Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study population

To determine if sudden cardiac death shows circadian variation, the time of day of sudden cardiac deaths in the Framingham Heart Study was analyzed. Analysis was based on mortality data collected in a standardized manner for the past 38 years for each death among the 5,209 persons in the original cohort. The necessary assumptions about the cause and timing of unwitnessed deaths were made in a manner likely to diminish the possibility of detecting an increased incidence of sudden cardiac death during the morning. In the Framingham study, analyses using these assumptions reveal a significant circadian variation (p less than 0.01) in occurrence of sudden cardiac death (n = 429), with a peak incidence from 7 to 9 AM and a decreased incidence from 9 AM to 1 PM. Risk of sudden cardiac death was at least 70% higher during the peak period than was the average risk during other times of the day. Further studies are needed to confirm this finding in other populations, to collect data regarding medications and to determine activity immediately before sudden cardiac death. Investigation of physiologic changes occurring during the period of increased incidence of sudden cardiac death may provide increased insight into its causes and suggest possible means of prevention.     

Cardiac innervation and sudden cardiac death

The heart is extensively innervated and its performance is tightly controlled by the nervous system. Cardiac innervation density varies in diseased hearts leading to unbalanced neural activation and lethal arrhythmia. Diabetic sensory neuropathy causes silent myocardial ischemia, characterized by loss of pain perception during myocardial ischemia, which is a major cause of sudden cardiac death in diabetes mellitus (DM). Despite its clinical importance, the mechanisms underlying the control and regulation of cardiac innervation remain poorly understood.We found that cardiac innervation is determined by the balance between neural chemoattractants and chemorepellents within the heart. Nerve growth factor (NGF), a potent chemoattractant, is induced by endothelin-1 upregulation during development and is highly expressed in cardiomyocytes. By comparison, Sema3a, a neural chemorepellent, is highly expressed in the subendocardium of early stage embryos, and is suppressed during development. The balance of expression between NGF and Seme3a leads to epicardial-to-endocardial transmural sympathetic innervation patterning. We also found that downregulation of cardiac NGF leads to diabetic neuropathy, and that NGF supplementation rescues silent myocardial ischemia in DM. Cardiac innervation patterning is disrupted in Sema3a-deficient and Sema3a-overexpressing mice, leading to sudden death or lethal arrhythmias. The present review focuses on the regulatory mechanisms underlying cardiac innervation and the critical role of these processes in cardiac performance.     

Cardiac arrhythmias and sudden cardiac death in women

Zusammenfassung. Hintergrund: Geschlechtsspezifische Unterschiede bei Herzrhythmusstörungen sind seit Jahrzehnten bekannt. Einflüsse von Sexualsteroiden auf das autonome Nervensystem und die zelluläre Elektrophysiologie des Erregungsbildungs- und -leitungssystems werden ebenso diskutiert wie direkte genetische Dispositionen auf zellulärer, funktioneller oder metabolischer Ebene. Zudem gilt es, die alters- und geschlechtsspezifischen Unterschiede im Hinblick auf unterschiedliche kardiale Grunderkrankungen zu berücksichtigen, die ihrerseits Häufigkeit, Form und Schwere maßgeblich mitbestimmen. Herzrhythmusstörungen bei Frauen: Eine im Vergleich zu Männern höhere Ruhefrequenz und ein längeres QTc-Intervall, beginnend nach der Pubertät, sind die auffälligsten EKG-Veränderungen bei Frauen und weisen eine enge Beziehung zu konstitutionellen und hormonellen Einflüssen auf. Supraventrikuläre Herzrhythmusstörungen, bei Frauen prädestiniert Sinus- und AV-Knoten-Reentry-Tachykardien, seltener Wolff-Parkinson-White-Tachykardien, können zyklusabhängigen Häufigkeitsschwankungen unterliegen. Vorhofflimmern ist bei Frauen ebenfalls häufiger als bei Männern, meist typischerweise symptomatisch, und die Therapie erweist sich als problematischer. Ventrikuläre Herzrhythmusstörungen, in der gesunden Allgemeinbevölkerung gleich häufig, weisen bei Männern eine enge und prognostisch bedeutsame Beziehung zur KHK auf, während diese bei Frauen weniger ausgeprägt ist und arrhythmogene Kofaktoren eine größere Rolle spielen. Frauen leiden häufiger an erworbenem und kongenitalem Long-QT-Syndrom, in deren Folge häufiger Torsade de pointes-Tachykardien auftreten (u. a. durch ausgeprägtere medikamentös induzierte QT-Verlängerung, häufigere Kurz-Lang-Sequenzen, Unterschiede der Ikr-Sensitivität), die allerdings seltener als bei Männern in Kammerflimmern degenerieren. Frauen sind von einem plötzlichen Herztod etwa dreimal seltener betroffen. Er ereignet sich etwa zehn Jahre später; die zugrunde liegende Ursache ist deutlich heterogener als bei Männern, und die Prognose, ein solches Ereignis zu überleben, ist deutlich schlechter. Frauen sind in Studien zu Primär- und Sekundärprävention deutlich unterrepräsentiert, wenngleich der Nutzen dieser Therapie sogar den bei Männern zu übersteigen scheint. Schlussfolgerungen: Auch wenn die Genese der geschlechtsspezifischen Unterschiede von kardialen Arrhythmien in einer Reihe von Punkten noch offen ist, implizieren die dargestellten Befunde die besondere Notwendigkeit eines entsprechend ausgerichteten Forschungsansatzes, da sich nur so geschlechtsspezifische Risikostratifikations- und Therapieansätze für die Zukunft entwickeln lassen.     

