Woźniak, Olgierd

Włodarska, Elżbieta Katarzyna

English

Via Medica Journals

HOW TO DOCardiology Journal2009, Vol. 16, No. 6, pp. 588–591Copyright © 2009 Via MedicaISSN 1897–5593588 www.cardiologyjournal.orgAddress for correspondence:  Olgierd Woźniak, Department of Congenital Heart Diseases, Institute of Cardiology,Alpejska 42, 04–628 Warszawa, Poland, e-mail: owozniak@wp.plReceived: 9.06.2009 Accepted: 21.07.2009Prevention of sudden cardiac deaths inarrhythmogenic right ventricular cardiomyopathy:How to evaluate risk and when to implanta cardioverter-defibrillator?Olgierd Woźniak, Elżbieta Katarzyna WłodarskaDepartment of Congenital Heart Diseases, Institute of Cardiology, Warsaw, PolandIntroductionArrhythmogenic right ventricular cardiomyo-pathy (ARVC) is a genetically determined myocar-dial disease resulting in fibrofatty degeneration ofmyocardium. Most known mutations associatedwith the development of this disease affect genesresponsible for coding information on desmosomalproteins. The primary function of these proteins isto form intercellular junctions. Disruption of desmo-somes invariably leads to cell death, and resultingtissue remodeling impairs electrical conduction cre-ating conditions for re-entry. The natural history ofARVC involves three clinical stages [1, 2]:— initial asymptomatic phase;— focal structural changes with electrical insta-bility;— global impairment of contractility with symp-tomatic heart failure.The incidence of ARVC is estimated at 1:5,000to 1:10,000. The disease usually manifests at youngage, mostly in the second or third decade of life.Patients present with ventricular arrhythmia fol-lowed later by symptoms of heart failure. Cardiacarrest may also be an initial presentation. Studiesshow that ARVC is one of the most common caus-es of sudden cardiac death in young, apparentlyhealthy people, accounting for 5–11% of suddendeaths in subjects below 35 years of age [3]. Thedisease is more common among men, although gen-der seems not to affect the risk of sudden cardiacdeath. Most fatal cases occur in the fourth decadeof life (mean age 35.5 ± 12.0 years), and yearlymortality rate is about 2.8%, with 1/3 of deathsoccuring suddenly and the remaining 2/3 due to ad-vanced heart failure [4].ARVC is also one of the most common causesof sudden deaths during sport participation. Accord-ing to some authors, up to 22% of sudden deathsamong athletes may be related to this form of car-diomyopathy. Studies performed in the 1980s ina large population of competitive athletes in Italyshowed that intensive physicial training is associa-ted with a 5-fold increase in risk of a sudden car-diac death.Sudden deaths in ARVC usually occur duringdaily life activities (76% of cases), stressful situa-tions (10%) or in the perioperative period (10%).Only 3.5% of deaths occur during intensive physi-cal activity, which is likely related to a limitednumber of subjects participating in competitivesports [3].Evaluation of riskEvaluation of risk factors of sudden cardiacdeath in ARVC should include [1, 3]:— previous episodes of cardiac arrest;— syncope;— a history of sudden cardiac death in a familymember below 35 years of age;— extensive right ventricular damage;— concomitant left ventricular dysfunction;— induction of ventricular tachycardia during pro-grammed electrical stimulation;— wide QRS complexes in V1–V3, QRS disper-sion, and the presence of epsilon wave (a mar-ker of ventricular late potentials).589Olgierd Woźniak, Elżbieta Katarzyna Włodarska, Prevention of sudden cardiac deaths in ARVCwww.cardiologyjournal.orgHow to identify patients at highest risk of sud-den death? According to most authors, the strong-est risk factor is history of previous cardiac arrestor syncope [3]. Opinions on the relative importanceof other risk factors are discordant. Long-term datapresented by a group of French authors indicatehigh risk of sudden cardiac death in patients withsevere righ ventricular dysfunction and symptomat-ic right-sided heart failure, as well as in patientswith concomitant left ventricular dysfunction andrecurrent sustained ventricular tachycardia [2].Some authors suggest that apart from clinical symp-toms of heart failure, additional electrocardiographic(ECG) criteria should also be taken into account,such as the presence of negative T waves in leadsV4–V6. Another risk factor of sudden cardiac deathin ARVC is QRS dyspersion ≥ 40 ms (specificity90%, sensitivity 77%). The risk of sudden deathseems to be particularly high in patients with QRSdyspersion ≥ 50 ms, negative T waves in precor-dial leads, and a history of syncope [3, 5].Analysis of risk factors may be supported withdata collected from patients with an implanted car-dioverter-defibrillator (ICD). These data show thatappropriate ICD therapy was most common in pa-tients with such risk factors as severe right ven-tricular dysfunction, previous cardiac arrest, histo-ry of hemodynamically unstable ventricular tachy-cardia, young age, left ventricular dysfunction, andinduction of a rapid ventricular tachycardia withprogrammed electrical stimulation