Sudden Cardiac Death in the Young: The Impact of Inherited Cardiovascular Disease
Srijita Sen-Chowdhry
William J. McKenna
Sudden cardiac death (SCD) is defined as natural death due to cardiac causes heralded by abrupt loss of consciousness within 1 hour of the onset of acute symptoms; preexisting heart disease may have been known to be present, but the time and mode of death are unexpected (1). The stipulation of a 1-hour time frame enhances specificity for instantaneous arrhythmic events but impedes categorization of unwitnessed deaths. Determining the burden of SCD in public health surveillance is also difficult because death certificates seldom cite the time interval between symptom onset and death. To circumvent this problem, epidemiologists frequently adopt an alternative classification that includes any cardiac death occurring out of hospital, in the emergency department, or on arrival therein (2). The prevalenceof SCD in the general population is estimated at 1 in 1,000, with coronary artery disease accounting for the overwhelming majority of deaths among those older than 35 years (3).
The profile of sudden cardiac death in the young, however, is distinct. Coronary artery disease remains significant, in the form of both premature atherosclerosis and congenital anomalies; however, the primary myocardial diseases become more prominent. Foremost among this group are hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy (ARVC). The terms sudden arrhythmic death syndrome (SADS) and Sudden Unexplained Death have been applied to the important minority of deaths that remain unexplained with apparently normal histopathology or post-mortem examination and a negative toxicology serum. Around 4% of deaths in individuals from 16 to 64 years old are attributed to SADS, which additionally encompasses cot deaths (sudden infant death syndrome) (4). Candidate diseases that may underlie SADS include the long-QT, short-QT, and Brugada syndromes, familial catecholaminergic polymorphic ventricular tachycardia, and progressive cardiac conduction defect. Collectively termed the inherited arrhythmia syndromes, the diseases are distinguished by the propensity for generating tachyarrhythmia or bradyarrhythmia in the structurally normal heart.
Early work evaluating the relatives of SADS victims revealed features consistent with long-QT syndrome in a significant proportion (5). However, hypertrophic cardiomyopathy and myotonic dystrophy were also identified, underscoring the need to exclude structural heart disease in SADS families in spite of the absence of pathologic findings in the index case. ARVC may also be missed on postmortem without extensive sampling of the right ventricle and should be considered in the differential diagnosis of SADS.
The cardiomyopathies and the inherited arrhythmia syndromes are single-gene disorders, highlighting the relatives of index cases as individuals potentially at risk and in need of prospective assessment. The concept of inherited cardiovascular disease clinics was born from the recognition that familial evaluation is central to timely diagnosis and prevention of SCD. In spite of the broad spectrum of diseases falling under this umbrella, the clinical approach to families with inherited cardiovascular disease is founded on a few unifying principles.
Inherited Cardiovascular Disease: Unifying Principles
The following characteristics are common to the cardiomyopathies and inherited arrhythmia syndromes.
Patterns of Inheritance
The genetic cardiovascular diseases are typically transmitted as autosomal dominant traits, although recessive and X-linked forms may also be recognized. Recessive variants are more frequently associated with extracardiac features. The Jervell-Lange-Nielsen syndrome consists of QT prolongation, ventricular tachyarrhythmia, and congenital sensorineural deafness; both homozygous and compound heterozygous ion channel mutations may be causative (6). Naxos disease and Carvajal syndrome are cardiocutaneous disorders in which ARVC occurs in conjunction with hair and skin defects (7).
The presence of affected male individuals and carrier female individuals on pedigree analysis is suggestive of X-linked inheritance. However, female heterozygotes may develop varying degrees of disease expression owing to random X-chromosome inactivation, a phenomenon observed in Anderson-Fabry disease and the dystrophinopathies, characterized by muscle weakness and/or dilated cardiomyopathy.
Incomplete Penetrance
Autosomal dominant inheritance confers on first-degree relatives a 50% probability of carrying the disease-causing mutation. However, the apparent prevalence of genetic cardiovascular disease is lower than would otherwise be predicted owing to incomplete penetrance. Penetrance is an all-or-none phenomenon that refers to the presence or absence of observable disease expression in a genetically affected individual. Although the genetic basis of dilated cardiomyopathy and ARVC has become apparent in the last decade, familial occurrence of both diseases was long underestimated because penetrance in some kindreds may be as low as 20% to 30%. Similarly, 32% of carriers of long-QT syndrome mutations have a normal corrected QT interval (8).
There is growing awareness that penetrance of inherited cardiovascular disease is variable not only in populations but in the individual, depending on age and environmental factors. In hypertrophic cardiomyopathy, for example, common wisdom held that relatives with normal clinical evaluation in early adulthood, after attainment of physical maturity, were unlikely to be genetically affected. This traditional view was overturned by recognition of late-onset disease, with first clinical manifestations occurring at middle age or beyond, particularly in conjunction with mutations in myosin binding protein C (9). More recently, penetrance of hypertrophic cardiomyopathy has been cited as 55% from the ages of 10 to 29 years, 75% from 30 to 49 years, and 95% in gene carriers older than the age of 50 years (10). Age-related penetrance is also well documented in dilated cardiomyopathy and ARVC. Current guidelines therefore recommend periodic reassessment of adult relatives without contemporaneous evidence of clinical disease expression.
A further consequence of incomplete penetrance is the presence of “silent” gene carriers within a family who are nevertheless able to transmit the disease-causing mutation to their offspring. Second-degree relatives of index cases may therefore be offered clinical evaluation, particularly in families with dilated cardiomyopathy or ARVC. The logistic difficulties of implementing this strategy in extended families highlight a key role for molecular genetic analysis in screening relatives.
Variable Expressivity
Expressivity refers to the nature and severity of the phenotype induced by a mutant allele. Variable expressivity is a common characteristic of autosomal dominant traits. Familial evaluation in the cardiomyopathies and inherited arrhythmia syndromes reveals that relatives often demonstrate milderphenotypes than index cases. One result of incomplete disease expression in relatives is the insensitivity of conventional diagnostic criteria for detection of familial disease. Modified diagnostic guidelines have been proposed in hypertrophic cardiomyopathy, dilated cardiomyopathy, and ARVC to facilitate evaluation of relatives (11,12,13).
Of note, incomplete disease expression does not necessarily confer low risk, particularly in ARVC and the inherited arrhythmia syndromes. Thus, clinically “silent” gene carriers in long-QT syndrome are nevertheless more susceptible than the age-matched general population to arrhythmic events. Similarly, ARVC is well known to have an early, concealed phase during which clinical features are subtle or absent but patients may nonetheless be at risk of SCD, particularly during highly strenuous activity (14).
Genetic Heterogeneity
Genetic heterogeneity in the inherited cardiovascular diseases occurs at two levels. Locus heterogeneity is present when more than one gene produces the same phenotype. Thus, mutations in a multitude of cytoskeletal, sarcomeric, and sarcolemmal genes may underlie dilated cardiomyopathy. Allele heterogeneity occurs when different mutations within the same gene produce the same phenotype; private mutations appear common in families with inherited cardiovascular disease.
Distinct mutations within the same gene may also be associated with disorders as disparate as hypertrophic and dilated cardiomyopathy. An example of a gene associated with both diseases is that for actin. In cardiac myocytes, actin thin filaments provide a link between the sarcomere (contractile apparatus) and the anchoring proteins dystrophin and α-actinin at the sarcolemma (cytoplasmic membrane). Mutations at the sarcomeric end of actin have been isolated in hypertrophic cardiomyopathy, whereas defects at its anchoring end cause dilated cardiomyopathy (15). Similarly, the long- and short-QT syndromes are produced by mutations with opposing functional effects in the same ion channel genes.
Dynamic Risk Profiles
Clinical experience suggests that individuals with inherited cardiovascular disease are at increased risk of arrhythmic events during discrete but difficult-to-define time intervals. The paroxysmal exacerbations may be a consequence of both intrinsic factors, such as age and the natural history of the disease, and environmental influences. For example, index cases with long-QT syndrome appear to be at higher risk of cardiac events during the postpartum period (16), whereas fever is a recognized trigger for arrhythmic episodes in Brugada syndrome (17). The clinical course of ARVC may be characterized by prolonged quiescent intervals punctuated by occasional “hot phases” during which the disease process becomes active and the previously stable patient may experience arrhythmic exacerbation. Among patients with hypertrophic cardiomyopathy, the peak incidence of SCD occurs in adolescents and young adults younger than the age of 35 years. However, SCD is not confined to the younger age group, and also manifests in midlife and beyond (9).
The observed fluctuations in risk for any individual with inherited cardiovascular disease necessitate periodic reassessment of all recognized prognostic indicators.
Establishing and Operating an Inherited Cardiovascular Disease Service
Operating an inherited cardiovascular disease service requires support from specialist nurses, cardiac technicians, and clinicians with experience in heart muscle disease, genetics, and arrhythmia. Expert interpretation of investigations is of particular importance in the diagnosis of ARVC and the inherited arrhythmia syndromes. The following considerations form the basis for a dedicated clinic.
The Referral Population
Patients referred to the inherited cardiovascular disease clinic may be subdivided into two main categories: (a) probands with suspected or established disease and (b) relatives of index cases with a clinical diagnosis of inherited cardiovascular disease or sudden cardiac death victims. The preliminary evaluation should focus on parents and adolescent siblings, although family anxiety will often center on the offspring of the deceased. Targeting adult members of the family is advocated owing to age-related penetrance, practical constraints to subjecting young children to cardiac investigations, and above all the difficulties in interpretation thereof. The clinical manifestations of the cardiomyopathies and inherited arrhythmia syndrome commonly arise during or after the pubertal growth spurt, although childhood onset is well recognized. Familial assessment may later extend to the pediatric age group, a process that will be facilitated by first establishing the diagnosis in adult relatives.
