© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Opportunities for sudden death prevention: Directions for new clinical and basic research
aDivision of Cardiology, University of Miami School of Medicine, Miami, FL, USA
bArrhythmia Research Group, DHVD, Heart, Lung & Blood Institute, 2 Rockledge Ctr., MSC-7940, 6071 Rockledge Dr., Bethesda, MD 20892, USA
* Corresponding author
Received 2 February 2001; accepted 8 February 2001
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Abstract |
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 Top Abstract 1 Introduction2 Clinical epidemiology3 Evaluating new therapeutic...4 Progress in risk...5 Predictors of SCD...6 Opportunities for progress7 ConclusionsReferences |
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Sudden cardiac death (SCD) represents an enormous public health problem in all developed countries of the world, yet its magnitude and precise incidence in different populations and disease subgroups remains unclear. There also remain major questions and research challenges in establishing the sensitive and specific markers of SCD risk needed for optimizing therapeutic strategies and allocation of resources, such as implantable defibrillators. In the past, risk factors for coronary artery disease (CAD) have been heavily relied on to identify risk for SCD. However, although a majority of SCD events continue to occur in the context of this disease etiology, risk factors for CAD appear to have relatively limited ability to predict risk in specific individuals and subgroups with enhanced progressive or inherited susceptibility to lethal arrhythmias. This commentary is intended to assess potentials for progress in developing improved approaches to SCD prediction and prevention through new clinical and basic research on the fundamental causes of ventricular arrhythmias, the development of new markers of electrical instability, and better understanding of the role of genetic variability in their origin.
KEYWORDS Epidemiology; Sudden death
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1 Introduction |
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TopAbstract1 Introduction2 Clinical epidemiology3 Evaluating new therapeutic...4 Progress in risk...5 Predictors of SCD...6 Opportunities for progress7 ConclusionsReferences |
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From the perspective of the clinician and basic scientist alike, sudden cardiac death (SCD) remains a most difficult problem, representing a public health threat that accounts for approximately half of all cardiovascular deaths in the US. Strategies for prevention depend heavily on risk profiling in population studies that have, for the most part, focused on the presence and extent of underlying coronary artery disease (CAD), even though the power of these approaches in individual patients remains low. Therapeutic interventions for primary or secondary prevention of cardiac arrest have not to date successfully targeted specific mechanisms of sudden cardiac death [1], except for the use of implantable defibrillators (ICDs) for some subsets of patients. ICD use for more general segments of the population remains unrealistic. Further, community-based programs using automatic external defibrillators (AEDs) have been limited by a lack of knowledge regarding the effectiveness of such strategies in the hands of expanded types of first responders, and information on the efficacy of various distribution strategies. Even in more focused populations, data have only recently become available to support the benefits hypothesized for the use of these devices. Predicting and preventing sudden cardiac death remains a major challenge for which new strategies are needed [2], and understanding its causes represents an enormous challenge for clinical and basic cardiovascular science.
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2 Clinical epidemiology |
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TopAbstract1 Introduction2 Clinical epidemiology3 Evaluating new therapeutic...4 Progress in risk...5 Predictors of SCD...6 Opportunities for progress7 ConclusionsReferences |
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The precise incidence of sudden cardiac death in the US is unknown and for several reasons is likely to remain difficult to assess. The frequently cited estimate of 250 000–300 000 sudden cardiac deaths annually is a figure derived from calculations made more than 25 years ago, based on an assumption of 600 000 cardiovascular deaths in the US annually, with 50% of those deaths occurring suddenly [2,3]. However, since then, two factors have come into play that could influence the reliability of that estimate. The first is a change in age-adjusted mortality from coronary heart disease, with present estimates indicating that deaths due to this category are occurring later, but not necessarily that the actual incidences of death or prevalence of disease are decreasing [4]. In addition, an improvement in short-term mortality from acute myocardial infarction experienced during the second half of the 20th century, in conjunction with an increased older population, has established a large population of older patients with chronic heart disease, resulting in an epidemiologic cohort at increased risk for events [5]. Whether these two factors have increased, decreased, or had no effect on the actual incidence of sudden cardiac death needs to be identified through contemporary prospective observations, designed to quantify the current sudden death burden.
