Uhl’s Anomaly Vs Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

(ARVD/C)

DR.NILESH TAWADEJHRC MUMBAI

CASE SCENARIO • 50 yr old Nigerian hypertensive gentleman• Came with complaints of on and off palpitations

since 3 yrs (2 -3 episodes per week) .– Sometimes related to exertion and many a times at

rest– Palpitations were sudden in onset and offset used to

relieve in few seconds .– No history of post palpitation syncope

/diuresis/blackout . – No Family history of palpitation Or Sudden Cardiac

Death

CASE SCENARIO • Gen exam/ systemic examination were un

-remarkable except for high blood pressure

• Patient was evaluated in Nigeria with 2 D Echo and Holter monitoring

• 2-d Echo revealed the normal left ventricle with mild hypertrophy , normal ejection fraction of LV and dilated right ventricle .

• Holter revealed 6993 ventricular ectopic beats with several episodes of nonsustained VT

BASE LINE ECG

NORMAL SINUS RHYTHM NORMAL QRS AXIS NO ABNORMALITIES OF QRS OR ST –T SEGMENTS

Exercise Stress Testing

STAGE 2 AT 3’ MIN STARTED DEVELOPING VPCS OF LBBB MORPHOLOGY

TILL LATE RECOVERY STAGE VPBS KEPT COMING AT REGULAR INTERVALS

HOLTER MONITORING

ECHO CARDIOGRAPHY

RV THICKNESS 2 mm

RV FUNCTION

21.2 mm

10.3cm/s

TAPSE

TASE

MRI

MRI Marked thinning of right ventricular myocardium with mild dilatation of the right ventricle and normal tricuspid valve No evidence of fat deposition suggestive of UHL’S ANOMALY

DIFFRENTIAL DIAGNOSTIC CONSIDERATIONS

• ARRHYTHMOGENIC RIGHT VENTRICLE

/CARDIOMYOPATHY (ARVD/C)

• UHL’S ANOMALY

• IDIOPATHIC RIGHT VENTRICULAR OUTFLOW

TRACT TACHYCARDIA (RVOT-VT)

• DILATED CRDIOMYOPATHY

DIFFRENTIAL DIAGNOSTIC CONSIDERATIONS

• Uhl anomaly– This is a rare congenital disorder characterized by total

lack of RV myocardium and results in a very thin-walled RV (parchment RV).

• ARVD/C – is an inherited cardiomyopathy characterized by structural

and functional abnormalities in the right ventricle (RV) resulting in ventricular arrhythmias.

– result from the fatty infiltration and fibrosis of the RV myocardium.

DIFFRENTIAL DIAGNOSTIC CONSIDERATIONS

• Idiopathic right ventricular outflow tract tachycardia– This is a benign disorder that may mimic

arrhythmogenic right ventricular dysplasia (ARVD) – the occurrence of exercise-induced left bundle branch

block (LBBB) morphology ventricular tachycardia.– The heart is structurally normal, and there is no history

of ARVD or sudden cardiac death in the family.– Electrocardiography (ECG) in RV tachycardia shows

upright T waves in V2 -V5, and epsilon waves are absent.

DIFFRENTIAL DIAGNOSTIC CONSIDERATIONS

• Dilated cardiomyopathy– Biventricular dilatation and congestive heart

failure may mimic advanced ARVD with LV involvement.

– Characteristic ECG and cardiac MRI (CMRI) abnormalities in ARVD help to distinguish the two entities.

ARVD VS UHL’S ANOMALY

SOMETHING ABOUT ARVD/C

Background

ARVD was first described in 1977 and was included in the WHO classification of cardiomyopathies in 1996.

Its is an inherited cardiomyopathy characterized by structural and functional abnormalities of RV mainly which causes ventricular arrhythmias.

It is an important cause of sudden cardiac death (SCD) in young adults, accounting for 11% of all cases and 22% of cases among athletes.

there have been significant advances in the understanding of its etiopathogenesis, diagnosis, and management

PathophysiologyThe structural abnormalities in ARVD result from the fatty infiltration and fibrosis of the RV myocardium. This leads to progressive RV dilatation and dysfunction.

•Apoptosis (programmed cell death)•Fatty replacement of myocardium

•Inflammation, enhanced fibrosis, and loss of function

The left ventricle (LV) is less commonly involved, and the septum is relatively spared.

However, in a cohort of 200 probands, Sen-Chowdhry et al 1 found that LV involvement may even precede the onset of significant RV dysfunction.

The prognosis is worse in patients with LV involvement.

The mechanisms for myocardial loss include the following:1.Circulation. 2007; 115(13):1710-20

ETIOLOGY• it is an inherited disorder and 30%-90% of cases are familial .• OTHER cases, it may result from an acquired etiology such as viral

infection (myocarditis) or unidentified inheritance.Genetics• The most common pattern of inheritance is autosomal dominance, with a

variable penetrance ranging from 20%-35% of family members.People living in the Veneto region of Italy have a higher penetrance.

