REVIEW ARTICLE

 SUDDEN CARDIAC DEATH IN APPARENTLY NORMAL YOUNG ADULTS

Bernard EF Hockings*, MD Cardiology Department, Sir Charles Gairdner Hospital, Mount Hospital & University of Western Australia, Perth, W. Australia

 ABSTRACT

 Introduction

 Table 1: Causes of sudden cardiac death
 HYPERTROPHIC CARDIOMYOPATHY (HCM)                                 

 CORONARY ARTERY ANOMALIES

 ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA/CARDIOMYOPATHY (ARVD)
 LONG QT SYNDROMES
 Table 2: Medication which may prolong the QT interval
 THE BRUGADA SYNDROME
 VENTRICULAR PRE-EXCITATION SYNDROMES
 CONCUSSION OF THE HEART (Commotio Cordis)
 AORTIC DISSECTION : MARFAN SYNDROME
 MYOCARDITIS
 CONGENITAL ABNORMALITIES OF THE LEFT VENTRICULAR OUTFLOW TRACT (LVOT)
 SUMMARY
 References
 DEATH NOTICES (1000 AD)

ABSTRACT

Most people who die suddenly from cardiac disease are elderly and develop symptoms prior to the fatal event. This review deals with apparently fit and healthy young adults who die suddenly and unexpectedly. The underlying cardiac causes are discussed. Many of the causes of sudden unexpected death discussed in this article do not cause abnormal physical findings and the subjects may be asymptomatic. Screening asymptomatic young adults for potential causes of sudden death remains controversial. Screening should pay particular attention to the subject’s family history, particularly if there are any relatives who have experienced sudden unexpected death. A resting ECG can reasonably be expected to be a cost effective screening tool but routine echocardiography for individuals with no symptoms and no physical findings is not recommended. Understanding the molecular basis for cardiac repolarisation will give better insight into the underlying mechanisms of arrhythmias. There has been progress in this direction in recent years and hopefully new therapies will be discovered.

(Heart Views. 2002;3(3):124 - 130) © 2002 Gulf Heart Association.

Key Words:

   sudden death   hypertrophic cardiomyopathy     coronary artery anomaly   

    right ventricular dysplasia    brugada syndrome    wolff-parkinson-white

   brugada syndrome   marfan syndrome   commotio cordis

Introduction

Most people who die suddenly from cardiac disease are elderly and develop symptoms prior to the fatal event. This review, however, concerns apparently fit and healthy young adults who die suddenly and unexpectedly often, but not always, during intense physical activity. Efforts to detect and treat potentially lethal underlying cardiac abnormalities in such a population where there are no symptoms, are clearly important to the individuals and also of relevance for screening prior to enrolment in pilot training, military service, and participation in sport. The literature appears to have arbitrarily taken an age of less than or equal to 35 years as the definition of “young”. At age greater than 35 years, coronary artery disease is the commonest cause of sudden unexpected cardiac death (SUCD) and it is still a relatively common cause even below this age.

Table 1: Causes of sudden cardiac death

Stary demonstrated fatty streaks in the coronary arteries of children as young as ten years1 but it may come as a shock to some to hear that Nissen and others2, using intracardiac ultrasound, detected evidence of significant coronary atherosclerosis in the arteries of more than 50% of donor hearts when these were screened prior to transplantation, particularly as the average age of the donors was only 26 years.

HYPERTROPHIC CARDIOMYOPATHY (HCM)

