Fatal familial cardiac arrhythmias

Case Reports

Fatal Familial Cardiac Arrhythmias Histologic Observations on the Cardiac Conduction System

JAMES H . GAULT, MD JOHN CANTWELL, MD MAURICE LEV, MD, FACC EUGENE BRAUNWALD, MD, FACC San Diego, California Chicago, Illinois

Alternating bidirectional tachycardia leading to death during attempted suppressive therapy was observed in a 16 year old girl without prior clinical evidence of cardiac disease . At autopsy, there was fatty and mononuclear cell infiltration in the atrioventricular conduction system and the main left bundle branch . A similar arrhythmia has been documented in an 18 year old sister who died suddenly 9 months after discovery of her arrhythmia ; autopsy revealed no gross cardiac abnormality although the conduction system was not studied . A brother, 21 years old, and the mother of the propositus, aged 45 years, also exhibited ventricular bigeminal rhythm, and a maternal uncle and grandmother had died suddenly, the latter with knowledge of an irregular heart beat . Q-T interval prolongation and auditory defects were not found . Histopathologic changes in the heart and in the conduction system in the propositus support the concept of the origin of the arrhythmia in degenerative change of the conduction system having a genetic base in this kindred .

During the past : 15 years there has been a resurgence of i nterest . i n the pathogenesis of sudden death and, as a result of this interest, a. number of familial occurrences of sudden death have been reported . It appears that many of the latter are precipitated by ectopic tachyarrhythmias .' '-The. present report describes a kindred in which ectopic arrhythmias occurred in 3 generations, and in which a bidirectional tachycardia was documented in 2 siblings, with fatal outcome in both . Histologic examination of the cardiac conduction system in 1 patient disclosed pathologic changes which suggest that an anatomic basis for the arrhythmia existed .

Case Report

From the Department of Medicine . University of California, San Diego, School of Medicine, and the Congenital Heart Disease Research and Training Center, Chicago, III . This investigation was supported by Grants HE-12373, HE-7605 and HE05846 . Manuscript received April 13, 1971, accepted May 26, 1971 . Address for reprints : Eugene Braunwald . MD, Department of Medicine, University Hospital, 225 W . Dickinson, San Diego, Calif . 92103 .

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A 16 Year old Caucasian girl was admitted to the University Hospital of San Diego County for evaluation of cardiac arrhythmia . At the age of 6 years an irregular heart beat was first noted on a routine school examination . At this time, cardiac examination and an electrocardiogram were said to be normal- She remained well, without cardiac symptoms (it- palpitations, until 2 weeks before admission, when she experienced pleuritic substernal pain associated with dyspnea and with numbness of the left arm after an episode of strenuous exertion . Site was taken to another hospital, where the pain was relieved by morphine . The electrocardiogram was interpreted as showing frequent ventricular extrasystoles with runs of ventricular tachycardia . Over the next 12 days treatment with intravenous lidoca .ine infusion (up to 4 .0 g daily), quinidine lup to 1 .5 g orally daily) and later propranolol (300 mg daily) was not successful in abolishing the arrhythmia, and she was transferred for further evaluation and treatment .

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On examination the patient was a well developed young woman who was comfortable at rest . The blood pressure was 130 :'80 mm Hg, and the apical pulse rate was 90,/min and irregular . There was a mild right ventricular lift and a grade 1/6 short systolic ejection murmur at the upper left sternal edge . The second heart sound was widely split but narrowed on expiration ; the pulmonic component was not accentuated . There was no cervical venous distention, hepatomegaly or pretibial edema . The chest roentgenograma revealed alterations in the cardiac silhouette consistent with a narrow anteroposterior thoracic diameter ; there were no abnormalities of the heart or of the pulmonary vascular pattern . The hemogram and urinalysis and blood sugar, blood urea nitrogen, electrolytes and enzyme determinations were normal . A lung isotope scan revealed no evidence of a pulmonary perfusion defect . The electrocardiogram on admission revealed repetitive runs of a regular tachycardia at 128/min (Fig . 1) . Frequently, paroxysms of arrhythmia assumed the characteristic form of "bidirectional" tachycardia, with alternating left anterior and posterior hemiblock in the presence of right bundle branch block (Fig . 1, leads III, aVF and V,), a pattern which has been considered supportive evidence of a supraventricular origin of this arrhythmia .? However, a number of fusion beats were observed, as in the next to last ventricular complex of lead V, in Figure 1 . As this example illustrates, when fusion beats occurred, the result was to obscure the right bundle branch block . This finding is consistent with an ectopic focus in the main left bundle branch proximal to its bifurcation . During periods of arrhythmia, atrioventricular (A-V) dissociation was present, usually with a slow sinus rhythm . The P-R interval was not prolonged in conducted sinus beats, and the Q-T interval was normal . After the administration of atropine, 1 .0 mg intravenously, normal sinus rhythm was restored briefly (Fig . 2) although S-T segment and T wave abnormalities were suggestive of diaphragmatic myocardial ischemia ; these abnormalities might also have represented postarrhythmic changes . Suppressive drug treatment : Attempts to maintain an accelerated sinus rate by means of an oral regimen of propantheline bromide were unsuccessful . An attempt was then made to suppress the ectopic

