cardiovascular magnetic resonance imaging and ...scripties.umcg.eldoc.ub.rug.nl/files/root/... ·...

“CARDIOVASCULAR MAGNETIC RESONANCE IMAGING AND

ECHOCARDIOGRAPHY IN GOUT”

Patterns of cardiovascular dysfunction in patients with chronic gout

Student: M.S Stob

Student number: 1721275

E-mail: [email protected]

Location: Department of Cardiology, Medisch Spectrum Twente, Enschede, the Netherlands.

Supervisor:

L.J. Wagenaar, MD, PhD, Cardiologist, Medisch Spectrum Twente, Enschede.


External Supervisor:

E.O.F van Gorselen, MD, Cardiologist, Slingeland Ziekenhuis, Doetinchem


In cooperation with:

H.E. Vonkeman, MD, PhD, Rheumatologist, Medisch Spectrum Twente, Enschede.


mailto:[email protected]




M.S. Stob

Summary (½ A4)

Dutch Uit recente onderzoeken is gebleken dat mensen met jicht een verhoogd risico op

cardiovasculaire ziekte hebben. Jicht is een veelvoorkomende ziekte, met name onder

mannen, die gekarakteriseerd wordt door recidiverende ontstekingen van gewrichten. Eén van

de theorieën is dat chronische ontstekingen artherogenese en thrombogenese bevorderen. Met

behulp van cardiale beeldvormende technieken als echo en MRI hopen wij patronen te kunnen

vinden van subklinische cardiovasculaire dysfunctie. 10 mannen met intermitterende of

chronische jicht en minimaal verhoogd cardiovasculair risicoprofiel zijn geïncludeerd.

Daarvan hebben 6 personen zowel MRI als echo ondergaan en 1 persoon alleen MRI.

Gebruikelijke echografische parameters ter analyse van de systolische functie van de linker

ventrikel lieten vrijwel normale waarden zien. Opmerkelijk was wel dat 83.3% een

afwijkende diastolische functie liet zien, in totaal hadden 66.6% graad 1 en 16.6% graad 2

diastolische dysfunctie. Alle personen met diastolische dysfunctie hadden tevens een vergroot

linker atrium. Dit is hoger dan de normale prevalentie (29.8%) van diastolische dysfunctie

onder gezonde proefpersonen in dezelfde leeftijdscategorie. Gezien de zeer kleine

onderzoeksgroep is het onmogelijk te zeggen of de duur van de klachten, aantal aangedane

gewrichten en het wel of niet aanwezig zijn van tophi van invloed zijn op de kans op

diastolische dysfunctie. MRI liet geen afwijkende waarden zien, met name geen aanwijzingen

op oedeem of littekenweefsel in het myocard. Dit onderzoek laat zien dat er een verhoogde

prevalentie van diastolische dysfunctie is bij personen met intermitterende of chronische jicht.

Verder onderzoek is noodzakelijk om deze uitkomsten te toetsen. Prospectief onderzoek met

langdurige follow-up kan bijdragen aan de theorie dat jicht een onafhankelijke risicofactor is

voor diastolische dysfunctie.

English Recent studies have shown an increased cardiovascular (CV) risk amongst patients with gout.

Gout is a common worldwide disease, particularly amongst men, characterized by recurrent

arthritis. Most accepted theory for the increased CV risk amongst patients with gout is the

impact of chronic inflammation, which may promote atherogenesis and thrombogenesis.

Using cardiac imaging such as echocardiogram and cardiac MRI (CMR), we hope to

distinguish patterns of subclinical cardiovascular dysfunction. 10 men with intermittent or

chronic gout and a minimal increased cardiovascular risk profile were included. 6 participants

underwent both CMR and echocardiogram, 1 subject only had CMR. Usual

echocardiographic parameters used for analysis of left ventricle (LV) function showed normal

values. Remarkable, diastolic function was impaired in 83.3% of all participants,

accompanied by enlargement of the left atrium. A total of 66.6% showed grade I and 16.6%

showed grade II diastolic dysfunction. These percentages are higher than the normal

prevalence (29.8%) of diastolic dysfunction amongst a healthy population in the same age-

group. Because of the small study population it is impossible to say if the onset of symptoms,

number of affected joints or the presence of tophi are of influence on the chance to develop

diastolic dysfunction. CMR showed no abnormal parameters, especially no signs of edema or

scarring in the myocardium. This study shows an increased prevalence of diastolic

dysfunction in male patients with intermittent or chronic gout. Further research is needed to

test these findings. Prospective studies with long follow-up can be useful to contribute to the

concept of gout as an independent risk factor for diastolic dysfunction.

M.S. Stob

Table of Contents

Summary (½ A4) ........................................................................................................................ 2

Dutch .................................................................................................................................. 2

English ................................................................................................................................ 2

Introduction on Gout .................................................................................................................. 5

Incidence and prevalence ................................................................................................... 5

Pathophysiology and etiology ............................................................................................ 5

Risk Factors .................................................................................................................... 5

Classification .................................................................................................................. 5

Clinical presentation ....................................................................................................... 6

Symptoms ....................................................................................................................... 6

Diagnostic criteria .......................................................................................................... 6

Treatment ........................................................................................................................ 6

Problem definition ...................................................................................................................... 8

Cardiovascular risk ............................................................................................................. 8

Cardiac imaging ............................................................................................................... 10

Echocardiography ......................................................................................................... 10

Magnetic resonance imaging ........................................................................................ 12

Atherosclerosis ............................................................................................................. 12

Aim of the study ........................................................................................................... 12

Research questions ....................................................................................................... 12

Hypothesis .................................................................................................................... 12

Material & Methods ................................................................................................................. 14

Study population .............................................................................................................. 14

Demographics and medical data ................................................................................... 14

Cardiac Imaging ............................................................................................................... 15

Echocardiography ......................................................................................................... 15

Cardiac MRI ................................................................................................................. 15

Results ...................................................................................................................................... 17

Patient population ............................................................................................................. 17

Patient characteristics ....................................................................................................... 18

Echocardiography ............................................................................................................. 19

LV function .................................................................................................................. 19

M.S. Stob

LV diastolic function .................................................................................................... 19

LA function .................................................................................................................. 19

RV function .................................................................................................................. 19

Anatomy ....................................................................................................................... 19

Cardiac magnetic resonance imaging ............................................................................... 21

LV function .................................................................................................................. 21

RV function .................................................................................................................. 21

Anatomy ....................................................................................................................... 21

Conclusion ................................................................................................................................ 23

Discussion ................................................................................................................................ 24

References ................................................................................................................................ 26

Appendices ............................................................................................................................... 34

1. Drugs that raise and lower serum urate concentrations ......................................... 34

2. Echo parameters ..................................................................................................... 35

3. MRI parameters ..................................................................................................... 36

M.S. Stob

Introduction on Gout

Incidence and prevalence Gout is a common worldwide disease which can be very disabling. Over the past decades gout

has become more common across the entire world, including China, Polynesia, New Zealand

and urban sub-Saharan Africa (1-4). However the incidence and prevalence are difficult to

determine precisely because of the short and recurrent nature of the attacks of gouty arthritis

(5,6). The prevalence of gout in Dutch general practice is about 17 per 1000 patients (7),

which is similar to the prevalence of 1-2 percent in international literature and is more

common amongst men (3-4:1)(1,8). There are indications of an increase in incidence of gout

among Western populations (1,9-11). This can most likely be explained by increasing

longevity (1), higher percentages of obesity, and rise in prevalence of hypertension and

metabolic syndrome (12), which are all associated with gout (1,13). Along with the increase

in hypertension, a rise in prescriptions of diuretics might lead to an increase in the prevalence

of gout, since diuretics are highly associated with gout (14).

