Mechanism of sudden cardiac death in pigs with viable chronically dysfunctional myocardium and ischemic cardiomyopathy

Pigs with viable chronically dysfunctional myocardium and ischemic cardiomyopathy are at high risk of sudden cardiac death (SCD). We sought to identify the arrhythmic mechanism of SCD, the relation to changes in left ventricular (LV) function, and inducibility of malignant arrhythmias before SCD. Juvenile pigs (n = 72) were instrumented with chronic stenoses on proximal left anterior descending and circumflex arteries. Survival was only 29% 3 mo after instrumentation, and all deaths were sudden and without prodromal symptoms of heart failure. Triphenyltetrazolium chloride staining demonstrated necrosis in only nine animals averaging 2.3 +/- 0.9% of the LV, with no difference between SCD animals and survivors. Implantable loop recorders (n = 13) documented both ventricular fibrillation (n = 6) and bradyasystole (n = 2) as the arrhythmic mechanism of death. Although regional and global function were depressed [anteroseptal wall thickening 1.8 +/- 0.2 vs. 4.2 +/- 0.2 mm in Sham animals (P < 0.001); fractional shortening 21 +/- 2 vs. 31 +/- 1% in Sham animals (P < 0.01)], there were no differences between SCD animals and survivors. LV mass increased in animals with ischemic cardiomyopathy and was greater in animals with SCD (4.0 +/- 0.2 vs. 3.1 +/- 0.1 g/kg in survivors; P < 0.001). Serial programmed ventricular stimulation failed to induce any sustained arrhythmias. We conclude that pigs with viable dysfunctional myocardium and globally reduced LV function have a high rate of SCD with a spectrum of arrhythmias similar to patients with ischemic cardiomyopathy. The risk is independent of necrosis but appears to increase with LV hypertrophy. Like patients with ischemic cardiomyopathy, programmed stimulation is insensitive to predict SCD when viable dysfunctional myocardium is the pathological substrate.     

Risk stratification for sudden cardiac death

Recent advances in pharmacological and device-based therapies have provided a range of management options for patients at risk of sudden cardiac death (SCD). Since all such interventions come with their attendant risks, however, stratification procedures aimed at identifying those who stand to benefit overall have gained a new degree of importance. This review assesses the value of risk stratification measures currently available in clinical practice, as well as of others that may soon enter the market. Parameters that may be obtained only by performing invasive cardiac catheterisation procedures are considered separately from those that may be derived using more readily available non-invasive techniques. It is concluded that effective stratification is likely to require the use of composite parameters and that invasive procedures might only be justified in specific sub-groups of patients.     

Omega-3 consumption and sudden cardiac death in schizophrenia

People with schizophrenia show a two- to three-fold increased risk to die prematurely. Mortality is accounted for by a combination of factors (patients’ life style, suicide, premature cardiovascular disease, metabolic syndromes and, not so often mentioned, sudden death). The cause of sudden death in schizophrenia is unknown, but cardiac arrhythmia plays a potential role. Patients with schizophrenia are at high risk for cardiovascular disease, and some antipsychotics may be associated with cardiovascular adverse events (e.g., electrocardiograph QT interval prolongation), suggesting that this could lead to sudden cardiac death. Animal and clinical studies have shown that omega-3 fatty acids could be useful in the prevention and treatment of schizophrenia. As omega-3 fatty acids have been considered a cardioprotector agent, reducing cardiac arrhythmias and hence sudden cardiac deaths and given their relative safety and general health benefits, our update article summarizes the knowledge by the possible positive effects of omega-3 supplementation and fish consumption against sudden cardiac death in patients with schizophrenia. However, fish species should be selected with caution due to contamination with toxic methylmercury.     

Clinico-experimental study of histoenzymological changes in the ventricular myocardium in pulmonary embolism]

The SDH and LDH activity in ventricular myocardium was studied in early autopsies of 16 patients, which died from acute pulmonary thromboembolism, and also in 17 dogs with experimental pulmonary embolism. In general the data of histoenzymological study of experimental and sectional material were identical. We revealed some factors, which correlated with low activity of catabolic enzymes in ventricular myocardium of the patients with pulmonary embolism: small volume of embolic occlusion (the thromboembolism of lobar and segmental pulmonary arteries); the presence of prior chronic cardiopulmonary disease; the advanced age and the female sex. Preexisting cardiopulmonary disease, as well as age and sex changes of myocardial metabolism, may assist the development of heart failure by relatively small volume of embolic obstruction.     

