf of the European Society of Cardiology All rights reserved VC The Author(s) 2018 For permissions please email journalspermissionsoupcom

Europace (2018) 0 1ndash30 EHRA POSITION PAPERdoi101093europaceeuy051

Downloaded from httpsacademicoupcomeuropaceadvance-article-abstractdoi101093europaceeuy0514939247by kutuphane useron 03 April 2018

and Sociedad Latinoamericana de Estimulacion Cardıaca y Electrofisiologıa (SOLAECE) with the remit of compre-hensively reviewing the available evidence and publishing a joint consensus document on endocrine disorders andcardiac arrhythmias and providing up-to-date consensus recommendations for use in clinical practice

Keywords Endocrine disorders bull Arrhythmias bull Atrial fibrillation bull Ventricular arrhythmias bull Cardiac implantableelectronic device bull Pacemaker bull Implantable cardioverter-defibrillator bull Catheter ablation bull Diabetes

bull Thyroid disorders bull Hyperthyroidism bull Hypothyroidism bull Pheochromocytoma bull Growth hormonedysfunction bull Hyperaldosteronism bull Adrenal insufficiency bull Parathyroid disease bull Stroke bull Oralanticoagulation bull EHRA position paper

Table of Contents

Introduction 2Evidence review 2

Mechanisms and pathophysiology of cardiac arrhythmias in endocrinedisorders 2

Management of arrhythmias in specific endocrine disorders 3Pancreas dysfunction 3

Diabetes mellitus 3Thyroid dysfunction 10

Hyperthyroidism 10Hypothyroidism 11Amiodarone-induced thyroid dysfunction 14

Pheochromocytoma 18Growth hormone dysfunction 19

Acromegaly 19Growth hormone deficiency 19

Diseases of adrenal cortex 20Hyperaldosteronism 21Adrenal insufficiency 20

Parathyroid disease 21Sex hormones-related differences in the risk of arrhythmias 21

Stroke risk assessment and prevention of arrhythmias associated withendocrine disorders 22

Catheter ablation of arrhythmias associated with endocrine disorders 23Device-based therapy of arrhythmias in patients with endocrine

disorders 23Current research gaps ongoing trials and future directions 24

Introduction

However the ultimate judgement on the care of a specific patientmust be made by the healthcare provider and the patient in light of allindividual factors presented

Evidence reviewThis document was prepared by the Task Force with representationfrom EHRA APHRS and SOLAECE and peer-reviewed by official ex-ternal reviewers representing EHRA HRS APHRS and SOLAECETheir members made a detailed literature review weighing thestrength of evidence for or against a specific treatment or procedureand including estimates of expected health outcomes where dataexist In controversial areas or with respect to issues without evi-dence other than usual clinical practice a consensus was achieved byagreement of the expert panel after thorough deliberation

In contrast to guidelines we opted for an easier and user-friendlysystem of ranking using lsquocoloured heartsrsquo that should allow physiciansto easily assess the current status of the evidence and consequent guid-ance (Table 1) This EHRA grading of consensus statements does nothave separate definitions of the level of evidence This categorizationused for consensus statements must not be considered as directlysimilar to that used for official society guideline recommendationswhich apply a classification (Class IndashIII) and level of evidence (A B andC) to recommendations used in official guidelines

Thus a green heart indicates a lsquoshould do thisrsquo consensus statementor indicated treatment or procedure that is based on at least onerandomized trial or is supported by strong observational evidencethat it is beneficial and effective A yellow heart indicates generalagreement andor scientific evidence favouring a lsquomay do thisrsquo state-ment or the usefulnessefficacy of a treatment or procedure A lsquoyellowheartrsquo symbol may be supported by randomized trials based on a smallnumber of patients or which is not widely applicable Treatment strat-egies for which there is scientific evidence of potential harm andshould not be used (lsquodo not do thisrsquo) are indicated by a red heart

Mechanisms and pathophysiologyof cardiac arrhythmias inendocrine disorders

A number of cardiac arrhythmia mechanisms may underlie ventricu-lar and atrial arrhythmias such as reentry abnormal automaticity ortriggered activity Normally these mechanisms are not active in anormal (young) heart The only exceptions are inherited arrhythmiasyndromes in which cardiac remodelling may be present that makethe heart more vulnerable often under specific circumstances likethe excess of catecholamines

Acutely hormones can play a crucial role such as in catecholamine-induced polymorphic VT induced by exercise or in the long QT syn-drome (LQTS) induced either by sleep fear or excitement Often thechallenge provided acutely by these hormones exceeds the safety mar-gins (=reserve) of the vulnerable heart to overcome and ventricular ar-rhythmias ensue Thus endocrine disorders may play an acute role inthe triggering of cardiac arrhythmias (Figure 1)

However there are also chronic adaptations induced by endocrinedisorders that can underlie the formation of arrhythmias The action po-tential is controlled by numerous ion currents that either provides in-ward or outward currents It is this delicate balance that shapes the

2 B Gorenek et al


action potential and determines its duration often measured as QT-duration Overexpression or down-regulation of these ion currents canchronically increase or decrease conduction or repolarization reserve

A few examples have been listed

Diabetes mellitus In an experimental model mimicking diabetes type 1 itwas demonstrated that this metabolic disorder reduced repolarizationreserve by decreasing the outward current lsquoslowly delayed rectifier (IKs)rsquoin the rabbit thereby increasing the liability for drug induced Torsade dePointes1 More recently it has been suggested that the transcription ofion channels due to the involvement of the P13K pathway is responsiblefor this reduced transcription2

Gender differences The incidence and prevalence of AF and sustained ven-tricular arrhythmias and sudden cardiac death (SCD) are lower in womenthan in men However women have a greater chance to developTorsade de Pointes arrhythmias3 It has been shown that sex hormonesaccount for most of the differences in the cardiac electrophysiologicalproperties observed between females and males Human data demon-strate that the expression of a number of potassium channels is reduced

in females accounting for a prolonged duration of the ventricular actionpotential4 Testosterone reduces the ventricular action potential duration(APD) by enhancing the slow delayed rectifier current and by increasingthe l-type calcium current4

Adrenal dysfunction Glucocorticoid has been reported to be important forthe maintenance of membrane Calcium transport in the cardiac sarcoplas-mic reticulum and for the regulation of various ion channels including IKsand the rapid delayed rectifier (IKr) thereby manipulating QT duration5

Management of arrhythmias inspecific endocrine disorders

Diabetes mellitusDiabetes mellitus (DM) type 1 (reduced insulin production) or type 2(increased resistance to insulin) may increase the risk of cardiac ar-rhythmias via many factors including (i) cardiovascular risk factors (eghypertension) (ii) atherosclerotic cardiovascular disease [ie coronary

Table 1 Scientific rationale of recommendationsa

Definitions where related to a treatment or

procedure

Consensus statement

instruction

Symbol

Scientific evidence that a treatment or procedure is

beneficial and effective Requires at least one

randomized trial or is supported by strong observa-

tional evidence and authorsrsquo consensus (as indicated

by an asterisk)

lsquoShould do thisrsquo

General agreement andor scientific evidence favour

the usefulnessefficacy of a treatment or procedure

May be supported by randomized trials based on a

small number of patients or which is not widely

applicable

lsquoMay do thisrsquo

Scientific evidence or general agreement not to use or

recommend a treatment or procedure

lsquoDo not do thisrsquo

aThis categorization for our consensus document should not be considered as being directly similar to that used for official society guideline recommendations which apply aclassification (IndashIII) and level of evidence (A B and C) to recommendations

Slowed conduction - fibrosis

Neuro hormones = Trigger

Ectopy (non) sustained VT and VF when

conduction andrepolarisation reserve

Intracellular Ca handling ndash prolonged repolarization

Reentry

inherited

disease

Abnormal Automaticity Triggered activity

Figure 1 Mechanism of arrhythmias in endocrine disorders The balance between the strength of the heart to de- or repolarize is often challengedby the autonomic nervous system When the balance is off the heart has to allow arrhythmias which can be based upon numerous arrhythmogenicmechanisms VF ventricular fibrillation VT ventricular tachycardia

EHRA position paper on arrhythmia management in endocrine disorders 3


artery disease (CAD) prior myocardial infarction (MI) stroke or per-ipheral arterial disease]6ndash8 and (iii) DM-associated factors such as glu-cose control diabetic neuropathy or cardiomyopathy (Figure 2)6910

The risk for arrhythmias or SCD in DM patients is closely related tothe presence and severity of underlying cardiovascular disease611ndash13

but the aforementioned DM-related factors could induce arrhythmiasindependently of cardiovascular comorbidities Management of cardiacarrhythmias in DM patients is outlined in Figure 3

Atrial fibrillationMany epidemiological studies have reported an association of DMwith incident AF1415 The duration of DM and glycaemic control werealso associated with AF (each year with DM conferred a 3 increasein the risk of AF)16 whilst HbA1c of gt9 was associated with a nearlytwo-fold increase in AF risk17 A meta-analysis of 11 studies with atotal of 108 703 AF cases in 1 686 097 subjects showed a 40 greaterrisk of AF in the presence of DM but the effect was attenuated afteradjustment for multiple risk factors [relative risk 124 95 confidenceinterval (CI) 106ndash144] whilst the population-attributable estimatefor AF owing to DM was 25 (95 CI 01ndash39)18 In several observa-tional studies the age-adjusted association of DM with incident AFwas no longer significant after multiple adjustments for hypertensioncardiovascular comorbidity body mass index or obesity19ndash21 thus

suggesting that strategies for AF prevention in DM patients shouldfocus on the control of DM-associated comorbidities (especially theweight and blood pressure control)19

Indeed in the ADVANCE (Action in Diabetes and Vascular DiseasePreterax and Diamicron Modified Release Controlled Evaluation) studyDM patients with AF (76) had significantly greater risks for all-causedeath cardiovascular death major cerebrovascular events and heart fail-ure compared with DM patients without AF Blood pressure loweringyielded similar relative risk reduction in all-cause and cardiovascular mor-tality but owing to their higher risk of these events the absolute benefitsfrom blood pressure control appeared much greater in AF patients22 Inthe VALUE (Valsartan Antihypertensive Long-term Use Evaluation) trialhypertensive patients with new-onset DM had higher rates of new-onsetAF compared with non-DM patients and were at higher risk of heart fail-ure23 Hence AF in DM patients should be viewed as a marker ofadverse outcome which should prompt aggressive management of allconcomitant risk factors (Figure 3)24 Importantly intensive glucose low-ering (target HbA1c lt60) has been associated with similar incident AFrates as a less stringent approach (HbA1c lt80) but with increasedrisk of death and other cardiovascular events17

Since asymptomatic (silent) AF is not uncommon especially inpatients with DM25 at least opportunistic screening for AF with pulsepalpation should be performed in DM patients as also recommended

Hypoglycemia Hyperglycemia HypokalemiaInsulin

reduction

Ischemia Catecholamines Oxidave stress

Alteredintercellular

coupling

Reduced Na+

channel function

Cardiacfibosis

Ca++ handlingabnormalities

K+ channelsdysfunction

downregulation

ABNORMALCONDUCTION

PROLONGEDREPOLARIZATION

- Na+ channel dysfunction- Gap junction uncoupling downup regulation- Reduced gap junction conductivity- Fibrosis

- Impaired APD adaptation- APD alternans- EADs and DADs- Abnormal Ca++ cycling

ARRHYTHMOGENESIS

Diabetic

Cardiom

yopathy

Abnormalionchannelfunction

Electricalremodeling

Autonomicdysregulation

Structuralremodeling

Altered m

olecular signaling

ReentryTriggered

activity

CV riskfactors

atheroscleroticCV disease

Diabetic

Neuropathy

Figure 2 Arrhythmogenesis in diabetes mellitus APD action potential duration CV cardiovascular DADs delayed after depolarizations EADsearly after depolarizations dark blue conditions white disorders yellow pathophysiologic and physiologic pathways dark grey contributing dis-orders and risk factors pink structural cellular and ion channel abnormalities blue mechanisms of arrhythmogenesis red electrophysiologicalabnormalities and arrhythmogenesis

4 B Gorenek et al


Figure 3 General principles of management of cardiac arrhythmias in patients with diabetes mellitus AADs antiarrhythmic drugs ACEi angioten-sin-converting enzyme inhibitor AFL atrial flutter AHI apnoea-hypopnea index ARB angiotensin receptor blocker AVNRT atrioventricular nodalre-entrant tachycardia AVRT atrioventricular re-entrant tachycardia BMI body mass index BP blood pressure CAD coronary artery diseaseCPAP continuous positive airway pressure CRT cardiac resynchronization therapy CV cardiovascular DM diabetes mellitus ECG electrocardio-gram HT hypertension ICD implantable cardioverter-defibrillator LA left atrium LV left ventricle MRI magnetic resonance imaging NOACsnon-vitamin K antagonist oral anticoagulants OAC oral anticoagulant therapy PM pacemaker SE systemic embolism VKA vitamin K antagonistVPBs ventricular premature beats VT ns ventricular tachycardia non-sustained



Figure 3 Continued

6 B Gorenek et al


Table 2 Randomized controlled trials of intensive vs standard glycaemic control in adult patients with diabetesmellitus

Study year Cohort size Drug Intensive

glucose

control

Follow-up Study outcomes

(intensive vs standard

glucose control)

Significant

hypoglycaemia

ADVANCE72

2008

11 140

DM type 2

Gliclazide HbA1c lt_65 Median 5 years Microvascular events

94 vs 109

HR 086 (077ndash097) P = 001

Macrovascular events

100 vs 106

HR 094 (084ndash106) P = 032

Cardiovascular death

45 vs 52

HR 088 (074ndash104) P = 012

All-cause death

89 vs 96

HR 093 (083ndash106) P = 028

27 vs 15

HR 186 (142ndash240)

P lt 0001

ACCORD54 2008

ACCORD53 2011

10 251

DM Type 2

known CV dis-

ease or CV risk

factors

Various

The intensive

regimen

stopped

early due to

increased

mortality

HbA1c lt60 Mean 35 years All-cause death

141 vs 114

HR 122 (101ndash146) P = 004


26 vs 18

HR 135 (104ndash176) P = 002

Fatal arrhythmia

01 vs 02

Primary outcome (composite of

non-fatal MI stroke or CV

death)

69 vs 72

HR 090 (078ndash104) P = 016

At 5-year follow-up the

rates of non-fatal MI were

lower [118 vs 142 HR

082 (070ndash096) P = 001]

but the rates of CV death

(072 vs 057 HR 129

(104ndash160) P = 002) and

all-cause death [153 vs

127 HR 119 (103ndash138)

P = 002] were higher with

intensive glucose control

Fatal arrhythmia

01 vs 04

31 vs 10

P lt 0001

VADT73 2009 1791 military vet-

erans DM Type

2 40 with pre-

vious CV event

Various

Open-label

study

An absolute

reduction for

15 points in

HbA1c com-

pared with

standard glu-

cose control

Median 56 years 6-year event free rates stand-

ard vs intensive control


096 vs 095

HR 132 (081ndash214) P = 026

All-cause death

088 vs 087

HR 107 (081ndash142) P = 062

Time to first occurrence of a CV

event

HR 088 (074ndash105) P = 014

212 vs 99

P lt 0001

Continued



for all individuals aged gt_65 years26 High-risk DM patients would likelybenefit from an active screening for AF but more data are needed todefine optimal AF screening strategy(ies) in DM patients27 Beforetreatment initiation the presence of AF should be documented usinga 12-lead electrocardiogram (ECG)2628 In DM patients with estab-lished AF ventricular rate control is recommended to decrease symp-toms and prevent AF-related complications In patients withpersistent symptoms despite adequate rate control or in those withleft ventricular dysfunction attributable to poorly controlled high ven-tricular rate or as per patientrsquos preference rhythm control strategycould be attempted29 including catheter ablation30ndash32 or cardiover-sion Of note DM has been associated with increased AF recurrencepost successful cardioversion of persistent AF33 For AF-relatedstroke risk management see Stroke risk assessment and prevention inarrhythmias associated with endocrine disorders

Ventricular arrhythmias and sudden cardiac deathCompared with the general population DM patients have an increasedrisk of both SCD1332ndash35 and non-SCD36 In a meta-analysis of 14 studiesinvolving 346 356 participants and 5647 SCD cases the risk of SCD was

two-fold higher in patients with DM compared with non-DM patients[adjusted hazard ratio (HR) 225 95 CI 17ndash297]29 However DMpatients were also shown to be at nearly three-fold greater risk of non-SCD than non-DM patients (adjusted HR 290 95 CI 189ndash446)36

Observational studies reported marked QTc prolongation37 atypicalmicrovolt T-wave alternans patterns38 altered heart rate variability39ndash43

or heart rate turbulence44ndash46 in DM patients but none of these testshave been routinely used to stratify the risk for ventricular arrhythmiasor SCD in clinical practice47 Both hyper- and hypoglycaemia have beenindependently associated with increased risk of ventricular arrhythmias48

Insulin-induced hypoglycaemia has been associated with nocturnal death(so-called lsquodead-in-bed syndromersquo) in DM type 14950 and arrhythmicdeaths were reported in several DM type 2 trials51ndash54 (Table 2)

There is no DM-specific protocol of screening for SCD47 but asshown in Figure 3 all patients diagnosed with DM should undergo regu-lar screening for cardiovascular risk factors or structural heart diseaseand glycaemic targets should be set individually Patients with DMand symptoms suggestive of cardiac arrhythmias (eg palpitations pre-syncope or syncope) should undergo further detailed diagnostic assess-ment as shown in Figure 3

Table 2 Continued


glucose

control



glucose control)

Significant

hypoglycaemia

NICE-SUGAR74

2009

NICE-SUGAR51

2012

6104 critically ill

patients

Insulin Blood glucose

45ndash60 mmoll

90 days 90-Day all-cause mortality

275 vs 249

OR 114 (102ndash128) P = 002

Both moderate and severe

hypoglycaemia are associ-

ated with increased risk of

death

285 vs 235 HR 141

(121ndash162) P lt 0001

(moderate hypoglycaemia)

354 vs 235 HR 210

(159ndash277) P lt 0001

(severe hypoglycaemia)

68 vs 05

OR 147 (90ndash259)

P lt 0001

Moderate hypoglycae-

mia n = 2714

(450)

Severe hypoglycaemia

n = 223 (37)

ORIGIN52 2013 12 537

DM Type 2 with

additional CV

risk factors

Insulin glargine Normal glycaemia Median 62 years Severe hypoglycaemia vs others

Composite of CV deathMI or

stroke

HR 158 (124ndash202)

P lt 0001

All-cause mortality

HR 174 (139ndash219)

P lt 0001

CV mortality

HR 171 (127ndash230)

P lt 0001

Arrhythmic death

HR 177 (117ndash267) P = 007

Annual rates of severe

hypoglycaemia

09 vs 03

ACCORD The Action to Control Cardiovascular Risk in Diabetes trial ADVANCE The Action in Diabetes and Vascular Disease Preterax and Diamicron Modified ReleaseControlled Evaluation trial CV cardiovascular DM diabetes mellitus HR hazard ratio MI myocardial infarction NICE-SUGAR The Normoglycaemia in Intensive CareEvaluationmdashSurvival Using Glucose Algorithm Regulation trial OR odds ratio ORIGIN Outcomes Reduction with an Initial Glargine Intervention VADT Veterans AffairsDiabetes Trial

8 B Gorenek et al


Hypoglycaemia-associated arrhythmias are difficult to documentbut observational studies using continuous glucose monitoring(CGM) and Holter monitoring in small DM type 2 cohorts (n = 25)showed that hypoglycaemic episodes were common often asympto-matic and associated with various arrhythmias5556 Compared withdaytime hypoglycaemia nocturnal episodes were more common andassociated with greater risk for bradycardia or atrial ectopy whilstventricular arrhythmias were equally common55 In contrast to ani-mal studies57 in a recent retrospective analysis of the ACCORD(Action to Control Cardiovascular Risk in Diabetes) trial the use ofbeta-blockers in DM patients was associated with increased risk ofsevere hypoglycaemia and cardiovascular events58 but more evi-dence is needed to inform optimal use of beta-blockers in DMpatients without established CAD59 Otherwise the use of antiar-rhythmic drugs should follow the general principles and precautionsrelated to pharmacological treatment of cardiac arrhythmias2647

In high-risk patients with established cardiovascular disease andorlong-standing sub-optimally controlled DM type 2 a less stringent gly-caemic control (ie a target HbA1c of lt_8) is recommended60 sinceintensive glycaemic control has been associated with increased risk ofsevere hypoglycaemic episodes counterbalanced by significant reduc-tion only in microvascular but not macrovascular complications (egMI stroke and mortality) The addition of empagliflozine61 or liraglu-tide62 to standard care should be considered in order to reduce

cardiovascular and all-cause mortality or hospitalization for heartfailure63 In addition the LEADER (Liraglutide Effect and Action inDiabetes Evaluation of Cardiovascular Outcome Results) trial datasuggested that liraglutide may have a renal protective effect6264

Although cardiac arrhythmias were not specifically investigated ineither LEADER or EMPA-REG OUTCOME (EmpagliflozineCardiovascular Outcome Event Trial in Type 2 Diabetes MellitusPatients)60 trial an antiarrhythmic effect of these drugs (perhapsmediated via glucagon release stimulation) has been hypothesized tocontribute to the reduced risk for cardiovascular death6162

The CANVAS Program data showed that the use of anothersodium-glucose co-transporter 2 (SGLT2) inhibitor canagliflozinwas associated with significantly lower risk of cardiovascular eventsand a renal protective effect compared with placebo in patients withDM type 2 and an elevated risk of cardiovascular disease65 The inci-dence of cardiovascular events with dapagliflozine is currently investi-gated in the DECLARE-TIMI 58 trial66 and a meta-analysis of 21 trialswith this drug67 suggested the potential for a beneficial cardiovasculareffect consistent with the multifactorial benefits on cardiovascularrisk factors associated with other SGLT2 inhibitors6869 Concerningthe cardiovascular effects of the SGLT1 inhibitors other than liraglu-tide (ie exenatide and lixisenatide) there was no significant differ-ence in the rates of cardiovascular events with these agentscompared with placebo in the respective trial7071

Consensus statements Consensus

statement

instruction

Level of

evidence

References

Diagnostic assessment of patients with DM type 1 and type 2 requires aggressive screening for and a

detailed characterization of underlying cardiovascular risk factors atherosclerotic cardiovascular dis-

ease and DM-related factors (ie glucose regulation diabetic neuropathy and cardiomyopathy) all of

which may increase the risk of cardiac arrhythmias and SCD in DM patients

lsquoShould do thisrsquo 6

Glycaemic targets in patients with DM and cardiac arrhythmias should be defined individually taking into

account patient age individual risk profile life expectancy and patient values and preferences


Severe hypoglycaemia should be avoided in DM patients at risk of cardiac arrhythmias owing to

increased risk of malignant potentially lethal ventricular arrhythmias and all-cause death


Intensive glucose control with target HbA1c of lt70 (or even lt60) should not be attempted in eld-

erly andor high-risk DM patients owing to increased risk of severe hypoglycaemia and neutral (or

negative effect) on all-cause mortality

lsquoDo not do thisrsquo 60

Intense management of cardiovascular risk factors (eg obesity dyslipidaemia hypertension obstructive

sleep apnoea etc) in DM patients reduces the risk of cardiac arrhythmias (eg AF) by preventing (or

slowing) the development of atherosclerotic cardiovascular disease and arrhythmogenic substrate


Incident AF in DM patients should be viewed as a marker of increased risk of adverse cardiovascular

events and mortality Intensive glucose control does not reduce the risk of AF but aggressive manage-

ment of cardiovascular risk factors may delay or prevent AF


Screening for silent AF by pulse palpation (with ECG confirmation) should be performed in all DM

patients at each regular visit


The use of (non-selective) beta-blockers in DM patients without established CAD may be weighed

against the risk of severe hypoglycaemia

lsquoMay do thisrsquo 5859



Thyroid dysfunctionThyroid dysfunction is associated with atrial and ventricular tachyar-rhythmias as well as bradyarrhythmias Hyperthyroidism is accompa-nied by increased automaticity and triggered activity in the atria andpulmonary veins (PVs) while in hypothyroidism effective refractoryperiods of the atria atrioventricular (AV) node bypass tracts andHis-Purkinje system are prolonged75ndash77 Genetic mechanisms involv-ing ion channels and autoimmune mechanisms involving muscarinicand beta-adrenoreceptors that are also linked to long-QT syndromemay contribute to ventricular and atrial arrhythmias in thyroid dys-function7879 Tachy- and bradyarrhythmia occurrence is different inhyperthyroidism and hypothyroidism and the evidence on treatmentis limited (Table 3ndash5)

Hyperthyroidism

Hyperthyroidism overt or subclinical [ie reduced serum thyroidstimulating hormone (TSH) concentration but free thyroxine levelswithin reference ranges] (Table 3) is associated with increased risk ofAF80ndash90 before and after establishment of the diagnosis it is associ-ated with increased risk of cardiovascular disease development91

Hypothyroidism either overt or subclinical has been shown by sev-eral studies confer no AF risk808990 though lack of association is notwell-established92ndash97

Atrial fibrillationAntithyroid treatment and attainment of euthyroid state should bethe first line in management of AF in the setting of hyperthyroidism asin most cases AF reverses spontaneously to sinus rhythm once euthy-roid state is achieved usually after 13ndash15 weeks of therapy98ndash101

Treatment using antithyriod agents radioiodine therapy or thyroidec-tomy is accompanied by conversion to sinus rhythm in 75ndash100 ofcases but predictors of persistent arrhythmia are increased age lon-ger pre-treatment duration of AF and hyperthyroidism99100 For ratecontrol of AF and as an adjunct to antithyriod therapy non-selectivebeta-blockers like propranolol may be used as they exert not onlyantisympathetic effects slowing heart rate but also reduce metabolicrate and affect triiodthyronine levels in case of low-output heart

failure they should be used cautiously or other short-acting beta-blockers without intrinsic sympathomimetic activity should be consid-ered102ndash104 It is reasonable to recommend cardioversion in patientswith persistent AF after establishment of euthyroid state and in caseof recurrent AF when the patient is euthyroid ablation should be con-sidered101105ndash110 In patients with persistent AF related to hyperthyr-oidism cardioversion results in restoration of sinus rhythm in 88ndash924 in patients without accompanying structural heart disease 86and 67 of them were arrhythmia-free at 3 years and 67 years offollow-up respectively105106

Hyperthyroidism-related AF usually has a lower recurrence ratethan non-hyperthyroidism-related AF In one study where only elec-trical cardioversion was used the risk of AF recurrence was 36lower in hyperthyroidism than in non-hyperthyroidism AF(P = 0004) and the only predictor of AF recurrence was the longerduration of arrhythmia (P lt 001)107 Few studies have reported out-comes of AF ablation108ndash110 with no difference in long-term (4 years)recurrence rate between hyperthyroidism and non-hyperthyroidism-related AF after PV isolation109 while in another study recurrencewas two-fold higher in hyperthyroid than in non-hyperthyroidpatients after single procedure of PV isolation or substrate ablationwhile after multiple procedures there was no difference110

Hyperthyroidism does not independently confer higher risk forstrokesystemic embolic events as compared to non-hyperthyroidpatients111ndash113 and annual risk of stroke in hyperthyroid patientswith AF is lower than in non-hyperthyroid patients114 Warfarinreduced the risk of ischaemic stroke in non-self-limiting AF patientswith hyperthyroidism and CHA2DS2VASc gt_1114

Ventricular arrhythmiasWhile ventricular arrhythmias are rare in hyperthyroid patients oneof the earliest Holter monitoring studies did not demonstrate reduc-tion of ventricular ectopy with antithyroid therapy115 However QTprolongation is described in Graves disease with thyrotoxicosis116

Few cases of isolated VF without structural heart disease and electro-lyte imbalance in hyperthyroidism have been reported117 amongthem coronary vasospasm was confirmed in two one case was due

Table 3 Definitions of thyroid dysfunction6

TSH levels

(mIUL)

Free thyroxine

(pmolL)

Total thyroxine

(mmolL)

Thyroid function

Euthyroidism 02ndash50 9ndash22 60ndash140

Overt hypothyroidism gt50 lt9 lt60

Subclinical hypothyroidism gt50 9ndash22 60ndash140

Overt hyperthyroidism lt02 gt22 gt140

Subclinical hyperthyroidism lt02 9ndash22 60ndash140

TSH level dependent thyroid dysfunction


High-normal euthyroidism 02ndash04 9ndash22 60ndash140

Subclinical hyperthyroidism (reduced TSH) 01ndash02 9ndash22 60ndash140

Subclinical hyperthyroidism (suppressed TSH) lt01 9ndash22 60ndash140

TSH thyroid stimulating hormone

10 B Gorenek et al


to amiodarone-induced toxicity and one case was accompanied byearly repolarization All cases were treated with antithyroid therapyprednisolone beta-blockers and in some cases an implantablecardioverter-defibrillator (ICD) was used117 It should be noted alsothat antithyroid therapy might worsen early repolarization andarrhythmia117

BradyarrhythmiasBradyarrhythmias AV block and sick sinus syndrome (SSS) are rareentities in hyperthyroid patients118119 one study reported that only3 of AV block cases with pacemaker implantation were due to pri-mary hyperthyroidism118

Hypothyroidism

Hypothyroidism is accompanied by ventricular arrhythmias and con-duction disturbances One case-control study of 152 hypothyroidand 152 euthyroid patients revealed higher prevalence of VT(P = 004) and ventricular arrhythmias (P = 0007) in hypothyroidpatients120 and Torsades de Pointes with prolongation of QT intervaland bradycardia may develop in hypothyroidism121ndash127 It is advisedto consider hypothyroidism in differential diagnosis of polymorphic

VT The VTVF accompanying hypothyroidism requires correctionwith thyroid hormones DC shock in urgent cases correction of elec-trolyte balance and bradycardia if QT prolongation and Torsades dePointes arrhythmia If arrhythmia is sustained or recurs the implanta-tion of ICD could be considered128

Rarely in patients with implanted pacemakers and ICDs overt orsubclinical hypothyroidism due to functional changes in tissue mightincrease pacing threshold or create exit block in atrial and ventricularpacing leads that usually are reversible by correction of thyroid sta-tus129ndash132

Conduction abnormalities in the setting of hypothyroidism are rep-resented by fascicular blocks (142) 1st degree AV block (119)133

advanced AV block and sinus node dysfunction118134135 There arealso case reports on advanced AV block of 2nd and 3rd degreereversed by thyroid replacement therapy and temporary pace-maker implantation in overt and subclinical hypothyroidism136ndash140

Several reports describe underlying hypothyroidism playing a role indevelopment of lithium-induced sinus node dysfunction reversedafter treatment of hypothyroidism134135 Treatment of subclinicalhypothyroidism should follow the recent update on thyroid diseasemanagement88

Table 4 Evidence summary for arrhythmias associated with thyroid dysfunction

Study Design Subjects Follow-up Thyroid dysfunction Arrhythmia Risk (95CI)

Selmer et al80 Cohort 586 460 55 years Euthyroidism

Overt hyperthyroidism

Subclinical hyperthyroidism

Overt hypothyroidism

Subclinical hypothyroidism

TSH levels

Reduced TSH

Suppressed TSH

High-normal euthyroidism

AF

29

46

25

Reference

IRR 142 (122ndash163)

IRR 131 (119ndash144)

IRR 067 (05ndash09)

IRR 087 (07ndash097)

IRR 116 (099ndash136)

IRR 141 (135ndash189)

IRR 112 (103ndash121)

Colett et al86

Thyroid studies

collaborators

Meta-analysis 52 674 88 years Subclinical hyperthyroidism

Reduced TSH

Suppressed TSH

AF HR 168 (116ndash243)

HR 163 (11ndash24)

HR 254 (108ndash599)

Kim et al90

Framingham Heart

study

Cohort 5055 10 years TSH 045ndash45 lULndash54

TSH 45ndash100 lULndash70


AF Reference

HR 123 (077ndash197)

HR 057 (021ndash154)

Brandt et al91 Observational

cohort

2631 pts with

hyperthyroidism

10 524 controls

67 years

81 female

6 years HyperthyroidismControls CVD thorn arrhythmia

26

19 P lt 0001

HR 134 (115ndash156)

Kobayashi et al117 Summary

of cases

10 pts

wo CVD and

hypokalaemia

ndash Hyperthyroidism

1 patient with amiodarone-

induced thyroid dysfunction

1 early repolarization

2 cases coronary vasospasm

VF isolated

AF atrial fibrillation CI confidence interval CVD cardiovascular disease HR hazard ratio IRR incidence rate ratio pts patients TSH thyroid stimulating hormone VF ven-tricular fibrillation