Cardiac channelopathies and sudden infant death syndrome

Sudden infant death syndrome (SIDS) is always a devastating and unexpected occurrence. SIDS is the leading cause of death in the first 6 months after birth in the industrialized world. Since the discovery in 1998 of long QT syndrome as an underlying substrate for SIDS, around 10-20% of SIDS cases have been proposed as being caused by genetic variants in either ion channel or ion channel-associated proteins. Until now, 10 cardiac channelopathy susceptibility genes have been found to be implicated in the pathogenesis of SIDS. Four of the genes encode cardiac ion channel α-subunits, 3 genes encode ion channel β-subunits, and 3 genes encode other channel-interacting proteins. All 10 genes have been associated with primary electrical heart diseases. SIDS may hereby be the initial symptom of rare primary electric channelopathies such as long QT, short QT and Brugada syndrome, as well as catecholaminergic polymorphic ventricular tachycardia. In this review we describe the functional role of sodium, potassium and calcium channels in propagation, depolarization and repolarization in the context of the 4 arrhythmogenic diseases reported to be associated with SIDS. Lastly, the possibility of postmortem genetic testing and potential recommendations on how to deal with family members are discussed.     

Obesity,heart failure and sudden death

AIM: To review the direct unfavourable effect of obesity, the most prevalent nutritional and metabolic disease worldwide, on cardiovascular morbidity and mortality. DATA SYNTHESIS: Obesity is associated with high chronic cardiac workload due to the need to supply more blood to peripheral tissue. The high cardiac output is mainly a consequence of the greater requirements of increased lean body mass, and is maintained by an increased stroke volume and high normal heart rate, and sustained by an increase in ventricular mass. The increase in left ventricular (LV) mass also implies an increase in non-muscular tissue that plays a role in the development of electrical abnormalities, heart failure and sudden death. CONCLUSIONS: Obesity per se is a major risk factor for heart failure. Obesity-related LV hypertrophy is in turn associated with varying degrees of systolic and diastolic dysfunction that are not easily recognisable using traditional methods, but are potentially reversible after appropriate, stable moderate weight loss.     

Cardiac ion channel mutations in the sudden infant death syndrome

Sudden infant death syndrome (SIDS) is characterized by the sudden death of an infant that occurs during sleep and remains unexplained despite thorough examination. In addition to clinical associations such as prone sleeping and exposure to cigarette smoke, several genetic factors have been identified with regard to SIDS, including autonomic disorders, immunologic polymorphisms and metabolic disorders. In the past decade, postmortem genetic analysis (‘molecular autopsy’) of SIDS cases has revealed a number of cardiac ion channel mutations that are associated with arrhythmia syndromes, including the long QT syndrome, Brugada syndrome and short QT syndrome. Mutations have been found in genes encoding (subunits of) cardiac potassium, sodium and calcium channels, as well as in genes involved in the trafficking or regulation of these channels. Here, we review the literature on cardiac ion channel mutations in relation to SIDS. Combining data from population-based cohort studies, we conclude that at least one out of five SIDS victims carries a mutation in a cardiac ion channel-related gene and that the majority of these mutations are of a known malignant phenotype. Genetic analysis is therefore recommended in cases of sudden infant death. More research is required to further elucidate the pathophysiology of SIDS and to determine whether genetic or electrocardiographic screening of apparently healthy infants should be pursued.     