Physical activity and sudden cardiac death in elders--a Croatian study

The paper deals with the sudden cardiac death in elders due to physical activity in Croatia and to compare it to other population groups who practice physical activity. The data are a part of a retrospective study dealing with 59 sudden death due to physical activity in men in Croatia: from January 1, 1988 to December 31, 2008. Fifteen aged 65 to 82 years were recreationally engaged in physical activity: six in swimming, four in tennis, one in driving a bicycle, one in jogging, two in bowling and one died during sexual act. Only one had symptoms of pectoral angina, two suffered from arterial hypertension, and two had congestive heart failure. Eleven were without symptoms before exercise. At forensic autopsy, fourteen had coronary heart disease, seven had critical coronary artery stenosis, three had occluded left descendens anterior coronary artery and four critical coronary stenosis, four had a recent myocardial infarctions, and eleven had myocardial scars due to previous myocardial infarctions. Twelve of them had left ventricular hypertrophy: 15-25 mm. In Croatia, about 7per cent of the entire male population undertake recreational physical activity, while 13 per cent of them are elders. A sudden cardiac death due to recreational physical activity in elders reached 1.71/100 000 yearly, in the entire male population engaged in recreational physical exercise: 0.75/100 000 (p = 0.05730), in the total male population aged 15-40 engaged in sports and recreational physical exercise: 0.57/100.0000 (p = 0.00387), in young athletes: 0.15/100 000 (p = 0.00000). Medical examination of all elderly persons has to be done before starting of recreational physical activity: by clinical examination, searching for risk factors for atherosclerosis, performing ECG at rest, stress ECG, and echocardiography and to repeat the medical examination at least once a year Physical activity should start with a warm-up period and with a gradually increasing load, and usually not to exceed 6-7 metabolic equivalents (METs).     

The dawn of a new era in the struggle against sudden cardiac death

The year 2009 is important for Dutch cardiology. It marks not only the 75th anniversary of the Netherlands Society of Cardiology, but also the starting of ICD therapy, 25 years ago. The first ICD implant in the Netherlands was carried out in Utrecht by the cardiac surgeon Dr Penn with the technical assistance of Mr Seah Nisam in April 1984. The patient was referred from Maastricht by Professor Wellens. Referral was needed since Maastricht had no cardiac surgery department at that time.     

Role of non-coronarogenic injuries of the myocardium in sudden death at various stages of postnatal ontogenesis

The study was performed on white inbred young (1 and 3 weeks old), sexually immature (1.5 months old), sexually mature (6 months old) and old (over 24 months old) male rats, who were subcutaneously administered noradrenaline at a dose of 2 mg/kg body weight. The degree of myocardial injury was assessed on frontal histotopographic heart sections stained by the method of Leigh and Regaud, obtained from dead and killed rats 6 hours after noradrenaline injection. The reaction of the adrenal cortical substance was investigated, using quantitative histofluorescent method. It has been shown that young rats have low sensitivity to catecholamine stress, with the sensitivity increasing by the period of sexual maturation and again decreasing in old animals. The animals' death is associated with higher degree of myocardial injury that accompanies a drastic increase in catecholamine secretion by the adrenals.     

Genetic determinants of QT interval variation and sudden cardiac death

Electrocardiographic QT interval prolongation or shortening is a risk factor for sudden cardiac death. The study of Mendelian syndromes in families with extreme long and short QT interval duration and ventricular arrhythmias has led to the identification of genes encoding ion channel proteins important in myocardial repolarization. Rare mutations in such ion channel genes do not individually contribute substantially to the population burden of ventricular arrhythmias and sudden cardiac death. Only now are studies systematically testing the relationship between common variants in these genes--or elsewhere in the genome--and QT interval variation and sudden cardiac death. Identification of genetic variation underlying myocardial repolarization could have important implications for the prevention of both sporadic and drug-induced arrhythmias.     

Elevated myocardial calcium and its role in sudden cardiac death.

