Sudden cardiac death: Prevalence, pathogenesis, and prevention

Abstract

Sudden cardiac death (SCD), also known as sudden arrest, is a major health problem worldwide. It is usually defined as an unexpected death from a cardiac cause occurring within a short time in a person with or without preexisting heart disease. The pathogenesis of SCD is complex and multifaceted. A dynamic triggering factor usually interacts with an underlying heart disease, either genetically determined or acquired, and the final outcome is the development of lethal tachyarrhythmias or, less frequently, bradycardia. It has increasingly been highlighted that a reliable clinical and diagnostic approach might be effective to unmask the most important genetic and environmental factors, allowing the construction of a rational personalized medicine framework that can be applied in both the preclinical and clinical settings of SCD. The aim of the present article is to provide a concise overview of prevalence, pathogenesis, clinical presentation, and diagnostic approach to this challenging disorder.

• Cardiomyopathy
• genetic testing
• heart
• sudden cardiac death

Introduction

Sudden cardiac death (SCD) (also called sudden arrest) is defined as an unexpected death from a cardiac cause occurring within a short time, generally within 1 hour of symptom onset, in a person with or without preexisting heart disease 1. It is a major health problem worldwide, since the annual incidence of SCD in the general population is estimated as 1 in 1,000 2, and more than 3 million persons die annually 2, 3. Despite the multiple advances in the field of cardiovascular medicine and the efforts in medical care, neurologically intact survival rates remain poor, usually less than 20% 4. The prevalence of SCD has two peaks, one between birth and 6 months of age (sudden infant death syndrome (SIDS)) and the other between 45 and 75 years of age 2.

The pathogenesis of SCD is complex and multifaceted. Basically, a dynamic triggering factor interacts with an underlying heart disease, either genetically determined or acquired, and the final outcome is the development of lethal tachyarrhythmias or, less frequently, bradycardia 5. The acknowledgement of the most common precipitating factors, along with the early identification of individuals at highest risk, are essential requisites to limiting the burden of this challenging pathology. Major inroads into profiling individual or population risk of SCD both require better understanding of each of epidemiologic-clinical-physiologic interactions. The disciplines range from epidemiology, through clinical medicine, membrane channel physiology, genetic determinants, and molecular biology 6. A possible laboratory aid in the early identification of subjects at high risk might come from genetics and molecular biology. The so-called ‘personalized medicine’ may come to play an important role, for both prevention and treatment of SCD cases occurring in subjects affected by genetic cardiovascular disease. Accordingly, the identification of subjects at major risk through gene-based diagnosis of all family members should be regarded as a priority for health care practitioners. The genetic basis for cardiomyopathic processes vulnerable to sudden arrhythmic death—hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and ion channel diseases—is now largely acknowledged 7. However, the extension to routine genetic testing is currently limited by technical difficulties and costs.

Pathogenesis

The pathogenesis of SCD is apparently multifactorial and incompletely clear. It has been hypothesized that single or multiple dynamic factors, possibly transient, interact with a disease substrate to precipitate the arrhythmia. All known heart diseases can be the substrate in SCD, but in 60%–80% of cases SCD occurs in the setting of a preexisting coronary artery disease (CAD) 2, 3. Sudden cardiac death is the first presentation in about one-third of the patients with CAD, and it is three times more common in men than in women. Most other SCD events occur in non-ischemic cardiomyopathy, infiltrative, inflammatory, and acquired valvular diseases. A small percentage of SCDs manifests in the setting of ion channel mutations responsible for inherited abnormalities, such as the long/short QT syndromes, Brugada syndrome, and catecholaminergic ventricular tachycardia 2, 3. In children and young athletes the two main causes of sudden death are long QT syndrome and hypertrophic cardiomyopathy. Most instances of SCD involve ventricular tachycardia degenerating to ventricular fibrillation and subsequent asystole. Some cardiac arrests in SCD are due to bradycardia.

Wake-up time, first day of the working week, winter season, physical activity, emotional upset, overeating, lack of sleep, social drugs (cocaine, marijuana), anger, and sexual activity are among the most common triggers 8. Dynamic factors also include transient ischemia, pH and electrolytes imbalance, inflammation, hypoxia, stretch, and ion channel abnormalities. Other changes could also occur, such as plaque rupture 2. The role of external events and the nature of the pathophysiological mechanisms causing SCD are still poorly understood. A relative hyperadrenergic tone related to abnormalities of the autonomic nervous system is suspected in the triggering mechanisms of SCD 9. Moreover, in specific genetic situations, such as long QT-3 (LQT3) syndrome, in which it is demonstrated that torsade de pointes is bradycardia-dependent or pause-dependent, bradycardia is an important trigger of SCD 10. Patients with bradycardia can have severe tachyarrhythmias but it is unclear whether bradycardia alone can induce arrhythmias or whether an additional substrate is necessary 5. Depressed parasympathetic tone is also associated with an increased risk of SCD 11. Accordingly, involvement of the autonomic nervous system is suggested by the occurrence of ventricular tachyarrhythmias and SCD at rest or during sleep and by changes of typical electrocardiogram (ECG) signs in patients with Brugada syndrome 12.

Key messages

• Sudden cardiac death, also known as sudden arrest, is a major health problem worldwide.

• The pathogenesis of sudden cardiac death is complex and multifaceted, involving dynamic factors that usually interact with underlying heart diseases, and finally trigger lethal tachyarrhythmias or bradycardia.

• The implementation of preventive and diagnostic strategies might be effective to unmask the most important risk factors for sudden cardiac death, constructing personalized medicine frameworks that can be applied to limit the onset of this challenging disorder.