Table 5 Evidence summary for treatment of arrhythmias associated with thyroid dysfunction

Study Design Subjects Treatment Follow-up Arrhythmia after

treatment

Comment

Effect of antithyroid treatment on arrhythmia

Nakazawa et al98 Prospective 163 pts hyperthyr-

oidism and AF

467 years

Antithyroid therapy -

9

RITthorn antithyroid

therapy -87

Thyroidectomy 3

34 months 101 pts with spontaneous

AF conversion to sinus

rhythm upon attain-

ment of euthyroidism

63 pts

persistent AF

Intervals between return

to euthyroidism and

spontaneous AF con-

version to sinus rhythm

lt1 week 43

1ndash3 weeks 752

4ndash6 weeks ndash 871



13ndash15 weeks 100

gt16 weeks -100

Zhou et al99 Prospective 94 pts

hyperthyroidism

412 years

PAF 38 pts

Pers AF 45 pts

Radioiodine therapy 16 years PAF 0

Pers AF 60

Predictors of pers AF

Age gt55 years

RR 276 116ndash879

P lt 001

Duration of

hyperthyroidism

RR 308 122ndash1141

P lt 001

Duration of pre-treat-

ment AF

RR 296 131ndash768

P lt 001

Tsymbaluk et al100 Prospective 61 pts

hyperthyroidism due

to Graves disease

Antithyroid therapy Euthyroid state AF 25

PAC 7

AF rate before and after

antithyroid therapy

72 to 25 P lt 0001

PAC 71ndash7 P lt 0001

Gauthier et al101 Retrospective 40 pts with hyper-

thyroidism due to

GD and 40

euthyroidism mul-

tinodular goiter

Thyroidectomy Before and after

operation

AF 0 (sinus rhythm in

100)

Sinus tachycardia

-688

ndash

Treatment of persistent AF after antithyroid treatment

Nakazawa et al105 Prospective 33 pts with persis-

tent AF

Cardioversion after

Antithyroid treat-

ment for

hyperthyroidism

35 months AFmdash12

SRmdash88

AF free survivalmdash86

Nakazawa et al106 Retrospective 106 pts with persis-

tent AF

wo SHD

476 years

Cardioversion after

Antithyroid treat-

ment for 3

months for

hyperthyroidism

67 years AFmdash76

SRmdash924

Predictor of AF

recurrence

Duration of AF

HR 16 (114ndash226)

P = 0005

Late follow-up SRmdash67

Siu et al107 Prospective case-

controlled

116 pts

58 hyperthyroidism-

related persistent

AF

58 non-hyperthyoid-

ism AF

ECV after

Antithyroid treat-

ment for 3

months for

hyperthyroidism

24 months ndash AF recurrence

Hyperthyroidismmdash59

Non-hyperthyroidismmdash

83

Risk of AF recurrence

hyperthyroidism vs

non-hyperthyroidism

HR 064 (039ndash097)

P = 0004

Predictor of AF

recurrence

Longer duration of AF

HR 101 (10ndash101)

P lt 001

Continued

12 B Gorenek et al


Table 5 Continued


treatment

Comment

Machino et al109 Prospective 337 pts

Persistent AF with

history of hyper-

thyroidism 47

(16) wo

hyperthyroidism

953 (321)

First AF ablation

(PVI) after 3

months of antithy-

roid therapy for

hyperthyroidism

4 years ndash AF recurrence

hyperthyroidismmdash44

no hyperthyroidismmdash43

Predictors of AF

recurrence

hyperthyroidism

HR 087 (040ndash188)

P = 073

Wongcharoen

et al110

Prospective 717 pts First AF ablation (PVI

and substrate

modification 12)

gt3 month treatment

of hyperthyroidism

before ablation

ndash AF Predictor of AF recur-

rence after single

procedure

History of

hyperthyroidism

OR 207 (127ndash338)

AF recurrence did not

differ after multiple

procedures

Stroke risk in hyperthyroidism-related AF

Chan et al111 Observational

cohort

AntiT and risk of

ischemic stroke in

hyperthyroidism-

related AF

Of 9727 pts with

non-valvular AF

642 (66) pts with

hyperthyroidism

136 ptsmdashwarfarin

243mdashaspirin

263mdashno AntiT

719 years

678 female

Hyperthyroidism vs

non-

hyperthyroidism

2 years Non-valvular AF Warfarin

Reduced risk of stroke by

67

HR 033 (012ndash091)

Annual risk of stroke by

CHA2DS2Vas score

hyperthyroidism-AF vs

non-hyperthyroid-AF

0mdash0 vs 256

1mdash2ndash317 vs 702

gt_3mdash811 vs 1054

Ischaemic stroke 78

Warfarin reduced risk

of stroke in non-self -

limiting AF

CHA2DS2Vascgt_1mdash

P = 004

But not in self-limiting AF

Bruere et al114 Prospective 8962 pts

with AF

141 hyperthyroidism

history

510 hypothyroidism

history

8271 euthyroidism

929 days AF Stroke SE

hyperthyroidism

HR 085 (041ndash176)

hypothyroidism

HR 098 (073ndash134)

Bleeding

hypothyroidism

HR 13 (102ndash179)

Friberg et al112 Swedish Atrial

Fibrillation

Cohort Study

90 490 patients

No anticoagulation

at baseline

Thyroid disease 84

Thyrotoxicosis

553 pts

15 years AF Ischemic stroke

Thyroid disease

HR 095 070ndash119

Thyrotoxicosis

HR 092 (085ndash105)

StrokeTIAsystemic emboli

Thyroid disease

HR 100 (092ndash109)

Thyrotoxicosis

HR 103 (083ndash128)

Petersen et al113 Retrospective 610 patients Hyperthyroidism Stroke

Within 1 year

after 1 year

AF - 91 (149) Stroke n 1st year after

1st year

Sinus rhythm 8 7

AF 5 7

AF atrial fibrillation AIT amiodarone-induced toxicity AntiT antithrombotic therapy CA catheter ablation CI confidence interval CVD cardiovascular disease ECVelectrical cardioversion HR hazard ratio IRR incidence rate ratio OR odds ratio pts patients RIT radioiodine therapy RR relative risk TIA transient ischaemic attack TSHthyroid stimulating hormone VT ventricular tachycardia VF ventricular fibrillation



Amiodarone-induced thyroid dysfunction

About 103ndash147 of patients taking amiodarone for treatment ofventricular and atrial tachyarrhythmias and 167 of patients receiv-ing amiodarone for control of inappropriate ICD shocks developamiodarone-induced thyroid dysfunction (Table 6)

Amiodarone-induced thyroid dysfunction manifests asamiodarone-induced hyperthyroidism with two distinctive typestype 1 which develops in presence of underlying thyroid disease withexcessive hormone production in response to iodide load associatedwith amiodarone leading to true hyperthyroidism and type 2 destruc-tive thyroiditis that develops due to direct toxic effects if iodine associ-ated with amiodarone Differential diagnosis of two types ofhyperthyroidism usually is done using ultrasonography thyroid I131

uptake and thyroid [99m Tc] 2-methoxy-isobutyl-isonitrile (MIBI)scintigraphy142143 Management of amiodarone-induced thyroid dys-function depends on above-mentioned types of dysfunction with hor-mone replacement therapy for amiodarone-induced hypothyroidismantithyroid medications for amiodarone-induced hyperthyroidismtype 1 and steroids for amiodarone-induced hyperthyroidism type 2(thyroiditis) and use of antithyroid medications and steroids in casesof coexistence of hyperthyroidism and thyroiditis142144 Generallyaccepted approaches in prevention and early detection of

amiodarone-induced thyroid dysfunction are baseline assessment ofthyroid function (thyroxine and TSH levels) before initiation of amio-darone treatment and periodic monitoring of thyroid function (within3 months after initiation and every 3ndash6 months thereafter)145ndash147

though latest studies demonstrated conflicting results with no associa-tion of amiodarone-induced thyroid dysfunction occurrence and peri-odic testing of thyroid hormones it should be mentioned also that495 of patients had detectable abnormalities in thyroid functiontests prior to development of amiodarone-induced dysfunction148

Thyroid stimulating hormone receptor autoantibody test and ultraso-nography may be used for differential diagnosis of type I and type IIthyroid dysfunction147

Overt thyroid dysfunction occurs in 36ndash37 of patientsreceiving amiodarone for prevention of SCD and 103ndash147 ofpatients receiving amiodarone for treatment of ventriculararrhythmias and AF149ndash153 and 167 of patients taking amiodar-one for control of inappropriate ICD shocks154 Meta-analyses ofRCTs on secondary prevention of SCD and adverse effects ofamiodarone in patients treated for ventricular arrhythmiasreported 42ndash57-fold increased risk of thyroid dysfunction and178ndash218 times higher risk for development of bradyarrhyth-mias149150 when compared with placebo groups about 13rdndash1

Recommendations on management of tachy- and bradyarrhythmias associated with

thyroid dysfunction

Consensus

statement

instruction

Level of

evidence

References

Correction of thyroid dysfunction with restoration of euthyroid state is one of the primary goals in the

treatment of tachy- and bradyarrhythmias associated with hyperthyroidism or hypothyroidism

lsquoShould do thisrsquo 98ndash101

Correction of subclinical forms of thyroid dysfunction associated with tachy- and bradyarrhythmias may

be required


Referral to endocrinologists should be considered for selection of appropriate thyroid function therapy

(thyrosuppressive therapy radioiodine therapy and thyroidectomy)


Hyperthyroidism-related AF that persists after euthyroid condition has been achieved (gt3 months of

thyrosuppressive therapy) should be managed using cardioversion or ablation for rhythm control

Antithrombotic therapy should be applied as for non-hyperthyroid-AF


Rare cases of VTVF in the setting of hyperthyroidism should be managed using antiarrhythmics (caution

with amiodaronemdashsee below) DC shock in cases of hemodynamic compromise and therapy with an

ICD if indicated Associated conditionsmdashcoronary vasospasm early repolarisation amiodarone toxic-

ity should be taken in account


Severe bradyarrhythmias accompanying hyperthyroidism and hypothyroidism might require use of tem-

porary pacemaker in persistent cases after restoration of euthyroid condition bradyarrthythmias

should be managed according to the current guidelines


VTVF accompanying hypothyroidism associated with long QT interval should be managed with correc-

tion of bradycardia and electrolyte imbalance avoid antiarrhythmic drugs that prolong the QT inter-

val In acute cases DC shock may be necessary If VTVF persists therapy with an ICD should be

considered


Monitoring and correction of thyroid dysfunction may be considered if lead dysfunctionchange in atrial

or ventricular pacing thresholds appear in patients with implanted pacemakers and ICDs

lsquoMay do thisrsquo 129ndash132

14 B Gorenek et al


Table 6 Summary of evidence for amiodarone-induced thyroid dysfunction

Study Design Population Follow-up Thyroid dysfunction

toxicity arrhythmia

Predictors of toxicityOR

RRHR (95CI)

Piccini et al149 Met-analysis 15

RCTs of amio

vs placebo effi-

cacy in preven-

tion of SCD

safety

8522 pts

4260 amio arm

4262 placebo arm

12ndash455

months

Thyroid 36 vs 04

Pulmonary 29 vs 15

Hepatic 185 vs 07

Bradyarrhythmias 28

vs15

OR 568 (294-1098) P lt 00001

OR 197 (127-304) P = 0002

OR 21 (115-382) P = 0015

OR 178 (116-272) P = 0008

Amio discontinuation rate 316

Vorperian

et al150

Meta-analysis 4

RCTs amio vs

placebo

Adverse effects

738 pts amio arm

727 pts placebo

arm

low dose amio

100ndash400 mg

maintenance

dose

12ndash45

months

TD 37 vs 04

Bradycardia 33 vs 14

Discontinuation rate 229

vs 154

Skin 23 vs 07

Eye 15 vs 01

OR 423 (204ndash874) P = 0001

OR 218 (111ndash427) P = 0024

OR 160 (123ndash209) P lt00001

OR 248 (105ndash617) P = 005

OR 342 (122ndash364) P = 002

Bathcer et al151

Substudy

of SAFE-T

RCT substudy 612 pts with

persistent AF

Amio vs

Sotalolthorn placebo

1ndash45

years

Hypothyroidism

Subcl 258 vs 66

P lt 00001

Overt 50 vs 03

P lt 0001

Hyperthyroidism

Subcl 1 case amio Overt

53 vs 24 P = 007

ndash

Ross et al152 Cohort study 163 patients

Amio for SVT

102 pts VT 55

pts Prevention

3 pts Uncertain

1 pt

679

days

Hypothyroidism

Subclinical 74

Overt 8

Hyperthyroidism

Subcl 06

Transient hyperthyroidism

06

Overt 67

ndash

Kinoshita et al155 Retrospective

cohort study

For overt thyroid

dysfunctions

Indication for

amio

VA 667ndash80

AA 20ndash333

317 pts

Euthyroid 256

Subcl hypothy-

roid 52

Subcl hyperthy-

roid 9

585 years 735

males

5 years Overt hyperthyroidism

95


189

Predictors of hyperthyroidism

DCM OR 33 (126-89)

Sarcoidosis OR 647 (16ndash2577)

Predictors of hypothyroidism

Free T4mdashOR 013 (003ndash068)

TSHmdashOR 147 (126ndash174)

Ahmed et al153 Prospective 303 pts

Amio for AF-260

pts VA 43 pts

63 years 66

males

33 years Hyperthyroidism 8

Hypothyroidism 6

Hyperthyroidism

Age lt62 years

HR 24 (10ndash57) P lt 005

Hypothyroidism

TSH gt14 mUL

HR 51 (11ndash224) P = 003

LVEF lt45

HR 38 (11-133) P = 004

DM-HR 33 (11ndash103) P = 004

Lee et al154 Retrospective

Amio vs sotalol

and beta-

55 pts with ICD

Amio 24 pts

Sotalol 17 pts

4 years Hypothyroidism 167

Time to development

163(23) months

Continued



Table 6 Continued


toxicity arrhythmia


RRHR (95CI)

blockers for

inappropriate

shock reduction

in ICD pts

Beta-blockers 19 Treatment

Dose reduction in amio hypo-

thyroidism group and dis-

continuation in pulmonary

toxicity group (167) pts

Shiga et al156 Prospective

Recurrence of VT

VF during amio-

darone induced

toxicity as com-

pared to euthy-

roid state

Holter monitoring

and plasma amio

232 pts

amio therapy


No change in arrhythmia

recurrence and plasma

amio

Hyperthyroidism 125

VTVF recurrence euthyroid

1 vs hyperthyroid 9 pts

P lt 001 VPC three-fold

increase P lt 005 No

change in plasma amio

Treatment

Hypothyroidism 12-L-thyro-

xine no discontinuation of

amio

hyperthyroidism 6 methimi-

zole 2 prednisolone 3 amio

discontinuation 18mdashgrad-

ual improvement

Czarnywojtek

et al161

Cohort

RIT for pts on

amio and TD

Amio indication

SVT VT ICD

inappropriate

shocks AF

297 cases amio

A 78 euthyroid-

ism on amio

B118

hyperthyroidism

History amio

C 79 hyperthyr-

oidism amio

D 22

hypothyroidism

12 months Recurrence of hypothyroid-

ism after RIT A 538

B 339 C 341

Recurrence of hyperthyroid-

ism after RIT A 77 B

125 C 114

ABC reinstated amio after

3ndash6 weeks of RIT

D permanent hypothyroid-

ismndashthyroxine replacement

therapy

Diederichsen

et al164

RCT double-blind

placebo-

controlled

Amio vs place bo

for 8 weeks after

catheter ablation

of AF

Endpoint TD

212 patients after

catheter ablation

of AF without

history of thy-

roid dysfunction

Amio group 8

weeks amio

Placebo group

6 months Thyroid dysfunction

Amio discontinuation

Amio groupmdash3

Placebomdash1

Amio group significantly

higher TSH fT4 and T4 and

lower fT3 and T3 at 1 and 3

months as compared to

placebo

TD after 1 month of amio

treatment

AA atrial tachyarrhythmias AF atrial fibrillation Amio amiodarone CI confidence interval CVD cardiovascular disease DM diabetes mellitus ECV electrical cardioversionHR hazard ratio ICD implantable-cardioverter defibrillator IRR incidence rate ratio LVEF left ventricular ejection fraction OR odds ratio pts patients RCT randomizedcontrolled trial RIT radioiodine therapy RR relative risk subcl subclinical SVT supraventricular tachycardia TD thyroid dysfunction TSH thyroid stimulating hormone VAventricular arrhythmia VPC ventricular premature complexes VT ventricular tachycardia VF ventricular fibrillation

16 B Gorenek et al


4th of patients discontinued amiodarone treatment Amiodarone-induced thyroid dysfunction includes overt and subclinical hypo-thyroidism and hyperthyroidism151152 although changes in thy-roid hormone levels in euthyroid patients on amiodaronetreatment are common without clinical manifestations ofamiodarone-induced thyroid dysfunction142 In the SAFE-T(Sotalol-Amiodarone Fibrillation Efficacy) trial overt hypothyr-oidism developed in 50 subclinical hypothyroidism in 258 andovert hyperthyroidism in 53 and itrsquos subclinical form only in onepatient in amiodarone arm that were significantly higher than incontrol arm receiving sotalol or placebo for treatment of persis-tent AF (P lt 005 for all)151 In another cohort study of patientsreceiving amiodarone for ventricular and atrial tachyarrhythmiassubclinical and overt hypothyroidism developed in 74 and 8 ofpatients respectively and subclinical and overt hyperthyroidismin 06 and 67 respectively after 943 days of treatment152

Though the evidence on predictors of amiodarone-induced thy-roid dysfunction is limited two studies153155 addressed the issueof identifying patients at risk of thyroid dysfunction in one studypatients with low thyroxine and high TSH levels were at risk ofhypothyroidism development while patients with dilated cardio-myopathy and sarcoidosis had 33 and 647-fold increased risk ofhyperthyroidism development155 it should be noted that patientswith subclinical thyroid dysfunction at baseline were also included

in the study In another prospective study of patients with AF andventricular arrhythmias receiving amiodarone 8 of patientsdeveloped hyperthyroidism and 6 of patientsmdashhypothyroidismduring 33 years of follow-up and the only predictor for develop-ment of hyperthyroidism was age lt62 years while hypothyroidismrisk was associated with TSH levels gt14 mUL low ejection frac-tion and DM153

In summary amiodarone-induced overt thyroid dysfunctionoccurs in approximately 103ndash147 of patients with arrhythmiasreceiving amiodarone and should be suspected if symptoms of toxic-ity develop including tachy- and bradyarrhythmias other organslesions and change in thyroid tests (Table 3)

Of note amiodarone-induced thyroid dysfunction depends neitheron dose150 nor on plasma concentration of amiodarone156 buttachy- and bradyarrhythmias may occur Holter monitoring study inpatients with VTVF receiving amiodarone treatment demonstratedstatistically significant increase in recurrence of VT and ventricularpremature complexes in hyperthyroid state when compared withbaseline euthyroid state156 and in rare cases of thyroid storm VTVFmay develop128 Withdrawal of amiodarone and switching to otherantiarrhythmic drugs can be effective in treatment of VTVF episodesdue to amiodarone-induced thyroid dysfunction157

Bradyarrhythmias usually occur in hypothyroidism AV block tendsto develop in presence of pre-existing conduction abnormality77

Recommendations on management of amiodarone-induced thyroid

dysfunction

Consensus

statement

instruction

Level of

evidence

References

Before prescribing amiodarone therapy for long-term use it is recommended to weigh risk

benefit of its toxicity and strongly consider catheter ablation to cure or modify the sub-

strate for arrhythmias instead


It is recommended to carry out baseline thyroid tests (thyroxine and TSH) before initiation

of amiodarone treatment) thyroid-directed autoantibodies and ultrasonography should be

considered for differential diagnosis of type I and type II amiodarone-induced

hyperthyroidism


143145ndash147163

It is advised to monitor thyroid function tests and ECG for amiodarone-induced thyroid dys-

function screening


If hyperthyroidism occurs during treatment with amiodarone its discontinuation

MANDATORY The eventual decision to initiate or continue amiodarone once the euthy-

roid state is achieved for preventing life-threatening ventricular tachyarrhythmias should

be carefully evaluated in each individual case in terms of expected risk and benefits


Hypothyroidism should be treated with thyroid replacement agents and amiodarone therapy

may be continued if necessary


In case of VTVF withdraw amiodarone and treat using antiarrhythmics and DC shock if

hemodynamic compromise


The use of amiodarone in elderly patients increases the risk of bradyarrhythmias such as

advanced AV block or SSS requiring a permanent pacemaker




Amiodarone-induced thyroid dysfunction may manifest as SSS consti-tuting 22 of all causes of SSS158ndash160 In some circumstances correc-tion of thyroid dysfunction in patients with AF and bradycardiadeveloped on amiodarone treatment unmasks underlying tachycardia-bradycardia syndrome159

Withdrawal of amiodarone therapy should be strongly considered incases of hyperthyroidism proper management of VTVF AV block andSSS is required In a study of amiodarone-induced thyroid dysfunction inpatients receiving amiodarone for prevention of inappropriate shocksdose reduction of amiodarone was adequate to reduce signs ofamiodarone-induced thyroid dysfunction154 Latest studies on use ofantithyroid therapy in patients requiring long-term amiodarone treat-ment (ventricularatrial arrhythmias or inappropriate shock reduction inICD patients) demonstrated that application of antithyroid radioiodinetherapy might be an option to reinstitute amiodarone treatment161radioiodine ablation of thyroid is also an option in amiodarone-inducedthyroid dysfunction with resistant tachyarrhythmias162

It is recommended also to weigh the risk of amiodarone-inducedthyroid dysfunction before considering the long-term treatment orprefer treatment like catheter ablation Monitoring of thyroid func-tion every 6 months and electrocardiogram follow-up in patients onamiodarone therapy should be considered145148163

PheochromocytomaThe prevalence of pheochromocytoma (PCC) discovered duringlife is 015ndash04 however many cases remain undiscovered asthe prevalence noted in autopsy studies is higher166 The clinicalpicture ranges from totally asymptomatic patients to life-threatening complications including MI severe heart failure

Tako-tsubo cardiomyopathy and arrhythmias Typically addi-tional release of catecholamines by PCC is accompanied by par-oxysmal headache sweating hypertension and palpitationsTherefore recurrent arrhythmias in such clinical context shouldraise the suspicion of PCC Palpitations are present in one-halfto 70 of patients167

Arrhythmia mechanisms include beta-adrenergic stimulation ofthe heart alpha1-adrenergic stimulation (especially during myo-cardial ischemia and reperfusion)168 desensitization of adrenergiccardiovascular receptors due to prolonged adrenergic stimulationand reflex increase in vagal tone Most often sinus tachycardia isencountered However a large spectrum of arrhythmias could bepart or the first clinical manifestation of PCC before typical signsare present It includes mostly supraventricular arrhythmias andAF but also malignant and bidirectional VT169 Some PCC patientsmanifest with reflex bradycardia asystole AV dissociation Wolf-Parkinson-White syndrome or SSS170 Patients with PCC maypresent with repolarization abnormalities consisting of markedQT prolongation and deep wide inverted T wave171 with subse-quent risk for Torsades des Pointes

Esmolol a beta1-adrenergic cardioselective blocker with rapidonset of action can be used to control fast rate due to AF or atrialflutter (05 mgkg iv followed by continuous infusion of 01ndash03 mgkgmin)170 Associated alpha-blockade (ie phenoxybenzamine 10 mgonce to 10ndash30 mg twice or a1 blockade with prazosinmdashstarting with1 mg and increasing to 1 or 2 mg two or three times daily) may beused to prevent the incidence of hypertensive crisis during betablockade There is no specific treatment for other arrhythmias andVT could respond to lidocaine172

Recommendations on management of PCC Consensus

statement

instruction

Level of

evidence

References

Pheochromocytoma should be considered as possible diagnosis in patients with paroxysmal

headache hypertension palpitations and recurrent arrhythmia


Esmolol should be used to control rapid rate in AF and flutter Associated alpha blockade is

mandatory to prevent hypertensive crisis


Lidocaine may be used to treat sustained VT lsquoMay do thisrsquo 169172173

As PCC can prolong QTc interval antiarrhythmic drugs prolonging the QTc should be used

with caution and only after QTc monitoring


18 B Gorenek et al


Growth hormone dysfunctionAcromegaly

Acromegaly is a rare and debilitating disease with a prevalence of 40 permillion characterized by increased growth hormone (GH) and insulin-like growth factor-1 (IGF-1) Early clinical trials have demonstrated atwo-fold increase in overall mortality in patients with acromegaly whencompared with general population with cardiovascular causes account-ing for 40ndash60 of all deaths174ndash176 Acromegalic cardiomyopathy ischaracterized by biventricular hypertrophy progressing to diastolic andsystolic dysfunction culminating in heart failure in 10 of patients177ndash179

Recent cohorts with patients treated early in the disease course sug-gest lower rates of cardiovascular involvement180181 Classically mono-nuclear cell infiltration182 apoptosis183 myofibrillary abnormalities184

interstitial fibrosis oedema and cardiomyocyte hypertrophy are charac-teristic of acromegalic cardiomyopathy and may represent the histologi-cal substrate for arrhythmias184185

Cardiac arrhythmias in acromegalyThere is paucity of data on the prevalence and severity of cardiacarrhythmias in acromegaly186ndash188 Supraventricular arrhythmias areuncommon in patients with acromegaly with one study reportingsupraventricular arrhythmias in 627 patients while two other showabsence of any increase188ndash190 Asymptomatic sinus node disease hasalso been described in a small proportion of patients in anotherstudy191 However complex ventricular ectopy is common occur-ring in 40ndash48 of acromegalic patients188189192 and increasing withexercise188 The ventricular ectopy increased with duration of

acromegaly and severity of ectopy correlated with left ventricularmass but not GH levels188 Sustained VT and sudden death has beenreported in patients with acromegaly with severe cardi-omyopathy193ndash195 Late potentials are common in acromegalic cardi-omyopathy and correlate with frequency of ventricular ectopy181192

Similarly greater QT dispersion (dQT) and prolonged QTc intervalare seen in active acromegaly and may predispose to ventriculartachyarrhythmia196197

Impact of acromegaly specific treatment on cardiac arrhythmiasThere is lack of longitudinal studies evaluating the impact of treat-ment of acromegaly on associated cardiac arrhythmia Howeverthere is indirect evidence to suggest that control of acromegaly inearly stages may decrease cardiac remodelling180 development oflate potentials181 ventricular arrhythmia198ndash200 and cardiacmortality201

Growth hormone deficiency

Growth hormone deficiency is diagnosed in 01 of the population ingeneral clinical practice and is characterized by the short stature frontalbossing central obesity and high-pitched voice202 Growth hormonedeficiency usually manifests early in childhood while in adults it may beaccompanied by increased sensitivity to insulin in patients with diabetesand manifests with fine wrinkling around eyes and mouth Deficiency ofGH adrenocorticotropic hormone and gonadotropin and hypothyr-oidism are common in hypopituitarism203 Though rarely tachy- andbradyarrhythmias may accompany GH deficiency204205 In one prospec-tive study of pituitary hormone levels in patients who underwent

Aldosterone excess

BaroreceptorsCathecholexcess

Cardiacfibrosis

Cardiac failure Diastotlic andsystolicdysfunction

Na+ H2Oretention

K+ Mg++

loss

Fibrosis andvascularreactivity

Hypertension

Congestion

Arrhythmias

LVH

Figure 4 Effect of aldosterone on the cardiovascular system215 Cathechol cathecholamine LVH left ventricular hypertrophy



cardiopulmonary resuscitation due to VTVF GH deficiency waspresent in 275 of them204 with (GH)-IGF-1 being significantly lowerin a group of patients with GH deficiency when compared with groupof patients with normal GH values There are also reports on increasedcardiovascular morbidity in children with GH deficiency treated withGH due to cardiomegaly205 A complete AV block was described in achild with GH deficiency during therapy with hGH treated successfullyby pacemaker implantation205

Thus cardiac evaluation and monitoring is reasonable in patientswith GH deficiency and during its therapy

Diseases of adrenal cortexHyperaldosteronism

Primary hyperaldosteronism (PH) also known as Connrsquos disease isan endocrine disorder caused by an adrenal adenoma (uni- or bilat-

eral) It causes hypertension hypokalaemia metabolic alkalosis andrenin suppression206ndash208 Long-standing PH has been associated withmyocardial injury leading to heart failure and either atrial or ventricu-lar arrhythmias209ndash214 Figure 4 summarizes the effect of aldosteroneon the cardiovascular system215

Management of PH associated arrhythmias focuses on controllingmetabolic and electrolyte disturbances216 Deleterious cardiovascu-lar effects can be controlled by either performing aldosterone recep-tor blockade or adrenalectomy217 Tables 7 and 8 summarize PHrelated arrhythmias

Specific data on indications for device implantation in PH patientsis very limited and general guideline recommendations apply for thispopulation The main treatment approach for this condition is eithersurgical resection of the adrenal adenoma or pharmacological ther-apy targeting adrenal hyperplasia207ndash210

Adrenal insufficiency

Primary adrenal insufficiency (PAI) also known as Addisonrsquos diseaseit is characterized by corticosteroid and mineralocorticoiddeficiency230231 Patients with PAI typically present with hyponatrae-mia hyperkalaemia hypoglycaemia and hyperpigmentation Cardiacmanifestations include hypotension syncope arrhythmias and cardi-omyopathy Acute exacerbations are called Addisonian crises232

Table 9 summarizes the most common cardiac abnormalities andECG findings which are usually reversible with definitive treatmentof the underlying cause231233

Recommendations Consensus

statement

instruction

Level of

evidence

References

Primary hyperaldosteronism patients with atrial or ventricular arrhythmias should receive

treatment for stabilization of their electrolyte and metabolic disturbances


In PH patients with persistent rhythm abnormalities or myocardial damage pacemakers or

high voltage devices may be used according to life expectancy and response to optimal

medical therapy


Table 8 Description of the most important studies on PH

Study Type of study Number of

patients (n)

AF () VT () Sustained

arrhythmias ()

Milliez et al212 Case control 124 73 NA NA

Catena et al228 Prospective cohort 54 NA NA 15

Born et al222 Retrospective cohort 640 71 NA NA

Mulatero et al221 Case control 270 NA NA 78

Savard et al229 Case control 459 39 NA NA

AF atrial fibrillation NA data not available PH primary hyperaldosteronism VT ventricular tachycardia

Table 7 Electrocardiographic disorders associatedwith PH

Prolonged QT-interval218

Atrial fibrillation219220

Atrial flutter221

Ventricular tachycardia222

Polymorphic ventricular tachycardia223224

Ventricular fibrillation225ndash227

PH primary hyperaldosteronism

20 B Gorenek et al


Parathyroid diseaseHypoparathyroidism and hyperparathyroidism are rare hormone dis-orders characterized by abnormally low or high levels of the parathy-roid hormone (PTH) Physiologically PTH plays a critical role in the

regulation of calcium homeostasis through several mechanisms Theconsequence of PTH deficiency is hypocalcaemia which can causeQT interval prolongation and arrhythmias In clinical practice how-ever torsades de pointes or other life-threatening tachyarrhythmiasare infrequent in patients with hypoparathyroidism despite extremeQT prolongation242 In the literature there is only one case report ofa patients with hypoparathyroidism who suffered VF probably due toheart failure and severe hypocalcaemia243 Severe hypocalcaemiarequires treatment as soon as possible with intravenous calciumLong-term treatment of hypoparathyroidism includes calcium andVitamin D supplementation for the stable control of plasma calciumlevels243

The main biochemical feature of primary hyperparathyroidism ishypercalcaemia Hypercalcaemia may induce arrhythmias throughboth early and delayed ventricular after depolarization Previousstudies have shown that primary hyperparathyroidism and hypercal-caemia are directly related to electrocardiographic abnormalitiessuch as high-amplitude QRS complex short ST segment and QTinterval and T wave extension244 A variety of arrhythmias such assinus arrest supraVT and AF has been documented in patients withprimary hyperparathyroidism245 Furthermore ventricular arrhyth-mias in association with hyperparathyroidism have been reportedincluding ventricular bigeminy VT and VF246ndash248 Although patientswith hyperparathyroidism have an increased risk of death it is notknown if arrhythmias play any role in increased cardiovascular mor-tality The most effective method for the treatment of primary hyper-parathyroidism is parathyroidectomy However the role of surgeryregarding the effect on cardiac arrhythmia risk is controversial Somestudies did not report a reduced incidence of mortality in hyperpara-thyroidism after parathyroidectomy while the other showed thatparathyroidectomy reduced the occurrence of ventricular arrhyth-mias and restored the QTc adaptation during exercise test249ndash251

