Sudden Cardiac Death In Humans Research Articles

Chondroitin sulfate proteoglycan 4,6 sulfation regulates sympathetic nerve regeneration after myocardial infarction.

Sympathetic denervation of the heart following ischemia/reperfusion induced myocardial infarction (MI) is sustained by chondroitin sulfate proteoglycans (CSPGs) in the cardiac scar. Denervation predicts risk of sudden cardiac death in humans. Blocking CSPG signaling restores sympathetic axon outgrowth into the cardiac scar, decreasing arrhythmia susceptibility. Axon growth inhibition by CSPGs can depend on the sulfation status of the glycosaminoglycan (CS-GAG) side chains. Tandem sulfation of CS-GAGs at the 4th (4S) and 6th (6S) positions of n-acetyl-galactosamine inhibits outgrowth in several types of central neurons, but we don't know if sulfation is similarly critical during peripheral nerve regeneration. We asked if CSPG sulfation prevented sympathetic axon outgrowth after MI. Reducing 4S with the 4-sulfatase enzyme Arylsulfatase-B (ARSB) enhanced outgrowth of dissociated rat sympathetic neurons over CSPGs. Likewise, reducing 4S with ARSB restored axon outgrowth from mouse sympathetic ganglia co-cultured with cardiac scar tissue. We quantified enzymes responsible for adding and removing sulfation, and found that CHST15 (4S dependent 6-sulfotransferase) was upregulated, and ARSB was downregulated after MI. This suggests a mechanism for production and maintenance of sulfated CSPGs in the cardiac scar. We decreased 4S,6S CS-GAGs in vivo by transient siRNA knockdown of Chst15 after MI, and found that reducing 4S,6S restored tyrosine hydroxylase (TH) positive sympathetic nerve fibers in the cardiac scar. Reinnervation reduced isoproterenol induced arrhythmias. Our results suggest that modulating CSPG-sulfation after MI may be a therapeutic target to promote sympathetic nerve regeneration in the cardiac scar and reduce post-MI cardiac arrhythmias.

Sudden cardiac deaths have higher proportion of left stellate ganglionitis.

One of the hypothesized mechanisms of sudden cardiac death in humans is an arrhythmia precipitated by increased sympathetic outflow to a compromised heart. The stellate ganglia provide the main sympathetic innervation to the heart, where the left stellate ganglion appears to play a role in arrhythmogenesis. Case reports of sudden cardiac death have described left stellate ganglion inflammation but no larger studies have been performed. Thus, we have specifically assessed whether the left stellate ganglion was inflamed in those dying from sudden cardiac death versus other causes of death. Thirty-one left stellate ganglia were resected from cadavers diagnosed with sudden cardiac deaths and compared with 18 ganglia from cadavers diagnosed with non-sudden cardiac deaths. Ganglia were stained with hematoxylin and eosin and lymphocytic aggregates compared. The proportion of left stellate ganglion inflammation (77%) was significantly higher in deaths from sudden cardiac deaths than non-sudden cardiac deaths (33%). This study provides information on a previously recognized, but understudied, structure that may help understand sudden cardiac death. We found high prevalence of stellate ganglion inflammation and propose that this may trigger sympathetic storms.

Abstract 13286: Ryanodine Receptor Inhibition Prevents Sudden Cardiac Death by Preserving Cardiac Repolarization Reserve in Stressed Arrhythmogenic Hearts