The contribution of intracellular calcium to ventricular fibrillation (VF) was investigated using chronically instrumented dogs with healed myocardial infarctions. A 2-minute coronary occlusion was initiated during the last minute of exercise. Fourteen animals developed ventricular fibrillation (susceptible) whereas the remaining 12 did not (resistant) during this exercise plus ischemia test. The test was then repeated for the susceptible animals after pretreatment with the intracellular calcium chelator BAPTA-AM (1.0 mg/kg). BAPTA-AM significantly reduced left ventricular dp/dt max and prevented VF in 8 of 12 susceptible animals. Conversely, myocardial cytosolic calcium levels were increased in resistant animals using the calcium channel agonist Bay K 8644 (30 micrograms/kg) or phenylephrine (10 micrograms.kg-1.min-1 3-5 min before occlusion). Bay K 8644 induced VF in all 5 resistant animals tested whereas phenylephrine induced VF in 8 of 12 resistant animals. BAPTA-AM pretreatment attenuated the hemodynamic effects of Bay K 8644 or phenylephrine and prevented VF in five of five Bay K 8644- and four of seven phenylephrine-treated animals. Finally, the endogenous level of calcium/calmodulin (Ca-CaM)-dependent phosphorylation of 170- and 55-kDa substrate proteins was measured (as an index of intracellular free calcium concentration). In the susceptible dog heart, the endogenous level of Ca-CaM-dependent phosphorylation was estimated to be two- to threefold higher than that observed in resistant dog heart. Treatment of resistant dog tissue with the calcium ionophore A23187 increased the level of Ca-CaM-dependent phosphorylation of these two proteins to the level observed in susceptible dog heart. These data suggest that elevated cytosolic calcium facilitates development of malignant arrhythmias and that elevated cytosolic calcium levels may be present in animals particularly susceptible to ventricular fibrillation.     

Arrhythmogenic right ventricular dysplasia and sudden cardiac death in endurance athletes

Arrhythmogenic right ventricular dysplasia (ARVD) is a cardiomyopathy with several time-dependent clinical presentations. The clinical characteristics depend on the penetration grade of the disease. There are two different histological patterns consisting of a lipomatous and a fibrolipomatous form. The presence of arrhythmias in the ARVD syndrome constitutes an important risk factor for sudden cardiac death in athletes. In this article, we describe two professional endurance athletes who died suddenly. One of these athletes had asymptomatic ARVD, the other had symptomatic polymorphic ventricular tachycardias. Both athletes showed fatty penetration of the disease in both the right and left ventricle; one of them also showed fatty involvement at the atrial level and in the other there were signs of myocarditis consistent with ARVD. In the last few years magnetic resonance imaging has become an important diagnostic tool in patients with ARVD.     

Calstabin deficiency, ryanodine receptors, and sudden cardiac death

Altered cardiac ryanodine receptor (RyR2) function has an important role in heart failure and genetic forms of arrhythmias. RyR2 constitutes the major intracellular Ca2+ release channel in the cardiac sarcoplasmic reticulum (SR). The peptidyl-prolyl isomerase calstabin2 (FKBP12.6) is a component of the RyR2 macromolecular signaling complex. Calstabin2 binding to RyR2 is regulated by PKA phosphorylation of Ser2809 in RyR2. PKA phosphorylation of RyR2 decreases the binding affinity for calstabin2 and increases RyR2 open probability and sensitivity to Ca2+-dependent activation. In heart failure, a majority of studies have found that RyR2 becomes chronically PKA hyper-phosphorylated which depletes calstabin2 from the channel complex. Calstabin2 dissociation causes a diastolic SR Ca2+ leak contributing to depressed intracellular Ca2+ cycling and decreased cardiac contractility. Missense mutations linked to genetic forms of exercise-induced arrhythmias and sudden cardiac death also cause decreased calstabin2-binding affinity and leaky RyR2 channels. We review the importance of calstabin2 for RyR2 function and excitation-contraction coupling, and discuss new observations that implicate dysregulation of calstabin2 binding as a central mechanism for abnormal calcium cycling in heart failure and triggered arrhythmias.     

Influence of environmental stress on pathogenesis of sudden cardiac death.