For many years, clinicians have depended upon epidemiologic profiling of risk of development of coronary heart disease as a surrogate for sudden cardiac death prediction [6]. The logic for this approach derived from the fact that it has long been considered that 80% of all sudden cardiac deaths are due to coronary heart disease. It follows that the epidemiology of evolution of coronary heart disease is a general indicator of risk. Unfortunately, while this strategy applies generally to the population, it does not have sufficient power to identify individual total mortality risk, and even less so for sudden death specifically.
The limitations experienced in predicting sudden cardiac death due to coronary heart disease are even more confounding for sudden cardiac deaths due to other causes, such as the acquired myopathies, a diffuse array of other structural disorders and entities in which genetically heritable mechanisms have been implicated [7,8]. The cardiomyopathies, dilated and hypertrophic categories combined, account for approximately 10–15% of the cardiac arrest/sudden death burden. Numerically, and particularly in the middle aged-to-older adult population, these figures are dominated by dilated cardiomyopathies. Unfortunately, this category is poorly defined etiologically, including undefined acquired mechanisms among the idiopathic dilated cardiomyopathies, and various acquired causes such as myocarditis, alcohol-induced disorders, and other rare causes. The epidemiology for this cluster of disorders is not well understood, and risk factors and other specific etiologic characteristics remain unknown.
A different kind of epidemiologic problem exists for those cases that display a strong familial pattern, including the long QT-interval syndromes, familial hypertrophic cardiomyopathies, right ventricular dysplasia, Brugada's syndrome and idiopathic ventricular fibrillation [2]. Among these subgroups, epidemiologic considerations migrate into new territory, namely possible genetic predictors of cardiac arrest as a manifestation of disorders that may affect channels, contractile elements and other cellular proteins. However, it is also clear that risks of SCD due to mutations at a given gene locus and among members of families in which a specific mutation has been identified, are not necessarily uniform. This variance in disease expression may indicate mutation-specific variations in functional alterations, involvement of secondary linkages to other genes, environmental inducers or comorbidity. This area of clinical epidemiology is in its infancy and is hampered by the relatively small number of patients and families identified to date. Nevertheless, the potential ability to associate a specific genetic mutation with a specific risk of sudden death offers the hope of improved identification of susceptibility among affected families. Understanding genetic determinism in such small populations might ultimately provide road maps for risk identification in the more common entities such as coronary artery disease or the cardiomyopathies [2,9].
The magnitude of sudden cardiac death risk is age-dependent and cause-related (Fig. 1). A generally assumed risk of 0.1–0.2% (1–2 per 1000) per year among the population aged 35 years and older, is an average figure across that age spectrum. However, the risk of sudden cardiac death is strongly age-related with the most marked increase occurring between the ages of 40 and 65 years, with causation dominated largely by coronary artery disease. However, among the subgroup of patients with far-advanced structural heart disease, the extent of disease rather than age, influences risk more strongly and therefore, age-related risk curves blunt in that subgroup of population (Fig. 1). The adolescent and young adult populations (age range, 10–30 years) have a sudden death risk about 1% of that of the general adult population (1 per 100 000 individuals annually) and there appears to be an inverse age relationship with the adolescent group having a higher mortality risk than young adults. There is also an inverse relationship between the incidence of sudden cardiac death and absolute number of events in the various epidemiologic or clinical categories of coronary artery disease [3,10,11].