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focus . Administration of propranolol was begun, and the dose was progressively increased to a maximum of 480 mg daily without abolishing the arrhythmia . Propranolol was then discontinued and treatment with quinidine sulfate begun, the dose being gradually increased from 1 .6 g daily to 3 .5 g daily in divided doses over as day period . Continuous monitoring demonstrated periods of repetitive tachycardia as before and, because of symptoms of cinchonism, the dose was reduced to 1 .6 g daily . While quinidine was maintained at this dose level, propranolol was reinstituted and increased to a maximal dose of 300 mg daily, without appreciable effect on the frequency and severity of the arrhythmia . The dose of quinidine was reincreased to 3 .5 g daily while propranolol was continued at 300 mg daily, but the arrhythmia still remained unchanged . Accordingly, suppressive drug therapy was discontinued, and 12 days after admission right heart catheterization was performed in order to insert a temporary right atrial pacemaker electrode . At the time of this study the right heart, pulmonary arterial and pulmonary arterial wedge pressures and cardiac output were within normal limits, and there was no evidence of an intracardiac shunt . Cardiac pacing : It was possible to prevent the ectopic rhythm completely with atrial pacing at a rate of 110/min . An attempt was then made to establish a satisfactory suppressive drug regimen in combination

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Figure 2 . Twelve lead electrocardiogram recorded after transient restoration of sinus rhythm by means of atropine .

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Figure 3 . Photomicrographs . A, ap . proaches to the S-A node, showing fatty infiltration . (Hematoxylin and eosin x39, reduced by 50 percent .) B, A-V node, showing proliferation of mononuclear and interstitial cells . Hematoxylin and eosin x 104. with overdrive suppression before consideration of insertion of a permanent pacemaker . Quinidine sulfate was therefore begun and the dose increased to a maximum of 3 .0 g daily . No other drugs were given . Thirtysix hours after this dose was reached, the patient suddenly complained of nausea, emesis, visual blurring and tinnitus, and the previously normal QRS complex widened abruptly to 0 .20 second . Over the ensuing 12 hours, the patient had numerous bouts of ventricular tachycardia with a QRS configuration different from that of her previous tachycardia ; these episodes of tachycardia frequently deteriorated into ventricular fibrillation, and defibrillation was performed approximately 50 times . Attempts at right a trial and right ventricular pacing were unsuccessful in preventing recurrent ventricular fibrillation . The patient became comatose despite maintenance of adequate levels of systemic arterial pressure between episodes of ventricular fibrillation and prompt restoration of sinus rhythm . Sinus rhythm was restored spontaneously after 12 hours, but the patient remained comatose and died 6 days later .

Postmortem Examination Aside from the findings in the heart, there were no significant changes .

Gross Examination The heart weighed 370 g . The right atrium and right ventricle were hypertrophied and enlarged ; the left atrium and left ventricle were hypertrophied . The left ventricular endocardium was thickened . The large coronary arteries were not narrowed .