Pathophysiology and etiology Gout is the generic term for conditions which are characterized by periods of severe joint

inflammation with the presence of crystallized uric acid, called monosodium urate (MSU)

crystals, in the affected joints, bones and/or soft tissues. The precise correlation between the

deposition of these MSU crystals and the joint inflammation is not fully known. The

commonly accepted concept is that the body shows an auto-immune reaction against these

MSU crystals. Through absorption of the crystals by macrophages, a pro-inflammatory

cytokine called interleukin-1β is formed. Subsequently this leads to the production of

chemokines and inflammatory mediators, which in turn attracts leukocytes and which

eventually lead to a painful and/or chronic inflammation.

Researchers found a clear correlation between increased concentration of serum uric acid and

the prevalence of gout (1). In most cases this is caused by an abnormal increase in

reabsorption of uric acid in the kidneys (15-17). In most of the other cases the increase in uric

acid is caused by an increased production of uric acid as a result of breaking down purine

nucleotides such as RNA, DNA and ATP (16,17).

Risk Factors

Multiple risk factors are associated with the development of gout arthritis. These are divided

in two groups: non-modifiable and modifiable risk factors. Non-modifiable risk factors are:

male gender, increased age, postmenopausal status and ethnicity. Modifiable risk factors are:

obesity, hypertension, use of thiazide or loop diuretics and other medication (see appendix 1),

purine-rich meals like meat and seafood, beverages containing alcohol (mainly beer and

distilled liquors) or beverages high in fructose like soft drinks and fruit juice.

Classification

Gout is classified in primary and secondary gout, depending on the cause of the

hyperuricemia. Primary hyperuricemia is when an increase in serum urate is not caused by a

disease or by medication that has a positive influence on the production or an inhibitory effect

excretion of uric acid.

Secondary hyperuricemia is defined as an increase in serum urate caused by increased

production or impaired excretion due to a disease, medication, diet or toxin.

M.S. Stob

Clinical presentation

The clinical presentation of gout is divided in 3 clinical syndromes; acute gouty arthritis,

intercritical gout and chronic recurrent or tophaceous gout. After an acute gouty arthritis,

patients sometimes proceed to the intercritical stadium, a variable time period between

recurrent attacks which is usually asymptomatic. If untreated, this intercritical stadium will

progressively become shorter and attacks will recur more often until deformities, bone erosion

or tophi occur.

Symptoms

A typical gouty attack is limited to one joint in 85-90 percent of the cases (18), with the first

metatarsophalangeal joint being most often affected. Furthermore, a gouty arthritis attack has

a typical acute onset, prolongs for 2 to 5 days and has the characteristics of an inflammatory

reaction, with pain, redness, heat, swelling and dysfunction of the affected joint or joints.

After an asymptomatic period a second attack often occurs within 6 months to 2 years.

Figure 1: Deposits of uric acid (tophi) in the helix of the ear (left) and within the skin overlying the finger joints (right)

(19).

Diagnostic criteria

There are a lot of conditions which may mimic the clinical features of an acute gouty attack,

like septic arthritis, pseudogout, trauma or other crystal deposition arthritis. A definitive

diagnosis must exclude the previous named conditions to support the perhaps lifelong

treatment.

The golden standard for the diagnosis of gout is the identification of MSU crystals in the

synovial fluid from an affected joint during an acute gouty attack or from a punctate from a

tophus.

Sometimes it is necessary to maintain a tentative diagnosis, for example with a negative

outcome from a joint aspiration. The tentative diagnosis of gout can be based on clinical

(symptoms, previous episodes) and biochemical criteria and perhaps medical imaging.

Researchers found these findings less specific and hard to apply in the general practice, so

they made a risk calculator which general practitioners can use to predict the 3-years

probability of gout (20).

Treatment

The treatment of gout depends on the clinical presentation of the patient and is divided in

acute treatment and chronic treatment.

M.S. Stob

Acute attacks The goals of acute treatment is to relieve pain and stop the inflammatory reaction. Most

effective and applicable medications are colchicine, non-steroidal anti-inflammatory drugs

(NSAID) and corticosteroids (19). Medication should be started as soon as possible after the

onset of symptoms to get the best results. When the symptoms are gone, it is recommended to

discontinue the medication. NSAID’s are preferred above colchicine when there are no

contra-indications. In severe conditions, NSAID’s and colchicine can be combined. Recently,

intra-articular corticosteroids have been proven to be effective (21). However, this is mostly

used in refractory cases or in case of severe contra-indications. Researchers are currently

finding promising results from anti-IL-1 medication (canakinumab) for the treatment of acute

gouty arthritis when NSAID’s, corticosteroids or colchicines are out of option (19,22).

Besides medication, resting and cooling of the affected joint helps with recovery (23).

Chronic treatment Primary goal of chronic treatment is to prevent recurrence, thus preventing the complications

of chronic gout (figure 2). Frequently, allopurinol is used to accomplish this by reducing

serum levels of uric acid, preventing the formation of monosodium urate and dissolve the

already present crystals deposits (tophi). Long term follow-up of patients is recommended

with regular control of uric acid and other influencing factors like osteoarthritis, comorbid

conditions or co-medication. Just as in acute treatment, in chronic treatment research is still

ongoing and shows new and promising developments (24). Due to a high prevalence of

comorbidities known for increasing cardiovascular disease, it is advised to keep this in mind

while treating chronic gout. Therefore management of other risk factors, like hypertension,

diabetes, hyperlipidemia and obesity is recommended.

Figure 2: Complications of chronic gout (19)

Complications of chronic gout

Tophi and soft tissue damage

Erosive bone damage

Renal disease o Uric acid calculi o Chronic urate nephropathy o Acute uric acid nephropathy

(usually secondary to chemotherapy)

Disability and work absence

Avascular necrosis of the femoral head.