during the elec-trophysiological study [6–9]. Of note, the electro-physiological study itself has little prognostic val-ue in ARVC, as both positive and negative predic-tive values for the occurrence of malignantarrhythmia do not exceed 50%. This has been re-flected in the European Society of Cardiology (ESC)guidelines rating the performance of the electro-physiological study in patients with ARVC as classIIb recommendation (level of evidence: C).Very useful practical clues may be obtainedfrom the analysis of ECGs recorded during arrhyth-mia. Most typically, ventricular tachycardia with theleft bundle branch block morphology is seen, whichis not a risk factor of sudden cardiac death in he-modynamically stable patient with ARVC.Currently, risk stratification in ARVC is oftensupplemented by the findings of genetic studies.Variants of the disease associated with significant-ly higher risk of sudden deaths have beeen identi-fied, such as Naxos disease, which is a recessiveform of ARVC occuring predominantly in inhabi-tants of this Greek island. Another variant of ARVC,observed in inhabitants of Newfoundland, is asso-ciated with almost 7-fold increase in risk for malecarriers of the mutation in comparison to the femalecarriers. The most common genetic variants ofARVC in Europe and in the United States resultfrom autosomal dominant mutations of genes forplakophillin-2, desmoplakin, and desmoglein-2,seen in 11–50%, 6–16%, and 10% of patients, re-spectively. In Poland, the most prevalent mutationsoccur in plakophillin-2 gene and are associated witha significantly worse prognosis [4].How to decrease the riskof sudden cardiac death?The most important advice for patients withARVC is to refrain from competitive sports. Experi-mental studies showed that intensive exercise leadsto expression of the disease. Chronically increasedright ventricular volume load in patients withdefective desmosomal proteins results in disruptionof abnormal intercellular junctions, which initiatesthe cascade of apoptotic processes leading toremodelling of myocardium and predisposing tocardiac arrhythmias in the mechanism of re-entry.In addition to this unfavourable effect on myo-cardial remodelling, intensive exercise in patientswith ARVC may also directly trigger malignant ar-rhythmia, especially when extreme effort is accom-panied by stress, such as during participation incompetitive sports. In such conditions, disruptionof abnormal intercellular junctions ensues, leadingto focal cardiomyocyte necrosis and, when elevat-ed catecholamine levels are present, developmentof late afterdepolarizations that may result in ven-tricular fibrillation. This mechanism may also oc-cur in low-risk patients, even in an asymptomaticstage of the disease.Antiarrhythmic pharmacotherapy in patientswith ARVC is quite effective. Good treatment ef-fects are obtained in about 65% of patients, andpartial improvement is seen in additional 13% ofpatients. The most effective drug (in nearly 70% ofcases) is sotalol, usually administered in large dos-es (ranging from 320 to 640 mg/day). Low-risk pa-tients may be treated with beta-blockers, especial-ly if arrhythmia occurs mainly during daily or phy-sical activities [4]. In contrast, werapamil may beindicated in cases of arrhythmias occurring at rest,although this drug is effective only in about 44% ofpatients. Significant right ventricular dysfunction isan independent predictive factor for the ineffective-ness of antiarrhythmic pharmacoterapy. In patientswho do not respond to pharmacoterapy, as well asin patients with recurrent ventricular tachycardia590Cardiology Journal 2009, Vol. 16, No. 6www.cardiologyjournal.orgdespite optimal therapy, ablation of the arrhythmicsubstrate should be considered (class II recommen-dation in the ESC guidelines, level of evidence: C).Which patients shouldbe treated with an ICD?High-risk patients should be protected fromsudden cardiac death by ICD implantation. Thisgroup primarily includes patients after a cardiacarrest or syncope due to ventricular tachycardia,and patients with a history of unexplained syncopeif arrhythmia cannot be excluded as the cause of thissyncope. In the ESC guidelines, ICD implantationin patients with documented sustained ventriculartachycardia and/or ventricular fibrillation who re-ceive optimal pharmacotherapy, if their expectedsurvival in a good clinical condition exceeds one year,is a class I recommendation (level of evidence: B).The authors of the guidelines acknowledge that nolarge randomized clinical trials in patients withARVC have been published to support this recom-mendation, but the clinical situation in these pa-tients is thought to be very similar to that of patientsafter a myocardial infarction, in whom benefits ofprophylactic ICD implantation have been well es-tablished.In patients with severe form of ARVC (left ven-tricular involvement, sudden cardiac death in atleast one family member, or unexplained syncopeif ventricular tachycardia or ventricular fibrillationcannot be excluded as the cause of this syncope)fulfilling similar general requirements