Potential substrate in sudden cardiac death

Long QT syndrome

Long QT Syndrome (LQTS) is an inherited disorder of the heart's electrical system characterized by prolonged ventricular repolarization (QT interval) and by ventricular tachyarrhythmias. The exact prevalence of LQTS remains to be determined, although an estimate of 1 in 10,000 has been suggested 13. LQTS causes a sudden type of ventricular tachycardia commonly called ‘torsade de pointes’ (TDP), and patients are at high risk of developing syncope and sudden death, often at a young age. TDP is a polymorphic ventricular tachycardia with a peculiar electrocardiographic pattern of continuously changing morphology of the QRS complex twisting around an imaginary baseline 14. In LQTS patients, cardiac arrhythmias are often induced by stress and emotion, although in some cases they may also occur at rest or during sleep 15. Several genes have been identified and are responsible of different varieties of LQTS. The symptoms of LQTS occur only when the patient develops an episode of torsade de pointes, and the degree of symptoms depends on the length of time the arrhythmia persists. Two patterns of inheritance have been identified: the more common autosomal dominant Romano-Ward syndrome (RWS) and Timothy syndrome 16, and the much rarer autosomal recessive cases. Mutations in ten genes have been discovered, eight of them encoding cardiac ion channel subunits 17, 18, and two encoding an anchoring protein that has been implicated in controlling ion channel targeting specific membrane sites 19. The RWS is a genetically heterogeneous disease caused by mutations in at least four genes (LQT1 to LQT4). Three of them (LQT1 to LQT3) have been identified and encode for ion channel subunits, respectively for two potassium channels, and one sodium channel. To date, nearly 100 different mutations have been reported as responsible for the cardiac long QT syndrome 20. There is also a recessive form of LQTS, the Jervell and Lange-Nielsen syndrome (JLNS). Patients with JLNS experience a high rate of cardiac and fatal events from early childhood despite medical therapy 21.

The number of genetic carriers of LQTS mutations in the population is around 5–10 per 100,000. In the severe forms of RWS, the affected subjects usually experience syncope due to ventricular arrhythmias during the first decade of life and sometimes in early childhood, most often induced by physical exercise or emotion. Rarely, it can also occur at rest, and cardiac arrest can be the first presentation of the disease. The availability of genetic testing has led to an understanding of important clinical differences between the individual genetic disorders 22. Patients with LQT1 are at particularly high risk of cardiac events during physical exercise, especially swimming. Patients with LQT2 are susceptible to cardiac events during emotional or auditory stimuli and during the postpartum period 23. Unexpectedly, women affected by the common RWS mutations are at lower risk for cardiac events during pregnancy but regional anesthesia can represent a risk factor in such forms of RWS 24. The LQT8 form of long QT syndrome, also known as Timothy syndrome, is a multisystem disorder associated with gain-of-function mutations in cardiac calcium channel activity, particularly L-type calcium current (I(Ca,L)). The L-type Ca^2 + channel plays an important role in action potential generation, morphology, and duration. The result of calcium channel mutations is that they remain open for much more than a millisecond at any one time, and intracellular calcium is raised to toxic levels 25.

Short Q-T

The short QT syndrome (SQTS) is characterized by a short QT interval (QT and QTc ≤ 300 ms) during an electrocardiogram (ECG), and by a high risk of syncope or sudden death due to malignant ventricular arrhythmia. It is a clinical entity originally described in 2000 24 that usually affects young and healthy subjects with no structural heart disease and may be present in sporadic cases as well as in families 26. It has been associated with a gain of function in three distinct potassium channels (KCNH2, KCNQ1, and KCNJ2) 27. The possible substrate for the development of ventricular tachyarrhythmias in these patients may be a significant transmural dispersion of the repolarization due to a heterogeneous abbreviation of the action potential duration 27. The definitive link between short QT syndrome and familial sudden death was described by Gaita et al. in 2003, with the clinical report of two families with short QT syndrome and a high incidence of SCD 28. One year later, the genetic and biophysical basis for the disease, as well as a possible therapeutic approach, was acknowledged 28, 29. Hereditary short QT syndrome is a clinical ECG entity with an autosomal-dominant mode of transmission, and it is the most recently described channelopathy. The syndrome may affect infants, children, or young adults with a strong positive family background of SCD 26.

Ion channel dysfunction

Electrolyte depletion may represent an important but potentially reversible factor in the development of malignant ventricular arrhythmias causing SCD 30. Fundamental changes in calcium handling in heart failure (HF) are thought to account for abnormalities in excitation–contraction coupling. Although alteration of the calcium transient (CaF) is associated with and influences the static and dynamic changes in the ventricular action potential (AP), the precise relationship remains unclear, and the role of spatial and temporal dispersion of CaF in arrhythmogenesis in the failing heart remains to be clarified. The failing heart exhibits a defect in Ca^2 + cycling reserve, which may be particularly pronounced in the endocardium 31. A significant association between magnesium depletion and lethal arrhythmias has also been proposed by the finding of depressed myocardial magnesium content in victims of SCD 32. Hypomagnesemia and depletion of intracellular magnesium stores have been held responsible for a variety of cardiovascular and other functional abnormalities, including various arrhythmias, impairment of cardiac contractility, and vasoconstriction 33. Although serum magnesium measurement is not always a good surrogate for the magnesium body content, its measurement, as part of the electrolyte profile of congestive heart failure (CHF) patients, might, however, assist in the early prevention and detection of magnesium depletion. This would go a long way to reducing the susceptibility to lethal arrhythmias and sudden death, though it should also be mentioned that the role of intravenous magnesium, especially in the management of acute myocardial infarction, remains controversial 34.

In patients affected by sudden unexplained nocturnal death (SUND), even if this fatal event could be a consequence of arrhythmogenic cardiomyopathies like the long QT syndromes, potassium deficiency is probably one among the causal factors. Serum and urinary potassium have been measured and indicate a deficiency of the electrolyte 35. SCD occurs in other less frequent electrolyte diseases, such as Bartter and Gitelman syndromes 36. Patients affected by these syndromes are characterized by hypokalemia, and QTc prolongation has been proposed as a potential mechanism 36. Contrarily, exercise-induced hyperkalemia has been suggested as a factor in SCD in young athletes 37.

Coronary artery disease

SCD may be the first clinical manifestation of CAD in as many as one in five patients with coronary heart disease and about 20% of CAD patients have cardiac arrest as the first clinical manifestation 38. Many survivors of SCD suffer from concomitant CAD 39. Among the many manifestations of CAD, acute coronary syndrome (ACS), ranging from unstable angina to acute myocardial infarction, is the most catastrophic event and, despite improved treatments of CAD, ACS results in sudden death or permanent disability in a substantial percentage of patients 40. The presence of CAD is a major risk factor for SCD usually by reducing ejection fraction and by triggering ventricular tachycardia degenerating into ventricular fibrillation 41. Ventricular tachycardia, on the other hand, is mostly due to a reentrant mechanism caused by infarct-related scarring 42. The progression from conventional risk factors of CAD to arrhythmogenesis and SCD can be represented as a cascade of events: atherogenesis, changes in atherosclerotic plaque anatomy, disruption of active plaque, activation of the thrombotic cascade and acute occlusion, followed by acute changes in myocardial electrophysiology which become the immediate trigger for arrhythmogenesis and SCD 43. Moreover, it was observed that the risk of SCD among patients with acute coronary events is closely related to the family history. In particular, SCD as a manifestation of the first acute coronary event appears to cluster in certain families, which suggests a strong genetic background 44. 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 45. Clinical studies in patients with significant CAD without HF have implied that a primary arrhythmia without an acute ischemic event may be the primary mechanism of SCD in the majority of patients 45. In autopsy series, however, acute coronary findings are often present in patients who die suddenly, particularly those with CAD 46, 47. In autopsy studies, a fresh thrombus, recent myocardial infarction (MI), or plaque rupture was found in 57%–73% of CAD patients without HF who died suddenly 46, 47. Therefore, although significant progress has been made in the treatment of ischemic heart disease, SCD still remains a serious problem.

Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a relatively common primary cardiac disorder defined as the presence of a hypertrophied left ventricle, correlated with diastolic dysfunction, myocardial ischemia, and arrhythmias, in the absence of any other diagnosed etiology. Left ventricular hypertrophy is associated with myofibril disarray and interstitial fibrosis 48. The introduction of molecular genetics during the past decade has provided a new paradigm for the diagnosis of HCM, offering a better understanding of the pathogenetic mechanisms, along with the individualization of distinct anatomic and functional risk patterns. HCM is the most common form of genetic cardiovascular disease, and it is responsible for 1 case in every 500 individuals 48.

In 1989, HCM was mapped to chromosome 14 in a French-Canadian pedigree with autosomal dominant disease and, thereafter, mutations in cardiac β-myosin heavy chain (MHC) were shown to cause HCM 49. More than 250 mutations involving 11 disease genes have been identified so far, and 9 of these encode proteins that constitute the contractile apparatus of the cardiac muscle cell. Mutations scattered among at least ten sarcomeric genes confer the pathogenetic substrate for this disease of the sarcomere/myofilament 50. Recently, Ellinor et al. have mapped a novel locus for cardiomyopathy, diffuse myocardial fibrosis, and sudden death to chromosome 10q25-q26. It is principally inherited as an autosomal dominant pattern characterized by a considerable genetic heterogeneity, both intergenic and intragenic. Lately, the genetic spectrum of HCM has expanded to encompass mutations in Z-disc-associated genes (Z-disc HCM) and glycogen storage diseases 50. Genetic studies showed that approximately 20% of genetically affected adults are healthy carriers without any ECG or echocardiographic abnormality. The disease is caused by disorders that directly affect the generation or regulation of contractile energy. Recently, other proteins not related to sarcomeres, such as the adenosine monophosphate (AMP)-activated protein kinase, have been identified as contributors to the development of similar phenotypes 51. HCM remains the main cause of sudden death in top-class sportsmen and women; SCD also represents the most devastating aspect of obstructive and non-obstructive HCM. Particularly, loss of consciousness associated with ventricular arrhythmia identifies patients at very high risk of SCD. Genetic insights have now provided remarkable implications for a genotype-phenotype correlation. Although there is substantial clinical diversity among patients with the identical mutation, some polymorphisms might be associated with significant premature death, whereas life expectancy appears normal with others. Whether or not healthy carriers of a mutation are at risk of developing a later form of disease is presently unknown.

Dilated non-ischemic cardiomyopathy

Dilated cardiomyopathy (DCM) is associated with a high incidence of malignant ventricular arrhythmias and SCD. Abnormalities in repolarization of ventricular myocardium have been implicated in the development of these arrhythmias 52. In particular, the heart cells of patients affected by DCM display significantly prolonged action potentials compared with those from normal myocardium, regardless of the mechanism involved in the development of cardiomyopathy. In the DEFINITE (DEFIbrillators in Non-Ischemic cardiomyopathy Treatment Evaluation) study, the use of statins was associated with a reduction in mortality, probably associated with a reduction in arrhythmic sudden death 53. Patients with non-ischemic dilated cardiomyopathy and preserved heart rate variability (HRV) have an excellent prognosis and may not benefit from prophylactic implantable cardioverter defibrillator (ICD) placement 53.

Congenital and acquired structural heart diseases

One-third of sudden deaths in the young may be attributable to structural defects present since birth. A large spectrum of congenital heart disease involves the risk of sudden death, but most structural defects are usually not considered to be life-threatening 54. Several studies reported on the incidence of sudden death in patients with a broad variety of types of valvular heart disease 55. Studies with Holter monitoring in patients with aortic valve disease have demonstrated that the occurrence of ventricular arrhythmias is not apparently correlated with the type of the lesion (stenosis, regurgitation, or combined stenosis and regurgitation), nor with the transvalvular gradient or degree of regurgitation, nor with the presence of concomitant CAD 56. However, spontaneous ventricular arrhythmias have occurred in a large number of patients, being strongly influenced by the presence of impaired left ventricular function 56. Supravalvular aortic stenosis is an uncommon but well characterized congenital form of left ventricular outflow obstruction. The severity of supravalvular aortic stenosis varies; but if it is left untreated, it may result in heart failure, myocardial infarction, and sudden death 57. Other less frequent important causes of sudden death include ruptured aorta (due to cystic medial necrosis) and idiopathic concentric left ventricular hypertrophy 48. In young athletes the second most common category of diseases responsible for sudden death is a spectrum of congenital malformations of the coronary arteries; the most important of these is anomalous origin of the left main coronary artery from the right (anterior) sinus of Valsalva 58.