M.S. Stob

Problem definition

Cardiovascular risk Over the past decades it was shown that patients diagnosed with hyperuricemia or gout have

an increased risk of CV disease (25-29). This was first shown in 1988 in a large prospective

cohort study (30), and the latest review by Agabiti&Grassi states: “hyperuricemia and gout

have been identified as independent risk factors for the development and progression of CV

disease, CV mortality, and all-cause mortality in a variety of populations” (31). There is also a

correlation between the levels of hyperuricemia and the prevalence and severity of coronary

disease in non-gout populations. (32-34).

Analyses in several studies showed an increased prevalence of traditional CV risk factors,

including hypertension, dyslipidemia, smoking habits and obesity among patients with gout

compared to patients without gout (27,35-41). The correlations found between hyperuricemia

and diabetes have been contradictory (42). Most importantly, apart from an increase in CV

co-morbidity, hyperuricemia is also correlated with an increase in all-cause and CV disease

mortality (43-51). Hyperuricemia is associated with an average 1.5-1.7 fold risk of death by

CV disease, including myocardial infarction, heart failure and stroke (26,52). Niskanen et al.

showed that higher levels of serum uric acid increases the risk of death from CV disease and

all-cause death (53). After adjustment for cardiovascular risk factors and variables commonly

associated with gout, they showed an increased relative risk factor of 3,73 for the upper third

vs the lower third serum uric acid (figure 3 and table 2). Women with hyperuricemia appear to

have a higher relative risk of death from CV disease than men (54,55).

A larger and more recent retrospective cohort study (n=151,018) showed an adjusted hazard

ratio of 1.10 (95% CI 1.07-1.13) for CV mortality, corrected for gender, age, smoking habits,

alcohol related diseases, hypertension, hyperlipidemia and atrial fibrillation (52).

So we can say the increased prevalence of traditional CV risk factors among gout populations

can only partly explain the increased risk of CV disease and mortality.

Keeping this in mind, there might be other pathophysiological mechanisms for the increased

risk of CV mortality among patients with gout or hyperuricemia.

Figure 3: Kaplan-Meier hazard curves for cardiovascular (a) and all-cause (b) mortality for serum uric acid

categorized into tertiles. (53)

M.S. Stob

Table 1: Risk of death from CVD and any cause during the 11-year follow-up for serum uric acid levels categorized

into tertiles in 1423 middle-aged men. (53)

Mechanism

Several theories about potential mechanisms have been formed by professionals trying to

explain the observed increased CV death in patients with gout. Already established is that

hyperuricemia is associated with CV disease, although it remains unclear whether the

hyperuricemia itself plays a pathogenic role or if hyperuricemia can only be seen as a marker

for associated CV risk factors (56,57).

Independently of serum uric acid levels, one of the possible explanations for this increase in

CV disease is ongoing low-grade inflammation among patients with gout, may promote

atherogenesis and thrombogenesis. This hypothesis is based upon findings which suggest that

atherosclerosis itself, the main cause of acute coronary syndrome, is an inflammatory disease

(58,59). This has already been suggested in other chronic inflammatory rheumatic diseases

associated with higher CV disease risks, like rheumatoid arthritis (RA) or systematic lupus

erythematodes (SLE) (60,61). Recently RA has been included as an independent risk factor

for CV diseases in the guidelines for Dutch general practitioners (7). Other chronic

inflammatory rheumatic diseases like SLE and Bechterew (ankylosing spondylitis) have not

been included. However, practitioners must be aware of increased incidence of CV diseases

within these patient population (58).

Gouty arthritis can vary in frequency from once to several times a year, there are indications

that gout not only affects the joints but may also have a systemic inflammatory component

(62). The notion of a systemic inflammatory component in gout is based on several findings

showing urate crystals causing neutrophil- and platelet activation, which in turn release

cytokines, acute-phase proteins, chemokines and adhesion molecules, which could eventually

causes CV damage (63-65). Even in the intercritical periods, low-grade inflammatory activity

is still found in the synovial fluid of gout patients (66,67).

Researchers also found an association between hyperuricemia and several inflammatory

markers (e.i. CRP, IL-6, neutrophils, leucocytes and TNF-alpha (68-71) which further

contribute to the idea that inflammatory processes in patients with gout may play a role in the

development of atherosclerosis. The combination of both systemic inflammation and joint

inflammation might reinforce each other to increase CV risk (72).

M.S. Stob

Within both the hyperuricemic and the gout population there is 2-3 times higher incidence of

heart failure(73-75), which is associated with a high risk of morbidity, mortality and hospital

utilization. Interestingly, among people with HF, hyperuricemia differed significantly between

patients with and without an ischemic etiology (76). Moreover, hyperuricemia is associated

with an increased relative risk in mortality (77) and might be used as prognostic marker (78).

Cardiac imaging Cardiac imaging could be useful to detect signs of subclinical cardiac and/or CV dysfunction

in patients with long term gout. CMR has significantly been improved the past couple of years

and it’s applicability’s is still in development. Although CMR has such an impressive quality

of imaging, CMR has never been used to evaluate cardiac dysfunction in the gout population

thus far.

Echocardiography

Until now only a few studies performed echocardiography among patients with hyperuricemia

and gout. Looking at hyperuricemia, Krishnan et al. describes significant differences at

multiple parameters such as LV thickness, LV diastolic internal dimension and LV mass,

comparing highest and lowest serum uric acid quartile. They also found a multivariable-

adjusted odds ratio of 9.01 for abnormal LV ejection fraction (LVEF) and 4.58 for LV

systolic dysfunction, comparing highest and lowest serum uric acid quartile (79). Regarding

gout, Krishnan et al described significant difference between patients with or without gout.

Multiple echocardiographic parameters such as LV thickness, LV diastolic internal

dimension, LV mass, systolic function and ejection fraction were significantly impaired in

patients with gout. In addition to previous findings they found a relative risk of 3.6 and 3.7

for respectively systolic dysfunction and abnormally low ejection fraction (74).

One of the parameters which is interesting among the gout population to evaluate is diastolic

dysfunction. Diastolic dysfunction is described as impaired relaxation of the left ventricle

causing problems with the filling of the left ventricle. After a certain amount of time this will

cause stiffness of the LV wall, thus increasing left atrial pressure. Diastolic dysfunction is

associated with several diseases which have a high prevalence within the gout population,

such as hypertension, diabetes mellitus (DM) and kidney failure (Figure 4). Diastolic function

is of clinical significance because it is associated with incident heart failure after adjustment

for age, hypertension, diabetes and coronary artery disease with a hazard ratio of 1.81 (95%

CI, 1.01-3.48)(80).