Arrhythmogenic mechanisms for the sudden death in heart failure

Introduction
Heart failure （HF） is a major clinical manifestation of many cardiac disease processes when the cardiovascular compensatory mechanisms fail. Five million patients suffer from HF with an additional 555,000 new patients diagnosed HF annually. Moreover, there are an estimated 400,000 to 460,000 deaths attributable to sudden cardiac death （SCD） in the United States each year.1 Mortality in the heart failure population is about six to seven times higher than that of the agematched general population.     

Cardiac potassium channel dysfunction in sudden infant death syndrome

Life-threatening arrhythmias have been suspected as one cause of the sudden infant death syndrome (SIDS), and this hypothesis is supported by the observation that mutations in arrhythmia susceptibility genes occur in 5-10% of cases. However, the functional consequences of cardiac potassium channel gene mutations associated with SIDS and how these alleles might mechanistically predispose to sudden death are unknown. To address these questions, we studied four missense KCNH2 (encoding HERG) variants, one compound KCNH2 genotype, and a missense KCNQ1 mutation all previously identified in Norwegian SIDS cases. Three of the six variants exhibited functional impairments while three were biophysically similar to wild-type channels (KCNH2 variants V279M, R885C, and S1040G). When co-expressed with WT-HERG, R273Q and K897T/R954C generated currents resembling the rapid component of the cardiac delayed rectifier current (I_Kr) but with significantly diminished amplitude. Action potential modeling demonstrated that this level of functional impairment was sufficient to evoke increased action potential duration and pause-dependent early afterdepolarizations. By contrast, KCNQ1-I274V causes a gain-of-function in I_Ks characterized by increased current density, faster activation, and slower deactivation leading to accumulation of instantaneous current upon repeated stimulation. Action potential simulations using a Markov model of heterozygous I274V-I_Ks incorporated into the Luo-Rudy (LRd) ventricular cell model demonstrated marked rate-dependent shortening of action potential duration predicting a short QT phenotype. Our results indicate that certain potassium channel mutations associated with SIDS confer overt functional defects consistent with either LQTS or SQTS, and further emphasize the role of congenital arrhythmia susceptibility in this syndrome.     

心力衰竭猝死的防治

心力衰竭是一种终末期心脏疾病。随着人群年龄增高及心肌梗死等其他心脏疾病的成功救治,心力衰竭的患病率显著上升,我国心力衰竭患病率为0.9%。心力衰竭是心脏性猝死(sudden cardiac death,SCD)的常见病因。心脏性猝死发病机制复杂,但大部分由室性心动过速、心室颤动等恶性心律失常引起。因此预防恶性心律失常的发生,及时终止室性心动过速或心室颤动是防治心脏性猝死发生的关键。     

Cardiac imaging in evaluating patients prone to sudden death

Identifying subjects who are at risk for SCD and stratifying them correctly into low or high-risk groups is the holy grail of Cardiology. While imaging shows a lot of promise, it is plagued by the fact that most SCD occurs in relatively healthy subjects, a massive group who would not ordinarily be subjected to imaging. Left ventricular ejection fraction (LVEF) currently is our primary parameter for risk stratification for sudden cardiac death but is a poor marker with low sensitivity and specificity. Current data shows that sophisticated imaging with techniques, mainly Cardiac magnetic resonance Imaging (CMR), have the potential to identify novel high-risk markers underlying SCD, beyond ejection fraction. Imaging seems to further refine risk in patients with low LVEF as well as in those with normal EF; this is a major strength of advanced imaging. Clinical application has been slow and not fully prime time. It is important to remember that while promising, imaging techniques including CMR, have not been tested in rigorous prospective studies and thus have not as yet replaced EF as the gatekeeper to ICD implantation.     

Risk stratification for sudden death in heart failure

Clinical trials provide evidence that an empiric approach of implantable cardioverter-defibrillator (ICD) implantation in heart failure patients (ejection fraction =/< 35%) with mild to moderate symptoms reduces mortality rate as compared to the best available medical therapy. However, ejection fraction alone is unable to predict death by progressive pump failure or sudden arrhythmic death, and consequently over half of all patients will not require device therapy over long-term follow-up. Thus, the approach of empiric ICD implantation results in excessive cost in the absence of more specific risk stratification for sudden death. This review summarizes the current noninvasive risk stratifying strategies available in predicting susceptibility to sudden arrhythmic death in heart failure populations.     