Arrhythmic right ventricular dysplasia

Arrhythmic right ventricular dysplasia (ARVD) is a clinical and pathological entity characterized by replacement of ventricular myocardium with fatty and fibrous elements that preferentially involves the right ventricular (RV) free wall. ARVD is one of the major genetic causes of juvenile sudden death, whose prevalence is about 1 in 5000 persons 59. A familial occurrence in about 50% of cases has been reported, characterized by autosomal dominant inheritance, variable penetrance, and polymorphic phenotypic expression 60. ARVD is a disease of desmosomal dysfunction. Desmosomes are a family of proteins the function of which is to bind the myocardial cells to one another providing cellular contact that is necessary for electric conduction and mechanical contraction of the myocardial cells 61. The usual clinical presentation is characterized by palpitations, non-sustained ventricular tachycardia, and sustained ventricular arrhythmias. Uncommonly, SCD may be the first manifestation of the disease. The onset of these symptoms is normally between the ages of 20 and 40 years, and the disease shows a predisposition to occur in men 61. Although a potential predisposing mutation involving the PKP2 gene has been identified in nearly 30% of ARVD patients 62, there is little evidence so far to indicate that identification of a disease-causing mutation has any clinical or prognostic significance, but identification of disease-causing mutations facilitates rapid and accurate screening of family members. ARVD is a common finding in athletes with ventricular arrhythmia and an appropriate screening program may be effective to prevent and reduce the incidence of SCD 63. It is a typical ‘silent’ arrhythmogenic cardiomyopathy, with the possibility of normal ventricular performance and life-threatening arrhythmias 64. Prevalence of ARVD among Italian athletes with SCD is high (about 25%), confirming the observation that ARVD is one of the major causes of SCD in Italian athletes and indicating the potentiality of exercise as a cause of electrical destabilization in subjects with ARVD. Therefore, in athletes with documented ARVD intense sport activity should be prohibited 64.

Wolff-Parkinson-White syndrome

SCD is a rare complication of the Wolff-Parkinson-White (WPW) syndrome, which might occur without any apparent environmental triggers in young, previously asymptomatic persons. The most common mechanism of sudden death in WPW patients is ventricular fibrillation, which is triggered by an atrial fibrillation capable of conducting rapidly over the accessory pathway 65. Syncope, despite being induced by various mechanisms, has been considered an alarming sign of sudden death of WPW syndrome 66.

Brugada syndrome

The Brugada syndrome is a congenital syndrome of SCD first described in 1992. It is clinically characterized by the onset of syncopes or sudden death related to ventricular tachyarrhythmias in patients with a structurally normal heart. In Asian countries the prevalence is 1 per 1000, and probably lower elsewhere. In patients with Brugada syndrome, the clinical phenotype is 8 to 10 times more prevalent in males than in females 67. The transmission is autosomal dominant, with variable penetrance of cases. Screening for mutations in the cardiac Na⁺ channel-encoding gene for the alpha subunit of the sodium channel (SCN5A) uncovers a mutation in approximately 20% of Brugada syndrome cases 68. These genetic abnormalities cause a reduction of the density of the sodium current and explain the aggravation of ECG abnormalities caused by antiarrhythmic sodium channel blockers 10. Two additional genetic pathways have been associated with the disease over the past years. Moreover, an inflammatory or infectious etiology has recently been linked with this syndrome 69. In these patients, fever is a well recognized triggering factor, since it can precipitate ventricular tachycardia 69. Electrocardiographically characterized by a distinct coved-type ST segment elevation in the right precordial leads, the syndrome is associated with a high risk of SCD in young and otherwise healthy adults, and less frequently in infants and children 69.

Catecholaminergic polymorphic ventricular tachycardia (CPVT)

Polymorphous ventricular tachycardia was originally observed in 1918 by Wilson and Robinson, who described a tachyarrhythmia characterized by multiple extrasystoles of different types at a rapid rate 70. CPVT is hence characterized by ventricular tachyarrhythmias that develop during adrenergic stimulus, such as physical activity or acute emotion in the presence of an unremarkable resting ECG 71. The disease can be transmitted as an autosomal dominant as well as a recessive trait. Half of the autosomal dominant cases are caused by mutations in the gene encoding the cardiac ryanodine receptor (RyR2) 72. The RyR (ryanodine receptor) mediates rapid Ca^2 + efflux from the endoplasmic reticulum (ER) and is responsible for triggering numerous Ca^2 +-activated physiological processes. The recessive form is caused by mutations in the gene encoding calsequestrin (CASQ2), a calcium-buffering protein in the sarcoplasmic reticulum 73. The mortality rate in untreated individuals is 30%–50% by the age of 40 73. The molecular diagnostics of this disease have become increasingly important, since underlying mutations can be found in more than 60% of the identified CPVT patients 74.