• The autosomal-recessive (Naxos disease) pattern of inheritance is localized to the Greek island of Naxos and is associated with palmoplantar keratosis and wooly hair.

• Genetic abnormalities in ARVD are located on chromosomes 1, 2, 3, 6, 7, 10, 12, and 14.

ARVD Genes

The responsible genes include :

Plakoglobin (JUP),

Desmoplakin (DSP),

Plakophilin-2 (PKP2),

Desmoglein-2 (DSG2),

Desmocollin-2 (Dsc2), and others.

Molecular mechanism

The probable molecular mechanism hypothesized was that by mutating desmosomal protein impairs the desmosomal assembly by releasing free plakoglobin from the desmosomes

Provokes Adipogenesis, Fibrogenesis, And Apoptosis, The characteristic Hallmark Of ARVD.

Epidemiology

• As clinically silent cases may go unrecognized ,the exact incidence and prevalence of ARVD remains unknown,

• It is estimated incidence is 1 case per 1000-5000 population and is more common in individuals of Greek and Italian origin.

• In a cohort of 100 patients from the United States, the median age at presentation was 26 years, and 51% were males.

• The median time to diagnosis was one year from the initial presentation, and median survival in the entire cohort was 60 years.

History

Palpitation•It is the most frequent symptom and is caused by ventricular arrhythmias. •Supraventricular arrhythmias, including atrial flutter and fibrillation, may be seen in about 25% of cases•Depending on the disease severity, ventricular ectopics may be isolated or may result in nonsustained/sustained ventricular tachycardia, ventricular fibrillation,

Progressive RV and LV dysfunction

•Results In Dyspnea And Leg Swelling.• In more severe cases with LV involvement, patients may present with biventricular congestive heart failure that may mimic dilated cardiomyopathy.

SUDDEN CARDIAC DEATH

•ARVD accounts for 22% of sudden cardiac death cases among young athletes in northern Italy.•In the United States, hypertrophic cardiomyopathy was the most common cause, and ARVD was reported in only 4% cases

Clinical Phases Of ARVD/C

From Concealed Phase ,Overt Phase To Biventricular Pump Failure Phase

• Individuals are often asymptomatic but may be at a risk of sudden cardiac death, notably during extreme exertion.

• Structural changes are absent or subtle • Structural changes are frequently confined to one region of the ‘triangle

of dysplasia’: the inflow, outflow, and apical portions of the RV.

In The Early Concealed Phase :-

Overt Phase

• The second phase marks the onset of the overt electrical disorder, with symptomatic arrhythmia of RV origin

• More prominent RV morphological abnormalities readily identified by conventional imaging .

Biventricular failure

• In the third phase, diffuse RV disease results in an isolated right heart failure.

• LV involvement with biventricular pump failure occur in the final stage, leading to a phenotype that may resemble dilated cardiomyopathy

LABORATORY STUDIES• The diagnosis of (ARVD) poses a great challenge because of its

variable presentation.

• In 1994, an International task force first proposed the major and minor diagnostic criteria of ARVD based on family history, arrhythmias ,ECG abnormalities, tissue characterization, and structural and functional RV abnormalities.

• In 2010, the task force criteria were revised to include quantitative data in criteria.

• The proposed terminology for the diagnosis of ARVD include major or minor criteria from 6 different categories

Global or regional dysfunction and

structural alterations on

echocardiography, CMRI, and/or RV

angiography Tissue characterization of

RV wall as shown on endomyocardial

biopsy

Repolarization abnormalities on ECG

conduction abnormalities on ECG

and/or signal-averaged ECG (SAECG)

Arrhythmias on Holter monitoring

Family history

CRITERIA FOR DIAGNOSIS

• A definite diagnosis is defined as the presence of 2 major criteria, 1 major and 2 minor criteria, or 4 minor criteria.

• A borderline diagnosis is defined as the presence of 1 major and 1 minor criteria or 3 minor criteria.

• A possible diagnosis is defined as the presence of 1 major criterion or 2 minor criteria.

FAMILY HISTORYMajor :1. confirmed diagnosis of ARVD based on task force

criteria/autopsy or surgery in a first-degree relative.2. or identification of a pathogenic mutation categorized as

associated or probably associated with ARVD/C

Minor :

3. history of ARVD (not confirmed based on task force criteria) or premature sudden death (< 35 years) from suspected ARVD in a first-degree relative .

4. confirmed diagnosis of ARVD in a second-degree relative.

ECG• ECG findings may be normal in the latent phase of

ARVD, but abnormalities (depolarization/repolarization and/or conduction) are seen in most patients upon progression of the disease .

1. Intraventricular conduction abnormality.

2. T wave abnormalities in presence of right bundle branch block

3. Anteroseptal T wave inversion.

MAJOR ECG CRITERIA :

• Inverted T waves in right Precordial leads (V1 -V4) or beyond – in individuals older than 14 years– in the absence of complete right bundle branch

block (RBBB);– this feature is seen in 87% cases

• Epsilon waves – low-amplitude signals between end of QRS

complex to the onset of T wave) in leads V1 -V3– (33% of cases)

MINOR ECG CRITERIA

1. Inverted T waves in leads V1 and V2 in individuals older than 14 years in the absence of complete RBBB or in V4, V5, or V6

2. Terminal activation of QRS ≥55 ms measured from the nadir of the S wave to the end of the QRS, including R', in V1, V2, or V3, in the absence of complete RBBB

SIGNAL-AVERAGED ELECTROCARDIOGRAPHY

• Abnormalities on SAECG are common and have fair sensitivity and specificity but do not reliably predict spontaneous or inducible ventricular tachycardia.– Filtered ECG that is able to detect low amplitude potentials

filtered out of standard ECGs.– Myocardial scar (infarction, ARVD) creates zones of slow

conduction that appear as low amplitude late potentials on SAECG.

– Areas of slow conduction are necessary components for reentry

SAECG• SAECG abnormalities are included as minor criteria and

should have at least 1 of 3 parameters. These parameters include the following:

1. Filtered QRS duration ≥114 ms

2. Duration of terminal QRS < 40 μV (low-amplitude signal duration)is more than ≥38 ms

3. Root mean squared voltage of the terminal 40 msecs of QRS complex is less than 20 microvolts

Twenty-four–hour Holter Monitoring

• This is very helpful in detecting arrhythmias.

• Ventricular Tachycardia of LBBB morphology with superior axis is a major criterion,

• Ventricular Tachycardia with inferior axis and/or more than 500 ventricular extra systoles per 24 hours are considered minor criteria per the revised task force.

ECHOCARDIOGRAPHY

• Echocardiography serves as a good screening tool to evaluate patients with suspected ARVC.

ECHOCARDIOGRAPHY• Major criteria are defined as regional RV akinesia or dyskinesia

or aneurysm and one of the following (end-diastole):

1. PSAX RVOT >36 mm (≥21 mm/m2 BSA corrected)

2. Fractional area change ≤33%

• Minor criteria are defined as regional RV akinesia or dyskinesia and one of the following:

1. PSAX RVOT ≥32 to < 36 mm (≥18 to < 21 mm/m2 BSA corrected)

2. Fractional area change >33 to ≤40%

CMRI is used to evaluate

RV size, function, wall motion abnormalities,

Intramyocardial Fat (using fat suppression sequence), and

Late Gadolinium Enhancement to assess areas of fibrosis.

RV wall thickening or thinning and prominent trabeculations are also seen in ARVC

Revised task force criteria for RV abnormalities

• Major criteria are defined as regional RV akinesia or dyskinesia or dyschronous RV contraction and one of the following:

1. Ratio of RV end-diastolic volume to BSA in males ≥110 mL/m2 or BSA ≥100 mL/m2 in females

2. RV ejection fraction (RVEF) ≤40%

MINOR :

3. Ratio of RV end-diastolic volume to BSA ≥100 to < 110 mL/m2 in males or BSA ≥90 to < 100 mL/m2 in females

4. RVEF >40% to ≤45%

• RV angiography may show RV enlargement, hypertrophic trabeculae, and wall motion abnormalities.

• However, since this method is invasive, it is rarely used.

• RV regional akinesia, dyskinesia, or aneurysm on angiography is a major diagnostic criterion.

• The transversally arranged hypertrophic trabeculae, separated by deep fissures, were associated with the highest probability of ARVC

RIGHT VENTRICULOGRAPHY

Anatomy and histology• The most classic feature of ARVD is fatty infiltration of the RV

free wall.

• The typical sites of involvement include the RV apex, inflow, and outflow.

• This results in variable areas of fibrosis and scarring, causing aneurysm formation or generalized dilatation and loss of function. The RV wall may be thickened or thinned out

• There is variable involvement of the LV, and trabeculae at the the apex and septum are hypertrophied

Gross specimen

Right side of the heart is opened laterally to show the normal atrial wall and atrophic ventricular wall and small papillary muscle

Gross Specimen

Right Ventricle has been opened from the front and is illuminated from behind showing very thin and translucent free wall.

Apical trabeculations and papillary muscle are thin

The top left demonstrates an area of fat in the right ventricle, with fibrous tissue highlighted by the Masson trichrome stain.

(top right) the areas of involvement in the left ventricle often show fat and more fibrous tissue

bottom left). A higher magnification demonstrates altered myocyte with vacuoles, which are seen in all areas of fibrofatty infiltration.

Inflammation with myocyte necrosis is seen in over 25% of cases (bottom right).

Endomyocardial Biopsy• Endomyocardial biopsy is not routinely performed owing to

patchy distribution of the abnormalities, resulting in a poor diagnostic yield.

• RV free wall biopsy carries a small risk of perforation.

• Histological demonstration of fibrofatty infiltration is not pathognomonic of ARVC, as fatty infiltration may be a normal finding in elderly persons.

Endomyocardial Biopsy

• Major criteria include residual myocytes < 60% by morphometric analysis, with fibrous replacement of the RV free wall myocardium in ≥1 sample, with or without fatty replacement of tissue.

• Minor criteria include residual myocytes 60%-75% by morphometric analysis, with fibrous replacement of the RV free wall myocardium in ≥1 sample, with or without fatty replacement of tissue.

Genetic Testing• Family studies have suggested that ARVC is caused by genetic

alterations in desmosomal proteins, especially plakoglobin and desmoplakin , mutation of desmosomes is seen in 40%-50% cases.

• Genetic testing is indicated for symptomatic patients with ARVC/ARVD and family members of a patient with a positive mutation.

• At present, genetic testing is available for 7 types of abnormalities (DSC2, DSG2, DSP, JUP, PKP2, RYR2, TMEM43).

UHL’S ANOMALY• In 1952, Uhl described a case in which the wall of the right ventricle

was said to be paper thin and almost devoid of muscle fibers, an appearance akin to ‘parchment heart’.

• In Uhl’s anomaly, with no fatty tissue interposed between layers of myocardium.

• Uhl’s anomaly has been associated with other disorders like dysplasia of the tricuspid valve, pulmonary atresia and persistent ductus arteriosus

• Uhl’s malformation is usually diagnosed in neonatal or infant life

• The clinical presentation of Uhl’s anomaly includes cyanosis, dypnea and right-sided failure and less commonly arrhythmias.

Uhl’s Anomaly VS ARVD/C• The mechanism operating in ARVD/C should be essentially

different from the apoptosis triggered in Uhl’s anomaly

• As in Uhl’s anomaly there is complete loss of RV myocardium unlike in ARVD/C , where some myocardium is still present.

• Further, there is no fibrofatty replacement of myocytes observed in Uhl’s anomaly in contrast, which is the main pathological feature observed in ARVD/C.

ARVD/C VS RVOT-VTRVOT VT ARVD/C

AGE OF ONSET 3RD TO 4TH DECADE 3RD TO 4TH DECADE

SEX FEMALES PREDOM MALES PREDOM

FAMILY HISTORY ----- +++

SCD ------- +++

12 LEAD ECG NORMAL T WAVE ABNORMALITIES , EPSILON WAVES

SAECG NORMAL LATE POTENTIALS

ECHO NORMAL WALL MOTION ABNORMALITY OR DILATATION OF RV

ARRHYTHMIAS REPETATIVE MONOMORPHIC VT

SVT,NSVT,VF

ORIGIN OF ARRHYTHMIAS SEPTUM PARIETAL WALL OF RV

BNP LEVEL NORMAL ELEVATED

Treatment And Management• As the natural history of arrhythmogenic right ventricular

cardiomyopathy (ARVC) is poorly understood, it is difficult to define a definite therapeutic algorithm.

• The treatment is essentially empirical and based on presentation

Prevention of Sudden Cardiac Death• Major Goal of treatment• An implantable cardioverter-defibrillator (ICD) is

recommended for secondary prevention of SCD in patients with sustained VT/VF and for primary prevention in high-risk patients

Markers To Predict Sudden Cardiac Death

Induction of ventricular tachycardia during electrophysiology testing

Nonsustained ventricular tachycardia during noninvasive

evaluation/monitoring

Male sex

Early disease onset (< 5 years)

Severe RV dilatation

Extensive RV involvement

LV involvement

Prior cardiac arrest

Unexplained syncope

Suppression of Symptomatic Cardiac Arrhythmias

• Beta-blockers are generally considered the first line of drug therapy.

• Sotalol is the most effective drug for inducible or noninducible ventricular tachycardia.

• Amiodarone may not be useful because of side effects associated with long-term use in young patients.

• Pharmacotherapy is also used as an adjunct to ICD in selected patients with frequent life-threatening arrhythmias.

Radiofrequency Ablation

• Radiofrequency ablation has limited utility in treating arrhythmogenic foci in ARVC owing to the patchy and progressive nature of the disease.

• However, it has been used with some success in limited cases as an alternative or adjunct to ICD to reduce the burden of ventricular tachycardia

Lifestyle Modification

• In general, vigorous exercise should be avoided in persons with ARVD, as it can trigger arrhythmias.

• Patients should be advised against participation in competitive sports.

• It is also best to avoid cardiac stimulants such as caffeine/pseudoephedrine.