Figure 4: causes of diastolic LV-dysfunction (81)

Causes of diastolic LV-dysfunction

Coronary disease

Hypertension

Valvular abnormalities

Cardiomyopathy

Diabetes mellitus

Systemic diseases

Kidney failure

M.S. Stob

A few associations between hyperuricemia and diastolic dysfunction have been described.

Elevated uric acid levels are associated with diastolic dysfunction in patients with Chronic

Heart Failure (CHF) (76) and even has a correlation with LV diastolic dysfunction amongst

patients without CHF (82,83).

Cicoira et al. described a correlation between serum uric acid levels and several

echocardiographic parameters of diastolic function (E max, E/A ratio, DtE and A-A’), this

was only analysed in patients with ischemic cardiomyopathy (76). Tavil et al. compared

echocardiographic parameters of LV anatomy, systolic and diastolic function amongst

patients with hypertension and compared those with and without hyperuricemia. Results

showed significant differences in the isovolumic relaxation time (IVRT), tissue Doppler-

derived isovolumic relaxation time (IVRT-m) and the LV-myocardial performance index.

Furthermore they also found significant correlations between serum uric acid levels and other

echocardiographic parameters of diastolic function (E/A ratio & deceleration time) (83).

Therefore patterns of subclinical diastolic dysfunction in CMR might be present within the

gout population. As far as we know, there are no publications on valvular abnormalities or

pericardial disease among patients with gout.

Figure 5: Doppler criteria for classification of diastolic function(84).

M.S. Stob

Magnetic resonance imaging

Even though CMR probably still has its best years to come, CMR is already considered a

powerful tool to assess ventricular function, cardiac morphology, perfusion, viability, and

metabolism, as well as the vasculature. Particularly the sensitivity of CMR in defining cardiac

volumes, cardiac mass and the detection of previous ischemia can be of use in this study.

Up and coming within CMR is the possibility to measure previous mentioned diastolic

function. All of this imaging is possible without the need for ionizing radiation, and with high

resolution in three dimensions.

Atherosclerosis

The relationship between atherosclerosis and CV events is well known. However, to

determine the extent of atherosclerosis and the risk of cardiovascular events it is probably best

to visualize arterial plaques. There are multiple imaging techniques to do this. Most

commonly non-invasive techniques used are Computed Tomography (CT) and ultrasound.

Within the hyperuricemic population, researchers have used both techniques to see if there is

any relation between hyperuricemia and the presence of arthrosclerosis.

One of the markers for arthrosclerosis using CT is called Coronary Artery Calcification

(CAC). It has a positive correlation with the degree of coronary plaque (85,86) and is an

independent marker for the risk of coronary disease(87,88). Researchers found an independent

association between hyperuricemia and the presence and severity of calcification.

Hyperuricemic patients have a three times increased risk of presence and increased severity of

coronary calcification (89-91).

Carotid intima media thickness (IMT) is another marker for arthrosclerosis using ultrasound.

Like CAC this marker has a predictive value for clinical events (92,93). A positive association

is found between hyperuricemia and carotid IMT in both men and woman (94-99). One recent

study also found a significant difference in carotid IMT between patients with gouty attacks

and asymptomatic hyperuricemia (100). Furthermore, Ukurova noticed a trend that patients

with gout have a greater risk of subclinical atherosclerosis than patients with rheumatoid

arthritis (100).

Aim of the study

We wanted to find and describe patterns of CV dysfunction in patients diagnosed with gout

with a relative low prior probability of cardiovascular disease using CMR and

echocardiography.

To assess CV dysfunction, different variables will be scored including wall motion score,

diastolic function, valvular abnormalities, left and right ventricular ejection fraction, left

ventricular mass and presence of myocardial fibrosis.

Research questions

Because of the unique features and design of this study and the first time using CMR in

patients with gout the question we want to answer is:

Can we identify patterns of CV dysfunction using CMR and echocardiography in patients

diagnosed with gout with a relative low prior probability of cardiovascular disease?

Hypothesis

All findings stated in the problem definition contribute to the idea that despite the intermittent

nature, gout could play a chronic role in atherosclerosis, increasing CV risk (101). Even

though the increased CV risk is well researched within the gout population, besides CAC and

M.S. Stob

carotid IMT few studies have been performed using cardiac imaging techniques among the

gout population. Especially the contribution of CMR has not been researched so far. We

expect to find an increased prevalence of dysfunction in CV variables, especially diastolic

function, in this small cohort of gout population.

M.S. Stob

Material & Methods

Study population Patients were selected using a diagnosis specific code, from a large cohort of patients

(currently containing over 3000 patients) attending the outpatient department of the Arthritis

Center Twente of the University Twente & Medisch Spectrum Twente hospital group in

Enschede. Details on the methods of patient inclusion and data collection have been

previously published (102). Briefly, as part of routine clinical care, data are collected,

including traditional CV risks parameters used in the SCORE and PROCAM risk set, disease

duration, radiographic scores, extra-articular manifestations, ESR, hs-CRP and specific

medications. Patients are subsequently followed up to a first cardiovascular event or death.

Inclusion criteria gout patients Patients with crystal proven gouty arthritis and a maximum of one of the following

cardiovascular risk factors were invited to participate:

Smoking

Hypercholesterolemia/dyslipidemia (total serum cholesterol ≥ 6.5 mmol/l)

Hypertension (systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90

mmHg) or current use of antihypertensive medication

Exclusion criteria gout patients Previous CV disease

Age < 18 or > 75 years

Pregnancy

Kidney dysfunction (GFR < 60 ml/min)

Diabetes mellitus (fasting glucose level ≥ 7.0 mmol/l) or current use of anti-diabetic

medication

Body Mass Index > 30 kg/m2

Claustrophobia or other exclusion criteria for MRI, such as implanted metal materials

Demographics and medical data

Baseline data had already been collected in the Arthritis Center Twente Cardiovascular

Disease cohort (ACT-CVD) of the University Twente & Medisch Spectrum Twente hospital

group in Enschede.

Demographic and patient data include:

Demographics, including age, gender, family history of CV disease and smoking

habits

Medical history, including onset of symptoms, year of proven gouty arthritis, arterial

hypertension, diabetes mellitus, hypercholesterolemia, previous CV or cerebral events,

kidney failure and other co-morbidities.

Current medication

Body Mass Index, systolic and diastolic blood pressure, heart frequency

Laboratory testing: total cholesterol, triglycerides, high density lipoprotein, low

density lipoprotein and serum uric acid (maximum and last known).

M.S. Stob

Cardiac Imaging

Echocardiography

An echocardiogram was performed in all patients. Multiple parameters were measured in all

groups: LV ejection fraction, presence of wall motion abnormalities, diastolic function,

presence of valvular disease, right ventricle (RV) function and presence of cardiomyopathy.