Dynamic triggering factors

Circadian variability

The observation of a circadian variation in the incidence of SCD with a significant morning peak 75 suggests causation by identifiable triggers that may act alone or synergistically with physical morning activity, mental stress, blood pressure changes, working stress, blood viscosity, and platelet hyperaggregability 76. A circadian rhythm of platelet aggregability has been acknowledged. The first direct evidence of a circadian variation of SCD was reported in 1987 from a retrospective analysis of the mortality records of the Massachusetts population 75. In this study, 2203 individuals who presumably died of SCD outside of a hospital or nursing home were identified. The time of death showed a circadian variation, with a primary peak in the late morning, from 9 to 11 AM, and a minor secondary peak in the afternoon. Contrarily, in-hospital cardiac deaths were approximately evenly distributed over a 24-hour period. Analysis of death time in 264 individuals belonging to the Framingham Heart Study demonstrated a circadian variation with an approximately 3-fold increased risk of SCD during the morning, and a low incidence during the night 77. The prospective database of the West Berlin emergency medical services system also provides interesting insights into the epidemiology of SCD. It has been hypothesized that the greater risk of SCD in the first hours after awakening may be at least partially due to the morning increase in blood pressure and heart rate, increased vascular tone, changes in heart rate variability, elevated blood viscosity, and platelet hyperaggregability 77. The more pronounced increase of sudden death in younger subjects observed in the first working day of the week (usually Mondays) might be related to the employment status. In fact, employed subjects experience a more stressful change from the weekend leisure activities to work activities on Mondays 78. The frequency of disease onset also varies with the time of the year. A 20% increase of SCD was reported during the months of the climatic winter 78.

Psychological stress

Psychological stress increases SCD in populations during emotionally devastating disasters such as earthquake or war, alters induced arrhythmias, and precipitates spontaneous ventricular arrhythmias in patients with ICDs. Moreover, depression and social isolation predicted mortality independently of demographic and clinical status in heart failure outpatients 79. One hypothesis is that autonomically mediated repolarization changes may be one pathophysiologic link between emotion and arrhythmia 80. Psychological stress can act at two levels; by a chronic action it contributes to creating a sort of ‘myocardial background’, altering electrophysiological properties of the myocardium, whereas by an acute action it can create the transient trigger precipitating SCD, as through the actions of stress hormones. Moreover, some individuals have a hyperresponsivity of the sympathetic nervous system, characterized by exaggerated heart rate and blood pressure responses, which results in accelerated atherosclerosis 81. A variety of uneventful conditions have been reported to trigger SCD, including natural disasters and terrorist attacks 8. Anxiety disorders are often accompanied by an overactive autonomic nervous system, reflected in increased body temperature and heart rate (HR). Moreover, it has been postulated that cardiovascular reactivity to mental stress varies with tonic central sympathetic nervous system activity. For example, during normal daily activities, patients with HCM experience a significant autonomic alteration with decreased sympathetic tone 82. Sexual activity may be an additional triggering factor of acute coronary events and SCD, especially in combination with organic heart disease increasing the relative risk of spontaneous recurrence of sustained ventricular tachyarrhythmias 83.

Inflammation

It has been reported that the febrile condition can exacerbate a Brugada-type ECG pattern, polymorphic ventricular tachycardia and syncope 84. In this latter case, the ECG reveals a right bundle branch block and pattern of elevated ST segment in the anterior and inferior leads similar to the Brugada syndrome. These anomalies disappear when the temperature returns to normal. The potential explanation for this process is that the function of the ion channels is reportedly temperature-dependent 84. SCD is usually anticipated by progressive increases in inflammatory markers, such as neutrophil counts and C-reactive protein (CRP) 85. A key question is whether increase in inflammatory markers and worsening in HRV may be somehow related. A reliable hypothesis is the link between inflammation and endothelial dysfunction 86, which is also associated with reduced vascular nitric oxide. The outcome is a worsening of the autonomic function as indicated by decreased HRV 85. Recent data are generally consistent with this assumption, in that SCD in congestive heart failure (CHF) is often but not always associated with an identifiable acute coronary event at necropsy 87 which may be preceded by inflammation-induced endothelial dysfunction. Albert et al. 88 advanced the goal of improving individual SCD prediction by providing the first evidence that a marker of chronic inflammation, high-sensitivity CRP, may also appear as a long-term marker for unexpected SCD. They concluded that CRP levels were highly predictive in identifying SCD victims. Multivariate evaluation also suggested increased relative SCD risk signaled by CRP, independently of these and other traditional markers of CAD risk per se.

Stretch

Commotio cordis, or non-penetrating chest wall impact, is a mechanical induction of heart rhythm disturbances in the absence of corresponding structural damage. Reported with increasing frequency in young individuals participating in some sport activities, it may cause SCD by acute initiation of ventricular fibrillation 89. Commotio cordis is the second leading cause of death in young athletes and most events are caused by blows from projectiles, baseballs, or lacrosse balls, with a substantial proportion, nearly 40%, occurring despite the use of a chest protector 90. Particularly, baseball impacts induce ventricular fibrillation when directed at the center of the left ventricle during the vulnerable portion of repolarization just prior to the T wave peak 90. The electrophysiological changes have been attributed to mechanoelectric feedback, and particularly to the recruitment of stretch-activated ion channels. However, the underlying mechanisms by which a mechanical impact results in ventricular fibrillation remain mostly unknown 91. Li et al. 91 demonstrated that the region of impact is characterized by different types of cellular responses, including generation of a new action potential, and shortening or lengthening of action potential duration. The impact might produce sustained reentry only when a new activation is elicited by mechanical stimulation (caused by activation of cation-non-selective stretch-activated ion channels), and upon return to the original region of impact, this activation does not encounter an extension of action potential duration (prevented by activation of potassium-selective stretch-activated ion channels). It has also been demonstrated that vagotonic and sympathetic surges do not likely contribute to the syndrome of SCD due to chest blows 89. An important variable in the generation of ventricular fibrillation seems to be the energy of the impact. Impacts at 40 mph (64.4 km/h) are more likely to produce ventricular fibrillation than those with greater or lesser velocities, suggesting that the predilection for commotio cordis is related to the precise velocity of chest-wall impact 92.