The effects of 20th-century stress on the cardiovascular system are reviewed and correlated with experimental animal models. A classic example of such stress is drawn from a study of the aerospace workers at Cape Kennedy who were shown to be exposed to excessive occupational stress. Surprisingly, the usual risk factors did not predict a greater risk, yet the population exhibited a higher incidence of sudden cardiac death and acute myocardial infarction. Acute myocardial necrosis was much more frequently demonstrated than was acute coronary obstruction of any type. Retrospective coroner's studies revealed two types of myocardial necrosis: 1) elongated, thinned or wavy fibers and 2) anomalous contraction bands. Correlation of these clinical observations with experimental data was duplicated in canine models of myocardial infarcion and/or catecholamine-induced necrosis. Catecholamines can lead to irreversible myocardial necrosis but the underlying mechanisms appear to be complex. Extrapolation of the results from the experimental and clinical studies suggests that environmental stress can lead to myocardial necrosis.     

Repolarization abnormalities and afterdepolarizations in a canine model of sudden cardiac death

Ventricular tachyarrhythmias are the most common cause of sudden cardiac death (SCD); a healed myocardial infarction increases the risk of SCD. We determined the contribution of specific repolarization abnormalities to ventricular tachyarrhythmias in a postinfarction model of SCD. For our methods, we used a postinfarction canine model of SCD, where an exercise and ischemia test was used to stratify animals as either susceptible (VF(+)) or resistant (VF(-)) to sustained ventricular tachyarrhythmias. Our results show no changes in global left ventricular contractility or volumes occurred after infarction. At 8-10 wk postmyocardial infarction, myocytes were isolated from the left ventricular midmyocardial wall and studied. In the VF(+) animals, myocyte action potential (AP) prolongation occurred at 50 and 90% repolarization (P < 0.05) and was associated with increased variability of AP duration and afterdepolarizations. Multiple repolarizing K(+) currents (I(Kr), I(to)) and inward I(K1) were also reduced (P < 0.05) in myocytes from VF(+) animals compared with control, noninfarcted dogs. In contrast, only I(to) was reduced in VF(-) myocytes compared with controls (P < 0.05). While afterdepolarizations were not elicited at baseline in myocytes from VF(-) animals, afterdepolarizations were consistently elicited after the addition of an I(Kr) blocker. In conclusion, the loss of repolarization reserve via reductions in multiple repolarizing currents in the VF(+) myocytes leads to AP prolongation, repolarization instability, and afterdepolarizations in myocytes from animals susceptible to SCD. These abnormalities may provide a substrate for initiation of postmyocardial infarction ventricular tachyarrhythmias.     

Myopericarditis and sudden cardiac death due to physical exercise in male athletes

In the period 1998-, we registered four sudden and unexpected cardiac deaths in male athletes due to myopericarditis during or after physical exercise. Three of them were professional soccer players and the fourth was engaged in swimming. One aged 29, had symptoms of tiredness, heart enlargement and left ventricular premature beats during training. Three of them, aged 17-18-18, were without symptoms. Three died during training and the fourth died in the hospital after head trauma at training. In the first one, aged 29, forensic autopsy showed chronic myopericarditis, thickening of the left ventricular wall of 15 mm and enlargement of the whole heart. The second one, aged 17, had subacute diffuse myopericarditis, suppurative tonsillitis and narrowed ascending aorta. The third, aged 18, had chronic myopericarditis and cardiac aneurysm of the left ventricle. The fourth, aged 18, had fibrinous pericarditis, thickening of the left ventricle 20 mm, hypoplastic ascending aorta, bilateral bronchopneumonia and cerebral contusion with edema. In Croatia, death rate among athletes, including all its causes, reached 0.15/100,000, in athletes suffering from myopericarditis it was 0.34/100,000, in others who practice exercise recreatively it amounted to 0.57/100,000 (p=0.0068), and in all males who practice exercise it measured 0.75/100,000 (p=0.0014). Physical exercise has to be contraindicated in cases of myopericarditis for at least six months from the onset of the illness.     