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Among the general adult population beyond the age of 35 years, overall sudden death risk is 0.1–0.2% per year, and there is a gradient of increasing risk that correlates with the progressive clinical expression of coronary artery disease (Fig. 2). These subgroups progress from multiple high-risk markers through prior myocardial infarction, low ejection fraction and congestive heart failure, to survivors of out-of-hospital cardiac arrest and highly specific very-high-risk subgroups in post-myocardial infarction patients. There is as much as a 300-fold increase in risk across this sequence. However, the increase is accompanied by a progressive and steep decrease in the absolute number of victims in that risk category. The highest risk subgroups account for a minority of the sudden death victims, and the lowest risk groups have such a large denominator relative to event rates that they are impractical for specific therapeutic interventions. Thus, one of the most important challenges is to identify specific individuals at risk for sudden cardiac death within the large population pools that constitute the categories with lower overall incidence. This challenge will be met only by understanding the fundamental causes of lethal arrhythmias, through new basic, clinical and population studies.
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In the early years of appreciation of the magnitude of sudden cardiac death as a public health problem, risk factors for coronary atherosclerosis were used as general predictors for risk of SCD [12]. Such approaches are useful for general epidemiologic considerations, but lack the power to guide interventions for individual patients. Subsequently, clinical markers of risk received increasing attention. During the time period from the late 1970s through the early 1990s, the powerful clinical marker, ejection fraction, was combined with various arrhythmic markers (e.g. inducible VT, spontaneous non-sustained VT) in attempts to identify specific individuals or subgroups at particularly high risk. During this period, it was learned that as the ejection fraction fell below 40%, it was a powerful increase in mortality risk generally, including for SCD risk. There is no evidence that ejection fraction or other specific hemodynamic parameters has discriminating power for sudden death risk, however. At the same time, it gradually became appreciated that there were several electrophysiological and arrhythmic markers helpful in risk stratification, although it was still not clear that they identify arrhythmic risks specifically. Nonetheless, a combination of arrhythmic markers combined with a low ejection fraction appears to identify a population of patients who benefit from antiarrhythmic interventions with the ICD. The limitation of these observations is that they apply to only the highest risk subgroups and the magnitude of intervention benefit is limited by non-arrhythmic mortality risks that are not controlled by the interventions.
Other clinical approaches that have been studied in some detail have been disappointing. The use of electrophysiological surrogates has not yet provided tools that are useful for identifying higher risk subgroups in various categories of patients. Measures such as signal-averaged electrocardiography (SAECG) have been shown to provide excellent negative predictive value, but relatively low positive predictive value in postmyocardial infarctions. Its use as a discriminator for ICD benefit in a study of prophylactic ICD therapy in coronary bypass surgery patients (CABG-Patch) led to a disappointing outcome. There was no apparent ICD benefit [13], although the study was limited by confounding influences that may have partially hidden some benefit [14]. Other surrogate markers, such as QT interval dispersion and T-wave alternans, are still understudied. Their value as independent predictors of sudden cardiac death has been inconsistent [15], although preliminary data for T-wave alternans as a predictor appear promising. Another marker for arrhythmic risk centers on the interactions between autonomic nervous system activity and cardiac electrical function. These are expressed in measures such as heart rate variability and baroreflex sensitivity. For these, it is still not clear that they are specific arrhythmic mortality markers, and they are also of relatively low positive predictive accuracy.
Transient risk prediction and individual risk prediction based upon familial and genetic characteristics are in their infancy, but offer promise of better predictive accuracy. Transient risk has been of interest to clinical investigators for a number of years [16]. The concept is based on the premise that there is a cascade of risk that begins with general predictors for underlying disease (e.g. coronary artery disease risk factors), which is further conditioned by the presence of the disease (Fig. 2). The conditioning risk factor then forms the substrate for reaction to triggering events that lead to fatal arrhythmias. The triggering events are such diverse factors as transient ischemia, autonomic dysfunction, hemodynamic dysfunction, and various environmental influences, including ingested substances which may alter electrophysiologic properties. The notion for risk prediction based upon transient risk factors converts the transient risk factor from a pathophysiologic influence to a specific predictor of risk.