HCM is a relatively common genetic malformation of the heart with a prevalence of almost 1:500 of the population3,4. About half the patients inherit the disorder which is autosomal dominant with variable penetrance; the others are thought to be due to spontaneous mutation. The disorder is characterized by varying degrees of left ventricular hypertrophy often with disproportionate thickening of the interventricular septum. The abnormal septal thickening frequently leads to dynamic obstruction of the left ventricular outflow tract resulting in symptoms of chest pain, syncope and dyspnoea. Some patients with this condition, however, remain asymptomatic and HCM is frequently reported to be the commonest cause of SUCD in young adults5. Although a number of young people with this condition die suddenly, in some studies6 it was an uncommon cause of death although perhaps it was because subjects in this study were identified by screening programmes and subsequently excluded from undertaking vigorous physical activity. It is possible that the importance of HCM as a cause of SUCD has been over-emphasized by repeated reporting of the same cases in the literature. The severity of the gradient across the LVOT is related to symptoms but not to the patient’s prognosis. Factors linked to a poor prognosis for patients with HCM are a family history of sudden unexpected death, symptoms of syncope, and the presence of ventricular tachycardia found on Holter monitoring. There are several genotypes and if a number of family members are affected, then a subject’s genotype can be mapped and an estimate of prognosis made. Some patients with HCM have extensive myocardial fibre disarray on histologic examination but little in the way of hypertrophy, and yet these patients may be at high risk of sudden death. Certain genotypes have delayed phenotypic expression with some patients being in their sixties before exhibiting structural change in the heart. There is no definite evidence that treatment of the condition alters prognosis but symptoms are usually managed with beta blockers. Verapamil has also been used to treat symptoms and is beneficial in non-obstructive forms of the condition because of its negative inotrophic effect which results in left ventricular dilatation and a decrease in left ventricular pressure. There have been problems with the use of Verapamil for patients with the obstructive form of HCM because the vasodilatory properties of Verapamil may override the negative inotrophic effect, resulting in systemic vasodilatation with an increase in gradient. The use of this drug has been associated with sudden death in some instances. For severely symptomatic patients surgical myomectomy, sometimes coupled with mitral valve replacement, or, more recently, septal reduction by alcohol ablation7, can be performed.

CORONARY ARTERY ANOMALIES

The ostia of the coronary arteries are normally situated in the right and left coronary sinuses of the aortic root. Among congenital cardiac lesions anomalous origin of a coronary artery is relatively common but those anomalies which carry an increased risk of sudden death are fortunately rare. For certain specific anatomical variants the risk of SUCD may be high8,9. High risk anatomical variants include : origin of the left coronary artery from the pulmonary artery; origin of the left coronary artery from the right coronary or non-coronary sinus of the aortic root where the vessel courses between the aortic and pulmonary artery roots. A right coronary artery arising from the left coronary sinus was thought to carry less risk of SUCD but it is now known that this condition can also cause angina, syncope, ventricular fibrillation and occasionally sudden death10. Patients with coronary anomalies may die suddenly. If they present with symptoms and the abnormality is found, then surgical correction may be possible.

ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA/CARDIOMYOPATHY (ARVD)

This is a disease of unknown cause which can present as a cardiac arrhythmia, sudden death and rarely, cardiac failure (as the left ventricle is usually spared at least until late in the disease process). Basso et al11 suggested that ARVD may be a form of myocarditis as lymphocytic infiltrates can be found within the affected myocardial tissue. These authors also concluded that the term cardiomyopathy should replace dysplasia as there seems to be a progressive damage/repair process rather than a congenital abnormality. There is however, evidence that in some cases ARVD may be a genetically determined disorder12; a viral or environmental agent may possibly act in a genetically predisposed individual to cause the condition.