A series of case reports indicate that in rare cases ventricular storminduced by hyperparathyroidism may be controlled only after para-thyroid surgery247248252253

Sex hormones-related differences in therisk of arrhythmiasIt is well recognized that men and women differ with respect to therisk of developing arrhythmias3254ndash256 The mechanisms involved inthese differences have not been fully elucidated but may be relatedto the electrophysiological effects of sex hormones In experimentalstudies257258 17b-oestradiol has protective effects on ischemia-induced arrhythmias and reduces L-type Ca2thorn current (ICaL)Nevertheless estrogens may partially suppress the delayed rectifierKthorn current (IKr) thus enhancing drug-induced APD and QTc prolon-gation Progesterone increases slow activating delayed rectifier Kthorn

current (IKs) and modulates ICaL therefore promoting APD short-ening Testosterone also regulates both IKs and ICaL in a dose-dependent manner and results in shortening of APD257258

Women have higher resting heart rate shorter PR and QRS inter-vals and longer QTc intervals whereas men more frequently exhibitearly repolarization3254ndash256 Notably repolarization differencesbetween men and women do not occur in prepubertal children259

Repolarization is also affected by the ovarian cycle since repolarizingcurrents are increased by progesterone and decreased by oestrogen

Table 9 Cardiac abnormalities associated with PAI

Idiopathic dilated cardiomyopathy234

Tako-tsubo cardiomyopathy235

ECG

Low voltage236

Sinus bradycardia237

Prolonged PR-interval237


T-wave inversion239

Brugada like-pattern240


Ventricular fibrillation237

ECG electrocardiogram PAI primary adrenal insufficiency


statement

instruction

Level of

evidence

References

Patients with PAI and ECG

changes should be treated

for electrolyte and meta-

bolic disturbances

lsquoShould

do thisrsquo

230

Patients with PAI in the set-

ting of dilated cardiomy-

opathy andor heart

failure who receive opti-

mal medical therapy

should be started on

hydrocortisone and flu-

drocortisone

Fludrocortisone should be

used with caution

because excessive fluid

retention may lead to or

worsen heart failure

symptoms

lsquoShould

do thisrsquo

231232

Patients with PAI and persis-

tent rhythm abnormalities

or myocardial damage

may be candidates for

pacemakers or high volt-

age device therapy based

on life expectancy and

response to optimal medi-

cal therapy




QTc is longer in the follicular phase when compared with the lutealphase255258 The longer repolarization renders women more suscep-tible to drug-induced Torsades de Pointes260 Therefore QT pro-longing drugs should be used carefully in females particularly in thosewith other abnormalities such as electrolyte imbalance Accordinglyprogesterone may attenuate drug-induced QTc lengthening261 Alsowomen have greater arrhythmic risk than men in congenital LQTSespecially after puberty262 Further emphasizing the role of hormonalmodulation in arrhythmia development in congenital LQTS the riskof life-threatening events is reduced during pregnancy but increasedin the postpartum period263 On the other hand Brugada syndromeand AF predominate in men254ndash256 It is well known that women havea higher incidence of AV nodal re-entry tachycardia and inappropri-ate sinus tachycardia264 Exacerbation of supraventricular tachycar-dias may occur during pregnancy likely due to hormonal andautonomic tone changes265

Stroke risk assessment andprevention in arrhythmiasassociated with endocrinedisorders

As described in previous sections the presence of various endocrinedisorders can be associated with AF which is the arrhythmia mostcommonly associated with increased risk of stroke andthromboembolism

Older small studies113 have suggested an association between thy-roid disease and an increased risk of stroke in AF In the largest analysisfrom the Swedish AF cohort study112 a nationwide cohort of 182 678subjects with AF thyroid disease (HR 095 95 CI 085ndash105) or

thyrotoxicosis (HR 092 95 CI 070ndash119) were not independentpredictors of ischaemic stroke in multivariate analysis Similarly eitherthyroid disease or thyrotoxicosis were not independent predictors ofmajor bleeding or intracranial haemorrhage Similar observationswere noted in the Loire Valley AF project where history of hyper-thyroidism was not an independent risk factor for strokesystemicembolism whereas hypothyroidism was associated with a higher riskof bleeding events114 Thus AF patients with thyroid disease are asso-ciated with stroke or thromboembolism only in association with otherestablished stroke risk factors the most common of them areincluded within the CHA2DS2-VASc score266 Similar for stroke orthromboembolism risk assessment should be used to identify patientsat risk for bleeding and to address the potentially reversible bleedingrisk factors as advocated by validated practical bleeding risk scoressuch as the HAS-BLED score267

Diabetes mellitus is well established as a clinical stroke risk factorin AF and is incorporated into the CHA2DS2-VASc score266268

Duration of diabetes may accentuate stroke risk but not bleedingrisk269 Indeed duration of diabetes may be a more important predic-tor of ischaemic stroke than glycaemic control in such patients270

Whilst diabetic complications such as diabetic retinopathy areassociated with higher risks such evidence of lsquodiabetic target organdamagersquo does not independently add to stroke or bleeding riskprediction271

With regard to prevention of stroke the most important measureis oral anticoagulation (OAC) whether given as a Vitamin K antago-nist (VKA eg warfarin) with good quality anticoagulation control(with ldquotime in therapeutic rangerdquo or TTR gt70) or a non-VKA oralanticoagulant (NOAC eg dabigatran rivaroxaban apixaban oredoxaban) The NOACs are the preferred option in most patientsstarting anicoagulation but given the heterogeneity of AF patientsand the availability of different OAC options we should fit the drugto the patient profile In general NOACs appear relatively moreeffective and safer than VKA in reducing strokesystemic embolismand major bleeding irrespective of patient comorbidities272

In summary AF stroke risk stratification even with concomitantendocrine disorders should use the established CHA2DS2-VAScscore266 to initially identify lsquolow riskrsquo patients (CHA2DS2-VASc 0 inmales or 1 in females) who do not need any antithrombotic therapyfollowed by prevention of stroke (ie OAC) in patients with gt1 riskfactor

As OAC is being initiated a clinical bleeding risk score such asHAS-BLED score (see above) should be used to identify patients atrisk for bleeding and importantly to address the potentially reversi-ble bleeding risk factors (that should be considered in all patientsirrespective of HAS-BLED score value) The next step is to considerchoice of OAC and the SAMe-TT2R2 score273 can be used to aiddecision making between a VKA with likelihood of a good TTR (score0ndash2) or those less likely to achieve it thus requiring more regularINR checks or as a better option use of a NOAC274 This simplethree-step pathway has been advocated to help streamline decisionmaking for stroke prevention in AF274


statement

instruction

Level of

evidence

References

QT prolonging drugs (www

crediblemedsorg) should

always be used carefully in

both women and men

However due to an

increased risk of drug-

induced Torsades de

Pointes this recommenda-

tion should be further

emphasized for women

particularly in the pres-

ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al


Catheter ablation of arrhythmiasassociated with endocrinedisorders

Catheter ablation for atrial or ventricular arrhythmia is optimally per-formed in as much as possible stable electrolytic and metabolic con-ditions in order to avoid transient arrhythmias Arrhythmiasassociated with endocrine disorders would theoretically need noablation since they are supposed to spontaneously disappear oncereturn to steady state is obtained They may also alter the analysis oftargets to be ablated and interpretation of results for complex proce-dures However ablation sometimes needs to be performed inpatients with acute or subacute endocrine disorders This may applyto patients with severe ventricular tachyarrhythmia and electricalstorm or atrial tachyarrhythmia with haemodynamic compromisenot efficiently treated with other methods

DiabetesA meta-analysis of 15 studies and 1464 patients indicated that cathe-ter ablation of AF in patients with diabetes had similar safety and effi-cacy than that in the general population especially when performedin younger patients with satisfactory glycaemic control29 Catheterablation of AF reduces the amount of patients requiring antiarrhyth-mic drugs an additional benefit in a population commonly exposedto adverse effects of AF pharmacological treatments

Thyroid disordersFT4 levels may influence the success rate of AF ablation procedureseven within the normal range275276 It has been found that right atrialnon-PVs triggers were more prevalent in AF patients treated withthyroid hormone replacement After elimination of non-PV triggersthere was still a worse arrhythmia-free survival in these patients277

Patients with hyperthyroid history have a higher number of PVectopic beats and higher prevalence of non-PV ectopic foci com-pared with euthyroid patients which may result in a higher AF recur-rence rate after ablation procedure110 Catheter ablation for

paroxysmal AF in patients with amiodarone-induced hyperthyroidismis usually safe and effective albeit with higher rate of early AF recur-rences up to 3 months after PV isolation relative to controls but notbeyond 12 months278 Pulmonary vein isolation alone may have alower efficacy for preventing recurrence in paroxysmal AF in thesepatients with amiodarone-induced hyperthyroidism which may needrepeat ablations279

Device-based therapy ofarrhythmias in patients withendocrine disorders

Diabetes and long-term treatment with chronic corticosteroids (fre-quently prescribed in endocrine disorders) are important factorsassociated with an increased risk of infections of cardiac electricalimplanted devices (CIEDs) as shown in Table 8280ndash284 Pacemaker-and ICD-related infections represent one of the most difficult compli-cations that may occur in a patient implanted with a CIED There isincreasing concern on the important clinical and economic conse-quences of the rise in the incidence of CIEDs-related infections thathave occurred in the last 10 years280ndash284 The incidence of pace-maker- and ICD-related infections has been reported to rangebetween 01 and 199 for pacemakers and between 08 and95 for ICDs including biventricular devices in observational studieswith different follow-up durations280ndash284 Cardiac electrical implanteddevices infections usually appear as infections limited to the devicepocket often with fistulas and skin erosion but lead endocarditis maybe detected in around one out of 10 cases with an incidence of 006ndash06280ndash284 The outcome of CIED infections is characterized by seri-ous events including a high risk of death so preventive measures aremandatory on the basis of appropriate identification of risk factors(Table 10)

In patients with an ICD or a device for cardiac resynchronizationtherapy (CRT) implanted diabetes influences outcome similarly toother comorbidities included in the Charlson comorbidity score285

The comorbidities that are represented in the Charlson comorbidity


statement

instruction

Level of

evidence

References

Irrespective of underlying endocrine abnormalities (which should be concurrently managed)

the CHA2DS2-VASc score should be used to initially identify lsquolow riskrsquo patients

(CHA2DS2-VASc 0 in males or 1 in females) who do not need any antithrombotic therapy

followed by prevention of stroke (ie OAC) in patients with gt1 risk factor


As OAC is being initiated a clinical bleeding risk score such as HAS-BLED score should be

used to identify patients at risk for bleeding (HAS-BLED gt_3)


Importantly potentially reversible bleeding risk factors should be considered in all patients

irrespective of HAS-BLED score value

The SAMe-TT2R2 score may be used to aid decision making between a VKA with likelihood

of a good TTR (score 0ndash2) or those less likely to do so thus requiring more regular INR

checks or as a better option use of a NOAC




score are independent predictors of death all-cause and cardiovas-cular hospitalizations as well as of days spent alive and out of hospi-tal286 In a report from the United States on more than 18 000patients with a cardiac resynchronization therapy-defibrillator (CRT-D) device implanted patients with diabetes had a higher mortalitythan those without diabetes both at 1 and 3 years287 in agreementwith a meta-analysis based on five studies on cardiac resynchroniza-tion in heart failure288289 However these findings have to beanalysed in combination with the evidence derived from randomizedstudies that CRT is equally effective in reducing mortality vs controlin diabetic as compared to non-diabetic patients288290

The effectiveness of ICDs for primary prevention of SCD inpatients with diabetes has raised great interest since diabetes as wellas other comorbidities may be also associated with a high risk ofnon-arrhythmic cardiac and non-cardiac death This complex topichas been studied through subanalysis of randomized trials systematicreviews and meta-analysis291 The subanalysis of diabetic patients inrandomized clinical trials provides reassurance since the beneficialeffect of ICD on survival is confirmed both in patients with and with-out diabetes291ndash293 The frequent association between diabetes andchronic kidney disease (CKD) is of great relevance since CKD per semay condition the outcome and the benefits after implant of a ICDor a CRT device294

In patients implanted with a defibrillator the occurrence of AF dueto hyperthyroidism may induce inappropriate shocks and requiresproper management258 Hyperthyroidism either due to primary

thyroid disease or secondary to amiodarone treatment should beexcluded in any case of new-onset of atrial tachyarrhythmias295296

Hypothyroidism has been associated with poor outcomes inpatients with heart failure and therefore it is of interest to assess theoutcome of patients with previous diagnosis of hypothyroidism afterCRT device implantation In a case series of heart failure patientsimplanted with CRT a history of hypothyroidism was present in164 and was an independent predictor of poor outcome (cardiacdeath heart failure hospitalization or need for heart transplant)297298

Current research gaps ongoingtrials and future directions

Most of the information present in the literature is based on registriesand the communication of some exceptional cases Mostly there areno data on the specific effect of hormones on heart rate disturbancesand their effects are estimated based on structural remodelling andassociated comorbidities (ie changes in blood pressure obesitysleep disorders or increased catecholamine levels) Importantlythere is scarce evidence of the real incidence of arrhythmias in endo-crine diseases Indeed the lack of clinical trials with specific attentionto the effect on arrhythmias is general Specific randomized trials areneeded beyond drug safety where only the effect on heart rhythmdisturbances is very marginal

Different trials are searching for the biological effect of antidiabeticdrugs on heart rhythm For example it has led to study the effects ofintravenous exenatide on cardiac repolarisation299 exploring changes toQTc interval changes In the same line Addhope 2 trial300 studies theheart rate variability modifications with liraglutide in patients with ischae-mic heart disease and newly diagnosed DM type 2

An interesting field is the diagnosis of AF in patients treated forhyperthyroidism In this setting there is a thumb-ECG ambulantscreening for AF in this type of patients301 though in clinical settingother monitoring methods can be used Whereas TABLAS studyexplores the influence of subclinical hyperthyroidism on the resultsof AF ablation302

Regarding PCC the PRESCRIPT trial compares phenoxybenzaminevs doxazosin and assesses the differences in high blood pressure andtachycardia episodes303 There is also an ongoing study in acromegalypatients it is exploring the effects of repeated subcutaneous injectionwith BIM23B065mdasha somatostatin 2 receptor agonist-in acromegalicpatients304 on blood pressure heart rate and QT interval

Cardiac arrhythmias in endocrine disorders are frequent and mod-ify the natural history of the disease These facts invite cardiologists toparticipate in future research and trials to explore pathophysiologicpathways diagnosis and therapeutic approach in endocrine disorders

Supplementary material

Supplementary material is available at Europace online

AcknowledgementsThe authors thank EHRA Scientific Documents Committee GregoryYH Lip Laurent Fauchier David Arnar Carina Blomstrom-Lundqvist Zbigniew Kalarus Gulmira Kudaiberdieva Georges H

Table 10 Risk of CIED infection according to aseries of risk factors as reported in literature280ndash284

Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15

Younger age 14ndash45

Diabetes 23ndash35

Chronic kidney disease 46ndash63

Haemodialysis 86

Treatment with anticoagulants 26ndash34

Chronic corticosteroid use 91

History of malignancy 40

Underlying heart disease 31

High Charlson co-morbidity index 27ndash30

Fever systemic infection 58

Device or procedure-related factors

Prior CIED infection 113

gt_3 implanted leads 40ndash54

Device replacement device upgrades

or implant revision

17ndash31

Early reinterventions 27ndash15

Temporary pacing prior to implantation 25

Post-operative haematoma at pocket site 40ndash67

Physician experience 25

CIED cardiac electrical implanted device

24 B Gorenek et al


Mairesse Tatjana Potpara Irina Savelieva Jesper Hastrup SvendsenVassil B Traykov

Conflict of interest none declared

References1 Lengyel S Vira L Kova PP Kristo A Pacher P Kocsis E Role of slow delayed

rectifier K-current in QT prolongation in the alloxan-induced diabetic rabbitheart Acta Physiol 2008192359ndash62

2 Ballou LM Lin RZ Cohen IS Control of cardiac repolarization by phosphoino-sitide 3-kinase signaling to ion channels Circ Res 2015116127ndash37

3 Boriani G Lorenzetti S Cerbai E Oreto G Bronzetti G Malavasi VL et al Theeffects of gender on electrical therapies for the heart physiology epidemiologyand access to therapies a report from the XII Congress of the ItalianAssociation on Arrhythmology and Cardiostimulation (AIAC) Europace 2017191418

4 Gilles AM Atrial fibrillation and ventricular arrhythmias sex differences in elec-trophysiology epidemiology clinical presentation and clinical outcomeCirculation 2017135593ndash608

5 Lang F Shumilina E Regulation of ion channels by the serum and glucocortoidinducible kinase SGK1 FASEB J 2013273ndash12

6 American Diabetes A 9 Cardiovascular disease and risk management DiabetesCare 201740(Suppl 1) S75ndash87

7 Malmberg K Yusuf S Gerstein HC Brown J Zhao F Hunt D et al Impact ofdiabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction results of the OASIS (Organization to AssessStrategies for Ischemic Syndromes) Registry Circulation 20001021014ndash9

8 Scirica BM Bhatt DL Braunwald E Raz I Cavender MA Im K et al Prognosticimplications of biomarker assessments in patients with type 2 diabetes at highcardiovascular risk a secondary analysis of a randomized clinical trial JAMACardiol 20161989

9 Tse G Lai ET Tse V Yeo JM Molecular and electrophysiological mechanismsunderlying cardiac arrhythmogenesis in diabetes mellitus J Diabetes Res 201620161

10 Koektuerk B Aksoy M Horlitz M Bozdag-Turan I Turan RG Role of diabetesin heart rhythm disorders World J Diabetes 2016745ndash9

11 Fox CS Coady S Sorlie PD Levy D Meigs JB DrsquoAgostino RB Sr et al Trends incardiovascular complications of diabetes JAMA 20042922495ndash9

12 Cho E Rimm EB Stampfer MJ Willett WC Hu FB The impact of diabetes mel-litus and prior myocardial infarction on mortality from all causes and from cor-onary heart disease in men J Am Coll Cardiol 200240954ndash60

13 Balkau B Jouven X Ducimetiere P Eschwege E Diabetes as a risk factor forsudden death Lancet 19993541968ndash9

14 Chamberlain AM Agarwal SK Folsom AR Soliman EZ Chambless LE Crow Ret al A clinical risk score for atrial fibrillation in a biracial prospective cohort(from the Atherosclerosis Risk in Communities [ARIC] study) Am J Cardiol201110785ndash91

15 Kannel WB Wolf PA Benjamin EJ Levy D Prevalence incidence prognosisand predisposing conditions for atrial fibrillation population-based estimatesAm J Cardiol 1998822Nndash9N

16 Dublin S Glazer NL Smith NL Psaty BM Lumley T Wiggins KL et al Diabetesmellitus glycemic control and risk of atrial fibrillation J Gen Intern Med 201025853ndash8

17 Fatemi O Yuriditsky E Tsioufis C Tsachris D Morgan T Basile J et al Impactof intensive glycemic control on the incidence of atrial fibrillation and associatedcardiovascular outcomes in patients with type 2 diabetes mellitus (from theAction to Control Cardiovascular Risk in Diabetes Study) Am J Cardiol 20141141217ndash22

18 Huxley RR Filion KB Konety S Alonso A Meta-analysis of cohort and case-control studies of type 2 diabetes mellitus and risk of atrial fibrillation Am JCardiol 201110856ndash62

19 Krahn AD Manfreda J Tate RB Mathewson FA Cuddy TE The natural historyof atrial fibrillation incidence risk factors and prognosis in the Manitobafollow-up study Am J Med 199598476ndash84

20 Watanabe H Tanabe N Watanabe T Darbar D Roden DM Sasaki S et alMetabolic syndrome and risk of development of atrial fibrillation the Niigatapreventive medicine study Circulation 20081171255ndash60

21 Schoen T Pradhan AD Albert CM Conen D Type 2 diabetes mellitus and riskof incident atrial fibrillation in women J Am Coll Cardiol 2012601421ndash8

22 Du X Ninomiya T de Galan B Abadir E Chalmers J Pillai A et al Risks of car-diovascular events and effects of routine blood pressure lowering among pa-tients with type 2 diabetes and atrial fibrillation results of the ADVANCEstudy Eur Heart J 2009301128ndash35

23 Aksnes TA Schmieder RE Kjeldsen SE Ghani S Hua TA Julius S Impact ofnew-onset diabetes mellitus on development of atrial fibrillation and heart fail-ure in high-risk hypertension (from the VALUE Trial) Am J Cardiol 2008101634ndash8

24 Gallagher C Hendriks JM Mahajan R Middeldorp ME Elliott AD Pathak RKet al Lifestyle management to prevent and treat atrial fibrillation Expert RevCardiovasc Ther 201614799ndash809

25 Nichols GA et al Independent contribution of diabetes to increased prevalenceand incidence of atrial fibrillation Diabetes Care 2009321851ndash6

26 Kirchhof P Benussi S Kotecha D Ahlsson A Atar D Casadei B et al 2016 ESCGuidelines for the management of atrial fibrillation developed in collaborationwith EACTS Europace 2016181609ndash78

27 Freedman B Camm J Calkins H Healey JS Rosenqvist M Wang J et alScreening for atrial fibrillation a report of the AF-SCREEN international collab-oration Circulation 20171351851ndash67

28 Mairesse GH Moran P Van Gelder I Elsner C Rosenqvist M Mant J et alScreening for Atrial Fibrillation a European Heart Rhythm Association (EHRA)consensus document endorsed by the Heart Rhythm Society (HRS) Asia PacificHeart Rhythm Society (APHRS) and Societad Latinoamericana de EstimulationCardiaca y Electrofisiologia (SOLAECE) Europace 2017191851ndash67

29 Zaccardi F Khan H Laukkanen JA Diabetes mellitus and risk of sudden cardiacdeath a systematic review and meta-analysis Int J Cardiol 2014177535ndash7

30 Anselmino M Matta M DrsquoAscenzo F Pappone C Santinelli V Bunch TJ et alCatheter ablation of atrial fibrillation in patients with diabetes mellitus a sys-tematic review and meta-analysis Europace 2015171518ndash25

31 Bogossian H Frommeyer G Brachmann J Lewalter T Hoffman E Kuck KHet al Catheter ablation of atrial fibrillation and atrial flutter in patients with dia-betes mellitus who benefits and who does not Data from German ablationregistry Int J Cardiol 201621425ndash30

32 Forleo GB Mantica M De Luca L Leo R Santini L Panigada S et al Catheterablation of atrial fibrillation in patients with diabetes mellitus type 2 resultsfrom a randomized study comparing pulmonary vein isolation versus antiar-rhythmic drug therapy J Cardiovasc Electrophysiol 20092022

33 Jouven X Lemaıtre RN Rea TD Sotoodehnia N Empana JP Siscovick DSDiabetes glucose level and risk of sudden cardiac death Eur Heart J 2005262142ndash7

34 Potpara T Marinkovic-Eric J Grujic M Radojkovic-Cirovic B Vujisic-Tesic BPetrovic M [Effect of diabetes mellitus in recovery and maintenance of sinusrhythm in patients with persistent atrial fibrillation] Srp Arh Celok Lek 2002130189ndash92

35 Kucharska-Newton AM Couper DJ Pankow JS Prineas RJ Rea TDSotoodehnia N et al Diabetes and the risk of sudden cardiac death theAtherosclerosis Risk in Communities study Acta Diabetol 201047(Suppl 1)161ndash8

36 Eranti A Kerola T Aro AL Tikkanen JT Rissanen HA Anttonen O et alDiabetes glucose tolerance and the risk of sudden cardiac death BMCCardiovasc Disord 20161651

37 Cardoso CR Salles GF Deccache W Prognostic value of QT interval param-eters in type 2 diabetes mellitus results of a long-term follow-up prospectivestudy J Diabetes Complications 200317169ndash78

38 Molon G Costa A Bertolini L Zenari L Arcaro G Barbieri E et al Relationshipbetween abnormal microvolt T-wave alternans and poor glycemic control intype 2 diabetic patients Pacing Clin Electrophysiol 2007301267ndash72

39 OrsquoBrien IA OrsquoHare JP Lewin IG Corrall RJ The prevalence of autonomic neur-opathy in insulin-dependent diabetes mellitus a controlled study based on heartrate variability Q J Med 198661957ndash67

40 Tsuji H Venditti FJ Jr Manders ES Evans JC Larson MG Feldman CL et alReduced heart rate variability and mortality risk in an elderly cohort TheFramingham Heart Study Circulation 199490878ndash83

41 Vinik AI Ziegler D Diabetic cardiovascular autonomic neuropathy Circulation2007115387ndash97

42 Singh JP Larson MG OrsquoDonnell CJ Wilson PF Tsuji H Lloyd-Jones DM et alAssociation of hyperglycemia with reduced heart rate variability (TheFramingham Heart Study) Am J Cardiol 200086309ndash12

43 Cherney DZ Perkins BA Soleymanlou N Har R Fagan N Johansen OE et alThe effect of empagliflozin on arterial stiffness and heart rate variability in sub-jects with uncomplicated type 1 diabetes mellitus Cardiovasc Diabetol 20141328

44 Balcıoglu S Arslan U Turkoglu S Ozdemir M Cengel A Heart rate variabilityand heart rate turbulence in patients with type 2 diabetes mellitus with versuswithout cardiac autonomic neuropathy Am J Cardiol 2007100890ndash3

45 Miwa Y Miyakoshi M Hoshida K Yanagisawa R Abe A Tsukada T et al Heartrate turbulence can predict cardiac mortality following myocardial infarction inpatients with diabetes mellitus J Cardiovasc Electrophysiol 2011221135ndash40

46 Bissinger A Ruxer J Ahmed RB Lubinski A Heart rate turbulence in patientswith poorly controlled diabetes mellitus type 2 Arch Med Sci 2014101073ndash7



47 Priori SG Blomstrom-Lundqvist C Mazzanti A Blom N Borggrefe M Camm Jet al 2015 ESC Guidelines for the management of patients with ventricular ar-rhythmias and the prevention of sudden cardiac death Europace 2015171601ndash87

48 Chen-Scarabelli C Scarabelli TM Suboptimal glycemic control independentlyof QT interval duration is associated with increased risk of ventricular arrhyth-mias in a high-risk population Pacing Clin Electrophysiol 2006299ndash14

49 Secrest AM Becker DJ Kelsey SF Laporte RE Orchard TJ Characterizingsudden death and dead-in-bed syndrome in Type 1 diabetes analysis fromtwo childhood-onset Type 1 diabetes registries Diabet Med 201128293ndash300

50 Tanenberg RJ Newton CA Drake AJ Confirmation of hypoglycemia in theldquodead-in-bedrdquo syndrome as captured by a retrospective continuous glucosemonitoring system Endocr Pract 201016244ndash8

51 NICE-SUGAR Study Investigators Finfer S Liu B Chittock DR Norton RMyburgh JA et al Hypoglycemia and risk of death in critically ill patients N EnglJ Med 20123671108ndash18

52 ORIGIN Trial Investigators Mellbin LG Ryden L Riddle MC Probstfield JRosenstock J et al Does hypoglycaemia increase the risk of cardiovascularevents A report from the ORIGIN trial Eur Heart J 2013343137ndash44

53 Gerstein HC Miller ME Genuth S Ismail-Beigi F Buse JB Goff DC Jr et alACCORD Study Group Long-term effects of intensive glucose lowering oncardiovascular outcomes N Engl J Med 2011364818ndash28

54 Gerstein HC Miller ME Byington RP Goff DC Jr Bigger JT Buse JB et alAction to Control Cardiovascular Risk in Diabetes Study Group Effects ofintensive glucose lowering in type 2 diabetes N Engl J Med 20083582545ndash59

55 Chow E Bernjak A Williams S Fawdry RA Hibbert S Freeman J et al Risk ofcardiac arrhythmias during hypoglycemia in patients with type 2 diabetes andcardiovascular risk Diabetes 2014631738ndash47

56 Hay LC Wilmshurst EG Fulcher G Unrecognized hypo- and hyperglycemia inwell-controlled patients with type 2 diabetes mellitus the results of continuousglucose monitoring Diabetes Technol Ther 2003519ndash26

57 Reno CM Daphna-Iken D Chen YS Vander Weele J Jethi K Fisher SJ Severehypoglycemia-induced lethal cardiac arrhythmias are mediated by sympathoa-drenal activation Diabetes 2013623570ndash81

58 Tsujimoto T Sugiyama T Shapiro MF Noda M Kajio H Risk of cardiovascularevents in patients with diabetes mellitus on beta-blockers Hypertension 201770103ndash10

59 Bangalore S Messerli FH Kostis JB Pepine CJ Cardiovascular protection usingbeta-blockers a critical review of the evidence J Am Coll Cardiol 200750563ndash72

60 American Diabetes A 6 Glycemic targets Diabetes Care 201740(Suppl 1)S48ndash56

61 Zinman B Wanner C Lachin JM Fitchett D Bluhmki E Hantel S et alEmpagliflozin cardiovascular outcomes and mortality in type 2 diabetes N EnglJ Med 20153732117ndash28

62 Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JFE Nauck MAet al LEADER Steering Committee LEADER Trial Investigators Liraglutide andcardiovascular outcomes in type 2 diabetes N Engl J Med 2016375311ndash22

63 American Diabetes A 8 Pharmacologic approaches to glycemic treatmentDiabetes Care 201740(Suppl 1) S64ndash74

64 Mann JFE Oslashrsted DD Brown-Frandsen K Marso SP Poulter NR Rasmussen Set al Liraglutide and renal outcomes in type 2 diabetes N Engl J Med 2017377839ndash48

65 Neal B Perkovic V Mahaffey KW de Zeeuw D Fulcher G Erondu N et alCanagliflozin and cardiovascular and renal events in type 2 diabetes N Engl JMed 2017377644ndash57

66 Raz I Wiviott SD Multicenter trial to evaluate the effect of dapagliflozin on theincidence of cardiovascular events (DECLARE-TIMI58) ClinicalTrialsgovIdentifier NCT01730534

67 Sonesson C Johansson PA Johnsson E Gause-Nilsson I Cardovascular effectsof dapagliflozin in patients with type 2 diabetes and different risk categories ameta-analysis Cardiovasc Diabetol 20161537

68 Wu JHY Foote C Blomster J Toyama T Perkovic V Sundstrom J et al Effectsof sodium-glucose cotransporter-2 inhibitors on cardiovascular events deathand major safety outcomes in adults with type 2 diabetes a systematic reviewand meta-analysis Lancet Diabetes Endocrinol 20164411ndash9

69 Kalra S Sodium-glucose cotransporter 2 (SGLT2)inhibiotrs and cardiovasculardisease a systematic review Cardiol Ther 20165161ndash8

70 Holman RR Bethel MA Mentz RJ Thompson VP Lokhnygina Y Buse JB et alEffects of once-weekly exenatide on cardiovascular outcomes in type 2 dia-betes N Engl J Med 20173771228ndash39

71 Pfeffer MA Claggett B Diaz R Dickstein K Gerstein HC Kober LV et alLixisenatide in patients with type 2 diabetes and acute coronary syndrome NEngl J Med 20153732247ndash57

72 ADVANCE Collaborative Group Patel A MacMahon S Chalmers J Neal BBillot L et al Intensive blood glucose control and vascular outcomes in patientswith type 2 diabetes N Engl J Med 20083582560ndash72

73 Duckworth W Abraira C Moritz T Reda D Emanuele N Reaven PD et alGlucose control and vascular complications in veterans with type 2 diabetesN Engl J Med 2009360129ndash39

74 NICE-SUGAR Study Investigators Finfer S Chittock DR Su SY Blair D FosterD et al Intensive versus conventional glucose control in critically ill patientsN Engl J Med 20093601283ndash97

75 Chen YC Chen SA Chen YJ Chang MS Chan P Lin CI Effects of thyroid hor-mone on the arrhythmogenic activity of pulmonary vein cardiomyocytes J AmColl Cardiol 200239366ndash 7

76 Zhang Y Dedkov EI Lee B 3rd Li Y Pun K Gerdes AM Thyroid hormone re-placement therapy attenuates atrial remodeling and reduces atrial fibrillationinducibility in a rat myocardial infarction-heart failure model J Card Fail 2014201012ndash9

77 Mangiardi L Gaita F Brun S Presbitero P Nademanee K Singh BNAtrioventricular block complicating amiodarone-induced hypothyroidism in apatient with pre-excitation and rate-dependent bilateral bundle branch blockJ Am Coll Cardiol 19867180ndash4