Introduction: Current therapies for preventing sudden cardiac death (SCD) are limited. Prior studies have shown that cardiac stress-induced ryanodine receptor (RyR2) hyperactivity increases sarcoplasmic calcium leak, leading to ventricular tachyarrythmias (VT) and SCD. We hypothesized that inhibition of RyR2 with dantrolene sodium (DS) reduces Ca 2+ leak and mitigates VT and SCD risk in pressure-overloaded arrhythmogenic hearts. Methods: We used an established guinea pig model that uniquely recapitulates key features of human SCD, including a high incidence of spontaneous VT in freely ambulating animals, randomized to placebo vs. DS treatment. We performed in vivo (e.g., VT/SCD incidence, ECG heart rate and QT variability, echocardiographic measures of cardiac function) and ex vivo (e.g., pressure-volume, electrophysiology) studies. We performed intention to treat analysis for 4-week VT-free survival. Results: About half the animals receiving placebo had SCD by 4 weeks. By contrast, dantrolene treatment reduced SCD incidence by 50%. Compared to placebo, dantrolene treatment preserved chronotropic competency during transient β-adrenergic challenge, and improved heart rate variability (SDNN: 11±1.1 vs 17±2.8 ms, p<0.05), reduced QT variability (0.52±0.13 vs 0.19±0.08 (log, ms, p<0.05), and improved cardiac function (fractional shortening: 26±1.9 vs 45±4.5 %, p<0.05). In perfused excised hearts, dantrolene treatment mitigated VT (induced by isoproterenol or burst pacing). Conclusion: Inhibition of RyR2 hyperactivity by dantrolene treatment prevents VT and SCD by increasing cardiac repolarization reserve. Dantrolene also improved overall cardiac electromechanical function in stressed arrhythmogenic hearts. Targeted inhibition of RyR2 hyperactivity may be an effective therapeutic strategy for preventing VT and SCD.

Exercise-Associated Sudden Death in Finnish Standardbred and Coldblooded Trotters - A Case Series With Pedigree Analysis

Exercise-associated sudden deaths (EASDs) are deaths occurring unexpectedly during or immediately after exercise. Sudden cardiac death (SCD) is one cause of EASD. Cardiac arrhythmias caused by genetic variants have been linked to SCD in humans. We hypothesize that genetic variants may be associated with SCD in animals, including horses. Genetic variants are transmitted to offspring and their frequency might increase within a family. Therefore, the frequency of such variants might increase with the inbreeding factor. Higher inbreeding could have a negative impact on racing performance. Pedigree data and career earnings from racehorses diagnosed with SCD between 2002 and 2017 were compared using non-parametric tests with 1) control horses that died due to catastrophic musculoskeletal injuries and 2) horses that raced during the same period without reported problems. Diagnosis of SCD was based on necropsy reports, including macroscopic and microscopic examinations. Death was registered in the study period for 61 horses. Eleven of these horses were excluded due to missing autopsy reports. In 25 cases, the diagnosis remained unknown and death was possibly caused by cardiac arrhythmia, in two cases cardiac disease was identified, in seven cases a rupture of a major vessel had occurred. In addition, 16 horses died or were euthanized due to severe musculoskeletal injuries. No significant differences in inbreeding coefficients or in career earnings were found between the groups or between horses with EASD compared with other horses racing during the same period. The study provides no evidence for increased inbreeding factor in Finnish racehorses with SCD.

Zebrafish Heart as a Model to Elucidate the Mechanisms of Sudden Cardiac Death

The heart of zebrafish has been used as a simple, low-cost model to study development, structure and function of the heart from early to late stages of life. Also, it has been established as a model to study different cardiac pathologies generated through different methods. Cardiac pathologies include from functional disorders such as arrhythmia, to structural disorders such as hypertrophic heart disease; in many of them, genetic and molecular aspects have been associated. Noteworthy, some of these genetic and molecular factors have been invoked as causes of sudden cardiac death in humans. This adverse outcome is common in many cardiovascular pathologies and can occur at any age. Unfortunately, etiology and physiopathology of sudden cardiac death are unclear, so extensive research in this area is required. This mini-review highlight three related points: First, the relevance of sudden cardiac death in humans. Second, advances in knowledge of the development, function and pathologies in the zebrafish heart model. Finally, the possibility of using the zebrafish model for the study of sudden cardiac. For this review, a literature search was performed using the PubMed database and the search engine Google Scholar: the words sudden cardiac death, zebrafish, arrhythmias, cardiomyopathies were combined for this search.

Selenium protein identification and profiling by mass spectrometry: A tool to assess progression of cardiomyopathy in a whale model.

Non-ischemic cardiomyopathy is a leading cause of congestive heart failure and sudden cardiac death in humans and in some cases the etiology of cardiomyopathy can include the downstream effects of an essential element deficiency. Of all mammal species, pygmy sperm whales (Kogia breviceps) present the greatest known prevalence of cardiomyopathy with more than half of examined individuals indicating the presence of cardiomyopathy from gross and histo-pathology. Several factors such as genetics, infectious agents, contaminants, biotoxins, and inappropriate dietary intake (vitamins, selenium, mercury, and pro-oxidants), may contribute to the development of idiopathic cardiomyopathy in K. breviceps. Due to the important role Se can play in antioxidant biochemistry and protein formation, Se protein presence and relative abundance were explored in cardiomyopathy related cases. Selenium proteins were separated and detected by multi-dimension liquid chromatography inductively coupled plasma mass spectrometry (LC-ICP-MS), Se protein identification was performed by liquid chromatography electrospray tandem mass spectrometry (LC-ESI-MS/MS), and Se protein profiles were examined in liver (n=30) and heart tissue (n=5) by SEC/UV/ICP-MS detection. Data collected on selenium proteins was evaluated in the context of individual animal trace element concentration, life history, and histological information. Selenium containing protein peak profiles varied in presence and intensity between animals with no pathological findings of cardiomyopathy and animals exhibiting evidence of cardiomyopathy. In particular, one class of proteins, metallothioneins, was found to be associated with Se and was in greater abundance in animals with cardiomyopathy than those with no pathological findings. Profiling Se species with SEC/ICP-MS proved to be a useful tool to identify Se protein pattern differences between heart disease stages in K. breviceps and an approach similar to this may be applied to other species to study Se protein associations with cardiomyopathy.

The effect of supplementing feed with organic selenium on some hematological, biochemical, behavioral markers and egg quality

Non-ischemic cardiomyopathy is a leading cause of congestive heart failure and sudden cardiac death in humans and in some cases the etiology of cardiomyopathy can include the downstream effects of an essential element deficiency. Of all mammal species, pygmy sperm whales (Kogia breviceps) present the greatest known prevalence of cardiomyopathy with more than half of examined individuals indicating the presence of cardiomyopathy from gross and histo-pathology. Several factors such as genetics, infectious agents, contaminants, biotoxins, and inappropriate dietary intake (vitamins, selenium, mercury, and pro-oxidants), may contribute to the development of idiopathic cardiomyopathy in K. breviceps. Due to the important role Se can play in antioxidant biochemistry and protein formation, Se protein presence and relative abundance were explored in cardiomyopathy related cases. Selenium proteins were separated and detected by multi-dimension liquid chromatography inductively coupled plasma mass spectrometry (LC-ICP-MS), Se protein identification was performed by liquid chromatography electrospray tandem mass spectrometry (LC-ESI-MS/MS), and Se protein profiles were examined in liver (n = 30) and heart tissue (n = 5) by SEC/UV/ICP-MS detection. Data collected on selenium proteins was evaluated in the context of individual animal trace element concentration, life history, and histological information. Selenium containing protein peak profiles varied in presence and intensity between animals with no pathological findings of cardiomyopathy and animals exhibiting evidence of cardiomyopathy. In particular, one class of proteins, metallothioneins, was found to be associated with Se and was in greater abundance in animals with cardiomyopathy than those with no pathological findings. Profiling Se species with SEC/ICP-MS proved to be a useful tool to identify Se protein pattern differences between heart disease stages in K. breviceps and an approach similar to this may be applied to other species to study Se protein associations with cardiomyopathy.

Diurnal modulation and sources of variation affecting ventricular repolarization in Warmblood horses

ObjectivesIrregularities in cardiac repolarization are known to predispose for arrhythmias and sudden cardiac death in humans. The QT interval is a quantitative measurement of repolarization, and clinically, the QTc (QT interval corrected for heart rate) and Tpeak to Tend intervals (TpTe) are used as repolarization markers. To support the use of these markers in horses, we sought to describe the possible influence of the environment, time of day, day-to-day effects, T wave conformation, age, body weight (BW), and horse-to-horse variation on repolarization measurements. