Case 4 -

Sudden Death in a 35 Year Old Man with First Degree AV Block Right Bundle Branch Block and ST Segment Elevation in Right Precordial Leads Cristina Basso University of Padua Medical School Padua, Italy

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Clinical History A 35-year old truck driver had been admitted to the hospital at age 30 years for evaluation of recurrent syncopal episodes. He experienced an in-hospital sudden cardiac arrest due to recorded ventricular fibrillation and was successfully resuscrequired direct current cardioversion at 300 J. Results of a clinical examination were normal. Serial 12-lead ECGs showed sinus rhythm, first-degree atrioventricular (AV) block (PR interval 220 ms), right bundle branch block with left axis deviation, ST segment elevation and inverted T waves in the right precordial leads (Fig. 1). Chest roentgenogram showed a normal cardiothoracic ratio; the results of baseline hematologic and biochemical studies were within normal limits. Exercise stress testing and 24-h Holter ambulatory ECG monitoring showed no arrhythmias. Cardiac catheterisation revealed normal cardiac pressure, as well as normal findings on left ventricular and coronary angiography and ergonovine testing. Right ventricular angiography was not performed. Intracardiac electrophysiologic recordings revealed a “borderline” HV interval (70 ms); programmed ventricular stimulation was not performed. The patient was given bet-adrenergic blocking therapy and his clinical course was uneventful until he died suddenly at rest 5 years later. Case 4 - Figure 1 - 12 lead ECG showing sinus rhythm, first-degree atrioventricular (AV) block (PR interval 220 ms), right bundle branch block with left axis deviation, ST segment elevation and inverted T waves in the right precordial leads Case 4 - Figure 2 - Panoramic full thickness section of the RV wall at the level of moderator band showing transmural fatty infiltration of the myocardium, in the absence of replacement fibrosis Case 4 - Figure 3 - Serial histologic section of the specialized conduction system showing severe fibrosis of the bifurcating His bundle with sclerotic interruption of the right bundle branch Postmortem examination revealed a heart weight of 350 g. The coronary arteries were normal and there was no evidence of recent or healed myocardial infarction. All cardiac valves were normal. The right ventricle was moderately enlarged with dilatation of the pulmonary infundibulum. Despite preserved right ventricular wall thickness (4 to 5 mm), there was significant myocardial fatty infiltration in the right ventricular anterolateral wall. Histopatologic examination of the right ventricular myocardium showed remarkable transmural myocardial fibers dissociation by fatty infiltration and slight interstitial fibrosis, in the absence of wall thinning, inflammatory infiltrates and myocyte degenerative changes (Fig. 2). Study of the specialized conduction system showed normal findings in the sinoatrial node, crista terminalis, atrionodal approaches, AV node and penetrating AV bundle. Conversely, there was marked fibrosis of the bifurcating His and branch bundles with fibrous interruption of the proximal right bundle branch (Fig. 3). Pedigree analysis revealed that 50% of the investigated family members exhibited some degree of right bundle branch block or ST segment elevation, or both, in the right precordial leads, as to suggest a pattern of inheritance compatible with an autosomal dominant pattern with variable expression. Molecular genetic investigation in the affected family members disclosed a sodium channel gene mutation (SCN5A) probably accounting for both Brugada syndrome and Lenegre disease phenotypic expression (courtesy of Prof. Priori and Prof. Danieli). Differential Diagnosis: I. Arrhythmogenic right ventricular cardiomyopathy (ARVC) II. Fatty infiltration of the right ventricle III. Conduction system disease affecting the bundle branches (Lenegre disease) IV. Brugada syndrome (idiopathic VF) Final Diagnosis: Brugada syndrome with specialized conduction system pathology (Lenegre disease) Comment Sudden cardiac death usually occurs in the setting of structural disease (“mors cum materia”). The substrate is frequently identified at naked eye examination of the cardiac specimen, followed by a thorough histological