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.     

Pathology of sudden extra-hospital death. 1. Obstructive lesions of the coronary arteries and myocardial scars]

The coronary arteries and myocardium were examined morphologically by special unified methods in 127 cases of prehospital sudden coronary death among Kaunas male population from 45 to 65 years of age. Obstruction of at least one of four major coronary arteries was severe (75% or more) in 90% of patients and moderate (50--75%) in the remaining 10%. In most cases one or two coronary arteries had severe obstruction (77% of cases) located predominantly in the proximal and middle segments of the left anterior descending and right coronary arteries. Post-infarction scars and small foci of myocardial sclerosis were found in 72% of hearts any may be considered as special "morphological catamnesis" of past acute coronary events. In 85% of cases the heart mass was more than 400 g. The data presented indicate the undoubted role of coronarogenic factors in the development of an acute terminal episode such as sudden death, the unexpectedness of which is only imaginary.     

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 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.     

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 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 failure and sudden death in the Framingham Study

Mortality is examined in patients with cardiac failure in the Framingham study of 5209 subjects. During 30 years of follow-up, the incidence of cardiac failure doubled with each decade of age with a male predominance produced by higher rates of coronary heart disease. Most cardiac failure was associated with hypertension or coronary heart disease. Among 232 men and 229 women in whom cardiac failure developed, sudden death occurred at nine times the general age-adjusted population rate. Cardiac failure alone increased the risk of sudden death fivefold. In those who also had coronary heart disease there was a further doubling of risk. The major predisposing factors for cardiac failure included hypertension, obesity, glucose intolerance, heavy smoking, cardiac enlargement, ECG abnormality, and atrial fibrillation. These were also risk factors for sudden death. These shared modifiable risk factors and cardiac impairments did not entirely account for the markedly increased risk of sudden death in cardiac failure. This suggest that either the damaged myocardium or treatment needed to control the cardiac failure may be at fault.     

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.     

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.     

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.     

Precursors of sudden coronary death. Factors related to the incidence of sudden death.

Precursors of sudden death were sought in men--1838 civil servants in Albany, New York, and 2282 residents of Framingham, Massachusetts--under continuous surveillance for 16 years. In men 45-74 years old there were 234 deaths attributed to coronary heart disease (CHD) of which 109 occurred within one hour of onset of symptoms. More than half of all deaths due to CHD occurred outside the hospital and about 80 per cent of these were sudden. Most were unheralded by prior symptoms of CHD. Persons at high risk of death from CHD, including sudden death, can be identified long before the terminal unexpected catastrophe. The same precursive stigmata exist in persons subject ot coronary attacks whether or not immediately fatal. The risk of sudden death in these two populations was positively correlated with high blood pressure, the electrocardiographic pattern of left ventricular enlargement, obesity, and heavy cigarette usage. Sudden death is a common and possibly incidental expression of lethal coronary heart disease. The potential candidate for sudden death cannot be confidently distinguished from the individual who succumbs more slowly of myocardial infarction. The inescapable conclusion is that the prevention of sudden death requires the prevention of coronary attacks.     

Histopathology of the conduction system in the sudden infant death syndrome.

The cause of the sudden infant death syndrome (SIDS, crib death, or cot death) is unknown. Current hypotheses include lability of heart rate and/or rhythm as a pathogenetic factor. The conduction system of 50 infants coming to autopsy were examined by serial sections; the infants were from newborn to two years of age. Twenty-six were SIDS deaths and 24 were explained deaths (ED). The frequency of histologic abnormalities of the specialized tissue was almost identical in both groups of infants. Hemorrhage in or around different parts of the conduction system was present in 27% SIDS and 29% ED. There was no evidence of cell death or degeneration of conduction fibers, nor obstructive lesions of the atrioventricular (A-V) arteries. Apparent moulding of A-V node and His bundle was a universal finding in both SIDS and ED, and consisted of irregular interdigitation of A-V node and His bundle fibers with the myxoid central fibrous body (CFB). Isolated bundles of conduction fibers residing in CFB and membranous ventricular septum were seen in two SIDS, but no direct contact between these fibers and the working myocardium could be identified in serial sections in either case. Without corroborating antemortem electrophysiologic data, the functional significance of morphologic findings in the conduction system of SIDS must remain conjectural.     

Cardiac transplantation in an extreme emergency

Urgent cardiac transplantation in very unstable patients, kept alive in intensive care unit, is a significant (34 percent) part of the Henri-Mondor's transplantation program. Nineteen patients received a donor graft from january 1986 to october 1988. Sixteen were bridged pharmacologically as 5 received a mechanical bridge. Time on waiting list ranged from 12 to 21 days. Six patients died in the first post-operative month. Death was due to uncontrolled preoperative problems in 5, donor graft failure in one. The survival rate at one year was 52 percent, to be opposed to 76 percent in stable patients. These figures must be considered when selecting the priority of the transplantation candidates.     

Non-invasive sudden death risk stratification.

Most sudden cardiac deaths are caused by fatal ventricular arrhythmias (ventricular tachycardia [VT] and fibrillation) in patients with and without known structural heart diseases. Given the large number of patients potentially at risk for developing ventricular arrhythmias, any strategy for treating them prophylactically requires efficient and effective risk stratification. Both non-invasive and invasive testing may be used for prognostic evaluation of patients with heart diseases. The optimal way to use them in the risk stratification for sudden cardiac death will depend in part on the goals of screening. At present risk markers perform better at identifying low-risk patients who may not need an implantable cardioverter-defibrillator (ICD), because all tests have a high negative predictive accuracy. In our opinion an electrophysiological test should not be performed and an ICD should not be implanted in post-myocardial infarction patients with moderate left ventricular dysfunction (left ventricular ejection fraction 30-40%) with a preserved autonomic balance and without non-sustained VT. In MADIT II-like patients electrophysiological testing does not seem necessary and an ICD could not be implanted only in patients with a negative T-wave alternans test. Most of the data available refer to patients with ischemic cardiomyopathy but the preliminary data on T-wave alternans suggest its usefulness in patients with non-ischemic cardiomyopathy too, although a large definitive study has not yet been completed in this important population.