Nonetheless, it is not likely that transient risk factors alone will serve as a sufficiently powerful risk factor for sudden cardiac death that can be defined in advance of an acute event. More likely, the transient risk factor would have to be integrated with individual risk profiling based on other measures of individual susceptibility (see below).
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3 Evaluating new therapeutic interventions |
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TopAbstract1 Introduction2 Clinical epidemiology3 Evaluating new therapeutic...4 Progress in risk...5 Predictors of SCD...6 Opportunities for progress7 ConclusionsReferences |
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Therapeutic strategies for the prevention of sudden cardiac death are divided into two general categories, primary and secondary prevention. The term ‘primary’ in regard to prevention of sudden cardiac death is at variance with the conventional definition of primary prevention, the latter referring to prevention of the underlying disease. By usage in the arrhythmia field, ‘primary’ has come to mean prevention of the first potentially fatal arrhythmic event.
Secondary prevention in this field is used to describe prevention of a recurrence of a potentially fatal arrhythmia or cardiac arrest among patients who have had prior events. Within each category, the most common antiarrhythmic strategies have been antiarrhythmic drugs and implantable ICDs. Ancillary approaches, such as catheter and surgical revascularization and various types of ablation procedures, are less well-studied, but appear useful for some narrowly defined subgroups.
β-Adrenergic receptor antagonists have been demonstrated to have a total mortality benefit, including SCD prevention by secondary analyses, in a number of clinical settings. They have been especially useful in patients with prior myocardial infarction and ischemia, and beneficial even in the presence of a much reduced ejection fraction. Their effects to specifically reduce both total and arrhythmic mortality were demonstrated in the early 1980s in the BHAT trial and have been confirmed repeatedly in various populations since that time. In that study propranolol provided a reduction in mortality from 
10% to 5 or 6% when compared to placebo, in high risk postinfarction patients over a two year follow-up period [17]. Specific reductions in all cause and cardiac mortality, as well as arrhythmic deaths, were noted and have since been demonstrated in a wide range of at-risk cardiac patients, including those with confounding symptoms of heart failure, diabetes, pulmonary and renal diseases in individuals of various age, sex and racial distributions [18]. In general, absolute mortality reductions of 5–30% are observed, with relative reductions ranging from 20 to 50% depending on population studied and comorbidities. Also, although there remain major questions concerning whether amiodarone has significant total mortality benefits, despite antiarrhythmic properties, there is evidence from two recent trials (CAMIAT and EMIAT) that when used in combination with β-blockers, there is a synergistic protective action between the two drugs that results in additional mortality benefits [19]. Explanations for this synergism are still elusive and require confirmation by prospective studies, but considering the relatively limited absolute levels of protection achievable with either of these compounds alone, the pharmacological basis of the interaction deserves further investigation.
A great deal of earlier evidence suggests few, if any, traditional ion channel-directed drugs are clinically useful in most patients with common forms of ischemic or structural disease [1,20]. Because sudden cardiac death is closely related to the severity of underlying heart disease and ischemia, there has also been a growing interest to use alternate drug approaches that may halt or delay progress of cardiac diseases or prevent the occurrence of acute ischemic events. At present, it is difficult to evaluate the contribution of commonly used non-antiarrhythmic drugs, such as aspirin, angiotensin-converting enzyme-inhibitors or statins, to the reduction of sudden cardiac death because of the lack of trial evidence that these drugs reduce the incidence of arrhythmic deaths, despite their benefits in reducing cardiovascular morbidity, and perhaps total mortality, in patients with pre-existing clinical manifestations of heart disease. Event rates in primary prevention study populations have been too low to determine any potential impact [11].