Fig. 1. Torsades de Pointes

environmental agent may possibly act in a genetically predisposed individual to cause the condition. Typically, a young patient will present with syncope and be found to have ventricular tachycardia. Those who die suddenly are found at post mortem to have a variable amount of the right ventricular myocardium replaced by fat. The diagnosis of ARVD is often difficult. Physical examination is frequently normal but in some patients a widely split second heart sound may be heard as a result of right ventricular dysfunction. The resting ECG is abnormal in 70% of cases. T wave inversion in the chest leads is the commonest finding13. The presence of a so-called epsilon wave, a characteristic notch in the secondary R wave of the right precordial leads, is, if present, said to be almost pathognomonic of ARVD. The notch is the result of prolongation of the QRS complex as a consequence of slow conduction through the diseased right ventricular free wall. There may be anatomical changes in the right ventricle including right ventricular enlargement, multiple outpouchings (diastolic bulging), areas of akinesia and/or dyskinesia and right ventricular dysfunction. However, minor changes are easily missed by echocardiography. Cine magnetic resonance imaging is the most useful test for establishing the anatomical diagnosis as this may best demonstrate the sub-epicardial infiltration of fat. Endomyocardial biopsy will be abnormal if affected areas are sampled but the disease process is often patchy and usually affects the right ventricular free wall first, sparing the septum and it is the latter which is the usual site for taking biopsy specimens. Programmed electrical stimulation is indicated particularly as catheter ablation techniques to prevent ventricular tachycardia have proven useful in the treatment of some patients. Treatment with anti-arrhythmic drugs, particularly Sotalol, has been tried with variable success. An automatic implantable cardioverter defibrillator (AICD) is often the most appropriate therapy but given that the right ventricular wall is often very thin implantation of defibrillation leads in this chamber may be ineffective and consideration may need to be given to positioning the leads in the left ventricle, and surgery (myocardial resection; cryosurgical ablation of the arrhythmogenic area; transplantation) has been performed in refractory situations. With increasing awareness of this condition it may be that ARVD is more prevalent than previously thought. Some patients who have end stage dilated cardiomyopathy are found to have biopsy evidence of ARVD.

LONG QT SYNDROMES

These are inherited disorders of the sodium and potassium ion channel genes of the myocardium which result in prolongation of the QT interval on the resting electrocardiogram (QT interval corrected for heart rate [QTc] greater than or equal to 0.48 seconds in females and greater than or equal to 0.45 seconds in males) and T wave abnormalities particularly T wave alternans. Individuals with this disorder frequently develop a characteristic ventricular tachycardia called Torsades de Pointes which may cause syncope or cardiac arrest. At least six genotypes with over 120 gene mutations have been identified but as yet no specific gene has been determined.14 Syncope occurs in about two-thirds of gene carriers with sudden death in 10-15% of untreated patients.14 Certain individuals can acquire the long QT syndrome (LQTS) if they are exposed to some metabolic abnormalities, for example hypokalemia, or to certain drugs. There is an increased risk of drug-induced Torsades de Pointes for subjects who are female, who have had a recent bradycardia or hypokalemia. Susceptible individuals may have a mutation with a “silent” form of Long QT Syndrome where the patient remains asymptomatic until they are exposed to certain conditions or drugs which further impair repolarisation. A normal QTc there

Table 2: Medication which may prolong the QT interval

fore does not exclude LQTS and up to 12% of affected individuals may have normal electrocardiograms. The principal treatment for this congenital condition is high dose beta blocker therapy. Sodium channel blockers such as procainamide and flecainide or potassium administration, depending on the particular ion channel defect, have been used, as well as pacing and AICD implantation. Treatment is indicated for all symptomatic patients as well as asymptomatic children and young adults (below 40 at diagnosis). Patients older than 40-45 years, if asymptomatic, may not need to be treated; their risk of SUCD is low but not zero. Clearly precipitating agents must be avoided for all patients with congenital LQTS.

THE BRUGADA SYNDROME

This was originally described by Pedrou and Josep Brugada in 1991 in eight otherwise healthy patients with sudden and aborted cardiac death who had “right bundle branch block and persistent ST elevation in V1-V3”.15 The QT intervals were normal in these patients. Subsequently, it has been found that right bundle branch block is not an integral part of the syndrome. ST segment elevation in the right precordial leads in the absence of ischaemia, electrolyte or metabolic disorders, pulmonary, inflammatory or nervous system disease may identify subjects with the Brugada syndrome. Idiopathic ST segment elevation occurs in approximately 2.5% of individuals but is confined to the right precordial leads in less than 1% of all cases of ST segment elevation. Characteristically in this syndrome the ST elevation is downsloping and not accompanied by reciprocal ST depression .