78 Purtell K Roepke TK Abbot GW Cardiac arrhythmias and thyroid dysfunctiona novel genetic link Int J Biochem Cell Biol 2010421767ndash70

79 Galloway A Li H Vanderlinde-Wood M Khan M Benbrook A Liles C et alActivating autoantibodies to the b12-adrenergic and M2 muscarinic receptorsassociate with atrial tachyarrhythmias in patients with hyperthyroidismEndocrine 201549457ndash63

80 Selmer C Olesen JB Hansen ML Lindhardsen J Schjerning Olsen AMClausager J et al The spectrum of thyroid disease and risk of new onset atrialfibrillation a large population cohort study BMJ 2012345e7895

81 Frost L Vestergaard P Mosekilde L Hyperthyroidism and risk of atrial fibril-lation or flutter a population-based study Arch Intern Med 20041641675ndash8

82 Cappola AR Fried LP Arnold AM Danese MD Kuller LH Burke JL et alThyroid status cardiovascular risk and mortality in older adults JAMA 20062951033ndash41

83 Sawin CT Geller A Wolf PA Belanger AJ Baker E Bacharach P et al Lowserum thyrotropin concentrations as a risk factors for atrial fibrillation in olderpersons N Engl J Med 19943311249ndash52

84 Auer J Scheibner P Mische T Langsteger W Eber O Eber B Subclinicalhypothyroidism as a risk factor for atrial fibrillation Am Heart J 2001142838ndash42

85 Gammage MD Parle JV Holder RL Roberts LM Hobbs FDR Wilson S et alAssociation between free thyroxine concentration and atrial fibrillation ArchIntern Med 2007167928ndash34

86 Collet TH Gussekloo J Bauer DC den Elzen WPJ Wendy PJ Cappola ARet al MAS for the Thyroid Studies Collaboration Subclinical hyperthyroidismand the risk of coronary heart disease and mortality Arch Intern Med 2012172799ndash809

87 Heeringa J Hoogendoorn EH van der Deure WM Hofman A Peeters RP HopWCJ et al High-normal thyroid function and risk of atrial fibrillation Arch InternMed 20081682219ndash24

88 Floriani C Gencer B Collet TH Rodondi N Subclinical thyroid dysfunctionand cardiovascular diseases 2016 update Eur Heart J 2017 doi101093eurheartjehx050

89 Gorenek B Pelliccia A Benjamin EJ Boriani G Crijns HJ Fogel RI et alEuropean Heart Rhythm Association (EHRA)European Association ofCardiovascular Prevention and Rehabilitation (EACPR) position paper on howto prevent atrial fibrillation endorsed by the Heart Rhythm Society (HRS) andAsia Pacific Heart Rhythm Society (APHRS) Europace 201719190ndash225

90 Kim EJ Lyass A Wang N Massaro JM Fox CS Benjamin EJ et al Relation ofhypothyroidism and incident atrial fibrillation (from the Framingham HeartStudy) Am Heart J 2014167123ndash6

91 Brandt F Thvilum M Almind D Christensen K Green A Hegedu L et alMorbidity before and after the diagnosis of hyperthyroidism a nationwideregister-based study PLoS One 20118e66711

92 Chauhan V Hypothyroidism was 300 more frequent that hyperthyroidismin patients with atrial fibrillation enrolled over 10 years Am J Med 2015128e51

93 Martinez-Comendador J Marcos-Vidal JM Gualis J Martin CE Marin E Otero Jet al Subclinical hypothyroidism might increase the risk of postoperative atrialfibrillation after aortic valve replacement Thorac Cardiovasc Surg 201664427ndash33

94 Jolobe OMP Thyroid heart disease should include the coincidental associationof hypothyroidism and atrial fibrillation Am J Med 2015128e9

26 B Gorenek et al


95 Worku B Tortolani AJ Gulkarov I Isom OW Klein I Preoperative hypothy-roidism is a risk factor for postoperative atrial fibrillation in cardiac surgical pa-tients J Card Surg 201530307ndash12

96 Zhang Y Dedkov EI Teplitsky D Weltman NY Pol CJ Rajagopalan V et alBoth hypothyroidism and hyperthyroidism increase atrial fibrillation inducibilityin rats Circ Arrhythm Electrophysiol 20136952ndash9

97 Kolettis TM Tsatsoulis A Subclinical hypothyroidism an overlooked cause ofatrial fibrillation J Atr Fibrillation 20125710

98 Nakazawa HK Sakurai K Hamada N Momotani N Ito K Management of atrialfibrillation in the post-thyrotoxic state Am J Med 198272903ndash6

99 Zhou ZH Ma LL Wang LX Risk factors for persistent atrial fibrillation follow-ing successful hyperthyroidism treatment with radioiodine therapy Intern Med2011502947ndash51

100 Tsymbaliuk I Unukovych D Shvets N Dinets A Cardiovascular complicationssecondary to Gravesrsquo disease a prospective study from Ukraine PLoS One201510e0122388

101 Gauthier JM Mohamed HE Noureldine SI Nazari-Shafti TZ Thethi TK KandilE Impact of thyroidectomy on cardiac manifestations of Gravesrsquo diseaseLaryngoscope 20161261256ndash9

102 Feely J Peden N Use of beta-adrenoreceptor blocking drugs in hyperthyroid-ism Drugs 198427425ndash46

103 Jansson S Lie-Karlsen K Stenqvist O Korner U Lundholm K Tisell LE Oxygenconsumption in patients with hyperthyroidism before and after treatment withbeta-blockade vs thyrostatic treatment a prospective randomized study AnnSurg 200123360ndash4

104 Dalan R Leow MK Leow MC Leow M Cardiovascular collapse associatedwith beta-blockade in thyroid storm Exp Clin Endocrinol Diabetes 2007115392ndash6

105 Nakazawa HK Handa S Nakamura Y Oyanagi H Hasegawa M Ishikawa Net al High maintenance rate of sinus rhythm after cardioversion in post-thyrotoxic chronic atria1 fibrillation Int J Cardiol 19871647ndash55

106 Nakazawa H Lythall DA Noh J Ishikawa N Sugino K Ito K et al Is there aplace for the late cardioversion of atrial fibrillation A long-term follow-up studyof patients with post-thyrotoxic atrial fibrillation Eur Heart J 200021327ndash33

107 Siu C-W Jim M-H Zhang X Chan Y-H Pong V Kwok J et al Comparison ofatrial fibrillation recurrence rates after successful electrical cardioversion in pa-tients with hyperthyroidism-induced versus non-hyperthyroidism-induced per-sistent atrial fibrillation Am J Cardiol 2009103540ndash3

108 Ma CS Liu X Hu FL Dong JZ Liu XP Wang XH Catheter ablation of atrial fib-rillation in patients with hyperthyroidism J Interv Card Electrophysiol 200718137ndash42

109 Machino T Tada H Sekiguchi Y Yamasaki H Kuroki K Igarashi M Prevalenceand influence of hyperthyroidism on the long-term outcome of catheter abla-tion for drug-refractory atrial fibrillation Circ J 2012762546ndash51

110 Wongcharoen W Lin YJ Chang SL Lo LW Hu YF Chung FP History ofhyperthyroidism and long-term outcome of catheter ablation of drug-refractoryatrial fibrillation Heart Rhythm 2015121956ndash62

111 Chan PH Hai J Yeung CY Lip GY Lam KS Tse HF et al Benefit of anticoagula-tion therapy in hyperthyroidism-related atrial fibrillation Clin Cardiol 201538476ndash82

112 Friberg L Rosenqvist M Lip GY Evaluation of risk stratification schemes for is-chaemic stroke and bleeding in 182 678 patients with atrial fibrillation theSwedish Atrial Fibrillation cohort study Eur Heart J 2012331500ndash10

113 Petersen P Hansen JM Stroke in thyrotoxicosis with atrial fibrillation Stroke19881915ndash8

114 Bruere H Fauchier L Bernard Brunet A Pierre B Simeon E Babuty D et alHistory of thyroid disorders in relation to clinical outcomes in atrial fibrillationAm J Med 201512830ndash7

115 von Olshausen K Bischoff S Kahaly G Mohr-Kahaly S Erbel R Beyer J et alCardiac arrhythmias and heart rate in hyperthyroidism Am J Cardiol 198963930ndash3

116 Kulairi Z Deol N Tolly R Manocha R Naseer M QT prolongation due toGravesrsquo disease Case Rep Cardiol 201720171

117 Kobayashi H Haketa A Abe M Tahira K Hatanaka Y Tanaka S et al Unusualmanifestation of Gravesrsquo disease ventricular fibrillation Eur Thyroid J 20154207ndash12

118 Ozcan KS Osmonov D Erdinler I Altay S Yildirim E Turkkan C et alAtrioventricular block in patients with thyroid dysfunction prognosis aftertreatment with hormone supplementation or antithyroid medication J Cardiol201260327ndash32

119 Namura M Kanaya H Lkeda M Shibayama S Ohka T Hyperthyroidism compli-cated with sick sinus syndrome Jpn Circ J 199559824ndash8

120 Kannan L Kotus-Bart J Amanullah A Prevalence of cardiac arrhythmias inhypothyroid and euthyroid patients Horm Metab Res 201749430ndash3

121 Lim CH Lim P Recurrent ventricular tachycardia in hypothyroidism Aust N Z JMed 1976668ndash70

122 Fredlund BO Olsson SB Long QT interval and ventricular tachycardia of ldquotor-sade de pointerdquo type in hypothyroidism Acta Med Scand 1983213231ndash5

123 Kukla P Szczuka K Słowiak-Lewinska T Bromblik A Hajduk B Kluczewski MAcquired long QT syndrome with torsade de pointes in a patient with primaryhypothyroidism Kardiol Pol 200358224ndash6

124 Schenck JB Rizvi AA Lin T Severe primary hypothyroidism manifesting withtorsades de pointes Am J Med Sci 2006331154ndash6

125 Kandan SR Saha M Severe primary hypothyroidism presenting with torsadesde pointes BMJ Case Rep 20122012bcr1220115306 doi 101136bcr1220115306

126 Ellis CR Murray KT When an ICD is not the answer Hypothyroidism-induced cardiomyopathy and torsades de pointes J Cardiovasc Electrophysiol2008191105ndash7

127 Rosengarten M Brooks R Torsade de pointes ventricular tachycardia in a hypo-thyroid patient treated with propafenone Can J Cardiol 19873234ndash9

128 Pedersen CT Kay GN Kalman J Borggrefe M Della-Bella P Dickfeld T et alEHRAHRSAPHRS expert consensus on ventricular arrhythmias Europace2014161257ndash83

129 Esposito F Liguori V Maresca G Cerrone A De Filippo O Trimarco B et alSubclinical hypothyroidism a reversible cause of complete loss of ventricularlead capture Circ Arrhythm Electrophysiol 20147182ndash4

130 Schlesinger Z Rosenberg T Stryjer D Gilboa Y Exit block in myxedematreated effectively by thyroid hormone therapy Pacing Clin Electrophysiol 19803737ndash9

131 Patton KK Levy M Viswanathan M Atrial lead dysfunction an unusual featureof hypothyroidism Pacing Clin Electrophysiol 2008311650ndash2

132 Basu D Chatterjee K Unusually high pacemaker threshold in severe myx-edema Decrease with thyroid hormone therapy Chest 197670677ndash9

133 Lardoux H Cenac A Perlemuter L Bernheim R Hazard J Disorders of intra-cardiac conduction and hypothyroidism in adults A systematic study of 42cases Nouv Presse Med 197541859ndash62

134 Numata T Abe H Terao T Nakashima Y Possible involvement of hypothyroid-ism as a cause of lithium-indiced sinus node dysfunction Pacing ClinElectrophysiol 199922954ndash7

135 Blanco VM Moller I Castano G Casares G Reversible sick sinus syndrome andhypothyroidism due to lithium Med Clin (Barc) 2003120478ndash9

136 Schantz ET Dubbs AW Complete auriculoventricular block in myxedema withreversion to normal sinus rhythm on thyroid therapy Am Heart J 195141613ndash9

137 Chatzitomaris A Scheeler M Gotzmann M Koditz R Schildroth J Knyhala KMet al Second degree AV block and severely impaired contractility in cardiacmyxedema a case report Thyroid Res 201586

138 Seol SH Kim DI Park BM Kim DK Song PS Jin HY et al Complete atrioven-tricular block presenting with syncope caused by severe hypothyroidismCardiol Res 20123239ndash41

139 Schoenmakers N de Graaff WE Peters RH Hypothyroidism as the cause ofatrioventricular block in an elderly patient Neth Heart J 20081657ndash9

140 Nakayama Y Ohno M Yonemura S Uozumi H Kobayakawa N Fukushima Ket al A case of transient 2 1 atrioventricular block resolved by thyroxine sup-plementation for subclinical hypothyroidism Pacing Clin Electrophysiol 200629106ndash8

141 Brignole M Auricchio A Baron-Esquivias G Bordachar P Boriani G BreithardtOA et al 2013 ESC guidelines on cardiac pacing and cardiac resynchronizationtherapy the task force on cardiac pacing and resynchronization therapy of theEuropean Society of Cardiology (ESC) Developed in collaboration with theEuropean Heart Rhythm Association (EHRA) Europace 2013151070ndash118

142 Jabrocka-Hybel A Bednarczuk T Bartalena L Pach D Ruchała M Kaminski Get al Amiodarone and the thyroid Endokrynol Pol 201566176ndash96

143 Bogazzi F Bartalena L Martino E Approach to the patient with amiodarone-induced thyrotoxicosis J Clin Endocrinol Metab 2010952529ndash35

144 De Leo S Lee SY Braverman LE Hyperthyroidism Lancet 2016388906ndash18145 Vassallo P Trohman RC Prescribing amiodarone an evidence-based review of

clinical indications JAMA 20072981312ndash22146 Barbesino G Tomer Y Clinical Utility of TSH Receptor Antibodies J Clin

Endocrinol Metab 2013982247ndash55147 Ross DS Burch HB Cooper DS Greenlee MC Laurberg P Maia AL et al 2016

American Thyroid Association guidelines for diagnosis and management ofhyperthyroidism and other causes of thyrotoxicosis Thyroid 2016261343ndash421

148 Benjamens S Dullaart RPF Sluiter WJ Rienstra M van Gelder IC Links TP Theclinical value of regular thyroid function tests during amiodarone treatment EurJ Endocrinol 20171779ndash14

149 Piccini JP Berger JS OrsquoConnor CM Amiodarone for the prevention of suddencardiac death a meta-analysis of randomized controlled trials Eur Heart J 2009301245ndash53

150 Vorperian VR Havighurst TC Miller S January CR Adverse effects of low doseamiodarone a meta-analysis J Am Coll Cardiol 199730791ndash8



151 Batcher EL Tang XC Singh BN Singh SN Reda DJ Hershman JM SAFE-TInvestigators Thyroid function abnormalities during amiodarone therapy forpersistent atrial fibrillation Am J Med 2007120880ndash5

152 Ross IL Marshall D Okreglicki A Isaacs S Levitt NS Amiodarone-induced thy-roid dysfunction S Afr Med J 200595180ndash3

153 Ahmed S Van Gelder IC Wiesfeld AC Van Veldhuisen DJ Links TPDeterminants and outcome of amiodarone-associated thyroid dysfunction ClinEndocrinol (Oxf) 201175388ndash94

154 Lee CH Nam G-B Park H-G Kim HY Park K-M Kim J et al Effects of antiar-rhythmic drugs on inappropriate shocks in patients with implantable cardi-overter defibrillators Circ J 200872102ndash5

155 Kinoshita S Hayashi T Wada K Yamato M Kuwahara T Anzai T et al Risk fac-tors for amiodarone-induced thyroid dysfunction in Japan J Arrhythm 201632474ndash80

156 Shiga T Wakaumi M Matsuda N Shoda M Hagiwara N Sato K et alAmiodarone-induced thyroid dysfunction and ventricular tachyarrhythmias dur-ing long-term therapy in Japan Jpn Circ J 200165958ndash60

157 Pillarisetti J Vanga SR Lakkireddy D Amiodarone induced thyrotoxicosismdashfluctuating RVOT and LV scar VT J Atr Fibrillation 201357ndash9

158 Mun H-S Shen C Pak H-N Lee M-H Lin S-F Chen P-S et al Chronic amiodar-one therapy impairs the function of the superior sinoatrial node in patients withatrial fibrillation Circ J 2013772255ndash63

159 Cracana I Vasilcu TF Mardare A Alexa ID Marcu DT Severe amiodarone-induced bradycardia conceals sick sinus syndrome case report Rev Med ChirSoc Med Nat Iasi 2016120110ndash3

160 Essebag V Hadjis T Platt RW Pilote L Amiodarone and the risk of bradyar-rhythmia requiring permanent pacemaker in elderly patients with atrial fibrilla-tion and prior myocardial infarction J Am Coll Cardiol 200341249ndash54

161 Czarnywojtek A Plazinska MT Zgorzalewicz-Stachowiak M Wolinski KStangierski A Miechowicz I et al Dysfunction of the thyroid gland during amio-darone therapy a study of 297 cases Ther Clin Risk Manag 201612505ndash13

162 Hermida JS Tcheng E Jarry G Moullart V Arlot S Rey JL et al Radioiodine ab-lation of the thyroid to prevent recurrence of amiodarone-induced thyrotoxi-cosis in patients with resistant tachyarrhythmias Europace 20046169ndash74

163 UK Guidelines for the Use of Thyroid Function Tests 2002 wwwbritish-thyorid-associationorg (15 December 2017 date last accessed)

164 Diederichsen SZ Darkner S Chen X Johannesen A Pehrson S Hansen J et alShort-term amiodarone treatment for atrial fibrillation after catheter ablationinduces a transient thyroid dysfunction results from the placebo-controlledrandomized AMIO-CAT trial Eur J Intern Med 20163336ndash41

165 Hudzik B Zubelewicz-Szkodzinska B Amiodarone-related thyroid dysfunctionIntern Emerg Med 20149829ndash39

166 Zelinka T Petrak O Turkova H Holaj R Strauch B Krsek M et al High inci-dence of cardiovascular complications in pheochromocytoma Horm Metab Res201244379ndash84

167 Prejbisz A Lenders JWM Eisenhofer G Januszewicz A Cardiovascular mani-festations of phaeochromocytoma J Hypertens 2011292049ndash60

168 Dabrowska B Pruszczyk P Dabrowski A Feltynowski T Wocial B JanuszewiczW Influence of alpha-adrenergic blockade on ventricular arrhythmias QTcinterval and heart rate variability in phaeochromocytoma J Hum Hypertens19959925ndash9

169 Traykov VB Kotirkov KI Petrov IS Pheochromocytoma presenting with bidir-ectional ventricular tachycardia Heart 201399509

170 Brouwers FM Eisenhofer G Lenders JWM Pacak K Emergencies caused bypheochromocytoma neuroblastoma or ganglioneuroma Endocrinol Metab ClinNorth Am 200635699ndash724

171 Galetta F Franzoni F Bernini G Poupak F Carpi A Cini G et al Cardiovascularcomplications in patients with pheochromocytoma a mini-review BiomedPharmacother 201064505ndash9

172 Manger WM Gifford RW Pheochromocytoma J Clin Hypertens (Greenwich)2002462ndash72

173 Tewari P Sikora R Hypertension and tachycardia during adrenal manipulationCan J Anaesth 199542417ndash9

174 Colao A Ferone D Marzullo P Lombardi G Systemic complications of acro-megaly epidemiology pathogenesis and management Endocr Rev 200425102ndash52

175 McCabe J Ayuk J Sherlock M Treatment factors that influence mortality in ac-romegaly Neuroendocrinology 201610366ndash74

176 Dekkers OM Biermasz NR Pereira AM Romijn JA Vandenbroucke JPMortality in acromegaly a metaanalysis J Clin Endocrinol Metab 20089361ndash7

177 Katznelson L Laws ER Melmed S Molitch ME Murad MH Utz A et alAcromegaly an endocrine society clinical practice guideline J Clin EndocrinolMetab 2014993933ndash51

178 Ritvonen E Loyttyniemi E Jaatinen P Ebeling T Moilanen L Nuutila P et alMortality in acromegaly a 20-year follow-up study Endocr Relat Cancer 201623469ndash80

179 Bihan H Espinosa C Valdes-Socin H Salenave S Young J Levasseur S et alLong-term outcome of patients with acromegaly and congestive heart failureJ Clin Endocrinol Metab 2004895308ndash13

180 dos Santos Silva CM Gottlieb I Volschan I Kasuki L Warszawski L BalariniLima GA et al Low frequency of cardiomyopathy using cardiac magnetic reson-ance imaging in an acromegaly contemporary cohort J Clin Endocrinol Metab20151004447ndash55

181 Herrmann BL Bruch C Saller B Ferdin S Dagres N Ose C et al Occurrenceof ventricular late potentials in patients with active acromegaly Clin Endocrinol(Oxf) 200155201ndash7

182 Lie JT Grossman SJ Pathology of the heart in acromegaly anatomic findings in27 autopsied patients Am Heart J 198010041ndash52

183 Frustaci A Chimenti C Setoguchi M Guerra S Corsello S Crea F et al Celldeath in acromegalic cardiomyopathy Circulation 1999991426ndash34

184 Rossi E Zuppi P Pennestri F Biasucci LM Lombardo A De Marinis L et alAcromegalic cardiomyopathy Left ventricular filling and hypertrophy in activeand surgically treated disease Chest 19921021204ndash8

185 Lombardi G Galdiero M Auriemma RS Pivonello R Colao A Acromegaly andthe cardiovascular system Neuroendocrinology 200683211ndash7

186 Clayton RN Cardiovascular function in acromegaly Endocr Rev 200324272ndash7187 Hayward RP Emanuel RW Nabarro JD Acromegalic heart disease influence of

treatment of the acromegaly on the heart Q J Med 19876241ndash58188 Kahaly G Olshausen KV Mohr-Kahaly S Erbel R Boor S Beyer J et al

Arrhythmia profile in acromegaly Eur Heart J 19921351ndash6189 Surawicz B Mangiardi ML Electrocardiogram in endocrine and metabolic dis-

orders Cardiovasc Clin 19778243ndash66190 Marin F Pico AM Martinez JG Domınguez JR Alfayate R Sogorb F Heart dis-

ease in acromegaly Study of 27 patients Med Clin (Barc) 1996107326ndash30191 Rodrigues EA Caruana MP Lahiri A Nabarro JD Jacobs HS Raftery EB

Subclinical cardiac dysfunction in acromegaly evidence for a specific disease ofheart muscle Br Heart J 198962185ndash94

192 Maffei P Martini C Milanesi A Corfini A Mioni R de Carlo E et al Late poten-tials and ventricular arrhythmias in acromegaly Int J Cardiol 2005104197ndash203

193 Matturri L Varesi C Nappo A Cuttin MS Rossi L Sudden cardiac death in ac-romegaly Anatomopathological observation of a case Minerva Med 199889287ndash91

194 Rossi L Thiene G Caragaro L Giordano R Lauro S Dysrhythmias and suddendeath in acromegalic heart disease A clinicopathologic study Chest 197772495ndash8

195 Doimo S Miani D Finato N Driussi M Sinagra G Livi U et al Acromegalic car-diomyopathy with malignant arrhythmogenic pattern successfully treated withmechanical circulatory support and heart transplantation Can J Cardiol 201733830 e9ndashe11

196 Unubol M Eryilmaz U Guney E Ture M Akgullu C QT dispersion in patientswith acromegaly Endocrine 201343419ndash23

197 Baser H Akar Bayram N Polat B Evranos B Ersoy R Bozkurt E et al Theevaluation of QT intervals during diagnosis and after follow-up in acromegalypatients Acta Med Port 201427428ndash32

198 Warszawski L Kasuki L Sa R Dos Santos Silva CM Volschan I Gottlieb I et alLow frequency of cardniac arrhythmias and lack of structural heart disease inmedically-naive acromegaly patients a prospective study at baseline and after 1year of somatostatin analogs treatment Pituitary 201619582ndash9

199 Lombardi G Colao A Marzullo P Biondi B Palmieri E Fazio S Improvement ofleft ventricular hypertrophy and arrhythmias after lanreotide-induced GH andIGF-I decrease in acromegaly A prospective multi-center study J EndocrinolInvest 200225971ndash6

200 Auriemma RS Pivonello R De Martino MC Cudemo G Grasso LF Galdiero Met al Treatment with GH receptor antagonist in acromegaly effect on cardiacarrhythmias Eur J Endocrinol 201216815ndash22

201 Mercado M Gonzalez B Vargas G Ramirez C de los Monteros AL Sosa Eet al Successful mortality reduction and control of comorbidities in patientswith acromegaly followed at a highly specialized multidisciplinary clinicJ Endocrinol Metab 2014994438ndash46

202 Horner JM Thorsson AV Hintz R Growth deceleration patterns in childrenwith constitutional short statue an aid to diagnosis Pediatrics 197862529ndash34

203 Ascoli P Cavagnini F Hypopituitarism Pituitary 20069335ndash42204 Simsek Y Kaya MG Tanriverdi F Calapkorur B Diri H Karaca Z et al

Evaluation of long-term pituitary functions in patients with severe ventriculararrhythmia a pilot study J Endocrinol Invest 2014371057ndash64

205 Okada T Tomoda T Shinohara M Misaki Y Shiraishi T Fujieda M et alAtrioventricular block in a patient with growth hormone deficiency duringgrowth hormone therapy Pediatr Int 19994190ndash3

206 Conn JW Knopf RF Nesbit RM Clinical characteristics of primary aldosteron-ism from an analysis of 145 cases Am J Surg 1964107159ndash72

28 B Gorenek et al


207 Lim JS Park S Park SI Oh YT Choi E Kim JY et al Cardiac dysfunction in asso-ciation with increased inflammatory markers in primary aldosteronismEndocrinol Metab (Seoul) 201631567ndash76

208 Iravanian S Dudley SC Jr The renin-angiotensin-aldosterone system (RAAS)and cardiac arrhythmias Heart Rhythm 20085S12ndash7

209 Sechi LA Colussi G Di Fabio A Catena C Cardiovascular and renal damage inprimary aldosteronism outcomes after treatment Am J Hypertens 2010231253ndash60

210 Catena C Colussi G Nait F Martinis F Pezzutto F Sechi LA Aldosterone andthe heart still an unresolved issue Front Endocrinol (Lausanne) 20145168

211 Rhee SS Pearce EN Update systemic Diseases and the Cardiovascular System(II) The endocrine system and the heart a review Rev Esp Cardiol 201164220ndash31

212 Milliez P Girerd X Plouin PF Blacher J Safar ME Mourad JJ Evidence for anincreased rate of cardiovascular events in patients with primary aldosteronismJ Am Coll Cardiol 2005451243ndash8

213 Mihailidou AS Aldosterone in heart disease Curr Hypertens Rep 201214125ndash9214 He BJ Anderson ME Aldosterone and cardiovascular disease the heart of the

matter Trends Endocrinol Metab 20132421ndash30215 Stowasser M New perspectives on the role of aldosterone excess in cardiovas-

cular disease Clin Exp Pharmacol Physiol 200128783ndash91216 Weiss JN Qu Z Shivkumar K Electrophysiology of hypokalemia and hyperkale-

mia Circ Arrhythm Electrophysiol 201710e004667217 Seccia TM Caroccia B Adler GK Maiolino G Cesari M Rossi GP Arterial

hypertension atrial fibrillation and hyperaldosteronism the triple troubleHypertension 201769545ndash50

218 Zelinka T Holaj R Petrak O Strauch B Kasalicky M Hanus T et al Life-threatening arrhythmia caused by primary aldosteronism Med Sci Monit 200915CS174ndash7

219 Porodko M Auer J Eber B Connrsquos syndrome and atrial fibrillation Lancet 20013571293ndash4

220 Watson T Karthikeyan VJ Lip GY Beevers DG Atrial fibrillation in primary al-dosteronism J Renin Angiotensin Aldosterone Syst 200910190ndash4

221 Mulatero P Monticone S Bertello C Viola A Tizzani D Iannaccone A et alLong-term cardio- and cerebrovascular events in patients with primary aldos-teronism J Clin Endocrinol Metab 2013984826ndash33

222 Born-Frontsberg E Reincke M Rump LC Hahner S Diederich S Lorenz Ret al Cardiovascular and cerebrovascular comorbidities of hypokalemic andnormokalemic primary aldosteronism results of the German Connrsquos RegistryJ Clin Endocrinol Metab 2009941125ndash30

223 Ponikowski P Voors AA Anker SD Bueno H Cleland JG Coats AJ et al 2016ESC Guidelines for the diagnosis and treatment of acute and chronic heart fail-ure the Task Force for the diagnosis and treatment of acute and chronic heartfailure of the European Society of Cardiology (ESC) developed with the specialcontribution of the Heart Failure Association (HFA) of the ESC Eur Heart J2016372129ndash200

224 Sade E Oto A Oto A Oner Z Daver A Onalan O et al Adrenal adenomapresenting with torsade de pointesmdasha case report Angiology 200253471ndash4

225 Geist M Dorian P Davies T Greene M Newman D Hyperaldosteronism andsudden cardiac death Am J Cardiol 199678605ndash6

226 Aydin A Okmen E Erdinler I Sanli A Cam N Adrenal adenoma presentingwith ventricular fibrillation Tex Heart Inst J 20053285ndash7

227 Petramala L Savoriti C Zinnamosca L Marinelli C Settevendemmie A CalvieriC et al Primary aldosteronism with concurrent primary hyperparathyroidism ina patient with arrhythmic disorders Intern Med 2013522071ndash5

228 Catena C Colussi G Nadalini E Chiuch A Baroselli S Lapenna R et alCardiovascular outcomes in patients with primary aldosteronism after treat-ment Arch Intern Med 200816880ndash5

229 Savard S Amar L Plouin PF Steichen O Cardiovascular complications associ-ated with primary aldosteronism a controlled cross-sectional studyHypertension 201362331ndash6

230 Charmandari E Nicolaides NC Chrousos GP Adrenal insufficiency Lancet20143832152ndash67

231 Schumaecker MM Larsen TR Sane DC Cardiac manifestations of adrenal insuf-ficiency Rev Cardiovasc Med 201617131ndash6

232 Mozolevska V Schwartz A Cheung D Shaikh B Bhagirath KM Jassal DSAddisonrsquos disease and dilated cardiomyopathy a case report and review of theliterature Case Rep Cardiol 201620161

233 Fallo F Betterle C Budano S Lupia M Boscaro M Sonino N Regression of car-diac abnormalities after replacement therapy in Addisonrsquos disease Eur JEndocrinol 1999140425ndash8

234 Ikegami Y Fukuda T Jo R Momiyama Y Reversible cardiomyopathy accompa-nied by secondary adrenal insufficiency Circ Heart Fail 20169e002919

235 Singh G Manickam A Sethuraman M Rathod RC Takotsubo cardiomyopathyin a patient with pituitary adenoma and secondary adrenal insufficiency Indian JCrit Care Med 201519731ndash4

236 Somerville W The effect of cortisone on the cardiogram in chronic adrenal in-sufficiency Br Med J 19502860ndash2

237 Nishizawa S Nakamura T Hamaoka T Matsumuro A Sawada T Matsubara HLethal arrhythmia and corticosteroid insufficiency Am J Emerg Med 2009271167 e1ndash3

238 Kanamori K Yamashita R Tsutsui K Hara M Murakawa Y Long QT syndromeassociated with adrenal insufficiency in a patient with isolated adrenocortico-tropic hormone deficiency Intern Med 2014532329ndash31

239 Ozcan F Ustun I Berker D Aydin Y Delibasi T Guler S Inverted T waves inpatient with Addisonian crisis J Natl Med Assoc 2005971539ndash40

240 Dogan M Ertem AG Cimen T Yeter E Type-1 Brugada-like ECG patterninduced by adrenal crisis Herz 201540304ndash6

241 Komuro J Kaneko M Ueda K Nitta S Kasao M Shirai T Adrenal insufficiencycauses life-threatening arrhythmia with prolongation of QT interval HeartVessels 2016311003ndash5

242 Rentoukas E Lazaros G Sotiriou S Athanassiou M Tsiachris D Deftereos Set al Extreme but not life-threatening QT interval prolongation Take a closerlook at the neck J Electrocardiol 201346128ndash30

243 Cakerri L Husi G Minxuri D Roko E Vyshka G Primary hypoparathyroidismpresenting with heart failure and ventricular fibrillation Oxf Med Case Reports2014201477ndash9

244 Lind L Ljunghall S Serum calcium and the ECG in patients with primary hyper-parathyroidism J Electrocardiol 19942799ndash103

245 Voss DM Drake EH Cardiac manifestations of hyperparathyroidism with pres-entation of a previously unreported arrhythmia Am Heart J 196773235ndash9

246 Chadli MC Chaieb L Jemni L Chatti N Allegue M Zebidi A et al Bigeminal ar-rhythmia associated with hyperparathyroid crisis Cmaj 19881381115ndash6

247 Chang CJ Chen SA Tai CT Yu WC Chen YJ Tsai CF et al Ventricular tachy-cardia in a patient with primary hyperparathyroidism Pacing Clin Electrophysiol200023534ndash7

248 Kolb C Lehmann G Schreieck J Ndrepepa G Schmitt C Storms of ventriculartachyarrhythmias associated with primary hyperparathyroidism in a patient withdilated cardiomyopathy Int J Cardiol 200387115ndash6

249 Vestergaard P Mollerup CL Froslashkjaer VG Christiansen P Blichert-Toft MMosekilde L Cardiovascular events before and after surgery for primary hyper-parathyroidism World J Surg 200327216ndash22

250 Hedback G Oden A Tisell LE The influence of surgery on the risk of death inpatients with primary hyperparathyroidism World J Surg 199115399ndash405

251 Pepe J Curione M Morelli S Varrenti M Cammarota C Cilli M et alParathyroidectomy eliminates arrhythmic risk in primary hyperparathyroidismas evaluated by exercise test Eur J Endocrinol 2013169255ndash61

252 Speakman MT Kloner RA Viagra and cardiovascular disease CardiovascPharmacol Therapeut 19994269ndash71

253 Occhetta E Bortnik M Magnani A Francalacci G Vassanelli C Primary hyper-parathyroidism and arrhythmic storm in a patient with an implantable cardi-overter defibrillator for primary prevention of sudden death Europace 20046184ndash8

254 Di Fusco SA Palazzo S Colivicchi F Santini M World Society of ArrhythmiasThe influence of gender on heart rhythm disease Pacing Clin Electrophysiol 201437650ndash7

255 Tadros R Ton AT Fiset C Nattel S Sex differences in cardiac electrophysi-ology and clinical arrhythmias epidemiology therapeutics and mechanisms CanJ Cardiol 201430783ndash92

256 Curtis AB Narasimha D Arrhythmias in women Clin Cardiol 201235166ndash71257 Jonsson MK Vos MA Duker G Demolombe S van Veen TA Gender disparity

in cardiac electrophysiology implications for cardiac safety pharmacologyPharmacol Ther 20101279ndash18

258 Gaborit N Varro A Le Bouter S Szuts V Escande D Nattel S et al Gender-related differences in ion-channel and transporter subunit expression in non-diseased human hearts J Mol Cell Cardiol 201049639ndash46

259 Surawicz B Parikh SR Prevalence of male and female patterns of early ventricu-lar repolarization in the normal ECG of males and females from childhood toold age J Am Coll Cardiol 2002401870ndash6

260 Makkar RR Fromm BS Steinman RT Meissner MD Lehmann MH Female gen-der as a risk factor for torsades de pointes associated with cardiovascular drugsJAMA 19932702590 7

261 Tisdale JE Jaynes HA Overholser BR Sowinski KM Flockhart DA Kovacs RJInfluence of oral progesterone administration on drug-induced qt intervallengthening a randomized double-blind placebo-controlled crossover studyJACC Clin Electrophysiol 20162765ndash74

262 Locati EH Zareba W Moss AJ Schwartz PJ Vincent GM Lehmann MH et alAge- and sex-related differences in clinical manifestations in patients with con-genital long-QT syndrome findings from the International LQTS RegistryCirculation 1998972237ndash44

263 Seth R Moss AJ McNitt S Zareba W Andrews ML Qi M et al Long QT syn-drome and pregnancy J Am Coll Cardiol 2007491092ndash8



264 Rodriguez L-M de Chillou C Schlapfer J Metzger J Baiyan X van den Dool Aet al Age at onset and gender of patients with different types of supraventricu-lar tachycardias Am J Cardiol 1992701213ndash5

265 Silversides CK Harris L Haberer K Sermer M Colman JM Siu SC Recurrencerates of arrhythmias during pregnancy in women with previous tachyarrhythmiaand impact on fetal and neonatal outcomes Am J Cardiol 2006971206ndash12

266 Lip GY Nieuwlaat R Pisters R Lane DA Crijns HJ Refining clinical risk stratifi-cation for predicting stroke and thromboembolism in atrial fibrillation using anovel risk factor-based approach the Euro Heart survey on atrial fibrillationChest 2010137263ndash72

267 Pisters R Lane DA Nieuwlaat R de Vos CB Crijns HJGM Lip GYH A noveluser-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in pa-tients with atrial fibrillation Chest 20101381093ndash100

268 Pisters R Lane DA Marin F Camm AJ Lip GY Stroke and thromboembolismin atrial fibrillation Circ J 2012762289ndash304

269 Overvad TF Skjoth F Lip GY Lane DA Albertsen IE Rasmussen LH et alDuration of diabetes mellitus and risk of thromboembolism and bleeding inatrial fibrillation nationwide cohort study Stroke 2015462168ndash74

270 Ashburner JM Go AS Chang Y Fang MC Fredman L Applebaum KM et alEffect of diabetes and glycemic control on ischemic stroke risk in AF patientsaTRIA study J Am Coll Cardiol 201667239ndash47

271 Lip GY Clementy N Pierre B Boyer M Fauchier L The impact of associateddiabetic retinopathy on stroke and severe bleeding risk in diabetic patients withatrial fibrillation the Loire Valley atrial fibrillation project Chest 20151471103ndash10

272 Lega JC Bertoletti L Gremillet C Chapelle C Mismetti P Cucherat M et alConsistency of safety and efficacy of new oral anticoagulants across subgroupsof patients with atrial fibrillation PLoS One 20149be91398

273 Apostolakis S Sullivan RM Olshansky B Lip GY Factors affecting quality ofanticoagulation control among patients with atrial fibrillation on warfarin theSAMe-TT(2)R(2) score Chest 20131441555ndash63

274 Lip GYH Freedman B De Caterina R Potpara TS Stroke prevention in atrialfibrillation past present and future Comparing the guidelines and practical de-cision-making Thromb Haemost 20171171230ndash9

275 Tang RB Liu DL Dong JZ Liu XP Long DY Yu RH et al High-normal thyroidfunction and risk of recurrence of atrial fibrillation after catheter ablation Circ J2010741316ndash21

276 Sousa PA Providencia R Albenque JP Khoueiry Z Combes N Combes S et alImpact of free thyroxine on the outcomes of left atrial ablation procedures AmJ Cardiol 20151161863ndash8

277 Kim KH Mohanty S Mohanty P Trivedi C Morris EH Santangeli P et alPrevalence of right atrial non-pulmonary vein triggers in atrial fibrillation pa-tients treated with thyroid hormone replacement therapy J Interv CardElectrophysiol 201749111ndash7

278 Wang M Cai S Sun L Zhao Q Feng W Safety and efficacy of early radiofre-quency catheter ablation in patients with paroxysmal atrial fibrillation compli-cated with amiodarone-induced thyrotoxicosis Cardiol J 201623416ndash21

279 Mikhaylov EN Orshanskaya VS Lebedev AD Szili-Torok T Lebedev DSCatheter ablation of paroxysmal atrial fibrillation in patients with previousamiodarone-induced hyperthyroidism a case-control study J CardiovascElectrophysiol 201324888ndash93

280 Diemberger I Biffi M Martignani C Boriani G From lead management to im-planted patient management indications to lead extraction in pacemaker andcardioverter-defibrillator systems Expert Rev Med Devices 20118235ndash55

281 Mazzotti A Biffi M Massaro G Martignani C Ziacchi M Bacchi Reggiani MLet al From lead management to implanted patient management systematic re-view and meta-analysis of the last 15 years of experience in lead extractionExpert Rev Med Devices 201310551ndash73

282 Habib A Le KY Baddour LM Friedman PA Hayes DL Lohse CM et al MayoCardiovascular Infections Study Group Predictors of mortality in patients withcardiovascular implantable electronic device infections Am J Cardiol 2013111874ndash9

283 De Maria E Diemberger I Vassallo PL Pastore M Giannotti F Ronconi C et alPrevention of infections in cardiovascular implantable electronic devices beyondthe antibiotic agent J Cardiovasc Med (Hagerstown) 201415554ndash64

284 Nielsen JC Gerdes JC Varma N Infected cardiac-implantable electronic de-vices prevention diagnosis and treatment Eur Heart J 2015362484ndash90

285 Charlson ME Pompei P Ales KL MacKenzie CR A new method of classifying-prognostic comorbidity in longitudinal studies development and validationJ Chronic Dis 198740373ndash83

286 Boriani G Berti E Belotti LM Biffi M De Palma R Malavasi VL et al RERAI(Registry of Emilia Romagna on Arrhythmia Interventions) InvestigatorsCardiac device therapy in patients with left ventricular dysfunction and heartfailure 0real-world0 data on long-term outcomes (mortality hospitalizationsdays alive and out of hospital) Eur J Heart Fail 201618693ndash702

287 Echouffo-Tcheugui JB Masoudi FA Bao H Spatz ES Fonarow GC Diabetesand outcomes of cardiac resynchronization with implantable cardioverter defib-rillator therapy in older patients with heart failure Circ Arrhythm Electrophysiol20169e004132

288 Boriani G The impact of diabetes and comorbidities on the outcome of heartfailure patients treated with cardiac resynchronization therapy implications forpatient management Circ Arrhythm Electrophysiol 20169e004463

289 Sun H Guan Y Wang L Zhao Y Lv H Bi X et al Influence of diabetes on car-diac resynchronization therapy in heart failure patients a meta-analysis BMCCardiovasc Disord 20151525

290 Hoppe UC Freemantle N Cleland JG Marijianowski M Erdmann E Effect ofcardiac resynchronization on morbidity and mortality of diabetic patients withsevere heart failure Diabetes Care 200730722ndash4

291 Earley A Persson R Garlitski AC Balk EM Uhlig K Effectiveness of implantablecardioverter-defibrillators for primary prevention of sudden cardiac death insubgroups a systematic review Ann Intern Med 2014160111-121

292 Shahreyar M Mupiddi V Choudhuri I Sra J Tajik AJ Jahangir A Implantable car-dioverter defibrillators in diabetics efficacy and safety in patients at risk of sud-den cardiac death Expert Rev Cardiovasc Ther 201513897ndash906

293 Braunschweig F Boriani G Bauer A Hatala R Herrmann-Lingen C Kautzner Jet al Management of patients receiving implantable cardiac defibrillator shocksrecommendations for acute and long-term patient management Europace 2010121673ndash90

294 Boriani G Savelieva I Dan GA Deharo JC Ferro C Israel CW et al Chronickidney disease in patients with cardiac rhythm disturbances or implantable elec-trical devices clinical significance and implications for decision making-a positionpaper of the European Heart Rhythm Association endorsed by the HeartRhythm Society and the Asia Pacific Heart Rhythm Society Europace 2015171169ndash96

295 Roffi M Cattaneo F Brandle M Thyrotoxicosis and the cardiovascular systemMinerva Endocrinol 20053047ndash58

296 Marketou ME Simantirakis EN Manios EG Vardas PE Electrical storm due toamiodarone induced thyrotoxicosis in a young adult with dilated cardiomyop-athy thyroidectomy as the treatment of choice Pacing Clin Electrophysiol 2001241827ndash8

297 Sharma AK Vegh EM Orencole M Miller A Blendea D Moore S et alAssociation of hypothyroidism with adverse events in patients with heart failurereceiving cardiac resynchronization therapy Am J Cardiol 20151151249ndash53

298 Chen S Shauer A Zwas DR Lotan C Keren A Gotsman I The effect of thy-roid function on clinical outcome in patients with heart failure Eur J Heart Fail201416217ndash26

299 Study of the effects of intravenous exenatide on cardiac repolarizationClinicalTrialsgov Identifier NCT 02650479

300 Haugaard SB Sajadeh A The Effect of liraglutide on the treatment of coronaryartery disease and type 2 diabetes (AddHope2) ClinicalTrialsgov IdentifierNCT 01595789

301 Rosenqvist M Giesecke P Thumb-ECG ambulant screening for atrial fibrillationin patients treated for hyperthyroidism (TAMBOURINE) (TAMBOURINE)ClinicalTrialsgov Identifier NCT 01945229

302 Giesecke P Is a Low Thyreotropin level predictive of recurrent arrhythmiaafter catheter ablative surgery (TABLAS) ClinicalTrialsgov Identifier NCT01789541

303 Kerstens MN Links TP Wietasch GJ Phenoxybenzamine versus doxazosin inPCC patients (PRESCRIPT) ClinicalTrialsgov Identifier NCT 01379898

304 Zhang B Assessment of BIM23B065 given as repeated subcutaneous injectionin subjects with acromegaly (DOPAACRO 002) ClinicalTrialsgov IdentifierNCT03045302

30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10

and Sociedad Latinoamericana de Estimulacion Cardıaca y Electrofisiologıa (SOLAECE) with the remit of compre-hensively reviewing the available evidence and publishing a joint consensus document on endocrine disorders andcardiac arrhythmias and providing up-to-date consensus recommendations for use in clinical practice

Keywords Endocrine disorders bull Arrhythmias bull Atrial fibrillation bull Ventricular arrhythmias bull Cardiac implantableelectronic device bull Pacemaker bull Implantable cardioverter-defibrillator bull Catheter ablation bull Diabetes

bull Thyroid disorders bull Hyperthyroidism bull Hypothyroidism bull Pheochromocytoma bull Growth hormonedysfunction bull Hyperaldosteronism bull Adrenal insufficiency bull Parathyroid disease bull Stroke bull Oralanticoagulation bull EHRA position paper

Table of Contents

Introduction 2Evidence review 2

Mechanisms and pathophysiology of cardiac arrhythmias in endocrinedisorders 2

Management of arrhythmias in specific endocrine disorders 3Pancreas dysfunction 3

Diabetes mellitus 3Thyroid dysfunction 10

Hyperthyroidism 10Hypothyroidism 11Amiodarone-induced thyroid dysfunction 14

Pheochromocytoma 18Growth hormone dysfunction 19

Acromegaly 19Growth hormone deficiency 19

Diseases of adrenal cortex 20Hyperaldosteronism 21Adrenal insufficiency 20

Parathyroid disease 21Sex hormones-related differences in the risk of arrhythmias 21

Stroke risk assessment and prevention of arrhythmias associated withendocrine disorders 22

Catheter ablation of arrhythmias associated with endocrine disorders 23Device-based therapy of arrhythmias in patients with endocrine

disorders 23Current research gaps ongoing trials and future directions 24

Introduction

However the ultimate judgement on the care of a specific patientmust be made by the healthcare provider and the patient in light of allindividual factors presented

Evidence reviewThis document was prepared by the Task Force with representationfrom EHRA APHRS and SOLAECE and peer-reviewed by official ex-ternal reviewers representing EHRA HRS APHRS and SOLAECETheir members made a detailed literature review weighing thestrength of evidence for or against a specific treatment or procedureand including estimates of expected health outcomes where dataexist In controversial areas or with respect to issues without evi-dence other than usual clinical practice a consensus was achieved byagreement of the expert panel after thorough deliberation

In contrast to guidelines we opted for an easier and user-friendlysystem of ranking using lsquocoloured heartsrsquo that should allow physiciansto easily assess the current status of the evidence and consequent guid-ance (Table 1) This EHRA grading of consensus statements does nothave separate definitions of the level of evidence This categorizationused for consensus statements must not be considered as directlysimilar to that used for official society guideline recommendationswhich apply a classification (Class IndashIII) and level of evidence (A B andC) to recommendations used in official guidelines

Thus a green heart indicates a lsquoshould do thisrsquo consensus statementor indicated treatment or procedure that is based on at least onerandomized trial or is supported by strong observational evidencethat it is beneficial and effective A yellow heart indicates generalagreement andor scientific evidence favouring a lsquomay do thisrsquo state-ment or the usefulnessefficacy of a treatment or procedure A lsquoyellowheartrsquo symbol may be supported by randomized trials based on a smallnumber of patients or which is not widely applicable Treatment strat-egies for which there is scientific evidence of potential harm andshould not be used (lsquodo not do thisrsquo) are indicated by a red heart

Mechanisms and pathophysiologyof cardiac arrhythmias inendocrine disorders

A number of cardiac arrhythmia mechanisms may underlie ventricu-lar and atrial arrhythmias such as reentry abnormal automaticity ortriggered activity Normally these mechanisms are not active in anormal (young) heart The only exceptions are inherited arrhythmiasyndromes in which cardiac remodelling may be present that makethe heart more vulnerable often under specific circumstances likethe excess of catecholamines

Acutely hormones can play a crucial role such as in catecholamine-induced polymorphic VT induced by exercise or in the long QT syn-drome (LQTS) induced either by sleep fear or excitement Often thechallenge provided acutely by these hormones exceeds the safety mar-gins (=reserve) of the vulnerable heart to overcome and ventricular ar-rhythmias ensue Thus endocrine disorders may play an acute role inthe triggering of cardiac arrhythmias (Figure 1)

However there are also chronic adaptations induced by endocrinedisorders that can underlie the formation of arrhythmias The action po-tential is controlled by numerous ion currents that either provides in-ward or outward currents It is this delicate balance that shapes the

2 B Gorenek et al












procedure

Consensus statement

instruction

Symbol





by an asterisk)






applicable











Reentry

inherited

disease













reduction



coupling

Reduced Na+

channel function

Cardiacfibosis



downregulation

ABNORMALCONDUCTION




ARRHYTHMOGENESIS

Diabetic

Cardiom

yopathy





Altered m

olecular signaling

ReentryTriggered

activity

CV riskfactors


Diabetic

Neuropathy


4 B Gorenek et al





Figure 3 Continued

6 B Gorenek et al




glucose

control



glucose control)

Significant

hypoglycaemia

ADVANCE72

2008

11 140

DM type 2


94 vs 109

HR 086 (077ndash097) P = 001


100 vs 106

HR 094 (084ndash106) P = 032


45 vs 52

HR 088 (074ndash104) P = 012

All-cause death

89 vs 96

HR 093 (083ndash106) P = 028

27 vs 15

HR 186 (142ndash240)

P lt 0001

ACCORD54 2008

ACCORD53 2011

10 251

DM Type 2

known CV dis-

ease or CV risk

factors

Various

The intensive

regimen

stopped

early due to

increased

mortality


141 vs 114

HR 122 (101ndash146) P = 004


26 vs 18

HR 135 (104ndash176) P = 002

Fatal arrhythmia

01 vs 02



death)

69 vs 72

HR 090 (078ndash104) P = 016




082 (070ndash096) P = 001]


(072 vs 057 HR 129

(104ndash160) P = 002) and


127 HR 119 (103ndash138)



Fatal arrhythmia

01 vs 04

31 vs 10

P lt 0001


erans DM Type

2 40 with pre-

vious CV event

Various

Open-label

study

An absolute

reduction for

15 points in

HbA1c com-

pared with

standard glu-

cose control




096 vs 095

HR 132 (081ndash214) P = 026

All-cause death

088 vs 087

HR 107 (081ndash142) P = 062


event

HR 088 (074ndash105) P = 014

212 vs 99

P lt 0001

Continued










Table 2 Continued


glucose

control



glucose control)

Significant

hypoglycaemia

NICE-SUGAR74

2009

NICE-SUGAR51

2012

6104 critically ill

patients


45ndash60 mmoll


275 vs 249

OR 114 (102ndash128) P = 002




death

285 vs 235 HR 141

(121ndash162) P lt 0001


354 vs 235 HR 210

(159ndash277) P lt 0001


68 vs 05

OR 147 (90ndash259)

P lt 0001


mia n = 2714

(450)


n = 223 (37)

ORIGIN52 2013 12 537

DM Type 2 with

additional CV

risk factors



stroke

HR 158 (124ndash202)

P lt 0001

All-cause mortality

HR 174 (139ndash219)

P lt 0001

CV mortality

HR 171 (127ndash230)

P lt 0001

Arrhythmic death

HR 177 (117ndash267) P = 007


hypoglycaemia

09 vs 03


8 B Gorenek et al








statement

instruction

Level of

evidence

References

































Hyperthyroidism











TSH levels

(mIUL)

Free thyroxine

(pmolL)

Total thyroxine

(mmolL)

Thyroid function












10 B Gorenek et al




Hypothyroidism














TSH levels

Reduced TSH

Suppressed TSH


AF

29

46

25

Reference

IRR 142 (122ndash163)

IRR 131 (119ndash144)

IRR 067 (05ndash09)


IRR 116 (099ndash136)

IRR 141 (135ndash189)

IRR 112 (103ndash121)

Colett et al86

Thyroid studies

collaborators


Reduced TSH

Suppressed TSH

AF HR 168 (116ndash243)

HR 163 (11ndash24)

HR 254 (108ndash599)

Kim et al90

Framingham Heart

study




AF Reference

HR 123 (077ndash197)

HR 057 (021ndash154)


cohort

2631 pts with

hyperthyroidism

10 524 controls

67 years

81 female


26

19 P lt 0001

HR 134 (115ndash156)


of cases

10 pts

wo CVD and

hypokalaemia






VF isolated






treatment

Comment



oidism and AF

467 years


9


therapy -87

Thyroidectomy 3



rhythm upon attain-


63 pts

persistent AF


to euthyroidism and

spontaneous AF con-


lt1 week 43

1ndash3 weeks 752




13ndash15 weeks 100

gt16 weeks -100


hyperthyroidism

412 years

PAF 38 pts

Pers AF 45 pts


Pers AF 60


Age gt55 years

RR 276 116ndash879

P lt 001

Duration of

hyperthyroidism

RR 308 122ndash1141

P lt 001


ment AF

RR 296 131ndash768

P lt 001


hyperthyroidism due

to Graves disease


PAC 7


antithyroid therapy

72 to 25 P lt 0001



thyroidism due to

GD and 40

euthyroidism mul-

tinodular goiter


operation


100)

Sinus tachycardia

-688

ndash



tent AF

Cardioversion after

Antithyroid treat-

ment for

hyperthyroidism

35 months AFmdash12

SRmdash88



tent AF

wo SHD

476 years

Cardioversion after

Antithyroid treat-

ment for 3

months for

hyperthyroidism

67 years AFmdash76

SRmdash924

Predictor of AF

recurrence

Duration of AF

HR 16 (114ndash226)

P = 0005



controlled

116 pts

58 hyperthyroidism-

related persistent

AF

58 non-hyperthyoid-

ism AF

ECV after

Antithyroid treat-

ment for 3

months for

hyperthyroidism




83


hyperthyroidism vs

non-hyperthyroidism

HR 064 (039ndash097)

P = 0004

Predictor of AF

recurrence


HR 101 (10ndash101)

P lt 001

Continued

12 B Gorenek et al


Table 5 Continued


treatment

Comment


Persistent AF with

history of hyper-

thyroidism 47

(16) wo

hyperthyroidism

953 (321)

First AF ablation

(PVI) after 3

months of antithy-

roid therapy for

hyperthyroidism




Predictors of AF

recurrence

hyperthyroidism

HR 087 (040ndash188)

P = 073

Wongcharoen

et al110


and substrate

modification 12)

gt3 month treatment

of hyperthyroidism

before ablation


rence after single

procedure

History of

hyperthyroidism

OR 207 (127ndash338)



procedures



cohort

AntiT and risk of

ischemic stroke in

hyperthyroidism-

related AF

Of 9727 pts with

non-valvular AF

642 (66) pts with

hyperthyroidism


243mdashaspirin

263mdashno AntiT

719 years

678 female

Hyperthyroidism vs

non-

hyperthyroidism



67

HR 033 (012ndash091)


CHA2DS2Vas score


non-hyperthyroid-AF

0mdash0 vs 256



Ischaemic stroke 78



limiting AF


P = 004



with AF

141 hyperthyroidism

history

510 hypothyroidism

history

8271 euthyroidism


hyperthyroidism

HR 085 (041ndash176)

hypothyroidism

HR 098 (073ndash134)

Bleeding

hypothyroidism

HR 13 (102ndash179)


Fibrillation

Cohort Study

90 490 patients

No anticoagulation

at baseline

Thyroid disease 84

Thyrotoxicosis

553 pts


Thyroid disease

HR 095 070ndash119

Thyrotoxicosis

HR 092 (085ndash105)


Thyroid disease

HR 100 (092ndash109)

Thyrotoxicosis

HR 103 (083ndash128)


Within 1 year

after 1 year


1st year

Sinus rhythm 8 7

AF 5 7













thyroid dysfunction

Consensus

statement

instruction

Level of

evidence

References





be required





















considered





14 B Gorenek et al




toxicity arrhythmia


RRHR (95CI)


RCTs of amio

vs placebo effi-

cacy in preven-

tion of SCD

safety

8522 pts

4260 amio arm

4262 placebo arm

12ndash455

months

Thyroid 36 vs 04

Pulmonary 29 vs 15

Hepatic 185 vs 07

Bradyarrhythmias 28

vs15

OR 568 (294-1098) P lt 00001

OR 197 (127-304) P = 0002

OR 21 (115-382) P = 0015

OR 178 (116-272) P = 0008


Vorperian

et al150

Meta-analysis 4

RCTs amio vs

placebo

Adverse effects

738 pts amio arm

727 pts placebo

arm

low dose amio

100ndash400 mg

maintenance

dose

12ndash45

months

TD 37 vs 04



vs 154

Skin 23 vs 07

Eye 15 vs 01

OR 423 (204ndash874) P = 0001

OR 218 (111ndash427) P = 0024

OR 160 (123ndash209) P lt00001

OR 248 (105ndash617) P = 005

OR 342 (122ndash364) P = 002

Bathcer et al151

Substudy

of SAFE-T


persistent AF

Amio vs


1ndash45

years

Hypothyroidism

Subcl 258 vs 66

P lt 00001

Overt 50 vs 03

P lt 0001

Hyperthyroidism


53 vs 24 P = 007

ndash


Amio for SVT

102 pts VT 55

pts Prevention

3 pts Uncertain

1 pt

679

days

Hypothyroidism

Subclinical 74

Overt 8

Hyperthyroidism

Subcl 06


06

Overt 67

ndash


cohort study

For overt thyroid

dysfunctions

Indication for

amio

VA 667ndash80

AA 20ndash333

317 pts

Euthyroid 256

Subcl hypothy-

roid 52

Subcl hyperthy-

roid 9

585 years 735

males


95


189


DCM OR 33 (126-89)






Amio for AF-260

pts VA 43 pts

63 years 66

males


Hypothyroidism 6

Hyperthyroidism

Age lt62 years

HR 24 (10ndash57) P lt 005

Hypothyroidism

TSH gt14 mUL

HR 51 (11ndash224) P = 003

LVEF lt45

HR 38 (11-133) P = 004

DM-HR 33 (11ndash103) P = 004


Amio vs sotalol

and beta-

55 pts with ICD

Amio 24 pts

Sotalol 17 pts


Time to development

163(23) months

Continued



Table 6 Continued


toxicity arrhythmia


RRHR (95CI)

blockers for

inappropriate

shock reduction

in ICD pts







Recurrence of VT

VF during amio-

darone induced

toxicity as com-

pared to euthy-

roid state

Holter monitoring

and plasma amio

232 pts

amio therapy




amio

Hyperthyroidism 125






Treatment



amio




ual improvement

Czarnywojtek

et al161

Cohort

RIT for pts on

amio and TD

Amio indication

SVT VT ICD

inappropriate

shocks AF

297 cases amio

A 78 euthyroid-

ism on amio

B118

hyperthyroidism

History amio

C 79 hyperthyr-

oidism amio

D 22

hypothyroidism


ism after RIT A 538

B 339 C 341



125 C 114





therapy

Diederichsen

et al164

RCT double-blind

placebo-

controlled

Amio vs place bo

for 8 weeks after

catheter ablation

of AF

Endpoint TD

212 patients after

catheter ablation

of AF without

history of thy-

roid dysfunction

Amio group 8

weeks amio

Placebo group



Amio groupmdash3

Placebomdash1





placebo


treatment


16 B Gorenek et al









dysfunction

Consensus

statement

instruction

Level of

evidence

References








hyperthyroidism


143145ndash147163


function screening


























statement

instruction

Level of

evidence

References











18 B Gorenek et al












Aldosterone excess


Cardiacfibrosis


Na+ H2Oretention

K+ Mg++

loss


Hypertension

Congestion

Arrhythmias

LVH















statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10











procedure

Consensus statement

instruction

Symbol





by an asterisk)






applicable











Reentry

inherited

disease













reduction



coupling

Reduced Na+

channel function

Cardiacfibosis



downregulation

ABNORMALCONDUCTION




ARRHYTHMOGENESIS

Diabetic

Cardiom

yopathy





Altered m

olecular signaling

ReentryTriggered

activity

CV riskfactors


Diabetic

Neuropathy


4 B Gorenek et al





Figure 3 Continued

6 B Gorenek et al




glucose

control



glucose control)

Significant

hypoglycaemia

ADVANCE72

2008

11 140

DM type 2


94 vs 109

HR 086 (077ndash097) P = 001


100 vs 106

HR 094 (084ndash106) P = 032


45 vs 52

HR 088 (074ndash104) P = 012

All-cause death

89 vs 96

HR 093 (083ndash106) P = 028

27 vs 15

HR 186 (142ndash240)

P lt 0001

ACCORD54 2008

ACCORD53 2011

10 251

DM Type 2

known CV dis-

ease or CV risk

factors

Various

The intensive

regimen

stopped

early due to

increased

mortality


141 vs 114

HR 122 (101ndash146) P = 004


26 vs 18

HR 135 (104ndash176) P = 002

Fatal arrhythmia

01 vs 02



death)

69 vs 72

HR 090 (078ndash104) P = 016




082 (070ndash096) P = 001]


(072 vs 057 HR 129

(104ndash160) P = 002) and


127 HR 119 (103ndash138)



Fatal arrhythmia

01 vs 04

31 vs 10

P lt 0001


erans DM Type

2 40 with pre-

vious CV event

Various

Open-label

study

An absolute

reduction for

15 points in

HbA1c com-

pared with

standard glu-

cose control




096 vs 095

HR 132 (081ndash214) P = 026

All-cause death

088 vs 087

HR 107 (081ndash142) P = 062


event

HR 088 (074ndash105) P = 014

212 vs 99

P lt 0001

Continued










Table 2 Continued


glucose

control



glucose control)

Significant

hypoglycaemia

NICE-SUGAR74

2009

NICE-SUGAR51

2012

6104 critically ill

patients


45ndash60 mmoll


275 vs 249

OR 114 (102ndash128) P = 002




death

285 vs 235 HR 141

(121ndash162) P lt 0001


354 vs 235 HR 210

(159ndash277) P lt 0001


68 vs 05

OR 147 (90ndash259)

P lt 0001


mia n = 2714

(450)


n = 223 (37)

ORIGIN52 2013 12 537

DM Type 2 with

additional CV

risk factors



stroke

HR 158 (124ndash202)

P lt 0001

All-cause mortality

HR 174 (139ndash219)

P lt 0001

CV mortality

HR 171 (127ndash230)

P lt 0001

Arrhythmic death

HR 177 (117ndash267) P = 007


hypoglycaemia

09 vs 03


8 B Gorenek et al








statement

instruction

Level of

evidence

References

































Hyperthyroidism











TSH levels

(mIUL)

Free thyroxine

(pmolL)

Total thyroxine

(mmolL)

Thyroid function












10 B Gorenek et al




Hypothyroidism














TSH levels

Reduced TSH

Suppressed TSH


AF

29

46

25

Reference

IRR 142 (122ndash163)

IRR 131 (119ndash144)

IRR 067 (05ndash09)


IRR 116 (099ndash136)

IRR 141 (135ndash189)

IRR 112 (103ndash121)

Colett et al86

Thyroid studies

collaborators


Reduced TSH

Suppressed TSH

AF HR 168 (116ndash243)

HR 163 (11ndash24)

HR 254 (108ndash599)

Kim et al90

Framingham Heart

study




AF Reference

HR 123 (077ndash197)