Other primary prevention trials have focused on comparison of ICD therapy to drug therapy, largely with amiodarone, in higher risk patients. Three large-scale, randomized trials aimed at reducing mortality by prophylactic ICD therapy have been completed (see Fig. 3) [13,21–23]. MADIT and MUSTT tested the hypothesis that device therapy reduces mortality, compared to antiarrhythmic therapy [21,22] and CABG-Patch compared device therapy to usual therapy [13]. Two of the trials which used similar predefined risk variables, including left ventricular ejection fraction, documented non-sustained ventricular tachycardia, and inducibility of sustained ventricular tachycardia during programmed electrical stimulation, showed that prophylactic ICD therapy reduces mortality [12,22]. The third trial used an arrhythmia surrogate, a positive SAECG rather than manifest or inducible arrhythmias, to stratify patients for randomization to ICD therapy versus standard therapy after undergoing coronary revascularization surgery [13]. That study did not identify benefit from prophylactic ICD therapy, emphasizing the possible importance of specific risk markers and patient selection in this type of trial.
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A practical problem limiting the application of the published randomized trials showing the benefit of prophylactic cardioverter-defibrillator therapy is that there are few data on the prevalence of those patient subgroups studied in the disease population [23]. The patients included represent only a small subgroup of those consulting healthcare professionals because of symptoms, worsening of their health status, or other cause. Therefore, the need for routine screening of patients for prophylactic cardioverter-defibrillator therapy, the cost-efficacy of this screening and the clinical applicability of the results of the study are additional areas where a great deal more progress is required. In order to achieve this, highly-powered predictors of sudden death, easily applicable to large populations without identified heart disease or mild to moderate manifestations of disease, are required.
The only evidence-based therapeutic strategy today for SCD prevention in patients who have survived a life-threatening arrhythmic event, is implantation of a cardioverter-defibrillator. Even for this therapy, all the outcome data have been based on comparisons to other active therapies. Thus, absolute benefit compared to placebo or usual therapy remains unknown [24]. Since the introduction of the first implantable cardioverter-defibrillator in 1980, device prescription and acceptance for patients who have survived cardiac arrest or sustained ventricular tachycardia have increased remarkably, even though trial-based evidence supporting benefit has been lacking until recently [2]. The first secondary prevention trial demonstrated mortality benefit of cardioverter-defibrillator therapy compared to anti-arrhythmic therapy among patients with a clinical history of life-threatening arrhythmic events and depressed left ventricular function [25]. Similar results have been reported in two smaller randomized trials [26,27]. In a subgroup analysis, it was observed that patients with better-preserved left ventricular function, that is ejection fractions in the range 35–40%, enjoy no advantage of cardioverter-defibrillator therapy over drug therapy [28]. This is a secondary analysis, however, which suggests, but does not prove, that the device therapy does not provide a survival benefit in this subgroup. Because patients surviving a life-threatening arrhythmic event and an ejection fraction >35% represents a relatively large clinical patient group, more research effort and well-designed trials are needed to refine indications for use of this very important addition to clinical care.
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4 Progress in risk factor identification |
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TopAbstract1 Introduction2 Clinical epidemiology3 Evaluating new therapeutic...4 Progress in risk...5 Predictors of SCD...6 Opportunities for progress7 ConclusionsReferences |
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Much of the uncertainty in assessing SCD risk in large populations where incidence is low, but prevalence high, reflects the multifactorial nature of the causes of cardiac arrest and mechanistic complexities in the origins of potentially lethal arrhythmias. Another issue is that as indicated above, most of the early work on SCD prediction has focused almost exclusively on chronic conditioning factors that reflect coronary disease (e.g. LDL and total cholesterol levels, hypertension, obesity, diabetes, tobacco use, etc.), or secondary indicators of alterations in myocardial contractile and structural failure, such as ejection fraction, rather than on more discrete indicators of the immediate causes and triggers of electrical instability. More recently, this situation has changed somewhat, encompassing an interest in markers of thrombotic events associated with acute infarction. Although encouraging, this has not yet led to large improvements in SCD prediction. Most of these newer activities involve a focus on indicators of plaque progression, rupture and erosion, vascular reactivity, thrombosis and even calcium deposition. New markers, such as the inflammatory indicator c-reactive protein [29], or indicators of thrombolytic status, for example the fibrinolytic peptide, D-dimer [30], appear to be useful independent markers in some patient categories. Nevertheless, it appears the major use of most of these factors will be in enhancing specificity for secondary, rather than primary events. Thus, the preoccupation with indicators of atherothrombotic ischemic occlusion that has so characterized the focus of SCD risk assessment in the past, seems to continue to predominate thinking in this field today. Despite considerable evidence, this supposition needs to be carefully reexamined.