as statedabove, e.g. expected survival exceeding one year,ICD implantation is a class IIa recommendation (le-vel of evidence: C).Low-risk patients, particularly with hemody-namically stable monomorphic ventricular tachycar-dia, have no indications for ICD implantation andshould be treated with pharmacotherapy or ablation.The same applies to patients in whom ICD implan-tation is indicated but not possible for some reasons(class IIa recommendation, level of evidence: C).Data from patients with ARVC and implantedICD show that appropriate ICD therapy accountsfor 48–78% of all ICD interventions, including life-saving interventions in 24–50% of cases. If one con-siders only prophylactic ICD implantations (prima-ry prevention of sudden cardiac death), results arevery similar, with appropriate ICD interventions inabout 70% of patients, and life-saving interventionsreported in about 30% of cases.Despite these good outcomes, the decisionabout ICD implantation should always result fromcareful consideration. Reassuringly, only about15–30% of all ICD interventions are inappropriate,which usually is triggered either by an arrhythmia thatis not a life-threatening one (most commonly atrial fi-brillation or supraventricular tachycardia) or resultsfrom lead dysfunction or displacement. ICD shocksmay be a cause of serious discomfort for the patient,leading even to clinical depression. Moreover, lead im-plantation in patients with ARVC may be associatedwith disease-specific problems, including [7]:— risk of perforation of the thin-walled right ven-tricle;— difficulties in accurate lead placement relatedto low R wave amplitude;— potentially increased pacing and defibrillationthresholds;— sensing and pacing abnormalities and increaseddefibrillation threshold due to progression ofthe disease.Should dramatic complications ensue, it may benecessary to implant subcutaneous defibrillatingleads or refer a patient for urgent heart transplan-tation. Fortunately, such scenarios are very rare.Most patients tolerate ICD implantation well, andfrequent ICD shocks may be prevented by beta--blockers. In case of insufficient effectiveness ofantiarrhythmic treatment, patient’s referral for ra-diofrequency ablation should always be considered.SummaryEvaluation of the risk of sudden cardiac deathand assessment of indications for ICD implantationshould be performed individually in each patient,taking into account all aspects of the clinical pictureand the experience of the managing physician.AcknowledgementsThe authors greatly appreciate help of PiotrJędrusik with preparation of the authorized Englishversion of the manuscript.The authors do not report any conflict of inter-est regarding this work.References1. Buja G, Estes NA 3rd, Wichter T, Corrado D, Marcus F, Thiene G.Arrhythmogenic right ventricular cardiomyopathy/dysplasia:Risk stratification and therapy. Prog Cardiovasc Dis, 2008; 50:282–293.2. Hulot JS, Jouven X, Empana JP, Frank R, Fontaine G. Naturalhistory and risk stratification of arrhythmogenic right ven-tricular dysplasia/cardiomyopathy. Circulation, 2004; 110:1879–1884.591Olgierd Woźniak, Elżbieta Katarzyna Włodarska, Prevention of sudden cardiac deaths in ARVCwww.cardiologyjournal.org3. Turrini P, Corrado D, Basso C, Nava A, Thiene G. Noninvasiverisk stratification in arrhythmogenic right ventricular cardiomyo-pathy. Ann Noninvasive Electrocardiol, 2003; 8: 161–169.4. Włodarska EK. Analiza związków między patogennymi mutacjamigenu kodującego plakofilinę-2 z obrazem morfologicznym i prze-biegiem klinicznym arytmogennej kardiomiopatii prawej komory.Rozprawa habilitacyjna. Instytut Kardiologii, Warszawa 2009.5. Peters S. Arrhythmogenic right ventricular dysplasia-cardiomyo-pathy and provocable coved-type ST-segment elevation in rightprecordial leads: Clues from long-term follow-up. Europace,2008; 10: 816–820.6. Corrado D, Leoni L, Link MS et al. Implantable cardioverter--defibrillator therapy for prevention of sudden death in patientswith arrhythmogenic right ventricular cardiomyopathy/dyspla-sia. Circulation, 2003; 108: 3084–3091.7. Wichter T, Paul M, Wollmann C et al. Implantable cardioverter//defibrillator therapy in arrhythmogenic right ventricular cardio-myopathy: Single-center experience of long-term follow-up andcomplications in 60 patients. Circulation, 2004; 109: 1503–1508.8. Dalal D, Nasir K, Bomma C et al. Arrhythmogenic right ven-tricular dysplasia: A United States experience. Circulation, 2005;112: 3823–3832.9. Piccini JP, Dalal D, Roguin A et al. Predictors of appropriateimplantable defibrillator therapies in patients with arrhyth-mogenic right ventricular dysplasia. Heart Rhythm, 2005; 2:1188–1194.

Prevention of sudden cardiac deaths in arrhythmogenic right ventricular cardiomyopathy: How to evaluate risk and when to implant a cardioverter-defibrillator?

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Prevention of sudden cardiac deaths in arrhythmogenic right ventricular cardiomyopathy: How to evaluate risk and when to implant a cardioverter-defibrillator?

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