HR 057 (021ndash154)


cohort

2631 pts with

hyperthyroidism

10 524 controls

67 years

81 female


26

19 P lt 0001

HR 134 (115ndash156)


of cases

10 pts

wo CVD and

hypokalaemia






VF isolated






treatment

Comment



oidism and AF

467 years


9


therapy -87

Thyroidectomy 3



rhythm upon attain-


63 pts

persistent AF


to euthyroidism and

spontaneous AF con-


lt1 week 43

1ndash3 weeks 752




13ndash15 weeks 100

gt16 weeks -100


hyperthyroidism

412 years

PAF 38 pts

Pers AF 45 pts


Pers AF 60


Age gt55 years

RR 276 116ndash879

P lt 001

Duration of

hyperthyroidism

RR 308 122ndash1141

P lt 001


ment AF

RR 296 131ndash768

P lt 001


hyperthyroidism due

to Graves disease


PAC 7


antithyroid therapy

72 to 25 P lt 0001



thyroidism due to

GD and 40

euthyroidism mul-

tinodular goiter


operation


100)

Sinus tachycardia

-688

ndash



tent AF

Cardioversion after

Antithyroid treat-

ment for

hyperthyroidism

35 months AFmdash12

SRmdash88



tent AF

wo SHD

476 years

Cardioversion after

Antithyroid treat-

ment for 3

months for

hyperthyroidism

67 years AFmdash76

SRmdash924

Predictor of AF

recurrence

Duration of AF

HR 16 (114ndash226)

P = 0005



controlled

116 pts

58 hyperthyroidism-

related persistent

AF

58 non-hyperthyoid-

ism AF

ECV after

Antithyroid treat-

ment for 3

months for

hyperthyroidism




83


hyperthyroidism vs

non-hyperthyroidism

HR 064 (039ndash097)

P = 0004

Predictor of AF

recurrence


HR 101 (10ndash101)

P lt 001

Continued

12 B Gorenek et al


Table 5 Continued


treatment

Comment


Persistent AF with

history of hyper-

thyroidism 47

(16) wo

hyperthyroidism

953 (321)

First AF ablation

(PVI) after 3

months of antithy-

roid therapy for

hyperthyroidism




Predictors of AF

recurrence

hyperthyroidism

HR 087 (040ndash188)

P = 073

Wongcharoen

et al110


and substrate

modification 12)

gt3 month treatment

of hyperthyroidism

before ablation


rence after single

procedure

History of

hyperthyroidism

OR 207 (127ndash338)



procedures



cohort

AntiT and risk of

ischemic stroke in

hyperthyroidism-

related AF

Of 9727 pts with

non-valvular AF

642 (66) pts with

hyperthyroidism


243mdashaspirin

263mdashno AntiT

719 years

678 female

Hyperthyroidism vs

non-

hyperthyroidism



67

HR 033 (012ndash091)


CHA2DS2Vas score


non-hyperthyroid-AF

0mdash0 vs 256



Ischaemic stroke 78



limiting AF


P = 004



with AF

141 hyperthyroidism

history

510 hypothyroidism

history

8271 euthyroidism


hyperthyroidism

HR 085 (041ndash176)

hypothyroidism

HR 098 (073ndash134)

Bleeding

hypothyroidism

HR 13 (102ndash179)


Fibrillation

Cohort Study

90 490 patients

No anticoagulation

at baseline

Thyroid disease 84

Thyrotoxicosis

553 pts


Thyroid disease

HR 095 070ndash119

Thyrotoxicosis

HR 092 (085ndash105)


Thyroid disease

HR 100 (092ndash109)

Thyrotoxicosis

HR 103 (083ndash128)


Within 1 year

after 1 year


1st year

Sinus rhythm 8 7

AF 5 7













thyroid dysfunction

Consensus

statement

instruction

Level of

evidence

References





be required





















considered





14 B Gorenek et al




toxicity arrhythmia


RRHR (95CI)


RCTs of amio

vs placebo effi-

cacy in preven-

tion of SCD

safety

8522 pts

4260 amio arm

4262 placebo arm

12ndash455

months

Thyroid 36 vs 04

Pulmonary 29 vs 15

Hepatic 185 vs 07

Bradyarrhythmias 28

vs15

OR 568 (294-1098) P lt 00001

OR 197 (127-304) P = 0002

OR 21 (115-382) P = 0015

OR 178 (116-272) P = 0008


Vorperian

et al150

Meta-analysis 4

RCTs amio vs

placebo

Adverse effects

738 pts amio arm

727 pts placebo

arm

low dose amio

100ndash400 mg

maintenance

dose

12ndash45

months

TD 37 vs 04



vs 154

Skin 23 vs 07

Eye 15 vs 01

OR 423 (204ndash874) P = 0001

OR 218 (111ndash427) P = 0024

OR 160 (123ndash209) P lt00001

OR 248 (105ndash617) P = 005

OR 342 (122ndash364) P = 002

Bathcer et al151

Substudy

of SAFE-T


persistent AF

Amio vs


1ndash45

years

Hypothyroidism

Subcl 258 vs 66

P lt 00001

Overt 50 vs 03

P lt 0001

Hyperthyroidism


53 vs 24 P = 007

ndash


Amio for SVT

102 pts VT 55

pts Prevention

3 pts Uncertain

1 pt

679

days

Hypothyroidism

Subclinical 74

Overt 8

Hyperthyroidism

Subcl 06


06

Overt 67

ndash


cohort study

For overt thyroid

dysfunctions

Indication for

amio

VA 667ndash80

AA 20ndash333

317 pts

Euthyroid 256

Subcl hypothy-

roid 52

Subcl hyperthy-

roid 9

585 years 735

males


95


189


DCM OR 33 (126-89)






Amio for AF-260

pts VA 43 pts

63 years 66

males


Hypothyroidism 6

Hyperthyroidism

Age lt62 years

HR 24 (10ndash57) P lt 005

Hypothyroidism

TSH gt14 mUL

HR 51 (11ndash224) P = 003

LVEF lt45

HR 38 (11-133) P = 004

DM-HR 33 (11ndash103) P = 004


Amio vs sotalol

and beta-

55 pts with ICD

Amio 24 pts

Sotalol 17 pts


Time to development

163(23) months

Continued



Table 6 Continued


toxicity arrhythmia


RRHR (95CI)

blockers for

inappropriate

shock reduction

in ICD pts







Recurrence of VT

VF during amio-

darone induced

toxicity as com-

pared to euthy-

roid state

Holter monitoring

and plasma amio

232 pts

amio therapy




amio

Hyperthyroidism 125






Treatment



amio




ual improvement

Czarnywojtek

et al161

Cohort

RIT for pts on

amio and TD

Amio indication

SVT VT ICD

inappropriate

shocks AF

297 cases amio

A 78 euthyroid-

ism on amio

B118

hyperthyroidism

History amio

C 79 hyperthyr-

oidism amio

D 22

hypothyroidism


ism after RIT A 538

B 339 C 341



125 C 114





therapy

Diederichsen

et al164

RCT double-blind

placebo-

controlled

Amio vs place bo

for 8 weeks after

catheter ablation

of AF

Endpoint TD

212 patients after

catheter ablation

of AF without

history of thy-

roid dysfunction

Amio group 8

weeks amio

Placebo group



Amio groupmdash3

Placebomdash1





placebo


treatment


16 B Gorenek et al









dysfunction

Consensus

statement

instruction

Level of

evidence

References








hyperthyroidism


143145ndash147163


function screening


























statement

instruction

Level of

evidence

References











18 B Gorenek et al












Aldosterone excess


Cardiacfibrosis


Na+ H2Oretention

K+ Mg++

loss


Hypertension

Congestion

Arrhythmias

LVH















statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10









reduction



coupling

Reduced Na+

channel function

Cardiacfibosis



downregulation

ABNORMALCONDUCTION




ARRHYTHMOGENESIS

Diabetic

Cardiom

yopathy





Altered m

olecular signaling

ReentryTriggered

activity

CV riskfactors


Diabetic

Neuropathy


4 B Gorenek et al





Figure 3 Continued

6 B Gorenek et al




glucose

control



glucose control)

Significant

hypoglycaemia

ADVANCE72

2008

11 140

DM type 2


94 vs 109

HR 086 (077ndash097) P = 001


100 vs 106

HR 094 (084ndash106) P = 032


45 vs 52

HR 088 (074ndash104) P = 012

All-cause death

89 vs 96

HR 093 (083ndash106) P = 028

27 vs 15

HR 186 (142ndash240)

P lt 0001

ACCORD54 2008

ACCORD53 2011

10 251

DM Type 2

known CV dis-

ease or CV risk

factors

Various

The intensive

regimen

stopped

early due to

increased

mortality


141 vs 114

HR 122 (101ndash146) P = 004


26 vs 18

HR 135 (104ndash176) P = 002

Fatal arrhythmia

01 vs 02



death)

69 vs 72

HR 090 (078ndash104) P = 016




082 (070ndash096) P = 001]


(072 vs 057 HR 129

(104ndash160) P = 002) and


127 HR 119 (103ndash138)



Fatal arrhythmia

01 vs 04

31 vs 10

P lt 0001


erans DM Type

2 40 with pre-

vious CV event

Various

Open-label

study

An absolute

reduction for

15 points in

HbA1c com-

pared with

standard glu-

cose control




096 vs 095

HR 132 (081ndash214) P = 026

All-cause death

088 vs 087

HR 107 (081ndash142) P = 062


event

HR 088 (074ndash105) P = 014

212 vs 99

P lt 0001

Continued










Table 2 Continued


glucose

control



glucose control)

Significant

hypoglycaemia

NICE-SUGAR74

2009

NICE-SUGAR51

2012

6104 critically ill

patients


45ndash60 mmoll


275 vs 249

OR 114 (102ndash128) P = 002




death

285 vs 235 HR 141

(121ndash162) P lt 0001


354 vs 235 HR 210

(159ndash277) P lt 0001


68 vs 05

OR 147 (90ndash259)

P lt 0001


mia n = 2714

(450)


n = 223 (37)

ORIGIN52 2013 12 537

DM Type 2 with

additional CV

risk factors



stroke

HR 158 (124ndash202)

P lt 0001

All-cause mortality

HR 174 (139ndash219)

P lt 0001

CV mortality

HR 171 (127ndash230)

P lt 0001

Arrhythmic death

HR 177 (117ndash267) P = 007


hypoglycaemia

09 vs 03


8 B Gorenek et al








statement

instruction

Level of

evidence

References

































Hyperthyroidism











TSH levels

(mIUL)

Free thyroxine

(pmolL)

Total thyroxine

(mmolL)

Thyroid function












10 B Gorenek et al




Hypothyroidism














TSH levels

Reduced TSH

Suppressed TSH


AF

29

46

25

Reference

IRR 142 (122ndash163)

IRR 131 (119ndash144)

IRR 067 (05ndash09)


IRR 116 (099ndash136)

IRR 141 (135ndash189)

IRR 112 (103ndash121)

Colett et al86

Thyroid studies

collaborators


Reduced TSH

Suppressed TSH

AF HR 168 (116ndash243)

HR 163 (11ndash24)

HR 254 (108ndash599)

Kim et al90

Framingham Heart

study




AF Reference

HR 123 (077ndash197)

HR 057 (021ndash154)


cohort

2631 pts with

hyperthyroidism

10 524 controls

67 years

81 female


26

19 P lt 0001

HR 134 (115ndash156)


of cases

10 pts

wo CVD and

hypokalaemia






VF isolated






treatment

Comment



oidism and AF

467 years


9


therapy -87

Thyroidectomy 3



rhythm upon attain-


63 pts

persistent AF


to euthyroidism and

spontaneous AF con-


lt1 week 43

1ndash3 weeks 752




13ndash15 weeks 100

gt16 weeks -100


hyperthyroidism

412 years

PAF 38 pts

Pers AF 45 pts


Pers AF 60


Age gt55 years

RR 276 116ndash879

P lt 001

Duration of

hyperthyroidism

RR 308 122ndash1141

P lt 001


ment AF

RR 296 131ndash768

P lt 001


hyperthyroidism due

to Graves disease


PAC 7


antithyroid therapy

72 to 25 P lt 0001



thyroidism due to

GD and 40

euthyroidism mul-

tinodular goiter


operation


100)

Sinus tachycardia

-688

ndash



tent AF

Cardioversion after

Antithyroid treat-

ment for

hyperthyroidism

35 months AFmdash12

SRmdash88



tent AF

wo SHD

476 years

Cardioversion after

Antithyroid treat-

ment for 3

months for

hyperthyroidism

67 years AFmdash76

SRmdash924

Predictor of AF

recurrence

Duration of AF

HR 16 (114ndash226)

P = 0005



controlled

116 pts

58 hyperthyroidism-

related persistent

AF

58 non-hyperthyoid-

ism AF

ECV after

Antithyroid treat-

ment for 3

months for

hyperthyroidism




83


hyperthyroidism vs

non-hyperthyroidism

HR 064 (039ndash097)

P = 0004

Predictor of AF

recurrence


HR 101 (10ndash101)

P lt 001

Continued

12 B Gorenek et al


Table 5 Continued


treatment

Comment


Persistent AF with

history of hyper-

thyroidism 47

(16) wo

hyperthyroidism

953 (321)

First AF ablation

(PVI) after 3

months of antithy-

roid therapy for

hyperthyroidism




Predictors of AF

recurrence

hyperthyroidism

HR 087 (040ndash188)

P = 073

Wongcharoen

et al110


and substrate

modification 12)

gt3 month treatment

of hyperthyroidism

before ablation


rence after single

procedure

History of

hyperthyroidism

OR 207 (127ndash338)



procedures



cohort

AntiT and risk of

ischemic stroke in

hyperthyroidism-

related AF

Of 9727 pts with

non-valvular AF

642 (66) pts with

hyperthyroidism


243mdashaspirin

263mdashno AntiT

719 years

678 female

Hyperthyroidism vs

non-

hyperthyroidism



67

HR 033 (012ndash091)


CHA2DS2Vas score


non-hyperthyroid-AF

0mdash0 vs 256



Ischaemic stroke 78



limiting AF


P = 004



with AF

141 hyperthyroidism

history

510 hypothyroidism

history

8271 euthyroidism


hyperthyroidism

HR 085 (041ndash176)

hypothyroidism

HR 098 (073ndash134)

Bleeding

hypothyroidism

HR 13 (102ndash179)


Fibrillation

Cohort Study

90 490 patients

No anticoagulation

at baseline

Thyroid disease 84

Thyrotoxicosis

553 pts


Thyroid disease

HR 095 070ndash119

Thyrotoxicosis

HR 092 (085ndash105)


Thyroid disease

HR 100 (092ndash109)

Thyrotoxicosis

HR 103 (083ndash128)


Within 1 year

after 1 year


1st year

Sinus rhythm 8 7

AF 5 7













thyroid dysfunction

Consensus

statement

instruction

Level of

evidence

References





be required





















considered





14 B Gorenek et al




toxicity arrhythmia


RRHR (95CI)


RCTs of amio

vs placebo effi-

cacy in preven-

tion of SCD

safety

8522 pts

4260 amio arm

4262 placebo arm

12ndash455

months

Thyroid 36 vs 04

Pulmonary 29 vs 15

Hepatic 185 vs 07

Bradyarrhythmias 28

vs15

OR 568 (294-1098) P lt 00001

OR 197 (127-304) P = 0002

OR 21 (115-382) P = 0015

OR 178 (116-272) P = 0008


Vorperian

et al150

Meta-analysis 4

RCTs amio vs

placebo

Adverse effects

738 pts amio arm

727 pts placebo

arm

low dose amio

100ndash400 mg

maintenance

dose

12ndash45

months

TD 37 vs 04



vs 154

Skin 23 vs 07

Eye 15 vs 01

OR 423 (204ndash874) P = 0001

OR 218 (111ndash427) P = 0024

OR 160 (123ndash209) P lt00001

OR 248 (105ndash617) P = 005

OR 342 (122ndash364) P = 002

Bathcer et al151

Substudy

of SAFE-T


persistent AF

Amio vs


1ndash45

years

Hypothyroidism

Subcl 258 vs 66

P lt 00001

Overt 50 vs 03

P lt 0001

Hyperthyroidism


53 vs 24 P = 007

ndash


Amio for SVT

102 pts VT 55

pts Prevention

3 pts Uncertain

1 pt

679

days

Hypothyroidism

Subclinical 74

Overt 8

Hyperthyroidism

Subcl 06


06

Overt 67

ndash


cohort study

For overt thyroid

dysfunctions

Indication for

amio

VA 667ndash80

AA 20ndash333

317 pts

Euthyroid 256

Subcl hypothy-

roid 52

Subcl hyperthy-

roid 9

585 years 735

males


95


189


DCM OR 33 (126-89)






Amio for AF-260

pts VA 43 pts

63 years 66

males


Hypothyroidism 6

Hyperthyroidism

Age lt62 years

HR 24 (10ndash57) P lt 005

Hypothyroidism

TSH gt14 mUL

HR 51 (11ndash224) P = 003

LVEF lt45

HR 38 (11-133) P = 004

DM-HR 33 (11ndash103) P = 004


Amio vs sotalol

and beta-

55 pts with ICD

Amio 24 pts

Sotalol 17 pts


Time to development

163(23) months

Continued



Table 6 Continued


toxicity arrhythmia


RRHR (95CI)

blockers for

inappropriate

shock reduction

in ICD pts







Recurrence of VT

VF during amio-

darone induced

toxicity as com-

pared to euthy-

roid state

Holter monitoring

and plasma amio

232 pts

amio therapy




amio

Hyperthyroidism 125






Treatment



amio




ual improvement

Czarnywojtek

et al161

Cohort

RIT for pts on

amio and TD

Amio indication

SVT VT ICD

inappropriate

shocks AF

297 cases amio

A 78 euthyroid-

ism on amio

B118

hyperthyroidism

History amio

C 79 hyperthyr-

oidism amio

D 22

hypothyroidism


ism after RIT A 538

B 339 C 341



125 C 114





therapy

Diederichsen

et al164

RCT double-blind

placebo-

controlled

Amio vs place bo

for 8 weeks after

catheter ablation

of AF

Endpoint TD

212 patients after

catheter ablation

of AF without

history of thy-

roid dysfunction

Amio group 8

weeks amio

Placebo group



Amio groupmdash3

Placebomdash1





placebo


treatment


16 B Gorenek et al









dysfunction

Consensus

statement

instruction

Level of

evidence

References








hyperthyroidism


143145ndash147163


function screening


























statement

instruction

Level of

evidence

References











18 B Gorenek et al












Aldosterone excess


Cardiacfibrosis


Na+ H2Oretention

K+ Mg++

loss


Hypertension

Congestion

Arrhythmias

LVH















statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10




Figure 3 Continued

6 B Gorenek et al




glucose

control



glucose control)

Significant

hypoglycaemia

ADVANCE72

2008

11 140

DM type 2


94 vs 109

HR 086 (077ndash097) P = 001


100 vs 106

HR 094 (084ndash106) P = 032


45 vs 52

HR 088 (074ndash104) P = 012

All-cause death

89 vs 96

HR 093 (083ndash106) P = 028

27 vs 15

HR 186 (142ndash240)

P lt 0001

ACCORD54 2008

ACCORD53 2011

10 251

DM Type 2

known CV dis-

ease or CV risk

factors

Various

The intensive

regimen

stopped

early due to

increased

mortality


141 vs 114

HR 122 (101ndash146) P = 004


26 vs 18

HR 135 (104ndash176) P = 002

Fatal arrhythmia

01 vs 02



death)

69 vs 72

HR 090 (078ndash104) P = 016




082 (070ndash096) P = 001]


(072 vs 057 HR 129

(104ndash160) P = 002) and


127 HR 119 (103ndash138)



Fatal arrhythmia

01 vs 04

31 vs 10

P lt 0001


erans DM Type

2 40 with pre-

vious CV event

Various

Open-label

study

An absolute

reduction for

15 points in

HbA1c com-

pared with

standard glu-

cose control




096 vs 095

HR 132 (081ndash214) P = 026

All-cause death

088 vs 087

HR 107 (081ndash142) P = 062


event

HR 088 (074ndash105) P = 014

212 vs 99

P lt 0001

Continued










Table 2 Continued


glucose

control



glucose control)

Significant

hypoglycaemia

NICE-SUGAR74

2009

NICE-SUGAR51

2012

6104 critically ill

patients


45ndash60 mmoll


275 vs 249

OR 114 (102ndash128) P = 002




death

285 vs 235 HR 141

(121ndash162) P lt 0001


354 vs 235 HR 210

(159ndash277) P lt 0001


68 vs 05

OR 147 (90ndash259)

P lt 0001


mia n = 2714

(450)


n = 223 (37)

ORIGIN52 2013 12 537

DM Type 2 with

additional CV

risk factors



stroke

HR 158 (124ndash202)

P lt 0001

All-cause mortality

HR 174 (139ndash219)

P lt 0001

CV mortality

HR 171 (127ndash230)

P lt 0001

Arrhythmic death

HR 177 (117ndash267) P = 007


hypoglycaemia

09 vs 03


8 B Gorenek et al








statement

instruction

Level of

evidence

References

































Hyperthyroidism











TSH levels

(mIUL)

Free thyroxine

(pmolL)

Total thyroxine

(mmolL)

Thyroid function












10 B Gorenek et al




Hypothyroidism














TSH levels

Reduced TSH

Suppressed TSH


AF

29

46

25

Reference

IRR 142 (122ndash163)

IRR 131 (119ndash144)

IRR 067 (05ndash09)


IRR 116 (099ndash136)

IRR 141 (135ndash189)

IRR 112 (103ndash121)

Colett et al86

Thyroid studies

collaborators


Reduced TSH

Suppressed TSH

AF HR 168 (116ndash243)

HR 163 (11ndash24)

HR 254 (108ndash599)

Kim et al90

Framingham Heart

study




AF Reference

HR 123 (077ndash197)

HR 057 (021ndash154)


cohort

2631 pts with

hyperthyroidism

10 524 controls

67 years

81 female


26

19 P lt 0001

HR 134 (115ndash156)


of cases

10 pts

wo CVD and

hypokalaemia






VF isolated






treatment

Comment



oidism and AF

467 years


9


therapy -87

Thyroidectomy 3



rhythm upon attain-


63 pts

persistent AF


to euthyroidism and

spontaneous AF con-


lt1 week 43

1ndash3 weeks 752




13ndash15 weeks 100

gt16 weeks -100


hyperthyroidism

412 years

PAF 38 pts

Pers AF 45 pts


Pers AF 60


Age gt55 years

RR 276 116ndash879

P lt 001

Duration of

hyperthyroidism

RR 308 122ndash1141

P lt 001


ment AF

RR 296 131ndash768

P lt 001


hyperthyroidism due

to Graves disease


PAC 7


antithyroid therapy

72 to 25 P lt 0001



thyroidism due to

GD and 40

euthyroidism mul-

tinodular goiter


operation


100)

Sinus tachycardia

-688

ndash



tent AF

Cardioversion after

Antithyroid treat-

ment for

hyperthyroidism

35 months AFmdash12

SRmdash88



tent AF

wo SHD

476 years

Cardioversion after

Antithyroid treat-

ment for 3

months for

hyperthyroidism

67 years AFmdash76

SRmdash924

Predictor of AF

recurrence

Duration of AF

HR 16 (114ndash226)

P = 0005



controlled

116 pts

58 hyperthyroidism-

related persistent

AF

58 non-hyperthyoid-

ism AF

ECV after

Antithyroid treat-

ment for 3

months for

hyperthyroidism




83


hyperthyroidism vs

non-hyperthyroidism

HR 064 (039ndash097)

P = 0004

Predictor of AF

recurrence


HR 101 (10ndash101)

P lt 001

Continued

12 B Gorenek et al


Table 5 Continued


treatment

Comment


Persistent AF with

history of hyper-

thyroidism 47

(16) wo

hyperthyroidism

953 (321)

First AF ablation

(PVI) after 3

months of antithy-

roid therapy for

hyperthyroidism




Predictors of AF

recurrence

hyperthyroidism

HR 087 (040ndash188)

P = 073

Wongcharoen

et al110


and substrate

modification 12)

gt3 month treatment

of hyperthyroidism

before ablation


rence after single

procedure

History of

hyperthyroidism

OR 207 (127ndash338)



procedures



cohort

AntiT and risk of

ischemic stroke in

hyperthyroidism-

related AF

Of 9727 pts with

non-valvular AF

642 (66) pts with

hyperthyroidism


243mdashaspirin

263mdashno AntiT

719 years

678 female

Hyperthyroidism vs

non-

hyperthyroidism



67

HR 033 (012ndash091)


CHA2DS2Vas score


non-hyperthyroid-AF

0mdash0 vs 256



Ischaemic stroke 78



limiting AF


P = 004



with AF

141 hyperthyroidism

history

510 hypothyroidism

history

8271 euthyroidism


hyperthyroidism

HR 085 (041ndash176)

hypothyroidism

HR 098 (073ndash134)

Bleeding

hypothyroidism

HR 13 (102ndash179)


Fibrillation

Cohort Study

90 490 patients

No anticoagulation

at baseline

Thyroid disease 84

Thyrotoxicosis

553 pts


Thyroid disease

HR 095 070ndash119

Thyrotoxicosis

HR 092 (085ndash105)


Thyroid disease

HR 100 (092ndash109)

Thyrotoxicosis

HR 103 (083ndash128)


Within 1 year

after 1 year


1st year

Sinus rhythm 8 7

AF 5 7













thyroid dysfunction

Consensus

statement

instruction

Level of

evidence

References





be required





















considered





14 B Gorenek et al




toxicity arrhythmia


RRHR (95CI)


RCTs of amio

vs placebo effi-

cacy in preven-

tion of SCD

safety

8522 pts

4260 amio arm

4262 placebo arm

12ndash455

months

Thyroid 36 vs 04

Pulmonary 29 vs 15

Hepatic 185 vs 07

Bradyarrhythmias 28

vs15

OR 568 (294-1098) P lt 00001

OR 197 (127-304) P = 0002

OR 21 (115-382) P = 0015

OR 178 (116-272) P = 0008


Vorperian

et al150

Meta-analysis 4

RCTs amio vs

placebo

Adverse effects

738 pts amio arm

727 pts placebo

arm

low dose amio

100ndash400 mg

maintenance

dose

12ndash45

months

TD 37 vs 04



vs 154

Skin 23 vs 07

Eye 15 vs 01

OR 423 (204ndash874) P = 0001

OR 218 (111ndash427) P = 0024

OR 160 (123ndash209) P lt00001

OR 248 (105ndash617) P = 005

OR 342 (122ndash364) P = 002

Bathcer et al151

Substudy

of SAFE-T


persistent AF

Amio vs


1ndash45

years

Hypothyroidism

Subcl 258 vs 66

P lt 00001

Overt 50 vs 03

P lt 0001

Hyperthyroidism


53 vs 24 P = 007

ndash


Amio for SVT

102 pts VT 55

pts Prevention

3 pts Uncertain

1 pt

679

days

Hypothyroidism

Subclinical 74

Overt 8

Hyperthyroidism

Subcl 06


06

Overt 67

ndash


cohort study

For overt thyroid

dysfunctions

Indication for

amio

VA 667ndash80

AA 20ndash333

317 pts

Euthyroid 256

Subcl hypothy-

roid 52

Subcl hyperthy-

roid 9

585 years 735

males


95


189


DCM OR 33 (126-89)






Amio for AF-260

pts VA 43 pts

63 years 66

males


Hypothyroidism 6

Hyperthyroidism

Age lt62 years

HR 24 (10ndash57) P lt 005

Hypothyroidism

TSH gt14 mUL

HR 51 (11ndash224) P = 003

LVEF lt45

HR 38 (11-133) P = 004

DM-HR 33 (11ndash103) P = 004


Amio vs sotalol

and beta-

55 pts with ICD

Amio 24 pts

Sotalol 17 pts


Time to development

163(23) months

Continued



Table 6 Continued


toxicity arrhythmia


RRHR (95CI)

blockers for

inappropriate

shock reduction

in ICD pts







Recurrence of VT

VF during amio-

darone induced

toxicity as com-

pared to euthy-

roid state

Holter monitoring

and plasma amio

232 pts

amio therapy




amio

Hyperthyroidism 125






Treatment



amio




ual improvement

Czarnywojtek

et al161

Cohort

RIT for pts on

amio and TD

Amio indication

SVT VT ICD

inappropriate

shocks AF

297 cases amio

A 78 euthyroid-

ism on amio

B118

hyperthyroidism

History amio

C 79 hyperthyr-

oidism amio

D 22

hypothyroidism


ism after RIT A 538

B 339 C 341



125 C 114





therapy

Diederichsen

et al164

RCT double-blind

placebo-

controlled

Amio vs place bo

for 8 weeks after

catheter ablation

of AF

Endpoint TD

212 patients after

catheter ablation

of AF without

history of thy-

roid dysfunction

Amio group 8

weeks amio

Placebo group



Amio groupmdash3

Placebomdash1





placebo


treatment


16 B Gorenek et al









dysfunction

Consensus

statement

instruction

Level of

evidence

References








hyperthyroidism


143145ndash147163


function screening


























statement

instruction

Level of

evidence

References











18 B Gorenek et al












Aldosterone excess


Cardiacfibrosis


Na+ H2Oretention

K+ Mg++

loss


Hypertension

Congestion

Arrhythmias

LVH















statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10



glucose

control



glucose control)

Significant

hypoglycaemia

ADVANCE72

2008

11 140

DM type 2


94 vs 109

HR 086 (077ndash097) P = 001


100 vs 106

HR 094 (084ndash106) P = 032


45 vs 52

HR 088 (074ndash104) P = 012

All-cause death

89 vs 96

HR 093 (083ndash106) P = 028

27 vs 15

HR 186 (142ndash240)

P lt 0001

ACCORD54 2008

ACCORD53 2011

10 251

DM Type 2

known CV dis-

ease or CV risk

factors

Various

The intensive

regimen

stopped

early due to

increased

mortality


141 vs 114

HR 122 (101ndash146) P = 004


26 vs 18

HR 135 (104ndash176) P = 002

Fatal arrhythmia

01 vs 02



death)

69 vs 72

HR 090 (078ndash104) P = 016




082 (070ndash096) P = 001]


(072 vs 057 HR 129

(104ndash160) P = 002) and


127 HR 119 (103ndash138)



Fatal arrhythmia

01 vs 04

31 vs 10

P lt 0001


erans DM Type

2 40 with pre-

vious CV event

Various

Open-label

study

An absolute

reduction for

15 points in

HbA1c com-

pared with

standard glu-

cose control




096 vs 095

HR 132 (081ndash214) P = 026

All-cause death

088 vs 087

HR 107 (081ndash142) P = 062


event

HR 088 (074ndash105) P = 014

212 vs 99

P lt 0001

Continued










Table 2 Continued


glucose

control



glucose control)

Significant

hypoglycaemia

NICE-SUGAR74

2009

NICE-SUGAR51

2012

6104 critically ill

patients


45ndash60 mmoll


275 vs 249

OR 114 (102ndash128) P = 002




death

285 vs 235 HR 141

(121ndash162) P lt 0001


354 vs 235 HR 210

(159ndash277) P lt 0001


68 vs 05

OR 147 (90ndash259)

P lt 0001


mia n = 2714

(450)


n = 223 (37)

ORIGIN52 2013 12 537

DM Type 2 with

additional CV

risk factors



stroke

HR 158 (124ndash202)

P lt 0001

All-cause mortality

HR 174 (139ndash219)

P lt 0001

CV mortality

HR 171 (127ndash230)

P lt 0001

Arrhythmic death

HR 177 (117ndash267) P = 007


hypoglycaemia

09 vs 03


8 B Gorenek et al








statement

instruction

Level of

evidence

References

































Hyperthyroidism











TSH levels

(mIUL)

Free thyroxine

(pmolL)

Total thyroxine

(mmolL)

Thyroid function












10 B Gorenek et al




Hypothyroidism














TSH levels

Reduced TSH

Suppressed TSH


AF

29

46

25

Reference

IRR 142 (122ndash163)

IRR 131 (119ndash144)

IRR 067 (05ndash09)


IRR 116 (099ndash136)

IRR 141 (135ndash189)

IRR 112 (103ndash121)

Colett et al86

Thyroid studies

collaborators


Reduced TSH

Suppressed TSH

AF HR 168 (116ndash243)

HR 163 (11ndash24)

HR 254 (108ndash599)

Kim et al90

Framingham Heart

study




AF Reference

HR 123 (077ndash197)

HR 057 (021ndash154)


cohort

2631 pts with

hyperthyroidism

10 524 controls

67 years

81 female


26

19 P lt 0001

HR 134 (115ndash156)


of cases

10 pts

wo CVD and

hypokalaemia






VF isolated






treatment

Comment



oidism and AF

467 years


9


therapy -87

Thyroidectomy 3



rhythm upon attain-


63 pts

persistent AF


to euthyroidism and

spontaneous AF con-


lt1 week 43

1ndash3 weeks 752




13ndash15 weeks 100

gt16 weeks -100


hyperthyroidism

412 years

PAF 38 pts

Pers AF 45 pts


Pers AF 60


Age gt55 years

RR 276 116ndash879

P lt 001

Duration of

hyperthyroidism

RR 308 122ndash1141

P lt 001


ment AF

RR 296 131ndash768

P lt 001


hyperthyroidism due

to Graves disease


PAC 7


antithyroid therapy

72 to 25 P lt 0001



thyroidism due to

GD and 40

euthyroidism mul-

tinodular goiter


operation


100)