Reasons why markers of ventricular electrical instability and of membrane arrhythmogenesis have only been of limited value are, as noted above, that they have been generally ineffective for primary SCD prevention in the relatively large population subsets where improvements are so sorely needed. Also, although there has been much progress on the fundamental causes of potentially lethal arrhythmias, incorporation of this basic information into effective strategies for development of new, more efficacious risk factors, has only recently begun. Those electrical surrogates that have appeared, (e.g. SAECG, QT dispersion, etc.) have either been unreliable, or valid positive predictors only in relatively narrow subgroups, most of whom have already been identified clinically. New indicators, like microvolt T-wave alternans and related electrocardiographic approaches, await rigorous testing in different clinical populations at different stages of disease development. Longitudinal evaluation of large groups of non-symptomatic subjects, and comparisons using ICD discharge endpoint data in patients with well characterized and marginal pathologies, may eventually help overcome some of these limitations [31].
Developing better indicators of transient risk, in addition to those reflecting tissue-substrate arrhythmogenicity, has also been thought an especially useful area in which to expand on present efforts [15]. Unfortunately, there are very few clues here to build on, and there has been little information from epidemiological studies. The notion of modeling transient clinical risk factors as epidemiological markers is relatively new, and is awaiting development of useful approaches for guiding mechanistic interventions on factors associated with arrhythmogenesis. Only recently have these types of studies begun to provide information on environmental, drug, or familial factors associated with transient SCD risk. One large study currently underway, Triggers of Ventricular Arrhythmias or TOVA, enrolling high risk patients with ICDs, may help shed light on this aspect [J. Muller, personal communication]. More clinical data, and especially much greater attention to characterization of patient phenotypes, including detailed information on events preceding occurrence of SCD in individuals enrolled in the large epidemiological studies like Framingham, will be very important in establishing reference data useful for future efforts on this aspect of the problem. Also, as more experience is obtained with some of the newer markers of electrical stability, like T-wave alternans, it should be possible to establish better behavioral and environmental profiles useful in phenotyping for indicators of SCD vulnerability. Until more progress is achieved on these goals, invasive approaches, like programmed stimulation or electrogram fractionation analysis [32], are likely to remain clinically helpful for individuals, even if impractical for large populations. Also, as demonstrated in the recent MUSTT study [22], there remain limitations even with invasive approaches, that seriously limit sensitivity and specificity.
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5 Predictors of SCD susceptibility |
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TopAbstract1 Introduction2 Clinical epidemiology3 Evaluating new therapeutic...4 Progress in risk...5 Predictors of SCD...6 Opportunities for progress7 ConclusionsReferences |
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An accumulating body of research information has begun to suggest there may be molecular, genetic, and biophysical or biochemical indicators of ventricular arrhythmia risk that could be useful in widescale screening. These views are based on the mechanistic supposition that potentially lethal arrhythmias may arise as a result of a critical coincidence at three different levels or dimensions of cellular and tissue dysfunction [33,34]. The first involves alterations in structure and function of membrane elements of electrogenesis and transcellular activation (i.e. at the level of ion channel, exchange and gap junction proteins) as would occur during disease ‘conditioning’, cardiac remodeling, or in response to hypertension, structural failure or aging.