Cardiac sarcoidosis as a cause of sudden death

Sarcoidosis, also called Besnier-Boeck disease, is a systemic granulomatous disease of unknown etiology which was classified as a separate unit in 1958. Histopathology of the disease is based on epithelioid granulomas which infiltrate and damage different organs and tissues. The disease is most commonly located in the lungs; however, first complaints may be related to its manifestation in other organs. Symptomatic involvement of the heart is found in approx. 5% of patients and is one of the most dangerous forms of the disease.     

Cardiac ganglionitis associated with sudden unexpected death.

In a postmortem study of the hearts of two young women who died suddenly and unexpectedly, we found a remarkably similar and distinctive ganglionitis, predominantly in the region of the sinus node. Both women had ventricular fibrillation at the time of collapse. Vesicular neuritis and older neural degeneration were present in other regions of the heart. Except for focal fibromuscular dysplasia of the sinus node artery and atrioventricular node artery of one heart, there was no other significant anatomic abnormality in either heart. The functional significance of this cardiac ganglionitis is unclear, but its location in and around the conduction system makes it a possible cause of the fatal electrical instability. Recognition that ganglionitis of the heart may be associated with sudden death should stimulate a number of additionally useful studies.     

Risk of sudden death in heart failure patients

Sudden death is one of the more important cause of mortality in patients with chronic heart failure. The highest risk occurs among patients with less severe functional impairment, whereas patients in NYHA class IV usually die of progression of heart failure. Predictors of sudden death have been evaluated. Nevertheless, current methods of risk stratification for sudden death are still inadequate, especially in patients with advanced heart failure. Low left ventricular ejection fraction is widely used for the risk stratification, but it lacks of sensitivity and specificity in distinguishing patients with an increased arrhythmic mortality from those with an increased mortality due to pump failure. Unsustained ventricular tachycardia and inducibility at electrophysiological study may help identifying high-risk patients, requiring more aggressive therapy, as the ICD implantation. Heart rate variability and baroreflex sensitivity analysis have been utilized to obtain information on autonomic modulation, but with uncertain conclusion on the identification of high-risk patients. Increased QT dispersion, the presence of T-wave alternans and abnormal signal-averaged electrocardiography have also been proposed, but, up-to-now, any of these parameters showed a strong predictor power. In conclusion, our capability to identifying heart failure patients at risk for arrhythmic death is still far from being satisfactory.     

Genomics,heart failure and sudden cardiac death

Sudden cardiac death (SCD) is among the most common causes of death in developed countries throughout the world. Despite decreased overall cardiac mortality, SCD rates appear to be increasing in concert with escalating global prevalence of coronary disease and heart failure, the two major conditions predisposing to SCD. This unfavorable trend is a consequence of our inability to identify those who will die suddenly from lethal ventricular arrhythmias and to develop effective therapies for all populations at risk. The known risk factors for SCD lack the predictive power needed to generate preventive strategies for the large number of fatal arrhythmic events that occur among lower-risk subsets of the population. Even among recognized high-risk subsets, prediction of SCD remains challenging. With the exception of the implantable cardioverter defibrillator (ICD) there are few effective strategies for the prevention and treatment of SCD. This article discusses the prospect of genomic science as an approach to the identification of patients at high-risk for SCD. While the final common pathway for SCD is malignant ventricular arrhythmias, there are many potential contributors, pathways, and mechanisms by which common genetic variants (polymorphisms) could affect initiation and propagation of life-threatening cardiac arrhythmias. Recent advances in genomic medicine now provide us with novel approaches to both identify candidate genes/pathways and relatively common polymorphisms which may predispose patients to increased risk for SCD. Improved understanding of the relationship between common polymorphisms and SCD will not only improve risk stratification such that ICDs can be targeted to those patients most likely to benefit from them but also provide new insight into the pathophysiology of SCD.     

Heart failure therapy and sudden cardiac death prevention

Primary prophylaxis of sudden cardiac death by implantable defibrillators is an accepted therapeutic strategy because sudden cardiac death is reduced by their use. However, many patients at risk of sudden cardiac death due to left ventricular systolic dysfunction also suffer heart failure symptoms. There is increasing evidence that the morbidity of heart failure can be alleviated by device therapy in which ventricular dysynchrony is improved by biventricular pacing. Both therapies in the same device can reduce both morbidity and mortality. Device therapy is an important new aspect in the field of heart failure management.