Sinus tachycardia

-688

ndash



tent AF

Cardioversion after

Antithyroid treat-

ment for

hyperthyroidism

35 months AFmdash12

SRmdash88



tent AF

wo SHD

476 years

Cardioversion after

Antithyroid treat-

ment for 3

months for

hyperthyroidism

67 years AFmdash76

SRmdash924

Predictor of AF

recurrence

Duration of AF

HR 16 (114ndash226)

P = 0005



controlled

116 pts

58 hyperthyroidism-

related persistent

AF

58 non-hyperthyoid-

ism AF

ECV after

Antithyroid treat-

ment for 3

months for

hyperthyroidism




83


hyperthyroidism vs

non-hyperthyroidism

HR 064 (039ndash097)

P = 0004

Predictor of AF

recurrence


HR 101 (10ndash101)

P lt 001

Continued

12 B Gorenek et al


Table 5 Continued


treatment

Comment


Persistent AF with

history of hyper-

thyroidism 47

(16) wo

hyperthyroidism

953 (321)

First AF ablation

(PVI) after 3

months of antithy-

roid therapy for

hyperthyroidism




Predictors of AF

recurrence

hyperthyroidism

HR 087 (040ndash188)

P = 073

Wongcharoen

et al110


and substrate

modification 12)

gt3 month treatment

of hyperthyroidism

before ablation


rence after single

procedure

History of

hyperthyroidism

OR 207 (127ndash338)



procedures



cohort

AntiT and risk of

ischemic stroke in

hyperthyroidism-

related AF

Of 9727 pts with

non-valvular AF

642 (66) pts with

hyperthyroidism


243mdashaspirin

263mdashno AntiT

719 years

678 female

Hyperthyroidism vs

non-

hyperthyroidism



67

HR 033 (012ndash091)


CHA2DS2Vas score


non-hyperthyroid-AF

0mdash0 vs 256



Ischaemic stroke 78



limiting AF


P = 004



with AF

141 hyperthyroidism

history

510 hypothyroidism

history

8271 euthyroidism


hyperthyroidism

HR 085 (041ndash176)

hypothyroidism

HR 098 (073ndash134)

Bleeding

hypothyroidism

HR 13 (102ndash179)


Fibrillation

Cohort Study

90 490 patients

No anticoagulation

at baseline

Thyroid disease 84

Thyrotoxicosis

553 pts


Thyroid disease

HR 095 070ndash119

Thyrotoxicosis

HR 092 (085ndash105)


Thyroid disease

HR 100 (092ndash109)

Thyrotoxicosis

HR 103 (083ndash128)


Within 1 year

after 1 year


1st year

Sinus rhythm 8 7

AF 5 7













thyroid dysfunction

Consensus

statement

instruction

Level of

evidence

References





be required





















considered





14 B Gorenek et al




toxicity arrhythmia


RRHR (95CI)


RCTs of amio

vs placebo effi-

cacy in preven-

tion of SCD

safety

8522 pts

4260 amio arm

4262 placebo arm

12ndash455

months

Thyroid 36 vs 04

Pulmonary 29 vs 15

Hepatic 185 vs 07

Bradyarrhythmias 28

vs15

OR 568 (294-1098) P lt 00001

OR 197 (127-304) P = 0002

OR 21 (115-382) P = 0015

OR 178 (116-272) P = 0008


Vorperian

et al150

Meta-analysis 4

RCTs amio vs

placebo

Adverse effects

738 pts amio arm

727 pts placebo

arm

low dose amio

100ndash400 mg

maintenance

dose

12ndash45

months

TD 37 vs 04



vs 154

Skin 23 vs 07

Eye 15 vs 01

OR 423 (204ndash874) P = 0001

OR 218 (111ndash427) P = 0024

OR 160 (123ndash209) P lt00001

OR 248 (105ndash617) P = 005

OR 342 (122ndash364) P = 002

Bathcer et al151

Substudy

of SAFE-T


persistent AF

Amio vs


1ndash45

years

Hypothyroidism

Subcl 258 vs 66

P lt 00001

Overt 50 vs 03

P lt 0001

Hyperthyroidism


53 vs 24 P = 007

ndash


Amio for SVT

102 pts VT 55

pts Prevention

3 pts Uncertain

1 pt

679

days

Hypothyroidism

Subclinical 74

Overt 8

Hyperthyroidism

Subcl 06


06

Overt 67

ndash


cohort study

For overt thyroid

dysfunctions

Indication for

amio

VA 667ndash80

AA 20ndash333

317 pts

Euthyroid 256

Subcl hypothy-

roid 52

Subcl hyperthy-

roid 9

585 years 735

males


95


189


DCM OR 33 (126-89)






Amio for AF-260

pts VA 43 pts

63 years 66

males


Hypothyroidism 6

Hyperthyroidism

Age lt62 years

HR 24 (10ndash57) P lt 005

Hypothyroidism

TSH gt14 mUL

HR 51 (11ndash224) P = 003

LVEF lt45

HR 38 (11-133) P = 004

DM-HR 33 (11ndash103) P = 004


Amio vs sotalol

and beta-

55 pts with ICD

Amio 24 pts

Sotalol 17 pts


Time to development

163(23) months

Continued



Table 6 Continued


toxicity arrhythmia


RRHR (95CI)

blockers for

inappropriate

shock reduction

in ICD pts







Recurrence of VT

VF during amio-

darone induced

toxicity as com-

pared to euthy-

roid state

Holter monitoring

and plasma amio

232 pts

amio therapy




amio

Hyperthyroidism 125






Treatment



amio




ual improvement

Czarnywojtek

et al161

Cohort

RIT for pts on

amio and TD

Amio indication

SVT VT ICD

inappropriate

shocks AF

297 cases amio

A 78 euthyroid-

ism on amio

B118

hyperthyroidism

History amio

C 79 hyperthyr-

oidism amio

D 22

hypothyroidism


ism after RIT A 538

B 339 C 341



125 C 114





therapy

Diederichsen

et al164

RCT double-blind

placebo-

controlled

Amio vs place bo

for 8 weeks after

catheter ablation

of AF

Endpoint TD

212 patients after

catheter ablation

of AF without

history of thy-

roid dysfunction

Amio group 8

weeks amio

Placebo group



Amio groupmdash3

Placebomdash1





placebo


treatment


16 B Gorenek et al









dysfunction

Consensus

statement

instruction

Level of

evidence

References








hyperthyroidism


143145ndash147163


function screening


























statement

instruction

Level of

evidence

References











18 B Gorenek et al












Aldosterone excess


Cardiacfibrosis


Na+ H2Oretention

K+ Mg++

loss


Hypertension

Congestion

Arrhythmias

LVH















statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10








Table 2 Continued


glucose

control



glucose control)

Significant

hypoglycaemia

NICE-SUGAR74

2009

NICE-SUGAR51

2012

6104 critically ill

patients


45ndash60 mmoll


275 vs 249

OR 114 (102ndash128) P = 002




death

285 vs 235 HR 141

(121ndash162) P lt 0001


354 vs 235 HR 210

(159ndash277) P lt 0001


68 vs 05

OR 147 (90ndash259)

P lt 0001


mia n = 2714

(450)


n = 223 (37)

ORIGIN52 2013 12 537

DM Type 2 with

additional CV

risk factors



stroke

HR 158 (124ndash202)

P lt 0001

All-cause mortality

HR 174 (139ndash219)

P lt 0001

CV mortality

HR 171 (127ndash230)

P lt 0001

Arrhythmic death

HR 177 (117ndash267) P = 007


hypoglycaemia

09 vs 03


8 B Gorenek et al








statement

instruction

Level of

evidence

References

































Hyperthyroidism











TSH levels

(mIUL)

Free thyroxine

(pmolL)

Total thyroxine

(mmolL)

Thyroid function












10 B Gorenek et al




Hypothyroidism














TSH levels

Reduced TSH

Suppressed TSH


AF

29

46

25

Reference

IRR 142 (122ndash163)

IRR 131 (119ndash144)

IRR 067 (05ndash09)


IRR 116 (099ndash136)

IRR 141 (135ndash189)

IRR 112 (103ndash121)

Colett et al86

Thyroid studies

collaborators


Reduced TSH

Suppressed TSH

AF HR 168 (116ndash243)

HR 163 (11ndash24)

HR 254 (108ndash599)

Kim et al90

Framingham Heart

study




AF Reference

HR 123 (077ndash197)

HR 057 (021ndash154)


cohort

2631 pts with

hyperthyroidism

10 524 controls

67 years

81 female


26

19 P lt 0001

HR 134 (115ndash156)


of cases

10 pts

wo CVD and

hypokalaemia






VF isolated






treatment

Comment



oidism and AF

467 years


9


therapy -87

Thyroidectomy 3



rhythm upon attain-


63 pts

persistent AF


to euthyroidism and

spontaneous AF con-


lt1 week 43

1ndash3 weeks 752




13ndash15 weeks 100

gt16 weeks -100


hyperthyroidism

412 years

PAF 38 pts

Pers AF 45 pts


Pers AF 60


Age gt55 years

RR 276 116ndash879

P lt 001

Duration of

hyperthyroidism

RR 308 122ndash1141

P lt 001


ment AF

RR 296 131ndash768

P lt 001


hyperthyroidism due

to Graves disease


PAC 7


antithyroid therapy

72 to 25 P lt 0001



thyroidism due to

GD and 40

euthyroidism mul-

tinodular goiter


operation


100)

Sinus tachycardia

-688

ndash



tent AF

Cardioversion after

Antithyroid treat-

ment for

hyperthyroidism

35 months AFmdash12

SRmdash88



tent AF

wo SHD

476 years

Cardioversion after

Antithyroid treat-

ment for 3

months for

hyperthyroidism

67 years AFmdash76

SRmdash924

Predictor of AF

recurrence

Duration of AF

HR 16 (114ndash226)

P = 0005



controlled

116 pts

58 hyperthyroidism-

related persistent

AF

58 non-hyperthyoid-

ism AF

ECV after

Antithyroid treat-

ment for 3

months for

hyperthyroidism




83


hyperthyroidism vs

non-hyperthyroidism

HR 064 (039ndash097)

P = 0004

Predictor of AF

recurrence


HR 101 (10ndash101)

P lt 001

Continued

12 B Gorenek et al


Table 5 Continued


treatment

Comment


Persistent AF with

history of hyper-

thyroidism 47

(16) wo

hyperthyroidism

953 (321)

First AF ablation

(PVI) after 3

months of antithy-

roid therapy for

hyperthyroidism




Predictors of AF

recurrence

hyperthyroidism

HR 087 (040ndash188)

P = 073

Wongcharoen

et al110


and substrate

modification 12)

gt3 month treatment

of hyperthyroidism

before ablation


rence after single

procedure

History of

hyperthyroidism

OR 207 (127ndash338)



procedures



cohort

AntiT and risk of

ischemic stroke in

hyperthyroidism-

related AF

Of 9727 pts with

non-valvular AF

642 (66) pts with

hyperthyroidism


243mdashaspirin

263mdashno AntiT

719 years

678 female

Hyperthyroidism vs

non-

hyperthyroidism



67

HR 033 (012ndash091)


CHA2DS2Vas score


non-hyperthyroid-AF

0mdash0 vs 256



Ischaemic stroke 78



limiting AF


P = 004



with AF

141 hyperthyroidism

history

510 hypothyroidism

history

8271 euthyroidism


hyperthyroidism

HR 085 (041ndash176)

hypothyroidism

HR 098 (073ndash134)

Bleeding

hypothyroidism

HR 13 (102ndash179)


Fibrillation

Cohort Study

90 490 patients

No anticoagulation

at baseline

Thyroid disease 84

Thyrotoxicosis

553 pts


Thyroid disease

HR 095 070ndash119

Thyrotoxicosis

HR 092 (085ndash105)


Thyroid disease

HR 100 (092ndash109)

Thyrotoxicosis

HR 103 (083ndash128)


Within 1 year

after 1 year


1st year

Sinus rhythm 8 7

AF 5 7













thyroid dysfunction

Consensus

statement

instruction

Level of

evidence

References





be required





















considered





14 B Gorenek et al




toxicity arrhythmia


RRHR (95CI)


RCTs of amio

vs placebo effi-

cacy in preven-

tion of SCD

safety

8522 pts

4260 amio arm

4262 placebo arm

12ndash455

months

Thyroid 36 vs 04

Pulmonary 29 vs 15

Hepatic 185 vs 07

Bradyarrhythmias 28

vs15

OR 568 (294-1098) P lt 00001

OR 197 (127-304) P = 0002

OR 21 (115-382) P = 0015

OR 178 (116-272) P = 0008


Vorperian

et al150

Meta-analysis 4

RCTs amio vs

placebo

Adverse effects

738 pts amio arm

727 pts placebo

arm

low dose amio

100ndash400 mg

maintenance

dose

12ndash45

months

TD 37 vs 04



vs 154

Skin 23 vs 07

Eye 15 vs 01

OR 423 (204ndash874) P = 0001

OR 218 (111ndash427) P = 0024

OR 160 (123ndash209) P lt00001

OR 248 (105ndash617) P = 005

OR 342 (122ndash364) P = 002

Bathcer et al151

Substudy

of SAFE-T


persistent AF

Amio vs


1ndash45

years

Hypothyroidism

Subcl 258 vs 66

P lt 00001

Overt 50 vs 03

P lt 0001

Hyperthyroidism


53 vs 24 P = 007

ndash


Amio for SVT

102 pts VT 55

pts Prevention

3 pts Uncertain

1 pt

679

days

Hypothyroidism

Subclinical 74

Overt 8

Hyperthyroidism

Subcl 06


06

Overt 67

ndash


cohort study

For overt thyroid

dysfunctions

Indication for

amio

VA 667ndash80

AA 20ndash333

317 pts

Euthyroid 256

Subcl hypothy-

roid 52

Subcl hyperthy-

roid 9

585 years 735

males


95


189


DCM OR 33 (126-89)






Amio for AF-260

pts VA 43 pts

63 years 66

males


Hypothyroidism 6

Hyperthyroidism

Age lt62 years

HR 24 (10ndash57) P lt 005

Hypothyroidism

TSH gt14 mUL

HR 51 (11ndash224) P = 003

LVEF lt45

HR 38 (11-133) P = 004

DM-HR 33 (11ndash103) P = 004


Amio vs sotalol

and beta-

55 pts with ICD

Amio 24 pts

Sotalol 17 pts


Time to development

163(23) months

Continued



Table 6 Continued


toxicity arrhythmia


RRHR (95CI)

blockers for

inappropriate

shock reduction

in ICD pts







Recurrence of VT

VF during amio-

darone induced

toxicity as com-

pared to euthy-

roid state

Holter monitoring

and plasma amio

232 pts

amio therapy




amio

Hyperthyroidism 125






Treatment



amio




ual improvement

Czarnywojtek

et al161

Cohort

RIT for pts on

amio and TD

Amio indication

SVT VT ICD

inappropriate

shocks AF

297 cases amio

A 78 euthyroid-

ism on amio

B118

hyperthyroidism

History amio

C 79 hyperthyr-

oidism amio

D 22

hypothyroidism


ism after RIT A 538

B 339 C 341



125 C 114





therapy

Diederichsen

et al164

RCT double-blind

placebo-

controlled

Amio vs place bo

for 8 weeks after

catheter ablation

of AF

Endpoint TD

212 patients after

catheter ablation

of AF without

history of thy-

roid dysfunction

Amio group 8

weeks amio

Placebo group



Amio groupmdash3

Placebomdash1





placebo


treatment


16 B Gorenek et al









dysfunction

Consensus

statement

instruction

Level of

evidence

References








hyperthyroidism


143145ndash147163


function screening


























statement

instruction

Level of

evidence

References











18 B Gorenek et al












Aldosterone excess


Cardiacfibrosis


Na+ H2Oretention

K+ Mg++

loss


Hypertension

Congestion

Arrhythmias

LVH















statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10







statement

instruction

Level of

evidence

References

































Hyperthyroidism











TSH levels

(mIUL)

Free thyroxine

(pmolL)

Total thyroxine

(mmolL)

Thyroid function












10 B Gorenek et al




Hypothyroidism














TSH levels

Reduced TSH

Suppressed TSH


AF

29

46

25

Reference

IRR 142 (122ndash163)

IRR 131 (119ndash144)

IRR 067 (05ndash09)


IRR 116 (099ndash136)

IRR 141 (135ndash189)

IRR 112 (103ndash121)

Colett et al86

Thyroid studies

collaborators


Reduced TSH

Suppressed TSH

AF HR 168 (116ndash243)

HR 163 (11ndash24)

HR 254 (108ndash599)

Kim et al90

Framingham Heart

study




AF Reference

HR 123 (077ndash197)

HR 057 (021ndash154)


cohort

2631 pts with

hyperthyroidism

10 524 controls

67 years

81 female


26

19 P lt 0001

HR 134 (115ndash156)


of cases

10 pts

wo CVD and

hypokalaemia






VF isolated






treatment

Comment



oidism and AF

467 years


9


therapy -87

Thyroidectomy 3



rhythm upon attain-


63 pts

persistent AF


to euthyroidism and

spontaneous AF con-


lt1 week 43

1ndash3 weeks 752




13ndash15 weeks 100

gt16 weeks -100


hyperthyroidism

412 years

PAF 38 pts

Pers AF 45 pts


Pers AF 60


Age gt55 years

RR 276 116ndash879

P lt 001

Duration of

hyperthyroidism

RR 308 122ndash1141

P lt 001


ment AF

RR 296 131ndash768

P lt 001


hyperthyroidism due

to Graves disease


PAC 7


antithyroid therapy

72 to 25 P lt 0001



thyroidism due to

GD and 40

euthyroidism mul-

tinodular goiter


operation


100)

Sinus tachycardia

-688

ndash



tent AF

Cardioversion after

Antithyroid treat-

ment for

hyperthyroidism

35 months AFmdash12

SRmdash88



tent AF

wo SHD

476 years

Cardioversion after

Antithyroid treat-

ment for 3

months for

hyperthyroidism

67 years AFmdash76

SRmdash924

Predictor of AF

recurrence

Duration of AF

HR 16 (114ndash226)

P = 0005



controlled

116 pts

58 hyperthyroidism-

related persistent

AF

58 non-hyperthyoid-

ism AF

ECV after

Antithyroid treat-

ment for 3

months for

hyperthyroidism




83


hyperthyroidism vs

non-hyperthyroidism

HR 064 (039ndash097)

P = 0004

Predictor of AF

recurrence


HR 101 (10ndash101)

P lt 001

Continued

12 B Gorenek et al


Table 5 Continued


treatment

Comment


Persistent AF with

history of hyper-

thyroidism 47

(16) wo

hyperthyroidism

953 (321)

First AF ablation

(PVI) after 3

months of antithy-

roid therapy for

hyperthyroidism




Predictors of AF

recurrence

hyperthyroidism

HR 087 (040ndash188)

P = 073

Wongcharoen

et al110


and substrate

modification 12)

gt3 month treatment

of hyperthyroidism

before ablation


rence after single

procedure

History of

hyperthyroidism

OR 207 (127ndash338)



procedures



cohort

AntiT and risk of

ischemic stroke in

hyperthyroidism-

related AF

Of 9727 pts with

non-valvular AF

642 (66) pts with

hyperthyroidism


243mdashaspirin

263mdashno AntiT

719 years

678 female

Hyperthyroidism vs

non-

hyperthyroidism



67

HR 033 (012ndash091)


CHA2DS2Vas score


non-hyperthyroid-AF

0mdash0 vs 256



Ischaemic stroke 78



limiting AF


P = 004



with AF

141 hyperthyroidism

history

510 hypothyroidism

history

8271 euthyroidism


hyperthyroidism

HR 085 (041ndash176)

hypothyroidism

HR 098 (073ndash134)

Bleeding

hypothyroidism

HR 13 (102ndash179)


Fibrillation

Cohort Study

90 490 patients

No anticoagulation

at baseline

Thyroid disease 84

Thyrotoxicosis

553 pts


Thyroid disease

HR 095 070ndash119

Thyrotoxicosis

HR 092 (085ndash105)


Thyroid disease

HR 100 (092ndash109)

Thyrotoxicosis

HR 103 (083ndash128)


Within 1 year

after 1 year


1st year

Sinus rhythm 8 7

AF 5 7













thyroid dysfunction

Consensus

statement

instruction

Level of

evidence

References





be required





















considered





14 B Gorenek et al




toxicity arrhythmia


RRHR (95CI)


RCTs of amio

vs placebo effi-

cacy in preven-

tion of SCD

safety

8522 pts

4260 amio arm

4262 placebo arm

12ndash455

months

Thyroid 36 vs 04

Pulmonary 29 vs 15

Hepatic 185 vs 07

Bradyarrhythmias 28

vs15

OR 568 (294-1098) P lt 00001

OR 197 (127-304) P = 0002

OR 21 (115-382) P = 0015

OR 178 (116-272) P = 0008


Vorperian

et al150

Meta-analysis 4

RCTs amio vs

placebo

Adverse effects

738 pts amio arm

727 pts placebo

arm

low dose amio

100ndash400 mg

maintenance

dose

12ndash45

months

TD 37 vs 04



vs 154

Skin 23 vs 07

Eye 15 vs 01

OR 423 (204ndash874) P = 0001

OR 218 (111ndash427) P = 0024

OR 160 (123ndash209) P lt00001

OR 248 (105ndash617) P = 005

OR 342 (122ndash364) P = 002

Bathcer et al151

Substudy

of SAFE-T


persistent AF

Amio vs


1ndash45

years

Hypothyroidism

Subcl 258 vs 66

P lt 00001

Overt 50 vs 03

P lt 0001

Hyperthyroidism


53 vs 24 P = 007

ndash


Amio for SVT

102 pts VT 55

pts Prevention

3 pts Uncertain

1 pt

679

days

Hypothyroidism

Subclinical 74

Overt 8

Hyperthyroidism

Subcl 06


06

Overt 67

ndash


cohort study

For overt thyroid

dysfunctions

Indication for

amio

VA 667ndash80

AA 20ndash333

317 pts

Euthyroid 256

Subcl hypothy-

roid 52

Subcl hyperthy-

roid 9

585 years 735

males


95


189


DCM OR 33 (126-89)






Amio for AF-260

pts VA 43 pts

63 years 66

males


Hypothyroidism 6

Hyperthyroidism

Age lt62 years

HR 24 (10ndash57) P lt 005

Hypothyroidism

TSH gt14 mUL

HR 51 (11ndash224) P = 003

LVEF lt45

HR 38 (11-133) P = 004

DM-HR 33 (11ndash103) P = 004


Amio vs sotalol

and beta-

55 pts with ICD

Amio 24 pts

Sotalol 17 pts


Time to development

163(23) months

Continued



Table 6 Continued


toxicity arrhythmia


RRHR (95CI)

blockers for

inappropriate

shock reduction

in ICD pts







Recurrence of VT

VF during amio-

darone induced

toxicity as com-

pared to euthy-

roid state

Holter monitoring

and plasma amio

232 pts

amio therapy




amio

Hyperthyroidism 125






Treatment



amio




ual improvement

Czarnywojtek

et al161

Cohort

RIT for pts on

amio and TD

Amio indication

SVT VT ICD

inappropriate

shocks AF

297 cases amio

A 78 euthyroid-

ism on amio

B118

hyperthyroidism

History amio

C 79 hyperthyr-

oidism amio

D 22

hypothyroidism


ism after RIT A 538

B 339 C 341



125 C 114





therapy

Diederichsen

et al164

RCT double-blind

placebo-

controlled

Amio vs place bo

for 8 weeks after

catheter ablation

of AF

Endpoint TD

212 patients after

catheter ablation

of AF without

history of thy-

roid dysfunction

Amio group 8

weeks amio

Placebo group



Amio groupmdash3

Placebomdash1





placebo


treatment


16 B Gorenek et al









dysfunction

Consensus

statement

instruction

Level of

evidence

References








hyperthyroidism


143145ndash147163


function screening


























statement

instruction

Level of

evidence

References











18 B Gorenek et al












Aldosterone excess


Cardiacfibrosis


Na+ H2Oretention

K+ Mg++

loss


Hypertension

Congestion

Arrhythmias

LVH















statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10


Hyperthyroidism











TSH levels

(mIUL)

Free thyroxine

(pmolL)

Total thyroxine

(mmolL)

Thyroid function












10 B Gorenek et al




Hypothyroidism














TSH levels

Reduced TSH

Suppressed TSH


AF

29

46

25

Reference

IRR 142 (122ndash163)

IRR 131 (119ndash144)

IRR 067 (05ndash09)


IRR 116 (099ndash136)

IRR 141 (135ndash189)

IRR 112 (103ndash121)

Colett et al86

Thyroid studies

collaborators


Reduced TSH

Suppressed TSH

AF HR 168 (116ndash243)

HR 163 (11ndash24)

HR 254 (108ndash599)

Kim et al90

Framingham Heart

study




AF Reference

HR 123 (077ndash197)

HR 057 (021ndash154)


cohort

2631 pts with

hyperthyroidism

10 524 controls

67 years

81 female


26

19 P lt 0001

HR 134 (115ndash156)


of cases

10 pts

wo CVD and

hypokalaemia






VF isolated






treatment

Comment



oidism and AF

467 years


9


therapy -87

Thyroidectomy 3



rhythm upon attain-


63 pts

persistent AF


to euthyroidism and

spontaneous AF con-


lt1 week 43

1ndash3 weeks 752




13ndash15 weeks 100

gt16 weeks -100


hyperthyroidism

412 years

PAF 38 pts

Pers AF 45 pts


Pers AF 60


Age gt55 years

RR 276 116ndash879

P lt 001

Duration of

hyperthyroidism

RR 308 122ndash1141

P lt 001


ment AF

RR 296 131ndash768

P lt 001


hyperthyroidism due

to Graves disease


PAC 7


antithyroid therapy

72 to 25 P lt 0001



thyroidism due to

GD and 40

euthyroidism mul-

tinodular goiter


operation


100)

Sinus tachycardia

-688

ndash



tent AF

Cardioversion after

Antithyroid treat-

ment for

hyperthyroidism

35 months AFmdash12

SRmdash88



tent AF

wo SHD

476 years

Cardioversion after

Antithyroid treat-

ment for 3

months for

hyperthyroidism

67 years AFmdash76

SRmdash924

Predictor of AF

recurrence

Duration of AF

HR 16 (114ndash226)

P = 0005



controlled

116 pts

58 hyperthyroidism-

related persistent

AF

58 non-hyperthyoid-

ism AF

ECV after

Antithyroid treat-

ment for 3

months for

hyperthyroidism




83


hyperthyroidism vs

non-hyperthyroidism

HR 064 (039ndash097)

P = 0004

Predictor of AF

recurrence


HR 101 (10ndash101)

P lt 001

Continued

12 B Gorenek et al


Table 5 Continued


treatment

Comment


Persistent AF with

history of hyper-

thyroidism 47

(16) wo

hyperthyroidism

953 (321)

First AF ablation

(PVI) after 3

months of antithy-

roid therapy for

hyperthyroidism




Predictors of AF

recurrence

hyperthyroidism

HR 087 (040ndash188)

P = 073

Wongcharoen

et al110


and substrate

modification 12)

gt3 month treatment

of hyperthyroidism

before ablation


rence after single

procedure

History of

hyperthyroidism

OR 207 (127ndash338)



procedures



cohort

AntiT and risk of

ischemic stroke in

hyperthyroidism-

related AF

Of 9727 pts with

non-valvular AF

642 (66) pts with

hyperthyroidism


243mdashaspirin

263mdashno AntiT

719 years

678 female

Hyperthyroidism vs

non-

hyperthyroidism



67

HR 033 (012ndash091)


CHA2DS2Vas score


non-hyperthyroid-AF

0mdash0 vs 256



Ischaemic stroke 78



limiting AF


P = 004



with AF

141 hyperthyroidism

history

510 hypothyroidism

history

8271 euthyroidism


hyperthyroidism

HR 085 (041ndash176)

hypothyroidism

HR 098 (073ndash134)

Bleeding

hypothyroidism

HR 13 (102ndash179)


Fibrillation

Cohort Study

90 490 patients

No anticoagulation

at baseline

Thyroid disease 84

Thyrotoxicosis

553 pts


Thyroid disease

HR 095 070ndash119

Thyrotoxicosis

HR 092 (085ndash105)


Thyroid disease

HR 100 (092ndash109)

Thyrotoxicosis

HR 103 (083ndash128)


Within 1 year

after 1 year


1st year

Sinus rhythm 8 7

AF 5 7













thyroid dysfunction

Consensus

statement

instruction

Level of

evidence

References





be required





















considered





14 B Gorenek et al




toxicity arrhythmia


RRHR (95CI)


RCTs of amio

vs placebo effi-

cacy in preven-

tion of SCD

safety

8522 pts

4260 amio arm

4262 placebo arm

12ndash455

months

Thyroid 36 vs 04

Pulmonary 29 vs 15

Hepatic 185 vs 07

Bradyarrhythmias 28

vs15

OR 568 (294-1098) P lt 00001

OR 197 (127-304) P = 0002

OR 21 (115-382) P = 0015

OR 178 (116-272) P = 0008


Vorperian

et al150

Meta-analysis 4

RCTs amio vs

placebo

Adverse effects

738 pts amio arm

727 pts placebo

arm

low dose amio

100ndash400 mg

maintenance

dose

12ndash45

months

TD 37 vs 04



vs 154

Skin 23 vs 07

Eye 15 vs 01

OR 423 (204ndash874) P = 0001

OR 218 (111ndash427) P = 0024

OR 160 (123ndash209) P lt00001

OR 248 (105ndash617) P = 005

OR 342 (122ndash364) P = 002

Bathcer et al151

Substudy

of SAFE-T


persistent AF

Amio vs


1ndash45

years

Hypothyroidism

Subcl 258 vs 66

P lt 00001

Overt 50 vs 03

P lt 0001

Hyperthyroidism


53 vs 24 P = 007

ndash


Amio for SVT

102 pts VT 55

pts Prevention

3 pts Uncertain

1 pt

679

days

Hypothyroidism

Subclinical 74

Overt 8

Hyperthyroidism

Subcl 06


06

Overt 67

ndash


cohort study

For overt thyroid

dysfunctions

Indication for

amio

VA 667ndash80

AA 20ndash333

317 pts

Euthyroid 256

Subcl hypothy-

roid 52

Subcl hyperthy-

roid 9

585 years 735

males


95


189


DCM OR 33 (126-89)






Amio for AF-260

pts VA 43 pts

63 years 66

males


Hypothyroidism 6

Hyperthyroidism

Age lt62 years

HR 24 (10ndash57) P lt 005

Hypothyroidism

TSH gt14 mUL

HR 51 (11ndash224) P = 003

LVEF lt45

HR 38 (11-133) P = 004

DM-HR 33 (11ndash103) P = 004


Amio vs sotalol

and beta-

55 pts with ICD

Amio 24 pts

Sotalol 17 pts


Time to development

163(23) months

Continued



Table 6 Continued


toxicity arrhythmia


RRHR (95CI)

blockers for

inappropriate

shock reduction

in ICD pts







Recurrence of VT

VF during amio-

darone induced

toxicity as com-

pared to euthy-

roid state

Holter monitoring

and plasma amio

232 pts

amio therapy




amio

Hyperthyroidism 125






Treatment



amio




ual improvement

Czarnywojtek

et al161

Cohort

RIT for pts on

amio and TD

Amio indication

SVT VT ICD

inappropriate

shocks AF

297 cases amio

A 78 euthyroid-

ism on amio

B118

hyperthyroidism

History amio

C 79 hyperthyr-

oidism amio

D 22

hypothyroidism


ism after RIT A 538

B 339 C 341



125 C 114





therapy

Diederichsen

et al164

RCT double-blind

placebo-

controlled

Amio vs place bo

for 8 weeks after

catheter ablation

of AF

Endpoint TD

212 patients after

catheter ablation

of AF without

history of thy-

roid dysfunction

Amio group 8

weeks amio

Placebo group



Amio groupmdash3

Placebomdash1





placebo


treatment


16 B Gorenek et al









dysfunction

Consensus

statement

instruction

Level of

evidence

References








hyperthyroidism


143145ndash147163


function screening


























statement

instruction

Level of

evidence

References











18 B Gorenek et al












Aldosterone excess


Cardiacfibrosis


Na+ H2Oretention

K+ Mg++

loss


Hypertension

Congestion

Arrhythmias

LVH















statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10



Hypothyroidism














TSH levels

Reduced TSH

Suppressed TSH


AF

29

46

25

Reference

IRR 142 (122ndash163)