The second dimension relates to defects in propagation and macroscopic pathways of activation resulting in changes in normal waveform direction and stability, and hence conduction abnormalities and reentry. Such events might be explored in developing new imaging approaches or biochemical indicators, such as markers of altered collagen metabolism or changes in the activity of specific matrix metalloproteinases. Improved non-invasive indicators of activation dispersion, conduction, or heritable anisotropy (e.g. congenital abnormalities) might also be useful. The third dimension involves detection of biochemical or electrical triggers that affect cellular electrogenesis and tissue stability, or those that indicate compromises in normally protective mechanisms of electrical control. Effective indicators here could involve neurally-based approaches to detect imbalances in specific brain centers and pathways and in systemic autonomic states. For example, detection of changes in circulating transmitters or metabolites, minimally invasive measurements of regional tissue redox state, pH, energetic intermediates and alterations in compartmentalization of critical ions such as calcium, all may offer reflections of electrical stability. Given the biological complexity of the settings in which most SCD events occur, observations of specific constellations of arrhythmic endpoints or recognition of signature patterns of change in multiple markers, as might occur in response to specific ‘conditioning’ or remodeling events, may be among the most widely useful.
Much of the recent excitement about using these kinds of analyses on epithelial or blood samples, is derived from molecular-genetic studies over the past 5 years suggesting that the genetic mutations underlying SCD susceptibility in individuals with rare inherited arrhythmias, (i.e. long QT Syndrome, Brugada's Syndrome, Lev's disease, etc.) can be done routinely on very small DNA and protein samples using high-throughput individual and/or patterned array screening techniques. Approaches to detect high frequency changes in such parameters might eventually be developed in the same way that others used for detection of inborn errors of metabolism, are employed today (e.g. phenylketonuria, etc.). At this stage, the issues seem to be to determine which specific changes carry significant risk for which groups of individuals in order to justify development. Fig. 2 illustrates there are many levels where such variation might occur, with some events at each level being more proximal to the causes of electrical arrhythmogenesis than others. As suggested by the figure, focus on proximal final common mechanisms of electrogenic dysfunction, rather than distant atherothrombotic elements of risk, may be more generally useful in low incidence populations, especially those without presenting clinical symptoms.
The possibility that normally silent genetic changes contribute to increased vulnerability in proximal risk factors, resulting in increased likelihood of ventricular arrhythmias or fibrillation, is supported, but certainly far from proven, by two additional lines of evidence. First, longitudinal population studies in both Paris [35] and Seattle [36] have shown that relative SCD risk in offspring of parents with a history of SCD as the manifestation of acute coronary events, can be elevated and relative risks increased as much as 50% when compared to unaffected families. This threat appears independent of traditional atherothrombotic risk factors for CAD [34]. Second, very recent work on the frequency of nucleotide variability in critical ion channel genes, suggests single and multiple nucleotide polymorphisms are surprisingly common in the genes for such structures. Spontaneous and inherited variations in coding sequences for many of those same channel subunits responsible for rare inherited arrhythmia syndromes (i.e. HERG, KvLQT1, minK, miRP1, and SCN5A) are being found on almost a daily basis in different genotyping centers across the world. For example, there is now good evidence for the existence of at least ten such variations with overall population frequencies of at least 5% and discovery has only just begun [D. Roden, personal communication]. Also, such estimates presently do not include potential variation within non-coding regulatory sequences, nor variation in possible ‘modifying’ genes, only now beginning to be analyzed. Examples of the latter seem likely to include alterations in genes for cholinergic and adrenergic pathways and other regulatory molecules, like G-protein subunits or nuclear transcription factors that control regional expression of different electrogenic proteins in various cardiac tissues [34].