Neuroendocrine actions

The autonomic nervous system (ANS) plays an important role not only in physiological situations, but also in various pathological settings such as diabetic neuropathy, myocardial infarction (MI) and CHF. The study by Pozzati et al. suggests that sympathovagal imbalance, associated to increased sympathetic activity and reduced vagal tone, may trigger fatal arrhythmias during acute myocardial ischemia, resulting in sudden death. Autonomic dysfunction, as detected by a marked decrease in HRV, is commonly present in the period immediately preceding the onset of the ST shift precipitating ischemic sudden death 11. Specifically, sympathetic activation can trigger malignant arrhythmias, whereas vagal activity may exert a protective effect. Data from Perticone et al. 93 confirm a delayed maturation or impaired functioning of the autonomic nervous system in the first weeks of life in newborns affected by SIDS. In an established experimental model for sudden death involving conscious dogs with a healed myocardial infarction, either depressed reflex chronotropic responses during a blood pressure rise or reduced variability of heart rate (respectively, markers of reflex and tonic cardiac vagal activity) identify dogs at greater risk of developing malignant arrhythmias during a new ischemic episode 94. Moreover, activation of the renin-angiotensin-aldosterone system (RAAS) in left ventricular systolic dysfunction is a critically important determinant in the pathophysiologic processes that lead to progression of heart failure and SCD. The changes in the autonomic tone in the clinical setting can be evaluated by means of HRV, a sensitive measure of neurocardiac autonomic regulation 95. HRV, a beat-to-beat variation in cardiac cycle length resulting from autonomic influence on the sinus node of patients in sinus rhythm, has been shown to predict independently the risk of SCD. Reduced baroflex sensitivity, a quantitative assessment of the ability of the autonomic nervous system to react to acute stimulation involving primarily vagal reflexes, was also successful in assessing the risk of SCD, alone or in combination with HRV 96.

Drugs and illegal drug abuse

Both experimental studies and clinical observations have shown that drugs from various indication areas, such as psychotropic agents and antiarrhythmics can induce disturbances of cardiac rhythm and ECG abnormalities. The acquired long QT syndrome is usually associated with drugs and electrolyte imbalance and often causes syncopes or cardiac arrest that represent a high risk of recurrent events, including SCD. Non-antiarrhythmic drugs that prolong repolarization, along with class IA antiarrhythmic agents such as quinidine, procainamide, N-acetylprocainamide, and disopyramide, can cause torsade de pointes 97. SCD seems to be more frequent following treatment with neuroleptic drugs in patients with preexisting cardiac lesions, especially dilated and hypertrophic myocardiopathy. The observed cardiac lesions can be compared to those seen in toxic myocarditis. Most of antipsychotic drugs, including clozapine, olanzapine, sertindole, risperidone, and haloperidol, are associated with arrhythmia and sudden death 98. The use of droperidol by emergency departments and prehospital settings to sedate extremely agitated patients following illicit drug-taking, has been warned of as a possible cause of rare SCD 99. Diuretic agents can also trigger SCD, since they generate hypokalemia, hypomagnesemia, and increased intracellular calcium concentration 2. Moreover, clebopride, a class of antidopaminergic gastrointestinal prokinetic, has been reported to increase the risk of SCD, by inhibition of the potassium current I(Kr) and QT prolongation 100. Antimicrobial agents, such as fluoroquinolone, can also trigger SCD with a similar mechanism 100. Reliable scientific evidence, based on case reports and clinical observations, describes serious cardiovascular adverse effects, including SCD, from the use of performance-enhancing substances. Anabolic-androgenic steroids, including two synthetic substances, tetrahydrogestrinone and androstenedione (andro), stimulants such as ephedra, and non-steroidal agents such as recombinant human erythropoietin, human growth hormone, creatine, and beta-hydroxy-beta-methylbutyrate have been implicated 101. Due to the potential side effects (increased risk of stroke, myocardial infarction and sudden death) of herbal medicines containing ephedrine and guarana-derived caffeine, the US Food and Drug Administration (FDA) has recently banned the sale of ephedra-containing products, specifically over-the-counter dietary supplements. As previously reported, there are possible deleterious effects of beta-blockers in patients with Brugada syndrome 102. Drug-induced long QT syndrome, occurring with drugs that directly block a specific cardiac ion channel (KCNH2 or hERG) that carries the rapidly activating delayed rectifier potassium current, can lead to cardiac arrhythmias and SCD 103. Opioid abuse by mothers is associated with a high number of infant SCD 104. The finding of an association between methadone and prolongation of cardiac depolarization (QT prolongation) and TDP is of great concern 105. Body-packing, a quite common form of carrying illicit drugs by smugglers, can be a cause of SCD 106. The intentional inhalation of volatile substances such as isobutane has been reported as a cause of SCD 107. The use of cannabis by parents, either alone or in combination with tobacco smoke, has been associated with SCD in infants 108. Ecstasy (methylenedioxymethamphetamine (MDMA)) has been associated with sudden death following induction of myocardial hypertrophy, especially in young otherwise healthy individuals 109. The commonest cause of sudden death following amphetamines abuse is unintentional overdosing 110.

Ischemia

The ion channels have been demonstrated to be sensitive to changes in oxygen tension. Because they respond rapidly to hypoxia, it has been proposed that the channel itself is an oxygen sensor 111. Adenosine triphosphate (ATP)-dependent potassium (K(ATP)) channels exist in high density in the sarcolemmal membrane of heart muscle cells. Under normoxic conditions these channels are closed, but they become active when the intracellular ATP level falls. This leads to a shortening of the action potential duration, making the heart more susceptible to life-threatening arrhythmias. The appearance of arrhythmias is also related to the time from the onset of ischemia. Within the first few minutes there is abundant ventricular arrhythmogenesis, usually lasting for 30 min 112. In acute myocardial ischemia, the obstruction of coronary flow leads to the interruption of oxygen flow. Cellular metabolism is impaired, and severe electrophysiological changes in ionic currents and concentrations ensue, which favor the development of lethal cardiac arrhythmias such as ventricular fibrillation 113. In large animal hearts, regional ischemia induces two phases of ventricular arrhythmia. The first phase, associated with membrane depolarization, mild intracellular and extracellular acidification, and small membrane depolarization, occurs between 5 and 7 min after arrest of perfusion. A second phase occurs between 20 and 30 minutes after arrest of perfusion, when ischemia-induced K⁺ and pH changes are fairly stable. The arrhythmia is presumably related to the process of cell-to-cell electrical uncoupling, because a rapid increase of tissue impedance precedes the onset of the arrhythmia 114.

Hypoglycemia and hyperglycemia

Abnormal cardiac repolarization occurs consistently during insulin-induced hypoglycemia. Either potassium infusion or beta-blockade were proven effective to prevent increased QT dispersion, but they only partially prevent QT lengthening. The sympathoadrenal discharge induced by hypoglycemia alters cardiac repolarization by both direct and indirect (by reducing extracellular potassium) mechanisms. Autonomic neuropathy might also contribute to the clinical risk of cardiac arrhythmias during nocturnal hypoglycemia 115. Diabetes mellitus and impaired glucose tolerance patients are an elevated risk of SCD 116. HRV is inversely associated with plasma glucose levels, and it is reduced in diabetics as well as in subjects with impaired fasting glucose levels 117. The potential triggering mechanism is human ether-a-go-go-related gene (HERG) K⁺ dysfunction, which is a typical cause of diabetic QT prolongation (QT-P) 118. Contrarily, as reported by others, glycemic index might be a significant predictor of spontaneous ventricular tachycardia (VT), independently of QT interval 119.

Severe weight reduction

Low QRS voltage, QT interval prolongation, and both non-sustained ventricular arrhythmias and SCD have been described in subjects treated with weight reduction diets. Orthostatic hypotension may complicate very-low-calorie protein diets because of sodium depletion and depressed sympathetic nervous system activity 120. Moreover, the effect of weight loss on the electrocardiogram abnormalities of obesity appears to be dependent upon diet duration and whether protein and mineral nutritional status is maintained. Copper, potassium, and magnesium deficiencies may play important roles in promoting an electrically unstable heart. Stress, by eliciting autonomic imbalance, may also act upon an electrically unstable heart to provoke acute arrhythmias 121.

Identification of the patients at risk

The prevention of SCD requires detection of well known pathologies, which are often clinically latent but may develop in form of sudden death. As a paradigmatic example of effective prevention in high-risk categories, the European Society of Cardiology has proposed cardiovascular screening for young competitive athletes. Moreover, the German Society for Sports Medicine and Prevention recommend a medical check to be performed before a person starts to seriously practice sports, with the aim of identifying cardiovascular factors or anomalies 122. In Japan, both athletes and non-athletes have been screened for the presence or absence of cardiovascular diseases for more than 20 years 123. The screening protocols implicates different approaches: ECG is conventionally considered a much more effective screening tool than cardiac history and history/auscultation/inspection in detecting cardiovascular abnormalities 124. A standard resting 12-lead ECG not only allows the recognition of various congenital abnormalities associated with ventricular arrhythmias and SCD, but also the identification of various other ECG abnormalities, such as those due to electrolyte disturbances, or those reflecting underlying structural diseases, such as bundle branch block, atrio-ventricular (AV) block, ventricular hypertrophy, and Q waves indicative of ischemic heart disease or infiltrative cardiomyopathy 95. The resting ECG may be useful, in that it measures several variables of prognostic value, but is not often considered as part of SCD risk stratification. Prolonged conduction creates increased dispersion of depolarization and repolarization, thus promoting ventricular arrhythmias 125. QRS duration, which reflects intraventricular conduction time, and presence of left bundle branch block were found to be independent predictors of SCD and total mortality 126. A large proportion of cardiovascular diseases underlying sudden death in young competitive athletes may be detected by ECG 127. Silent but potentially lethal conditions, distinctively manifesting with ECG abnormalities, include cardiomyopathies (such as hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and dilated cardiomyopathy), conduction system diseases, and cardiac ion channel diseases 63. Echocardiography and exercise stress echocardiography are therefore indicated in patients with ventricular arrhythmias suspected of having structural heart disease or in acute myocardial infarction (AMI) survivors 128. A specific behavioral follow-up should also be addressed, as cocaine administration and doping, which both can lead to cardiac problems and SCD in sportsmen 129. Among AMI survivors the abnormal Holter variables, such as all HR variability indexes (except the high-frequency spectral component of HR variability), predict the occurrence of SCD, but only among the patients with slightly reduced or preserved left ventricular (LV) systolic function 96. Moreover, elevated brain natriuretic peptide (BNP) provides information on the risk of subsequent SCD, independently of clinical variables and left ventricular ejection fraction (EF) 130.

New hypothesis: potential role of laboratory testing in the early identification of subjects at high risk

Basic research could be a potential aid to evaluating specific individuals and subgroups with enhanced progressive or inherited susceptibility to lethal arrhythmias. Efforts in risk stratification for SCD have primarily focused on predicting unfavorable events in patients with structural heart disease, since the incidence of SCD increases 6- to 10-fold in this subset of patients (43). However, despite the ubiquity of tests that have been purported to predict SCD vulnerability in these patients, there is little consensus on which test, in addition to the left ventricular ejection fraction, should be used to determine which patients will finally benefit from an implantable cardioverter defibrillator 131. A variety of studies demonstrated familial clustering of events. Allelic variation in candidate genes in a number of signaling systems that alter myocardial electrical substrate or triggers, cell survival pathways, and thrombotic cascades may enhance susceptibility to SCD in the failing heart 132. Therefore, a first reliable step in risk stratification might be the assessment of a genetic predisposition. The completion of the Human Genome Project in 2003 is shifting the focus of modern health care from disease management based on clinical signs to genomic-based treatment and prevention. The personalized medicine includes the use of genomic information to improve the diagnosis of disease, as well as the prevention and treatment. Single-gene disorders predominate as causes of SCD in the young, and molecular genetic analysis may facilitate familial assessment (1). Therefore, genetics would allow not only an early but a definitive diagnosis to be made in SCD. Accordingly, identification of the causal gene mutation and additional genotype–phenotype correlation studies will provide a fundamental insight into mechanisms of cardiac remodeling (132).