See Appendix 2 for an overview of the echocardiographic parameters.

Research protocol echocardiography Echocardiography was performed, using a Philips iE33 xMATRIX Ultrasound system

machine (Philips Healthcare, Best, the Netherlands). Final interpretation of the images and

measurements was done by two investigators (EvG, LJW).

Conventional two dimensional echocardiograms were acquired in the parasternal long axis

and short axis, apical four-chamber, apical two-chamber, apical long axis and subcostal

views. Colour tissue Doppler images were acquired in parasternal and apical views. M-mode

echocardiograms were acquired at the level of the left atrium and aortic valve, the mitral valve

and tips of the mitral leaflets. Tissue Doppler images were acquired from the left ventricle in

the apical view. Tissue Doppler signals from septal, lateral, inferior and anterior LV-wall and

the lateral RV-wall will be recorded. For each wall, the basal and mid-segments will be

recorded. Measurements will be done for left ventricle outflow tract (LVOT) diameter, peak

mitral E and A wave velocities with and without Valsalva maneuver, systolic aortic velocity

and isovolumic relaxation time (IVRT), pulmonary venous inflow (left atrial pressure wave:

A-Ar interval) and tricuspid annular plane systolic excursion (TAPSE).

Three dimensional echocardiograms acquired to obtain a full volume 3D dataset.

Measurements from this dataset of end systolic and end diastolic volumes done to derive

stroke volume and ejection fraction.

When applicable, measurements are corrected for body surface area (BSA).

LV analysis performed according to the guidelines of the European Association of

Echocardiography (103). LV function was defined as normal, mildly, moderately or severely

impaired. Wall motion scores scored using the 17 segment model (104). Valvular disease was

classified as none, mild, moderate or severe, according to the guidelines of the European

Association of Echocardiography(105). Diastolic dysfunction was classified as none or grade

I to III (84).

Using the wall motion score, patients were scored as normal LV-function (1 or 0

abnormalities), one vessel disease or multivessel disease.

In case of ventricular dysfunction, patterns of cardiomyopathy were scored in three

categories, dilated cardiomyopathy (diffuse abnormalities without regional differences),

ischemic cardiomyopathy (regional wall abnormalities) and hypertrophic cardiomyopathy

(wall thickness > 15 mm). When there is presence of left ventricular hypertrophy, the pattern

of hypertrophy will be scored as concentric or asymmetric.

Valvular calcification was scored as absent or present. Grading of stenosis of regurgitation

was classified as mild, moderate or severe.

Cardiac MRI

A CMR was performed in all patients. Multiple parameters were measured in all groups: LV

and RV systolic and diastolic dimension, LV and RV ejection fraction, LV mass, wall motion

abnormalities and presence of fibrosis. See appendix 3 for an overview of the CMR

parameters. To detect possible myocardial fibrosis it is important to perform contrast imaging

during this investigation, as this offers the unique possibility of tissue characterization.

M.S. Stob

Research protocol Cardiac MRI CMR examination was performed on a 1.5-T whole body scanner (Achieva scan, Philips

Medical System, Best, The Netherlands) using commercially available CMR software. For

signal-reception a five-element cardiac synergy coil was used. Electrocardiogram triggering

will be done with a vector-electrocardiogram-set-up. Subjects were examined in the supine

position. Morphologic images in the cardiac short axis, four chamber long axis, three

chamber, and two chamber long axis, and left ventricular outflow tract views were acquired

by using fast field echo cine images (slice thickness 8.0mm; repetition time 3.4ms; echo time

1.7ms; flip angle 60°; matrix 256×256).

Subsequently, a breath-hold, black-blood, T2-weighted double-inversion recovery sequence

with a fat-saturation pulse was performed in 8-10 short-axis slices, covering the base, mid and

apex of the heart, with the following parameters: repetition time 1800-2400ms; echo time

80ms; matrix 256x256; field of view 32-40cm; slice thickness 12mm; number of excitations

1. Myocardial scar was assessed on contrast enhanced multislice short-axis, long-axis, and

four chamber views, obtained approximately 10 minutes after intravenous bolus injection of

0.5 mmol gadoteric acid (gadoterate meglumine) per kilogram body weight (Dotarem ®,

Guerbet SA, Villepinte, France). A three-dimensional Turbo Field Echo-inversion recovery

T1-weighted sequence was used with the following parameters: repetition time 4.0ms; echo

time 1.3ms; flip angle 15°; inversion time individually optimized to null myocardial signal

(usually between 180-250ms); matrix 157; slice thickness 10 mm.

Cine imaging was used to determine volumes (end-systolic and end-diastolic) and LV mass

and LV mass index. Cardiac output was defined as (end-diastolic volume minus end-systolic

volume) x heart rate. Ejection fraction was defined as stroke volume/end-diastolic volume.

RV ejection fraction was determined in the same way as LV ejection fraction.

Regional wall motion abnormalities were scored using the 17 segment model.

LV mass was calculated by substracting the endocardial border tracings of the LV from the

epicardial border tracings and were compared with reference values adjusted to age and sex.

Percentages of fibrosis and patterns will be determined.

LV geometry and function: Left ventricular end-diastolic and end-systolic volumes (EDV and

ESV; ml), left ventricular ejection fraction (LVEF; %), and end-diastolic wall mass (EDWM;

g) were calculated from contiguous short-axis loops by segmentation of endocardial and

epicardial borders on each frame. Papillary muscles was regarded as part of the ventricular

cavity.

The left ventricular wall regions were divided into 17 segments according to a standardized

myocardial segmentation model. Wall motion was assigned the following scores: normal wall

motion is 0, hypokinesia 1, severe hypokinesia 2, akinesia 3, and dyskinesia 4. The wall

motion score index (WMSI) was calculated by dividing the sum of scores in each segment by

the total number of observed segments. WMSI of 0 was considered as normal, 0-1 as

moderate, 1-2 as poor, and >2 as bad.

At the end of the research protocol delayed enhancement, 10minutes after Gadolineum-

injetion, was acquires to search for infarction or fibrosis. The infarcted myocardium is defined

as the zone of hyper-enhancement on the contrast enhanced (CE) images, in contrast with the

dark-gray signal of the normal myocardium. New techniques to determine diastolic function

will be used such as left atrium transit time (LATT) and E/A ratio of LV and RV inflow.

Contraindications to cardiac MRI included mobile implanted metallic devices, reported

metallic particles in eye, exposure to metalworking or welding in past without available skull

radiographs, renal insufficiency and claustrophobia.

M.S. Stob

Results

Patient population

For this present sub study we were able to include a total of 10 patients over a 5 month period

between June 2013 and October 2013. No adverse events occurred during the study period.