investigation. Gross and histologic features in our case were first indicative for fatty infiltration of the right ventricle, however fat replacement of the right ventricle is not sufficient for the diagnosis of ARVC (either fatty or fibro-fatty types) [1]. Massive fatty infiltration of the right ventricle without any evidence of fibrosis and myocyte degeneration should be considered as a separate clinico-pathologic entity from ARVC [2]. In nearly 10% of cases, sudden cardiac death may appear as “mors sine materia” in so far as even a skilled morphologic examination fails to detect structural abnormalities and the heart is apparently normal [3]. This condition was known as “idiopathic” ventricular fibrillation. A thorough histologic investigation of the working myocardium as well as of the specialized conduction system should be carried out before ruling out a diagnosis of normal heart. The underlying diseases are mostly heredo-familiar and the recent development of molecular genetics demonstrated that we are dealing with abnormalities which affect the molecular mechanisms of electrical cardiac stability and electro-mechanical coupling. A series of clinical entities, known as channellopaties, have been discovered in the last decades and have been related to gene defects which account for the great majority of so called idiopathic ventricular fibrillation. They include long QT syndrome, Brugada syndrome, and effort-induced polymorphic ventricular tachicardia [4, 5, 6, 7, 8, 9] . A part from the channellopathies, sudden cardiac death may occur in the setting of a grossly and histologically normal heart, since the abnormality may reside in the cardiac conduction system (AV node, bundle branches -Lenegre disease-, and anomalous pathways) 10). Noteworthy, among the gene defects discovered to account for so-called “idiopathic” ventricular fibrillation, the sodium channel gene mutation (SCN5A) has been implied not only in the long QT syndrome -LQT3-, but also in Brugada syndrome and more recently it has been demonstrated to underlie cardiac conduction defects with progressive disease of specialized AV junction and AV block [11, 12] . References Basso C, Thiene G, Corrado D, et al. Arrhythmogenic right ventricular cardiomyopathy. Displasia, dystrophy or myocarditis ? Circulation 1996;94:983-991 Burke Burke AP, Farb A, Tashko G, Virmani R. Arrhythmogenic right ventricular cardiomyopathy and fatty replacement of the right ventricular myocardium: are they different diseases? Circulation 1998;97:1571-1580 Basso C, Calabrese F, Corrado D, Thiene G. Postmortem diagnosis in sudden cardiac death victims: macroscopic, microscopic and molecular findings. Cardiovasc Res 2001;50:290-300 Martini B, Nava A, Thiene G, et al. Ventricular fibrillation without apparent heart disease: description of six cases. Am Heart J 1989;118:1203-9. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sdden cardiac death: a distinct clincal and electrocardiographic sindrome. J Am Coll Cardiol 1992;20:1391-6. Corrado D, Nava A, Buja G, et al. Familial cardiomyopathy underlies syndrome of right bundle branch bloch, ST segment elevation and sudden death. J Am Coll Cardiol 1996;27:443-8. Corrado D, Basso C, Buja G, et al. Right bundle branch block, right precordial ST segment elevation and sudden death in young people. Circulation 2001; 103:710-717 Napolitano C, Rivolta I, Priori S. Cardiac sodium channel diseases. Clin Chem Lab Med 2003;41:439-444 Bauce B, Rampazzo A, Basso C, et al. Screening for ryanodine receptor type 2 mutations in families with effort-induced polymorphic ventricular arrhythmias and sudden death: early diagnosis of asymptomatic carriers. J Am Coll Cardiol 2002;40:341-349. Thiene G, Pennelli N, Rossi L. Cardiac conduction system abnormalities as a possibile cause of sudden death in young athletes. Hum Pathol 1983;318:129-33. Chen Q, Kirsch GE, Zhang D et al. Genetic basis and molecular mechanisms for idiopathic ventricular fibrillation. Nature 1998;392:293-296. Kyindt F, Probst V, Potet F et al. Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family. Circulation 2001;104:3081-3086 Bezzina CR, Rook MB, Groenewegen WA et al. Compound heterozygosity for mutations (W156X and R225W) in SCN5A associated with severe cardiac conduction disturbances and degenerative changes in the conduction system. Circ Res 2003;92:159-168