Microscopic Examination The S-A and A-V nodes and their approaches, the atrial septum, the A-V bundle and the bundle branches up to the level of the moderator band were serially sectioned at 7µ, and every tenth section was retained . The entire remainder of the heart was cut into blocks, and

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2 sections were taken from each block . Alternate sea tions were stained with hematoxylin and eosin and elastic-van Gieson stains . Myocardium : Fatty infiltration of both ventricles was present, with a slight infiltration of mononuclear and mast cells, and distinct fibroblasic proliferation . This was more prominent at the summit of the ventricular septum, where arteriolosclerosis was also in evidence . Endocardium : The endocardium of the left ventricle showed focal fibroelastosis . Conduction system : There was distinct fatty infiltration of the approaches to the sinoatrial (S-A) (Fig . 3A) and A-V nodes, and the penetrating portion of the A-V bundle . A fine infiltration of mononuclear cells was present in the S-A and A-V nodes (Fig . 3B) and their approaches, the nerve trunks around the S-A node, the penetrating (Fig . 4) and branching portions of the A-V bundle (bundle of His) . The A-V node was especially involved, showing in addition a proliferation of sheath cells (Fig . 3R) . The main left bundle branch (Fig . 5A), the radiations (Fig . 5B) and the peripheral Purkinje cells showed distinct vacuolar degeneration with an infiltration of mononuclear cells . The right bundle branch presented only a slight infiltration of mononuclear cells . The ramus septi fibrosi was slightly thickened and narrowed .

Family of the Propositus Ectopic tachyarrhythmias were documented electrocardiographically in both siblings of the propositus, as well as in her mother . The patient's sister at age 18 years had developed recurrent ectopic tachycardias often resembling the alternating bidirectional arrhythmias exhibited by the propositus (Fig . 6) . Her episodes of arrhythmia were less frequent although incompletely controlled, after treatment with quinidine, and she died suddenly in 1968, 6 months after the rhythm disorder was first dis-

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Figure 4. Photomicrographs of penetrating portion of A-V bundle (arrows) showing fatty infiltration and infiltration of mononuclear cells . (Hematoxylin and eosin, [A] X39, [B] X104, both reduced by 50 percent .) B is enlargement of part of A . V - ventricular septum .

Photomicrographs . A, main left Figure 5 . bundle branch (arrows) showing vacuolar degeneration . B, fasciculi of posterior radiation of left bundle branch (arrows) showing irregular staining with an infiltration of mononuclear cells . (Hematoxylin and eosin X104, reduced by 471/2 percent .) V - ventricular septum .

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Figure 6 . Electrocardiogram of sister of propositus .

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Figure 7 . Electrocardiogram of brother of propositus .

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covered and several months before the hospital admission of the propositus . A postmortem examination performed by the medical examiner failed to disclose gross cardiac abnormality . After the death of the propositus, we reviewed the sections of blocks of cardiac tissues which had been preserved but found that they did not contain conduction tissue . Focal mononuclear cell infiltration was noted in sections of myocardium . The patient's 21 yea)' old brother gave no history of palpitations or other cardiac symptoms . The physical examination, a resting electrocardiogram and chest roentgenogram were normal . However, with exercise he consistently had bigeminal extrasystoles which exhibited a right bundle branch block configuration (Fig . 7) . Prolongation of the Q-T interval was not observed in either sibling . The mother of the propositus, a 45 year old woman, had been aware of episodes of irregular cardiac rhythm since adolescence, and extrasystoles of right bundle branch configuration had been documented repeatedly electrocardiographically . The patient's maternal grandmother died suddenly at age 45 years with previous knowledge of "extra heart beats," and a maternal uncle also died suddenly at age 40 years, apparently without previous symptoms of heart disease or knowledge of ,in abnormal cardiac rhythm . There was no history of hearing difficulties in the propositus or any member of the family . Discussion The familial occurrence of sudden death as a consequence of cardiac arrhythmias unassociated with other evidence of heart disease has now been well documented, initially by the studies of Jervell and Lange-Nielsen' and by other investigators in patients with congenital deaf-mutism and Q-T interval prolongation ; subsequently, familial arrhythmias have been observed in patients without hearing defects, both with" ', and without" "' delayed ventricular repolarization . Histologic changes in fibers of the conduction system suggesting an absence of glycogen stores, with or without occlusive lesions of small blood vessels, have been observed ,-, in patients with the syndrome described by Jervell and Lange-Nielsen . However, it is uncertain whether these changes bear any causal relation to the repolarization abnormality which appears to be responsible for impulse reentry and ventricular arrhythmias .