Using the long-term gout specific diagnosis code, a total of 660 patients, both male and

female were identified for further screening. After age exclusion a total of 490 patients were

screened for eligibility. Patients with an age >75 were not screened for comorbidities. After

applying both in- and exclusion criteria of the remaining patients, only 2 female and 90 male

patients were potentially eligible. Table 2 shows the numbers and percentages of patients who

met exclusion critera. In 18% of all cases, patients met more than one of the exclusion criteria.

Table II shows the total amount of exclusion criteria met by excluded patients, including those

who were excluded because they met more than one criteria. DM, glomerular filtration rate

(GFR) <60, >1 risk factor, body mass index (BMI) >30 and previous cardiovascular event

(CVE) were the main reasons for exclusion. The other reasons for exclusions were contra

indications, non-punctate proven gout, non-sufficient information or other causes (for

example; psychiatric conditions and terminal malignancies).

Table II. Reasons to exclude subjects from participating

Reason n %

Contra indication

29

5,90%

Diabetes 81 16,50% GFR<60 72 14,70% >1 risk factor 81 16,50% BMI>30 78 15,90% CVE 98 20,00% NPP 43 8,80% <information 18 3,70% Other 11 2,20%

Data are expressed as numbers (%). GFR. glomerular filtration rate; RF, risk factor; BMI, body mass index; CVE, cardiovascular event; NPP, not punctate proven.

Invitations to enroll this study were sent by the rheumatic research department of the Medisch

Spectrum Twente (MST). Patients were not randomly selected. The patients without any

comorbidity were invited in the first place to preserve the healthiest population. Only 10

invitations at the same time were allowed to be in circulation, because no more than 10 spots

were available for research. A total of 16 invitations were sent before we had 10 responders.

One patient was excluded after responding, he had gained weight and therefore had a

BMI>30. Due to troubles with the logistics during the holiday season not all patients

underwent both examinations yet. So far, 6 patients underwent an echocardiography and

CMR. One subject only underwent cardiac CMR.

M.S. Stob

Patient characteristics

The median age of the studied population was 61.5 years (IQR 53.8-67.8). All patients

included were male. Due to the strict in- and exclusion criteria the prevalence of co-morbidity

was very low. None of the studied population was obese, 6 subjects were overweight. There

were no current smokers. Only 3 patients met the criteria of hypertension when measured at

one of the 2 examinations. 30% had a positive familial history. 80% of the patients obeyed

their restrictive diet of alcoholic consumptions. 2 patients used cholesterol-lowering

medication, 100% had a normal to slightly elevated cholesterol but still below the 6,5 mmol/l

mark. The median last known serum uric acid was 0.29 mmol/l (IQR 0.20-0.33). For some of

the patients the maximum serum uric acid could be underreported, some of their data was not

present before they already used serum acid lowering medication. Still the median remained

0.56 mmol/L (IQR 0.51-0.60). Most of the patients had oligoarticular gout (70%), only 1

(10%) had polyarticular gout. 40% of the patients had current signs or a history of tophi, only

1 patient had radiographic signs of erosion due to gouty attacks. The median time since onset

of symptoms and the median time since punctate proven diagnosis were 8 years (IQR 7-10)

and 2.5 years (IQR 1-6) respectively.

Table III. Clinical characteristics of study population

Parameter Median (IQR) or N(%)

Age (years) 61.5 (53.8-67.8)

Male sex 10 (100%)

BMI (kg/m2) 27 (25-27)

Smoking 0 (0%)

SBP (mm Hg) 138 (128-145)

DBP (mm Hg) 79 (76-87)

Alcohol (units per week)

<10 8 (80%)

10-20 1 (10%)

>20 1 (10%)

Cholesterol (mmol/L) 5.4 (4.8-5.7)

Triglycerides (mmol/L) 2.2 (0.7-2.5)

HDL (mmol/L) 1.3 (1.2-1.4)

LDL (mmol/L) 2.9 (2.8-3.6)

Maximum serum uric acid (mmol/L) 0.59 (0.53-0.60)

Last known S-uric acid (mmol/L) 0.29 (0.20-0.33)

Familial history 3 (30%)

Symptom duration (years) 8 (7-10)

Time since diagnosis (years) 2.5 (1-6)

Affected joints

Monoarticular 2 (20%)

Oligoarticular 7 (70%)

Polyarticular 1 (10%)

Tophi 4 (40%)

Erosion 1 (10%)

Continuous data are expressed as median (25%-75% interquartile range) and categorical as number (%). BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

M.S. Stob

Echocardiography

A total of 6 participants underwent echocardiography so far. Some parameters could not be

measured due to poor signal. In one exam biplane parameters (LV end systolic dimensions

and LV diastolic dimensions) could not be measured and another exam showed an incomplete

3D examination, these outcomes were not included in table III.

LV function

LV ejection fraction in 2D echocardiography was slightly impaired in 66% (n=4) of the

participants, although LV dimensions in 2D echocardiography showed almost no

abnormalities. There was one subject whose end diastolic volume (EDV) and end systolic

volume (ESV) were respectively moderate and severely abnormal. 3D echocardiography did

not show any impaired LV ejection fraction, nor did it show any abnormalities in LV

dimensions. It is remarkable that the dimensions from 3D echocardiography were a lot lower

than the 2D echocardiographic dimensions.

LV diastolic function

According to 2D echocardiography, 83% (n=5) showed some form of diastolic dysfunction.

66.6% of the participants (n=4) had grade I diastolic dysfunction and 1 participant (16,6%)

had grade II diastolic dysfunction. The time since onset of symptoms was no longer among

the subjects with diastolic dysfunction compared to the subjects without diastolic dysfunction.

All subjects with diastolic dysfunction had either oligoarticular arthritis or polyarticular

arthritis and just one was diagnosed with topheus gout.

Amongst participants with diastolic dysfunction grade I, 2 out of 4 showed a prolonged

deceleration time. Isovolumetric relaxation time was abnormal in 4 out of 5 participants with

diastolic dysfunction. At first glance, table IV shows no abnormal values for diastolic

dysfunction. However this table shows all participants joined together. The subjects who had

diastolic dysfunction grade I had a median E/A ratio of 0,83 which is impaired as expected.

LA function

When we look at the left atrium (LA), 83.3% (n=5) of all subjects had an increased LA

volume when corrected for BSA with a median (IQR 25%-75%) of 31.1 (29.2-33.8). 33.3%

(n=2) of all subjects had an moderate increased LA volume index (LAVI >34 ml/m2) and

50% (n=3) showed a mildly increased LA volume index (LAVI 28<34 ml/m2). 3D

echocardiography however showed normal LA volumes corrected for BSA, reference range

<28 ml/m2 according to the American association of echocardiography (103). It is important

to remember this threshold was based on 2D measurements.