Fig 2. ECG tracing from a patient with Brugada Syndrome

This syndrome appears to be a familial primary electrical disease caused by a defect in an ion channel gene. A strong link has been found between Brugada syndrome and sudden unexpected death particularly in South East Asian males.16 Death often occurs during sleep and autopsy findings are usually negative. The syndrome is complicated because the ECG manifestations of the Brugada syndrome may transiently normalise leading to under-diagnosis. Provocation with sodium channel blockers (procainamide and flecainide) can unmask the ECG abnormality. The syndrome is consistent with autosomal dominant inheritance with variable expression (similar to ARVD) but the relationship of the Brugada syndrome to ARVD is unclear.17 There is a high incidence of familial clustering. Programmed electrical stimulation almost always induces malignant ventricular tachycardia or ventricular fibrillation in Brugada syndrome patients with aborted sudden death or syncope. Implantable cardiac defibrillators are the only effective treatment and are indicated for symptomatic individuals with the syndrome and for those who have been identified but are asymptomatic if malignant arrhythmias are induced by electrophysiological studies.17

.

VENTRICULAR PRE-EXCITATION SYNDROMES

Many young people have episodes of paroxysmal supraventricular tachycardia for which the underlying anatomical substrate is usually an accessory conduction pathway between the atria and the ventricles. These so-called pre-excitation syndromes are a heterogenous group of which the best known is the Wolff-Parkinson-White syndrome (WPW). When these patients present with rapid supraventricular tachycardia, conduction usually proceeds down the normal His Purkinje conduction system antegradely and then returns to the atrium retrogradely via the accessory pathway to complete the circuit. In some patients the accessory pathway is also capable of conducting antegradely from atria to ventricle sometimes at very rapid rates. Patients with WPW have a propensity to develop atrial fibrillation and in the event of pre-excited atrial fibrillation (with conduction to the ventricle via the accessory pathway) they may develop very rapid ventricular rates and rarely ventricular fibrillation.

CONCUSSION OF THE HEART (Commotio Cordis)

There have been several case reports where a blow to the precordial area, often without undue force, has resulted in the sudden death of the recipient. Hockey, baseball and lacrosse players are particularly susceptible to such injuries. Link et al18 demonstrated in a swine model that a blow to the chest wall which coincides with the T wave results in ventricular fibrillation 90% of the time. If the blow falls on the QRS complex, heart block or asystole occurs 30% of the time. A blow timed elsewhere in the cardiac cycle causes ST segment elevation on the subsequent ECG complex; the significance of this is unclear. If ventricular fibrillation occurs and lasts for more than four minutes without defibrillation, successful resuscitation is unlikely. This raises the question as to whether defibrillators should be available at large public gatherings and, if so, who should be trained in their use.

AORTIC DISSECTION : MARFAN SYNDROME

Marfan syndrome is an autosomal dominant generalised abnormality of connective tissue but there is variable phenotypic expression in subsequent generations. The archetypal Marfanoid patient, a tall, thin, shortsighted basketballer with aortic regurgitation, would be easily recognised. It is important to remember however that this is a generalized disorder of connective tissue affecting many body systems apart from the heart. Mitral regurgitation may be more common than aortic regurgitation.19 In one study of 257 patients followed for thirty years, 72 patients died at an average age of 32 years and in 80% the cause of death was aortic dissection or rupture.20 In view of the risk of aortic dissection, subjects with Marfan syndrome should receive close follow up including serial echocardiography. Medical treatment consists of vigorous control of hypertension usually with beta blockers. Surgical treatment of the dilated aortic root is recommended even in asymptomatic individuals with Marfan syndrome as the risk of dissection increases significantly as aortic diameter increases. Current guidelines for surgery are: 1) aortic root diameter >55mm; 2) positive family history of aortic dissection and aortic root diameter > 50mm; 3) aortic root growth > 2mm/year.21

MYOCARDITIS

Myocarditis or inflammation of the myocardium can be caused by any one of a heterogeneous group of conditions and may be an acute or chronic process. The end stage of the inflammatory process is thought to result in severe global impairment of cardiac contraction but some individuals who die suddenly with no evidence of any other cause, are found to have histological evidence of myocarditis at post mortem.