IRR 131 (119ndash144)

IRR 067 (05ndash09)


IRR 116 (099ndash136)

IRR 141 (135ndash189)

IRR 112 (103ndash121)

Colett et al86

Thyroid studies

collaborators


Reduced TSH

Suppressed TSH

AF HR 168 (116ndash243)

HR 163 (11ndash24)

HR 254 (108ndash599)

Kim et al90

Framingham Heart

study




AF Reference

HR 123 (077ndash197)

HR 057 (021ndash154)


cohort

2631 pts with

hyperthyroidism

10 524 controls

67 years

81 female


26

19 P lt 0001

HR 134 (115ndash156)


of cases

10 pts

wo CVD and

hypokalaemia






VF isolated






treatment

Comment



oidism and AF

467 years


9


therapy -87

Thyroidectomy 3



rhythm upon attain-


63 pts

persistent AF


to euthyroidism and

spontaneous AF con-


lt1 week 43

1ndash3 weeks 752




13ndash15 weeks 100

gt16 weeks -100


hyperthyroidism

412 years

PAF 38 pts

Pers AF 45 pts


Pers AF 60


Age gt55 years

RR 276 116ndash879

P lt 001

Duration of

hyperthyroidism

RR 308 122ndash1141

P lt 001


ment AF

RR 296 131ndash768

P lt 001


hyperthyroidism due

to Graves disease


PAC 7


antithyroid therapy

72 to 25 P lt 0001



thyroidism due to

GD and 40

euthyroidism mul-

tinodular goiter


operation


100)

Sinus tachycardia

-688

ndash



tent AF

Cardioversion after

Antithyroid treat-

ment for

hyperthyroidism

35 months AFmdash12

SRmdash88



tent AF

wo SHD

476 years

Cardioversion after

Antithyroid treat-

ment for 3

months for

hyperthyroidism

67 years AFmdash76

SRmdash924

Predictor of AF

recurrence

Duration of AF

HR 16 (114ndash226)

P = 0005



controlled

116 pts

58 hyperthyroidism-

related persistent

AF

58 non-hyperthyoid-

ism AF

ECV after

Antithyroid treat-

ment for 3

months for

hyperthyroidism




83


hyperthyroidism vs

non-hyperthyroidism

HR 064 (039ndash097)

P = 0004

Predictor of AF

recurrence


HR 101 (10ndash101)

P lt 001

Continued

12 B Gorenek et al


Table 5 Continued


treatment

Comment


Persistent AF with

history of hyper-

thyroidism 47

(16) wo

hyperthyroidism

953 (321)

First AF ablation

(PVI) after 3

months of antithy-

roid therapy for

hyperthyroidism




Predictors of AF

recurrence

hyperthyroidism

HR 087 (040ndash188)

P = 073

Wongcharoen

et al110


and substrate

modification 12)

gt3 month treatment

of hyperthyroidism

before ablation


rence after single

procedure

History of

hyperthyroidism

OR 207 (127ndash338)



procedures



cohort

AntiT and risk of

ischemic stroke in

hyperthyroidism-

related AF

Of 9727 pts with

non-valvular AF

642 (66) pts with

hyperthyroidism


243mdashaspirin

263mdashno AntiT

719 years

678 female

Hyperthyroidism vs

non-

hyperthyroidism



67

HR 033 (012ndash091)


CHA2DS2Vas score


non-hyperthyroid-AF

0mdash0 vs 256



Ischaemic stroke 78



limiting AF


P = 004



with AF

141 hyperthyroidism

history

510 hypothyroidism

history

8271 euthyroidism


hyperthyroidism

HR 085 (041ndash176)

hypothyroidism

HR 098 (073ndash134)

Bleeding

hypothyroidism

HR 13 (102ndash179)


Fibrillation

Cohort Study

90 490 patients

No anticoagulation

at baseline

Thyroid disease 84

Thyrotoxicosis

553 pts


Thyroid disease

HR 095 070ndash119

Thyrotoxicosis

HR 092 (085ndash105)


Thyroid disease

HR 100 (092ndash109)

Thyrotoxicosis

HR 103 (083ndash128)


Within 1 year

after 1 year


1st year

Sinus rhythm 8 7

AF 5 7













thyroid dysfunction

Consensus

statement

instruction

Level of

evidence

References





be required





















considered





14 B Gorenek et al




toxicity arrhythmia


RRHR (95CI)


RCTs of amio

vs placebo effi-

cacy in preven-

tion of SCD

safety

8522 pts

4260 amio arm

4262 placebo arm

12ndash455

months

Thyroid 36 vs 04

Pulmonary 29 vs 15

Hepatic 185 vs 07

Bradyarrhythmias 28

vs15

OR 568 (294-1098) P lt 00001

OR 197 (127-304) P = 0002

OR 21 (115-382) P = 0015

OR 178 (116-272) P = 0008


Vorperian

et al150

Meta-analysis 4

RCTs amio vs

placebo

Adverse effects

738 pts amio arm

727 pts placebo

arm

low dose amio

100ndash400 mg

maintenance

dose

12ndash45

months

TD 37 vs 04



vs 154

Skin 23 vs 07

Eye 15 vs 01

OR 423 (204ndash874) P = 0001

OR 218 (111ndash427) P = 0024

OR 160 (123ndash209) P lt00001

OR 248 (105ndash617) P = 005

OR 342 (122ndash364) P = 002

Bathcer et al151

Substudy

of SAFE-T


persistent AF

Amio vs


1ndash45

years

Hypothyroidism

Subcl 258 vs 66

P lt 00001

Overt 50 vs 03

P lt 0001

Hyperthyroidism


53 vs 24 P = 007

ndash


Amio for SVT

102 pts VT 55

pts Prevention

3 pts Uncertain

1 pt

679

days

Hypothyroidism

Subclinical 74

Overt 8

Hyperthyroidism

Subcl 06


06

Overt 67

ndash


cohort study

For overt thyroid

dysfunctions

Indication for

amio

VA 667ndash80

AA 20ndash333

317 pts

Euthyroid 256

Subcl hypothy-

roid 52

Subcl hyperthy-

roid 9

585 years 735

males


95


189


DCM OR 33 (126-89)






Amio for AF-260

pts VA 43 pts

63 years 66

males


Hypothyroidism 6

Hyperthyroidism

Age lt62 years

HR 24 (10ndash57) P lt 005

Hypothyroidism

TSH gt14 mUL

HR 51 (11ndash224) P = 003

LVEF lt45

HR 38 (11-133) P = 004

DM-HR 33 (11ndash103) P = 004


Amio vs sotalol

and beta-

55 pts with ICD

Amio 24 pts

Sotalol 17 pts


Time to development

163(23) months

Continued



Table 6 Continued


toxicity arrhythmia


RRHR (95CI)

blockers for

inappropriate

shock reduction

in ICD pts







Recurrence of VT

VF during amio-

darone induced

toxicity as com-

pared to euthy-

roid state

Holter monitoring

and plasma amio

232 pts

amio therapy




amio

Hyperthyroidism 125






Treatment



amio




ual improvement

Czarnywojtek

et al161

Cohort

RIT for pts on

amio and TD

Amio indication

SVT VT ICD

inappropriate

shocks AF

297 cases amio

A 78 euthyroid-

ism on amio

B118

hyperthyroidism

History amio

C 79 hyperthyr-

oidism amio

D 22

hypothyroidism


ism after RIT A 538

B 339 C 341



125 C 114





therapy

Diederichsen

et al164

RCT double-blind

placebo-

controlled

Amio vs place bo

for 8 weeks after

catheter ablation

of AF

Endpoint TD

212 patients after

catheter ablation

of AF without

history of thy-

roid dysfunction

Amio group 8

weeks amio

Placebo group



Amio groupmdash3

Placebomdash1





placebo


treatment


16 B Gorenek et al









dysfunction

Consensus

statement

instruction

Level of

evidence

References








hyperthyroidism


143145ndash147163


function screening


























statement

instruction

Level of

evidence

References











18 B Gorenek et al












Aldosterone excess


Cardiacfibrosis


Na+ H2Oretention

K+ Mg++

loss


Hypertension

Congestion

Arrhythmias

LVH















statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10



treatment

Comment



oidism and AF

467 years


9


therapy -87

Thyroidectomy 3



rhythm upon attain-


63 pts

persistent AF


to euthyroidism and

spontaneous AF con-


lt1 week 43

1ndash3 weeks 752




13ndash15 weeks 100

gt16 weeks -100


hyperthyroidism

412 years

PAF 38 pts

Pers AF 45 pts


Pers AF 60


Age gt55 years

RR 276 116ndash879

P lt 001

Duration of

hyperthyroidism

RR 308 122ndash1141

P lt 001


ment AF

RR 296 131ndash768

P lt 001


hyperthyroidism due

to Graves disease


PAC 7


antithyroid therapy

72 to 25 P lt 0001



thyroidism due to

GD and 40

euthyroidism mul-

tinodular goiter


operation


100)

Sinus tachycardia

-688

ndash



tent AF

Cardioversion after

Antithyroid treat-

ment for

hyperthyroidism

35 months AFmdash12

SRmdash88



tent AF

wo SHD

476 years

Cardioversion after

Antithyroid treat-

ment for 3

months for

hyperthyroidism

67 years AFmdash76

SRmdash924

Predictor of AF

recurrence

Duration of AF

HR 16 (114ndash226)

P = 0005



controlled

116 pts

58 hyperthyroidism-

related persistent

AF

58 non-hyperthyoid-

ism AF

ECV after

Antithyroid treat-

ment for 3

months for

hyperthyroidism




83


hyperthyroidism vs

non-hyperthyroidism

HR 064 (039ndash097)

P = 0004

Predictor of AF

recurrence


HR 101 (10ndash101)

P lt 001

Continued

12 B Gorenek et al


Table 5 Continued


treatment

Comment


Persistent AF with

history of hyper-

thyroidism 47

(16) wo

hyperthyroidism

953 (321)

First AF ablation

(PVI) after 3

months of antithy-

roid therapy for

hyperthyroidism




Predictors of AF

recurrence

hyperthyroidism

HR 087 (040ndash188)

P = 073

Wongcharoen

et al110


and substrate

modification 12)

gt3 month treatment

of hyperthyroidism

before ablation


rence after single

procedure

History of

hyperthyroidism

OR 207 (127ndash338)



procedures



cohort

AntiT and risk of

ischemic stroke in

hyperthyroidism-

related AF

Of 9727 pts with

non-valvular AF

642 (66) pts with

hyperthyroidism


243mdashaspirin

263mdashno AntiT

719 years

678 female

Hyperthyroidism vs

non-

hyperthyroidism



67

HR 033 (012ndash091)


CHA2DS2Vas score


non-hyperthyroid-AF

0mdash0 vs 256



Ischaemic stroke 78



limiting AF


P = 004



with AF

141 hyperthyroidism

history

510 hypothyroidism

history

8271 euthyroidism


hyperthyroidism

HR 085 (041ndash176)

hypothyroidism

HR 098 (073ndash134)

Bleeding

hypothyroidism

HR 13 (102ndash179)


Fibrillation

Cohort Study

90 490 patients

No anticoagulation

at baseline

Thyroid disease 84

Thyrotoxicosis

553 pts


Thyroid disease

HR 095 070ndash119

Thyrotoxicosis

HR 092 (085ndash105)


Thyroid disease

HR 100 (092ndash109)

Thyrotoxicosis

HR 103 (083ndash128)


Within 1 year

after 1 year


1st year

Sinus rhythm 8 7

AF 5 7













thyroid dysfunction

Consensus

statement

instruction

Level of

evidence

References





be required





















considered





14 B Gorenek et al




toxicity arrhythmia


RRHR (95CI)


RCTs of amio

vs placebo effi-

cacy in preven-

tion of SCD

safety

8522 pts

4260 amio arm

4262 placebo arm

12ndash455

months

Thyroid 36 vs 04

Pulmonary 29 vs 15

Hepatic 185 vs 07

Bradyarrhythmias 28

vs15

OR 568 (294-1098) P lt 00001

OR 197 (127-304) P = 0002

OR 21 (115-382) P = 0015

OR 178 (116-272) P = 0008


Vorperian

et al150

Meta-analysis 4

RCTs amio vs

placebo

Adverse effects

738 pts amio arm

727 pts placebo

arm

low dose amio

100ndash400 mg

maintenance

dose

12ndash45

months

TD 37 vs 04



vs 154

Skin 23 vs 07

Eye 15 vs 01

OR 423 (204ndash874) P = 0001

OR 218 (111ndash427) P = 0024

OR 160 (123ndash209) P lt00001

OR 248 (105ndash617) P = 005

OR 342 (122ndash364) P = 002

Bathcer et al151

Substudy

of SAFE-T


persistent AF

Amio vs


1ndash45

years

Hypothyroidism

Subcl 258 vs 66

P lt 00001

Overt 50 vs 03

P lt 0001

Hyperthyroidism


53 vs 24 P = 007

ndash


Amio for SVT

102 pts VT 55

pts Prevention

3 pts Uncertain

1 pt

679

days

Hypothyroidism

Subclinical 74

Overt 8

Hyperthyroidism

Subcl 06


06

Overt 67

ndash


cohort study

For overt thyroid

dysfunctions

Indication for

amio

VA 667ndash80

AA 20ndash333

317 pts

Euthyroid 256

Subcl hypothy-

roid 52

Subcl hyperthy-

roid 9

585 years 735

males


95


189


DCM OR 33 (126-89)






Amio for AF-260

pts VA 43 pts

63 years 66

males


Hypothyroidism 6

Hyperthyroidism

Age lt62 years

HR 24 (10ndash57) P lt 005

Hypothyroidism

TSH gt14 mUL

HR 51 (11ndash224) P = 003

LVEF lt45

HR 38 (11-133) P = 004

DM-HR 33 (11ndash103) P = 004


Amio vs sotalol

and beta-

55 pts with ICD

Amio 24 pts

Sotalol 17 pts


Time to development

163(23) months

Continued



Table 6 Continued


toxicity arrhythmia


RRHR (95CI)

blockers for

inappropriate

shock reduction

in ICD pts







Recurrence of VT

VF during amio-

darone induced

toxicity as com-

pared to euthy-

roid state

Holter monitoring

and plasma amio

232 pts

amio therapy




amio

Hyperthyroidism 125






Treatment



amio




ual improvement

Czarnywojtek

et al161

Cohort

RIT for pts on

amio and TD

Amio indication

SVT VT ICD

inappropriate

shocks AF

297 cases amio

A 78 euthyroid-

ism on amio

B118

hyperthyroidism

History amio

C 79 hyperthyr-

oidism amio

D 22

hypothyroidism


ism after RIT A 538

B 339 C 341



125 C 114





therapy

Diederichsen

et al164

RCT double-blind

placebo-

controlled

Amio vs place bo

for 8 weeks after

catheter ablation

of AF

Endpoint TD

212 patients after

catheter ablation

of AF without

history of thy-

roid dysfunction

Amio group 8

weeks amio

Placebo group



Amio groupmdash3

Placebomdash1





placebo


treatment


16 B Gorenek et al









dysfunction

Consensus

statement

instruction

Level of

evidence

References








hyperthyroidism


143145ndash147163


function screening


























statement

instruction

Level of

evidence

References











18 B Gorenek et al












Aldosterone excess


Cardiacfibrosis


Na+ H2Oretention

K+ Mg++

loss


Hypertension

Congestion

Arrhythmias

LVH















statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10

Table 5 Continued


treatment

Comment


Persistent AF with

history of hyper-

thyroidism 47

(16) wo

hyperthyroidism

953 (321)

First AF ablation

(PVI) after 3

months of antithy-

roid therapy for

hyperthyroidism




Predictors of AF

recurrence

hyperthyroidism

HR 087 (040ndash188)

P = 073

Wongcharoen

et al110


and substrate

modification 12)

gt3 month treatment

of hyperthyroidism

before ablation


rence after single

procedure

History of

hyperthyroidism

OR 207 (127ndash338)



procedures



cohort

AntiT and risk of

ischemic stroke in

hyperthyroidism-

related AF

Of 9727 pts with

non-valvular AF

642 (66) pts with

hyperthyroidism


243mdashaspirin

263mdashno AntiT

719 years

678 female

Hyperthyroidism vs

non-

hyperthyroidism



67

HR 033 (012ndash091)


CHA2DS2Vas score


non-hyperthyroid-AF

0mdash0 vs 256



Ischaemic stroke 78



limiting AF


P = 004



with AF

141 hyperthyroidism

history

510 hypothyroidism

history

8271 euthyroidism


hyperthyroidism

HR 085 (041ndash176)

hypothyroidism

HR 098 (073ndash134)

Bleeding

hypothyroidism

HR 13 (102ndash179)


Fibrillation

Cohort Study

90 490 patients

No anticoagulation

at baseline

Thyroid disease 84

Thyrotoxicosis

553 pts


Thyroid disease

HR 095 070ndash119

Thyrotoxicosis

HR 092 (085ndash105)


Thyroid disease

HR 100 (092ndash109)

Thyrotoxicosis

HR 103 (083ndash128)


Within 1 year

after 1 year


1st year

Sinus rhythm 8 7

AF 5 7













thyroid dysfunction

Consensus

statement

instruction

Level of

evidence

References





be required





















considered





14 B Gorenek et al




toxicity arrhythmia


RRHR (95CI)


RCTs of amio

vs placebo effi-

cacy in preven-

tion of SCD

safety

8522 pts

4260 amio arm

4262 placebo arm

12ndash455

months

Thyroid 36 vs 04

Pulmonary 29 vs 15

Hepatic 185 vs 07

Bradyarrhythmias 28

vs15

OR 568 (294-1098) P lt 00001

OR 197 (127-304) P = 0002

OR 21 (115-382) P = 0015

OR 178 (116-272) P = 0008


Vorperian

et al150

Meta-analysis 4

RCTs amio vs

placebo

Adverse effects

738 pts amio arm

727 pts placebo

arm

low dose amio

100ndash400 mg

maintenance

dose

12ndash45

months

TD 37 vs 04



vs 154

Skin 23 vs 07

Eye 15 vs 01

OR 423 (204ndash874) P = 0001

OR 218 (111ndash427) P = 0024

OR 160 (123ndash209) P lt00001

OR 248 (105ndash617) P = 005

OR 342 (122ndash364) P = 002

Bathcer et al151

Substudy

of SAFE-T


persistent AF

Amio vs


1ndash45

years

Hypothyroidism

Subcl 258 vs 66

P lt 00001

Overt 50 vs 03

P lt 0001

Hyperthyroidism


53 vs 24 P = 007

ndash


Amio for SVT

102 pts VT 55

pts Prevention

3 pts Uncertain

1 pt

679

days

Hypothyroidism

Subclinical 74

Overt 8

Hyperthyroidism

Subcl 06


06

Overt 67

ndash


cohort study

For overt thyroid

dysfunctions

Indication for

amio

VA 667ndash80

AA 20ndash333

317 pts

Euthyroid 256

Subcl hypothy-

roid 52

Subcl hyperthy-

roid 9

585 years 735

males


95


189


DCM OR 33 (126-89)






Amio for AF-260

pts VA 43 pts

63 years 66

males


Hypothyroidism 6

Hyperthyroidism

Age lt62 years

HR 24 (10ndash57) P lt 005

Hypothyroidism

TSH gt14 mUL

HR 51 (11ndash224) P = 003

LVEF lt45

HR 38 (11-133) P = 004

DM-HR 33 (11ndash103) P = 004


Amio vs sotalol

and beta-

55 pts with ICD

Amio 24 pts

Sotalol 17 pts


Time to development

163(23) months

Continued



Table 6 Continued


toxicity arrhythmia


RRHR (95CI)

blockers for

inappropriate

shock reduction

in ICD pts







Recurrence of VT

VF during amio-

darone induced

toxicity as com-

pared to euthy-

roid state

Holter monitoring

and plasma amio

232 pts

amio therapy




amio

Hyperthyroidism 125






Treatment



amio




ual improvement

Czarnywojtek

et al161

Cohort

RIT for pts on

amio and TD

Amio indication

SVT VT ICD

inappropriate

shocks AF

297 cases amio

A 78 euthyroid-

ism on amio

B118

hyperthyroidism

History amio

C 79 hyperthyr-

oidism amio

D 22

hypothyroidism


ism after RIT A 538

B 339 C 341



125 C 114





therapy

Diederichsen

et al164

RCT double-blind

placebo-

controlled

Amio vs place bo

for 8 weeks after

catheter ablation

of AF

Endpoint TD

212 patients after

catheter ablation

of AF without

history of thy-

roid dysfunction

Amio group 8

weeks amio

Placebo group



Amio groupmdash3

Placebomdash1





placebo


treatment


16 B Gorenek et al









dysfunction

Consensus

statement

instruction

Level of

evidence

References








hyperthyroidism


143145ndash147163


function screening


























statement

instruction

Level of

evidence

References











18 B Gorenek et al












Aldosterone excess


Cardiacfibrosis


Na+ H2Oretention

K+ Mg++

loss


Hypertension

Congestion

Arrhythmias

LVH















statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10










thyroid dysfunction

Consensus

statement

instruction

Level of

evidence

References





be required





















considered





14 B Gorenek et al




toxicity arrhythmia


RRHR (95CI)


RCTs of amio

vs placebo effi-

cacy in preven-

tion of SCD

safety

8522 pts

4260 amio arm

4262 placebo arm

12ndash455

months

Thyroid 36 vs 04

Pulmonary 29 vs 15

Hepatic 185 vs 07

Bradyarrhythmias 28

vs15

OR 568 (294-1098) P lt 00001

OR 197 (127-304) P = 0002

OR 21 (115-382) P = 0015

OR 178 (116-272) P = 0008


Vorperian

et al150

Meta-analysis 4

RCTs amio vs

placebo

Adverse effects

738 pts amio arm

727 pts placebo

arm

low dose amio

100ndash400 mg

maintenance

dose

12ndash45

months

TD 37 vs 04



vs 154

Skin 23 vs 07

Eye 15 vs 01

OR 423 (204ndash874) P = 0001

OR 218 (111ndash427) P = 0024

OR 160 (123ndash209) P lt00001

OR 248 (105ndash617) P = 005

OR 342 (122ndash364) P = 002

Bathcer et al151

Substudy

of SAFE-T


persistent AF

Amio vs


1ndash45

years

Hypothyroidism

Subcl 258 vs 66

P lt 00001

Overt 50 vs 03

P lt 0001

Hyperthyroidism


53 vs 24 P = 007

ndash


Amio for SVT

102 pts VT 55

pts Prevention

3 pts Uncertain

1 pt

679

days

Hypothyroidism

Subclinical 74

Overt 8

Hyperthyroidism

Subcl 06


06

Overt 67

ndash


cohort study

For overt thyroid

dysfunctions

Indication for

amio

VA 667ndash80

AA 20ndash333

317 pts

Euthyroid 256

Subcl hypothy-

roid 52

Subcl hyperthy-

roid 9

585 years 735

males


95


189


DCM OR 33 (126-89)






Amio for AF-260

pts VA 43 pts

63 years 66

males


Hypothyroidism 6

Hyperthyroidism

Age lt62 years

HR 24 (10ndash57) P lt 005

Hypothyroidism

TSH gt14 mUL

HR 51 (11ndash224) P = 003

LVEF lt45

HR 38 (11-133) P = 004

DM-HR 33 (11ndash103) P = 004


Amio vs sotalol

and beta-

55 pts with ICD

Amio 24 pts

Sotalol 17 pts


Time to development

163(23) months

Continued



Table 6 Continued


toxicity arrhythmia


RRHR (95CI)

blockers for

inappropriate

shock reduction

in ICD pts







Recurrence of VT

VF during amio-

darone induced

toxicity as com-

pared to euthy-

roid state

Holter monitoring

and plasma amio

232 pts

amio therapy




amio

Hyperthyroidism 125






Treatment



amio




ual improvement

Czarnywojtek

et al161

Cohort

RIT for pts on

amio and TD

Amio indication

SVT VT ICD

inappropriate

shocks AF

297 cases amio

A 78 euthyroid-

ism on amio

B118

hyperthyroidism

History amio

C 79 hyperthyr-

oidism amio

D 22

hypothyroidism


ism after RIT A 538

B 339 C 341



125 C 114





therapy

Diederichsen

et al164

RCT double-blind

placebo-

controlled

Amio vs place bo

for 8 weeks after

catheter ablation

of AF

Endpoint TD

212 patients after

catheter ablation

of AF without

history of thy-

roid dysfunction

Amio group 8

weeks amio

Placebo group



Amio groupmdash3

Placebomdash1





placebo


treatment


16 B Gorenek et al









dysfunction

Consensus

statement

instruction

Level of

evidence

References








hyperthyroidism


143145ndash147163


function screening


























statement

instruction

Level of

evidence

References











18 B Gorenek et al












Aldosterone excess


Cardiacfibrosis


Na+ H2Oretention

K+ Mg++

loss


Hypertension

Congestion

Arrhythmias

LVH















statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10



toxicity arrhythmia


RRHR (95CI)


RCTs of amio

vs placebo effi-

cacy in preven-

tion of SCD

safety

8522 pts

4260 amio arm

4262 placebo arm

12ndash455

months

Thyroid 36 vs 04

Pulmonary 29 vs 15

Hepatic 185 vs 07

Bradyarrhythmias 28

vs15

OR 568 (294-1098) P lt 00001

OR 197 (127-304) P = 0002

OR 21 (115-382) P = 0015

OR 178 (116-272) P = 0008


Vorperian

et al150

Meta-analysis 4

RCTs amio vs

placebo

Adverse effects

738 pts amio arm

727 pts placebo

arm

low dose amio

100ndash400 mg

maintenance

dose

12ndash45

months

TD 37 vs 04



vs 154

Skin 23 vs 07

Eye 15 vs 01

OR 423 (204ndash874) P = 0001

OR 218 (111ndash427) P = 0024

OR 160 (123ndash209) P lt00001

OR 248 (105ndash617) P = 005

OR 342 (122ndash364) P = 002

Bathcer et al151

Substudy

of SAFE-T


persistent AF

Amio vs


1ndash45

years

Hypothyroidism

Subcl 258 vs 66

P lt 00001

Overt 50 vs 03

P lt 0001

Hyperthyroidism


53 vs 24 P = 007

ndash


Amio for SVT

102 pts VT 55

pts Prevention

3 pts Uncertain

1 pt

679

days

Hypothyroidism

Subclinical 74

Overt 8

Hyperthyroidism

Subcl 06


06

Overt 67

ndash


cohort study

For overt thyroid

dysfunctions

Indication for

amio

VA 667ndash80

AA 20ndash333

317 pts

Euthyroid 256

Subcl hypothy-

roid 52

Subcl hyperthy-

roid 9

585 years 735

males


95


189


DCM OR 33 (126-89)






Amio for AF-260

pts VA 43 pts

63 years 66

males


Hypothyroidism 6

Hyperthyroidism

Age lt62 years

HR 24 (10ndash57) P lt 005

Hypothyroidism

TSH gt14 mUL

HR 51 (11ndash224) P = 003

LVEF lt45

HR 38 (11-133) P = 004

DM-HR 33 (11ndash103) P = 004


Amio vs sotalol

and beta-

55 pts with ICD

Amio 24 pts

Sotalol 17 pts


Time to development

163(23) months

Continued



Table 6 Continued


toxicity arrhythmia


RRHR (95CI)

blockers for

inappropriate

shock reduction

in ICD pts







Recurrence of VT

VF during amio-

darone induced

toxicity as com-

pared to euthy-

roid state

Holter monitoring

and plasma amio

232 pts

amio therapy




amio

Hyperthyroidism 125






Treatment



amio




ual improvement

Czarnywojtek

et al161

Cohort

RIT for pts on

amio and TD

Amio indication

SVT VT ICD

inappropriate

shocks AF

297 cases amio

A 78 euthyroid-

ism on amio

B118

hyperthyroidism

History amio

C 79 hyperthyr-

oidism amio

D 22

hypothyroidism


ism after RIT A 538

B 339 C 341



125 C 114





therapy

Diederichsen

et al164

RCT double-blind

placebo-

controlled

Amio vs place bo

for 8 weeks after

catheter ablation

of AF

Endpoint TD

212 patients after

catheter ablation

of AF without

history of thy-

roid dysfunction

Amio group 8

weeks amio

Placebo group



Amio groupmdash3

Placebomdash1





placebo


treatment


16 B Gorenek et al









dysfunction

Consensus

statement

instruction

Level of

evidence

References








hyperthyroidism


143145ndash147163


function screening


























statement

instruction

Level of

evidence

References











18 B Gorenek et al












Aldosterone excess


Cardiacfibrosis


Na+ H2Oretention

K+ Mg++

loss


Hypertension

Congestion

Arrhythmias

LVH















statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10

Table 6 Continued


toxicity arrhythmia


RRHR (95CI)

blockers for

inappropriate

shock reduction

in ICD pts







Recurrence of VT

VF during amio-

darone induced

toxicity as com-

pared to euthy-

roid state

Holter monitoring

and plasma amio

232 pts

amio therapy




amio

Hyperthyroidism 125






Treatment



amio




ual improvement

Czarnywojtek

et al161

Cohort

RIT for pts on

amio and TD

Amio indication

SVT VT ICD

inappropriate

shocks AF

297 cases amio

A 78 euthyroid-

ism on amio

B118

hyperthyroidism

History amio

C 79 hyperthyr-

oidism amio

D 22

hypothyroidism


ism after RIT A 538

B 339 C 341



125 C 114





therapy

Diederichsen

et al164

RCT double-blind

placebo-

controlled

Amio vs place bo

for 8 weeks after

catheter ablation

of AF

Endpoint TD

212 patients after

catheter ablation

of AF without

history of thy-

roid dysfunction

Amio group 8

weeks amio

Placebo group



Amio groupmdash3

Placebomdash1





placebo


treatment


16 B Gorenek et al









dysfunction

Consensus

statement

instruction

Level of

evidence

References








hyperthyroidism


143145ndash147163


function screening


























statement

instruction

Level of

evidence

References











18 B Gorenek et al












Aldosterone excess


Cardiacfibrosis


Na+ H2Oretention

K+ Mg++

loss


Hypertension

Congestion

Arrhythmias

LVH















statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10








dysfunction

Consensus

statement

instruction

Level of

evidence

References








hyperthyroidism


143145ndash147163


function screening


























statement

instruction

Level of

evidence

References











18 B Gorenek et al












Aldosterone excess


Cardiacfibrosis


Na+ H2Oretention

K+ Mg++

loss


Hypertension

Congestion

Arrhythmias

LVH















statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10









statement

instruction

Level of

evidence

References











18 B Gorenek et al












Aldosterone excess


Cardiacfibrosis


Na+ H2Oretention

K+ Mg++

loss


Hypertension

Congestion

Arrhythmias

LVH















statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10











Aldosterone excess


Cardiacfibrosis


Na+ H2Oretention

K+ Mg++

loss


Hypertension

Congestion

Arrhythmias

LVH















statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10












statement

instruction

Level of

evidence

References






medical therapy




patients (n)


arrhythmias ()










Atrial flutter221





20 B Gorenek et al













ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10












ECG

Low voltage236




T-wave inversion239






statement

instruction

Level of

evidence

References




bolic disturbances

lsquoShould

do thisrsquo

230



opathy andor heart


mal medical therapy



drocortisone


used with caution




symptoms

lsquoShould

do thisrsquo

231232









cal therapy
















statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10













statement

instruction

Level of

evidence

References




both women and men

However due to an


induced Torsades de





ence of electrolyte

imbalance

lsquoShould

do thisrsquo

260261

22 B Gorenek et al













statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10












statement

instruction

Level of

evidence

References
































Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10
















Odds ratio for

the risk of

CIED infection

Patient factors

Male gender 15


Diabetes 23ndash35


Haemodialysis 86











or implant revision

17ndash31






24 B Gorenek et al





































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10




































































































26 B Gorenek et al




















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10



















































































































28 B Gorenek et al






































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10





































































































30 B Gorenek et al


euy051-TF1

euy051-TF2

euy051-TF3

euy051-TF4

euy051-TF5

euy051-TF6

euy051-TF8

euy051-TF7

euy051-TF9

euy051-TF10