RV function

Valvular or annulus calcification was present in 50% (n=3) of the subjects. All three of the

subjects had diastolic dysfunction. Two of them had grade I diastolic dysfunction and one had

grade II diastolic dysfunction. The subject with grade II diastolic dysfunction also had a mild

aortic valve stenosis. Median RV basal diameter is 3.6, which is moderately abnormal (103).

A total of 66,6% (n=4) of the subjects had an enlarged RV basal diameter, 2 were moderately

abnormal and 2 were severely abnormal.

Anatomy

Anatomical analysis showed normal IVSd, LVIDd, LVPWd and LV mass/BSA in both

subjects with and without diastolic dysfunction.

M.S. Stob

Table IV. Echocardiographic parameters of study population Parameters Median (IQR 25%-75%)

LV function

2D EF (%) 53.8 (51.8-53.8)

2D EDV (ml) 137.3 (126.9-138.0)

2D ESV (ml) 61.2 (54.0-63.5)

2D SV (ml) 73.8 (65.7-90.5)

3D EF(%) 58.9 (57.7-59.3)

3D EDV (ml) 88.7 (79.2-106.4)

3D ESV (ml) 36.5 (34.1-39.4)

3D SV (ml) 52.2 (45.1-67.0)

Diastolic function E (cm/s) 62.3 (58.7-77.6)

E/A 0.9 (0.8-1.1)

IVRT (sec) 0.08 (0.06-0.09)

Dec time (sec) 0.19 (0.15-0.22)

e’ (lateral) (cm/s) 13.9 (11.7-15.1)

e’ (septal) (cm/s) 8.5 (8.0-9.7)

PV S/D ratio 1.4 (1.2-1.5)

PV A max (cm/s) 23.4 (20.7-25.1)

PV A dur (sec) 0.11 (0.11-0.13)

Grade (no, %)

Normal 1 (16,6%)

I 4 (66.6%)

II 1(16,6%)

III 0 (0%)

LA function LAVI (ml/m

2) 31.1 (29.2-33.8)

3D EDV (ml) 29.4 (28.3-33.1)

3D ESV (ml) 8.4 (8.1-10.5)

3D SV (ml) 20.2 (18.9-24.8)

3D EF(%) 69.0 (64.3-71.4)

RV function Diameter, basal (cm) 3.6 (3.0-3.8)

RV S’ (cm/s) 14.7 (13.0-15.8)

TAPSE (cm) 2.7 (2.6-3.0)

Anatomy IVSd (cm) 1.1 (1.0-1.2)

LVIDd (cm) 4.8 (4.4-5.2)

LVPWd (cm) 0.94 (0.85-0.97)

LV mass index (g/m

2) 88.6 (83.7-93.6)

LVOT area (cm

2) 4.1 (4.1-4.9)

Continuous data are expressed as median (25%-75% interquartile range) and

categorical as number (%). EF, ejection fraction; EDV, end diastolic volume; ESV, end systolic volume; SV, stroke volume; E, mitral peak velocity of early filling; E/A, ratio

between the early mitral peak velocity and the late mitral peak velocity; IVRT, isovolumetric relaxation time; Dec time, deceleration time; e’, mitral annulus tissue velocity; PV S/D, ratio between systolic and diastolic pulmonary vein velocity, PV A

max, maximum end diastolic pulmonary vein velocity; PV A dur, duration of end diastolic pulmonary vein flow; LAVI, left atrial volume index; RV S’, velocity of tricuspid anular systolic motion; TAPSE, tricuspid annular plane systolic excursion; IVSd, diastolic

intraventricular septal thickness; LVIDd, diastolic left ventricular internal dimension; LVPWd, diastolic left ventricular posterior wall dimension; LVOT, left ventricular

outflow tract.

M.S. Stob

Cardiac magnetic resonance imaging

A total of 7 participants underwent CMR. Appendix 3 shows the parameters we examined in

preformed CMR’s. Some experimental scans were performed but not yet examined.

LV function

The LV function on 2 patients (28,6%) was impaired although their LV volumes were not

particularly abnormal. LV mass corrected for BSA was lower than reference values in both

patients, however this was the case in a total of 3 participants (42.9%). Cardiac index

however was clearly lower in both patients compared to the other participants. In total 2

patients (28.6%) showed an impaired cardiac index.

RV function

Right ventricular function was within normal borders in all participants. Overall, RV volumes

were of normal value, except the RV EDV was slightly impaired in 2 participants (28,6%)

Anatomy

Wall motion score, delayed enhancement, edema and the anatomy of the great vessels were

normal in all patients.

Table V. Cardiac MRI parameters of study population

Parameters Median (IQR 25%-75%)

LV function

EF (%) 61.2 (54.6-62.4)

EDV (ml) 150.0 (132.1-161.6)

EDV/BSA (ml/m

2) 70.2 (68.2-80.7)

ESV (ml) 62.4 (46.6-68.7)

ESV/BSA (ml/m

2) 30.5(22.9-34.6)

SV (ml) 80.0 (72.8-106.4)

LV mass/BSA (g/m

2) 43.6 (40.7-50.0)

RV function

EF (%) 56.6 (53.3-58.2)

EDV (ml) 167.8 (130.8-170.0)

EDV/BSA (ml/m

2) 75.0 (62.9-86.2)

ESV (ml) 61.8 (56.1-79.3)

ESV/BSA (ml/m

2) 32.3 (25.8-38.9)

SV (ml) 89.2 (75.4-102.5)

Continuous data are expressed as median (25%-75% interquartile range). (%). EF, ejection fraction; EDV, end diastolic volume; ESV, end systolic volume; SV, stroke volume; BSA, body surface area; LV, left ventricular; RV, right ventricular.

M.S. Stob

Figure 3. Cardiac imaging from one patient. a) Black blood sequence, short axis. b) cine image, short axis. c) delayed

enhancement sequence, no delayed enhancement is visible.

M.S. Stob

Conclusion

The main finding of this study is a high prevalence of 83.3% in impaired diastolic function in

patients with intermittent or chronic gout. Overall, this small study group showed relatively

normal echocardiographic parameters of LV systolic function, RV function and anatomy.

Cardiac MRI did not show any remarkable abnormalities on LV or RV function, nor did

cardiac MRI showed signs of edema or scarring. The impact from several characteristics such

as time since onset of symptoms, the presence of mono-, oligo- or polyarthritis, the presence

of calcification, regurgitation or stenosis, nor the presence of tophi and erosions on x-ray

could be evaluated in such small study population.