Because the inherited cardiovascular disease clinic combines arrhythmia expertise with facilities for echocardiography, exercise testing, and electrocardiogram (ECG) monitoring, it also provides an optimal environment for rapid evaluation of young patients with palpitation and/or syncope, a significant minority of whom are likely to have underlying cardiac disease.
Importance of the Postmortem
The first step toward evaluating the families of SCD victims is to obtain a complete postmortem report. When performing an autopsy on a young person who has died suddenly, the expert pathologist will systematically attempt to exclude all structural cardiac abnormalities, including coronary artery disease, accessory pathways, conduction system defects, valve lesions, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), left ventricular noncompaction, and ARVC. This examination entails rigorous macroscopic and histologic assessment of the heart. Confirmation of a sporadic disorder, such as anomalous coronary arteries, may obviate the need for familial evaluation. The presence of premature coronary artery disease may prompt familial screening for hyperlipidemias and plasma homocysteine and lipoprotein (a) levels. Identification of an inherited cardiomyopathy facilitates subsequent evaluation of relatives along disease-specific guidelines.
If the cardiac examination appears incomplete from the autopsy report and details are lacking, the clinician or nurse counselor may seek the consent of the family to release retained tissue for expert review. Reassessment by a specialist cardiac pathologist may unmask new abnormalities in cases in which the cause of death was unascertained and/or consolidate a borderline diagnosis. ARVC, in particular, has been diagnosed from expert pathologic review of retained blocks and slides in cases of sudden unexplained death (18).
Determining the Expectations of the Family
The sudden unexpected death of a young person is a devastating event. Anger and grief will frequently surface during familial assessment. Eliciting a diagnosis of inherited cardiovascular disease in a parent will often precipitate feelings of guilt which, although entirely misplaced, may be difficult to allay. Asymptomatic individuals participating in any screening program are frequently seeking reassurance of their own well being; abnormal findings may lead to distress, denial, and reluctance to attend for further investigations and follow-up. Conversely, many families attending for evaluation are motivated by the desire to rationalize the unexplained death of a loved one. Failure to establish a diagnosis is a common outcome in SADS families, which may lead to disappointment and disillusionment with the screening process.
It is therefore critical to determine and rationalize the expectations of family members from the outset. The initial counseling should include an open discussion of the cause of death in the proband and, in the case of SADS victims, the diseases suspected to underlie such deaths. The prospect of abnormal findings in family members should be raised. Furthermore, it is important to emphasize the limitations of clinical evaluation in the diagnosis of cardiac disease, notably ARVC and the inherited arrhythmia syndromes. Confidentiality is another issue that should be addressed before the main consultation. Contrary to accepted practice in most other areas of medicine, it may be both appropriate and preferable for family members to be seen together. However, the views of participating individuals on disclosure of medical details to relatives should be clarified before the consultation.
Antecedent Events in the Proband
Questioning families regarding premonitory symptoms in the proband and the circumstances of death may provide clues to the diagnosis. A longstanding history of sustained palpitation and syncope, for example, is strongly suggestive of underlying cardiac disease.
Long-QT syndrome has several subtypes caused by mutations in different ion channel genes. The triggers for arrhythmic events vary among subtypes. Exercise-induced events predominate in LQT1; swimming and diving, in particular, are recognized precipitants. In contrast, both LQT3 and Brugada syndrome are associated with arrhythmic events during sleep, whereas the LQT2 subtype shows an intermediate pattern. Auditory stimuli and emotional stress are particularly common triggers in LQT2. These observations represent general trends rather than absolutes; thus, 3% of LQT1 patients experience events while asleep, and 13% of LQT3 patients had arrhythmia during exercise (19). Similarly, although intense physical exertion may induce arrhythmia in HCM and ARVC, the majority of events in both diseases occur at rest or during everyday life activities.
Clinical History and Pedigree Analysis
Patients are questioned specifically about the presence of cardiac symptoms such as sustained palpitation, presyncope, syncope, chest pain, and breathlessness. Compilation of a detailed family history, covering a minimum of three generations, is an integral component of the evaluation. A history of sudden
infant death syndrome (“cot death”), drowning, or congenital sensorineural deafness may be compatible with long-QT syndrome; heart failure and/or cardiac transplantation in a relative are more suggestive of a primary myocardial disorder. Cardiac symptoms in a family member may also be relevant; many patients will recollect parents or siblings suffering from recurrent palpitation or blackouts. Subsequent pedigree analysis may indicate which side of the family is affected and should be targeted for evaluation.
infant death syndrome (“cot death”), drowning, or congenital sensorineural deafness may be compatible with long-QT syndrome; heart failure and/or cardiac transplantation in a relative are more suggestive of a primary myocardial disorder. Cardiac symptoms in a family member may also be relevant; many patients will recollect parents or siblings suffering from recurrent palpitation or blackouts. Subsequent pedigree analysis may indicate which side of the family is affected and should be targeted for evaluation.
The Diagnostic Work-up
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