The propositus in the present study showed distinct fatty infiltration of the myocardium of both ventricles and the conduction system . This is ordinarily not found in a patient of this age . In addition, there was an infiltration of mononuclear cells in the conduction system, more so than in the ventricular myocardium and in the nerve trunks around the S-A node . The Purkinje cells of the left bundle branch showed distinct vacuolar degeneration . These findings cannot be construed as representing a myocarditis, since the conduction system is more involved than the myocardium, which is not the case in myocarditis . Nor can one incriminate the slight narrowing of the ramus septi fibrosi in the pathogenesis of these findings . These findings must therefore be interpreted as a degenerative disease of the heart, involving especially the conduction system and its nerve supply, which forms the anatomic correlate of the arrhythmia present . Perhaps arteriosclerosis of the summit of the ventricular septum plays a role in this disease . The occurrence of an almost identical arrhythmia with fatal outcome in a sibling, the documented family history of arrhythmia, and the consistent demonstration of ectopic beats exhibiting a right bundle branch block configuration in all affected members of the family support the contention that the pathologic changes in the conduction system of the propositus have a genetic background . Because of the fatal outcome of an identical bidirectional tachycardia in a sibling, and the family history of sudden death, it was considered essential that the arrhythmia in the propositus be suppressed . Substantial doses of quinidine and propranolol were employed without effect, although overdrive suppression was achieved by means of atrial pacing . It appears likely that quinidine toxicity, developing abruptly at a lower oral dose than the patient had previously tolerated, was a principal factor in the appearance of recurrent ventricular fibrillation and the fatal outcome . It is postulated that the presence of the demonstrated pathologic changes in the conduction system may have contributed, together with quinidine,to continuing unsuppressed reentry phenomena and uncontrollable ventricular fibrillation .

References Lange-Nielsen F : Congenital deaf-mutism, functional heart disease with prolongation of the QT interval, and sudden death . Amer Heart J 54 :59-68,

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Thingstad R, Endsjo T : The surdocardiac syndrome . Amer Heart J 72 : 582-593 . 1966 James TN : Congenital deafness and cardiac arrhythmias . Amer J Cardiol 19 :627-643, 1967 Puletti M, Jacobellis GF, Borghi F: La sindrome di Jervell e Lange-Nielsen studio cardiologico di 211 sordomuti . Cuore Circ 51 :251-256, 1967

Fraser GR, Froggatt P, James TN : Congenital deafness associated with electrocardiographic abnormalities, fainting attacks, and sudden death . Quart J Med 33 :361364, 1964

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Fraser GR, Froggatt P, Murphy T: Genetical aspects of the cardioauditory syndrome of Jervell and Lange- Nielsen (congenital deafness and electrocardiographic abnor malities) . Ann Horn Genet 28 :133-139, 1964 Sanchez Cascos A, Sanchez-Harguindey L, De Rabago P: Cardio-auditory syndromes . Cardiac and genetic study of 511 deaf-mute children . Brit Heart J 31 : 26-33,

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1969 8 . Ward DC: A new familial cardiac syndrome in children . J Irish Med Ass 54 :103-106, 1964 9 . Ward OC: The electrocardiographic abnormality in fa . malial cardiac arrhythmia . Irish J Med Sci 491 :553-559, 1966 10 . Ramano C, Gemme G, Pongiglione R : Aritmie cardiache rare dell' eta' pediatrica . Clinica Pediat (Bologna) 45 :656-671, 1963 11 . Barlow JB, Bosman CK, Craig Cochrane JW : Congenital cardiac arrhythmia (letter) . Lancet 2 :531, 1964 12 . Gamstorp l, Nielsen R, Westling H : Congenital cardiac arrhythmia (letter) . Lancet 2 :965, 1964 13 . Garza LA, Vick RL, Nora JJ, et al : Heritable Q-T prolongation without deafness . Circulation 41 :39-48, 1970

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14 . Berg KJ : Multifocal ventricular extrasystoles with Adams-Stokes syndrome in siblings . Amer Heart J 60 :965-970, 1960 15 . Akaiski K, Yokoyama T: Two cases of Adams-Stokes syndrome-with special reference to electrocardiograms in attack . Ann Paediat Jap 8 :224-232, 1962 16 . Green R, Korevetz MJ, Shanklin DR, et al : Sudden unexpected death in three generations . Arch Intern Med (Chicago) 124 :359-363, 1969 17 . Ward OC : The inheritance of paroxysmal tachycardia . In, Symposium on Cardiac Arrhythmias (E Sandoe, ed) . Astra, Sodertalje, Sweden, 1970, p 97-106 18 . Rosenbaum MB, Elizari MV, Lazzari JO : The mecha . nism of bidirectional tachycardia . Amer Heart J 78 :4-12, 1969

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