M.S. Stob

Discussion

This study is the first study which performed cardiac MRI and echocardiography on patients

with gout, to find out if there are any leads on finding patterns of CV dysfunction. Some

studies analyzed correlations for echocardiographic parameters amongst patients with

hypertension or heart failure who also happened to have hyperuricemia, but none amongst

gout. Unfortunately none of them described the prevalence of subjects actually having

diastolic dysfunction, only the parameters of diastolic function. None of the previous studies

explicitly researched diastolic dysfunction among subjects with just hyperuricemia or gout. So

it is not possible to make a good comparison between previous performed studies and the

results of this study.

We tried to exclude as many confounders as possible by only allowing ≤1 traditional risk

factor so only the effect of gout with/without current hyperuricemia will be examined and

therefore exclude any comorbidities influencing on diastolic function like hypertension or

chronic heart failure.

The main finding of this study is an increased percentage of diastolic function in this small

group of patients with intermittent or chronic gout. So far, systolic function looked relatively

normal compared to healthy subjects. Kane et al. studied diastolic function in a healthy

subgroup, these 531 participants were without hypertension, diabetes, coronary artery disease,

heart failure or use of cardiovascular medication (80). In this healthy subgroup the prevalence

of diastolic dysfunction was 11.9% at examination and 29.8% at examination 2 after a 4 year

follow up, showing age-related increase in diastolic dysfunction. Previous studies already

described an increased prevalence in impaired parameters of diastolic function in subjects

with hyperuricemia (76,82,83). This study shows a prevalence of 83,3% in a small group with

gout and low CV risk. With extreme caution we could say intermittent or chronic gout can be

associated with an increased prevalence of diastolic dysfunction.

We also saw a high prevalence of atrial dilatation. The theory behind this is that impaired

relaxation of the left ventricle will cause problems with the filling of the left ventricle. After a

certain amount of time this will cause stiffness of the LV wall and eventually chronic volume

overload of the left atrium. After a long time of increased left atrial pressure, this eventually

will cause atrial dilatation.

Krishnan et al described significant anatomical differences such as LV thickness, LV diastolic

internal dimension, LV mass, systolic function and ejection fraction between subject with the

highest levels of serum uric acid and subjects with low levels of serum uric acid(79). They did

not described if these subjects actually had dilated atria, left ventricular hypertrophy or an

impaired ejection fraction.

We excluded subjects with a high risk for cardiovascular disease and subjects who already

had an cardiovascular event, so the probability of finding signs of myocardial infarction in

CMR was low. Therefore we weren’t surprised none of the subjects showed any delayed

enhancement, abnormal wall motion score or edema on CMR, nor did we expect any

cardiovascular events during the study, which did not occur.

This study contributes to the already performed studies in favor for the association between

hyperuricemia/gout and cardiovascular disease. The high prevalence of diastolic dysfunction

M.S. Stob

does contribute to the hypothesis that gout is not just a local inflammation but there also plays

a systemic role, which impairs the cardiac vasculature and therefore impairs cardiac function.

We have to consider the possibility of a publication bias that over-represents study results in

favor of the association between hyperuricemia and cardiovascular disease (106).

The main limitation of this study was the very small sample size of subjects, this was because

it was a subgroup of the entire CAMERA population. A study being performed at the moment

to find patterns of CV dysfunction in subjects with RA using both echocardiography and

CMR. Also logistic problems caused a delay in the time between enrolling subject and

actually performing echocardiography and CMR. Therefore no hard conclusions could be

made with the results provided. However it did show a high prevalence in diastolic

dysfunction amongst this subgroup with gout.

Other limitations of this study were the lack of comparison in time, there were no subjects

with a recent onset of first symptoms so we could not really compare the effect of time of

symptoms and the grade of diastolic function. Also we did not knew if subject already had

some form of diastolic dysfunction previous at the onset of their gouty arthritis.

In addition to the already performed cardiac imaging in this study, coronary CT could be

performed to compare the coronary artery calcification with the subjects who showed

diastolic dysfunction.

For the future more research is needed to establish the relation between gout and

cardiovascular disease. Regarding cardiac imaging, diastolic function parameters in MRI has

yet to be validated and standardized. Prospective studies, studying echo parameters amongst

patients with acute, intermittent and chronic gout with long follow-up could be useful for

evaluating the impact of gout on diastolic function in time.

M.S. Stob

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Appendices

1. Drugs that raise and lower serum urate concentrations

Drugs that raise serum urate concentrations

Diuretics

Tacrolimus

Ciclosporin

Ethambutol

Pyrazinamide

Cytotoxic chemotherapy

Ethanol

Salicylates (low dose)

Levodopa

Ribavirin and interferon

Teriparatide

Drugs that lower serum urate concentrations

Ascorbic acid

Benzbromarone

Calcitonin

Citrate

Oestrogens

Fenofibrate

Losartan

Probenecid

Salicylates (high dose)

sulfinpyrazone

M.S. Stob

2. Echo parameters

1. LVF/EF (Biplane en 3D full volume)

a. Normal (EF ≥55%)

b. Mild (EF 45-54%)

c. Moderate (EF 36-44%)

d. Severe (EF ≤ 35%)

2. WMA (wall motion abnormalities)

a. Absent

b. Single-vessel disease

c. Multi-vessel disease

3. Diastolic function (E/A, E’, Color Doppler M-mode, IVRT, pulmonary venous

inflow, TDI, dimensions LA)

a. Normal

b. Grade I (abnormal relaxation)

c. Grade II (pseudonormal relaxation)

d. Grade III (restrictive)

4. Valvular disease

a. Calcification? Yes or no

b. Stenosis? None, mild, moderate, severe

c. Regurgitation? None, mild, moderate, severe

5. RVF (TAPSE)

a. Good > 20 mm

b. Normal 16-20 mm

c. Mild 13-15 mm

d. Moderate 10-12 mm

e. Severe <10 mm

6. Left ventricular hypertrophy

a. Absent

b. Concentric

c. Asymmetric

7. Cardiomyopathy

a. Absent

b. Dilating

c. Hypertrophic

d. Ischemic

M.S. Stob

3. MRI parameters

1. LV ESD and EDD (corrected for BSA)

a. Normal

b. Dilatation

2. LV ESV and EDV (corrected for BSA)

a. Normal

b. Increased

3. LVEF (EDD – ESD/EDD)

a. Normal

b. Abnormal

4. Cardiac index

5. RV ESD and EDD (corrected for BSA)

a. Normal

b. Dilatation

6. RV ESV and EDV

a. Normal

b. Abnormal

7. RVEF (EDD-ESD/EDD) (corrected for BSA)

a. Normal

b. Abnormal

8. LV mass (corrected for BSA)

a. Normal

b. Low

c. High

9. Wall motion score

a. Normal

b. Single vessel disease

c. Multivessel disease

10. Wall motion score index

11. Delayed enhancement (fibrosis)

a. Absent

b. Present

12. Myocardial edema

a. Absent

b. Present

13. Aspect of great vessels

a. Normal

b. Abnormal

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