CONGENITAL ABNORMALITIES OF THE LEFT VENTRICULAR OUTFLOW TRACT (LVOT)

The most common site of stenosis is at the aortic valve level but supravalvular and infravalvular stenoses are well recognised. The major symptoms of congenital LVOT obstruction are angina, syncope, and symptoms related to congestive cardiac failure. Many patients with significant degrees of stenosis may remain asymptomatic. Sudden death, usually during exercise, may occur but in previously asymptomatic individuals with aortic stenosis, this is rare.22

SUMMARY

Fortunately sudden cardiac death in apparently normal young adults is an uncommon event but always seems a particularly poignant tragedy, which, in developed countries at least, usually receives considerable publicity. Screening asymptomatic young adults for potential causes of sudden death remains controversial. It is performed prior to individuals being enrolled in the Armed Forces and certain occupations. Several sporting codes also require medical screening prior to participation. Many of the causes of sudden unexpected death discussed in this article do not cause abnormal physical findings and the subjects may be asymptomatic. Screening should pay particular attention to the subject’s family history, particularly if there are any relatives who have experienced sudden unexpected death. A resting ECG can reasonably be expected to be a cost effective screening tool but routine echocardiography for individuals with no symptoms and no physical findings is not recommended. It remains to be proven, that appropriate screening of children and young adults to identify potential causes will result in a reduction of these deaths, but experience from screening programmes undertaken in Italy is encouraging6. Wider availability of cardiac defibrillators in airport lounges, on aircraft and at sites of large public gatherings may save individuals who develop malignant cardiac arrhythmias and who would otherwise die, although clearly the great majority of these individuals would not be young and would have underlying coronary disease. Recent progress in understanding the molecular basis for cardiac repolarisation will aid in further understanding of arrhythmias and help identify new therapies. This progress may extend to a better understanding of the causes of sudden death not only in young and apparently healthy individuals but also of death associated with heart failure, cardiac hypertrophy, myocardial infarction and even sudden infant death syndrome, where abnormal repolarisation has been linked to sudden death.23

Reference

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2. Nissen S. Personal communication.

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17. Gussak I, Antzelevitch C, Bjerregaarde P, Towbin JA and Chaitman BR. The Brugada syndrome: clinical electrophysiologic & genetic aspects. JACC 1999;33:5 –15.

18. Link MS et al. An experimental model of sudden death due to low energy chest-wall impact (Commotio Cordis). N Engl J Med 1998;338(25):1805 –1811.

19. Phomphutkul C, Rosenthal A & Nadas A. Cardiac manifestation of Marfan syndrome in infancy and childhood. Circulation 1973;47:587.

20. Murdoch JL, Walker BA, Halpern BI, Kuzma JW & McKusick VA. Life expectancy and causes of death in the Marfan syndrome. N Engl J Med 1972;286:804.

21. Groenink M, Lohuis TAJ, Tijssen JGP, Naeff MSJ, Hennekam RCM, Van der Wall EE, Mulder BJM. Survival and complication free survival in Marfan’s syndrome: implications of current guidelines. Heart 1999;82: 499- 504.

22. Hossack KF, Heutze JM, Iowe JB & Barratt-Boyes BG. Congenital valvular aortic stenosis – natural history and assessment of operation. Br Heart J . 1980;43: 561.

23. Roden DM, Spooner PM. Inherited long QT syndromes: a paradigm for understanding arrhythmogenesis. Journal of Cardiovascular Electrophysiology. 1999;10 (12): 1664- 1683.

DEATH NOTICES (1000 AD)

*Clinical Associate Professor of Medicine University of Western Australia; Consultant Cardiologist Sir Charles Gairdner and Mount Hospitals Perth Western Australia. Correspondence to Dr. Bernard Hockings, Mount Cardiology Suite 3, 140 Mounts Bay Road, Western Australia