Risk stratification for sudden cardiac death in patients with non-ischemic dilated cardiomyopathy

Non ischemic dilated cardiomyopathy (NIDCM) is a disorder of myocardium. It has varying etiologies. Albeit the varying etiologies of this heart muscle disorder, it presents with symptoms of heart failure, and rarely as sudden cardiac death (SCD). Manifestations of this disorder are in many ways similar to its counterpart, ischemic dilated cardiomyopathy (IDCM). A proportion of patients with NIDCM carries a grave prognosis and is prone to sudden cardiac death from sustained ventricular arrhythmias. Identification of this subgroup of patients who carry the risk of sudden cardiac death despite adequate medical management is a challenge. Yet another method is a blanket treatment of patients with this disorder with anti arrhythmic medications or anti tachyarrhythmia devices like implantable cardioverter defibrillators (ICD). However this modality of treatment could be a costly exercise even for affluent economies. In this review we try to analyze the existing data of risk stratification of NIDCM and its clinical implications in practice.     

Cardiac response to submaximal exercise in dogs susceptible to sudden cardiac death

The hemodynamic response to submaximal exercise was investigated in 38 mongrel dogs with healed anterior wall myocardial infarctions. The dogs were chronically instrumented to measure heart rate (HR), left ventricular pressure (LVP), LVP rate of change, and coronary blood flow. A 2 min coronary occlusion was initiated during the last minute of an exercise stress test and continued for 1 min after cessation of exercise. Nineteen dogs had ventricular fibrillation (susceptible) while 19 animals did not (resistant) during this test. The cardiac response to submaximal exercise was markedly different between the two groups. The susceptible dogs exhibited a significantly higher HR and left ventricular end-diastolic pressure (LVEDP) but a significantly lower left ventricular systolic pressure (LVSP) in response to exercise than did the resistant animals. (For example, response to 6.4 kph at 8% grade; HR, susceptible 201.4 +/- 5.1 beats/min vs. resistant 176.2 +/- 5.6 beats/min; LVEDP, susceptible 19.4 +/- 1.1 mmHg vs. resistant 12.3 +/- 1.7 mmHg; LVSP, susceptible 136.9 +/- 7.9 mmHg vs. resistant 154.6 +/- 9.8 mmHg.) beta-Adrenergic receptor blockade with propranolol reduced the difference noted in the HR response but exacerbated the LVP differences (response to 6.4 kph at 8% grade; HR, susceptible 163.4 +/- 4.7 mmHg vs. resistant 150.3 +/- 6.4 mmHg; LVEDP susceptible 28.4 +/- 2.1 mmHg vs. resistant 19.6 +/- 3.0 mmHg; LVSP, susceptible 122.2 +/- 8.1 mmHg vs. resistant 142.8 +/- 10.7 mmHg). These data indicate that the animals particularly vulnerable to ventricular fibrillation also exhibit a greater degree of left ventricular dysfunction and an increased sympathetic efferent activity.     

Stress-induced susceptibility to sudden cardiac death in mice with altered serotonin homeostasis

In humans, chronic stressors have long been linked to cardiac morbidity. Altered serotonergic neurotransmission may represent a crucial pathophysiological mechanism mediating stress-induced cardiac disturbances. Here, we evaluated the physiological role of serotonin (5-HT) 1A receptors in the autonomic regulation of cardiac function under acute and chronic stress conditions, using 5-HT(1A) receptor knockout mice (KOs). When exposed to acute stressors, KO mice displayed a higher tachycardic stress response and a larger reduction of vagal modulation of heart rate than wild type counterparts (WTs). During a protocol of chronic psychosocial stress, 6 out of 22 (27%) KOs died from cardiac arrest. Close to death, they displayed a severe bradycardia, a lengthening of cardiac interval (P wave, PQ and QRS) duration, a notched QRS complex and a profound hypothermia. In the same period, the remaining knockouts exhibited higher values of heart rate than WTs during both light and dark phases of the diurnal rhythm. At sacrifice, KO mice showed a larger expression of cardiac muscarinic receptors (M2), whereas they did not differ for gross cardiac anatomy and the amount of myocardial fibrosis compared to WTs. This study demonstrates that chronic genetic loss of 5-HT(1A) receptors is detrimental for cardiovascular health, by intensifying acute, stress-induced heart rate rises and increasing the susceptibility to sudden cardiac death in mice undergoing chronic stress.