Some genetic substrates confer susceptibility to development of dangerous cardiac rhythms and maladaptive responses to stressors 133. For example, the diagnostic utility of genetic testing for HCM or other genetic diseases predisposing to SCD is clearly evident. Identification of such high-risk mutations calls for intensive evaluation and possibly an implanted defibrillator. The Harvard Medical School-Partners HealthCare Center for Genetics and Genomics (HPCGG) provides an example in the diagnosis of genetic cardiomyopathy 134. Eight of the most commonly mutated genes have been selected and clustered within three tests panels. The panel A includes the most common mutations. If it comes up negative, the panel B is then performed, which picks up rarer mutations. If also the B panel is negative, panel C is performed, which tests for other causes of hypertrophy with signs and symptoms that mimic cardiomyopathy. The reason for three smaller tests, rather than a larger one, is to cut down the costs. In case a patient tests positive for one or more of these panels, other family members including younger children who would otherwise go undiagnosed for years can be offered with the same diagnostic strategy. From this perspective, genetic testing appears financially reasonable. For example, in LQTS patients, genotyping can be very important for the approximately 35% of gene carriers with normal to borderline QTc intervals of 0.41–0.46 seconds, since they are difficult to diagnose and separate from the large percentage of normals with these same QTc values. Importantly, recent evidence indicates that these gene carriers with reduced penetrance of the QTc have essentially the same risk of syncope and sudden death as LQTS patients as a whole (22). In this circumstance, a correct diagnosis allows life-saving treatment to be instituted (23). For LQTS, genotype–phenotype correlations have been developed along with important improvement in risk stratification and genetic-guided treatment. Genetic screening has shown that LQTS is more frequent than expected, and, interestingly, ethnic-specific polymorphisms conferring increased susceptibility to drug-induced QT prolongation and torsade de pointes have been identified 135. Although genetic testing forms a part of the process of early identification of high-risk subjects, its role varies with different tests and in different conditions 136. At present, genetic tests are usually reserved for confirming a clinically suspected diagnosis. In fact, the standard ECG can identify patients with inherited arrhythmogenic diseases. Other diseases, such as familial HCM or arrhythmogenic right ventricular cardiomyopathy, may require echocardiography and further cardiac investigations to be diagnosed correctly 137. Moreover, a number of factors should be taken into consideration: sensitivity and specificity of testing, a cost-efficacy benefit, implications of test results on patient life-style, and the potential consequences of the screening on the clinical management and the prognosis (136). Indeed, the definition of a risk status is unsuitable for the screening of large ‘healthy’ populations, but usually starts with a positive clinical diagnosis in an affected family member. Once the disease has been recognized, results can be easily used to assess which other members of the family may carry that particular genotype. These subjects, who might be at higher risk of developing SCD, might also benefit from prevention, appropriate clinical management, and early triage (136).

The second step of laboratory evaluation might be the identification of transient risk markers, potentially triggers for SCD, such as inflammatory markers (43), aberrant intracellular Ca handling, ionic imbalances, or neurohumoral changes. Recently, other laboratory markers, such as non-esterified fatty acids (NEFA) 138, EPA (eicosapentaenoic acid/arachidonic acid) 139 and plasma N-terminal (NT) fragment of pro-brain natriuretic peptide (BNP) (130), have been proposed, but there is no definitive evidence on their clinical usefulness in this specific circumstance so far.

Prevention of SCD

Primary prevention of SCD requires identification of potential SCD victims ahead of the first arrhythmia episode. For example, actions for primary prevention of CAD, the first cause of SCD, should be targeted to reduce the impact of major and independent risk factors (137). Patients with acute bradyarrhythmias often retain a basal circulation, for example due to ventricular escape rhythms. Thereby, the appropriate treatment (often a pacemaker) can usually be deployed in time to prevent irreversible organ damage when a sudden bradyarrhythmia occurs (137).

Correct identification of future SCD victims is especially important as there is an effective treatment, namely defibrillation via an external or internal (implanted) defibrillator. Implantable cardioverter defibrillators (ICD) are effective at terminating malignant arrhythmias. These devices are not much larger than a pacemaker, and they have full pacemaker capabilities in addition to being able to shock patients out of life-threatening ventricular arrhythmias. Recently, their effectiveness has been demonstrated in patients with severely reduced left ventricular function 140. However, it should be mentioned that even with the increase in defibrillator use, the impact on overall incidence of SCD may be modest, as many individuals experience SCD as the first manifestation of cardiovascular disease 141. Accordingly, the Cardiomyopathy Trial (CAT) did not provide evidence in favor of prophylactic ICD implantation in patients with dilated cardiomyopathy (DCM) of recent onset and impaired left ventricular ejection fraction 142.

Pharmacological prevention of SCD includes the use of several drugs targeting the early (upstream) processes of the complex cascade leading to SCD, such as beta-blockers, aldosterone antagonists, angiotensin-converting enzyme inhibitors, angiotensin receptor-blocker agents (41), or others drug that prevent acute ischemic cardiac events (aspirin, statins, and omega-3 fatty acids).

Conclusions

Systems biology attempts to elucidate the complex interaction between genes, proteins, and metabolites to provide a mechanistic understanding of most biological functions and how the human biology is affected by disease processes, drug toxicity, or drug efficacy effects. SCD is emerging as a major health care problem worldwide. Although the pathogenesis is still partially unclear, a variety of predisposing and triggering conditions have been identified, whose interaction might discriminate a subset of patients characterized by a greater risk. A reliable clinical and diagnostic approach might hence be effective to unmask the most important genetic and environmental factors, allowing the construction of a rational personalized medicine framework that can be applied in both preclinical and clinical settings of SCD.