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6 Opportunities for progress |
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TopAbstract1 Introduction2 Clinical epidemiology3 Evaluating new therapeutic...4 Progress in risk...5 Predictors of SCD...6 Opportunities for progress7 ConclusionsReferences |
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A number of additional questions need to addressed to determine whether detection of molecular variation in genes which may participate in arrhythmogenesis have a place in future approaches to SCD risk stratification. These include whether, which, and to what extent such nucleotide substitutions actually alter in vivo cardiac electrical stability and whether they can be developed into reliable screens for large populations. Many different approaches to these issues are likely to be required in future studies, but two present activities stand out as especially important. First, alterations in amino acid sequences resulting from those mutations that have been detected, are beginning to be analyzed in systematic ways to determine the type and extent of molecular dysfunction resulting from different types of protein structural change. Biophysical studies on some of these mutant proteins are also beginning to show how a change in specific functional domains and tertiary structures alters electrogenesis and its regulation within the membrane. Second, whole animal transgenic models can now be readily constructed to evaluate the in vivo consequences of particularly suspect mutations. Studies of this type have recently been highly successful in examining molecular alterations of specific myosin mutations underlying elevated incidence of SCD in patients with familial hypertrophic cardiomyopathy, and the results as well as the approach lead the way in developing new methods of understanding the causes of lethal arrhythmias [37,38].
Other new advances useful in SCD risk assessment are those likely to emerge from genetic epidemiological investigations of populations where enhanced levels of vulnerability to SCD have already been established. Longitudinal studies such as some of those in Paris and Seattle have already identified individuals with high familial risks of SCD not associated with atherothrombotic disease, and some of these cohorts are currently being evaluated for mutations in the same genes implicated in patients with rare inherited arrhythmic syndromes. Other investigators are approaching the problem using genome-wide scans in ongoing cardiovascular surveillance studies, looking for secondary modifiers and additional linkage sites, but as yet this work is only just beginning.
Finally, in closing, it would seem worthwhile to very briefly consider the extent patients in average community populations might benefit from improvements in individualized SCD risk assessment using these new molecular approaches. While the majority of SCDs occur in patients known to be at risk for coronary heart disease or with manifest disease [3], the results of a recent study which reported on a series of 270 sudden deaths over a 13-year period in the Minneapolis-St. Paul area are of interest [39]. In this work, autopsy and medical records indicated, not surprisingly, that specific cardiac structural explanations could be detected in a majority of SCD cases (i.e. 180 out of 270, 67% of cases) and that findings indicative of CAD (i.e. 117 cases) were most common. Congenital abnormalities, especially valvular and atrial-septal defects, were also frequent (25 cases), while diverse findings including myocarditis, right ventricular dysplasia and hypertrophic cardiomyopathies, accounted for the remainder. In addition, ‘non-specific’ structural abnormalities, wall thickening, fibrosis, and other findings were noted in 76 cases (28%), while the number with no apparent pathology, where unexpected death was the only manifestation of disease, was only 14. In this sample then, the number not associated with detectable pathologies was about 5%, while those occurring without overt indications of athero-thrombotic CAD was about a third.
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7 Conclusions |
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TopAbstract1 Introduction2 Clinical epidemiology3 Evaluating new therapeutic...4 Progress in risk...5 Predictors of SCD...6 Opportunities for progress7 ConclusionsReferences |
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In coming years, we anticipate that further developments in individual clinical profiling, advancements in applications of non-invasive markers of risk, better methods to detect latent cardiac structural deficiencies, and an increasing application of molecular and genetic profiling will lead to the identification of SCD risk. If successful, this approach could have a substantial positive impact on SCD risk assessment. The challenge will be to determine which new methodologies and combinations of specific markers are best suited to particular categories of individuals and to establish their validity through rigorous clinical assessment.
Time for primary review 3 days.
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Acknowledgements |
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Dr. Myerburg is funded in part by the Louis Lemberg Chair in Cardiology and the American Heart Association Chair in Cardiovascular Research at the University of Miami, Miami, Florida, and by a grant from the NIH, NHLBI, HL21735.
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TopAbstract1 Introduction2 Clinical epidemiology3 Evaluating new therapeutic...4 Progress in risk...5 Predictors of SCD...6 Opportunities for progress7 ConclusionsReferences |
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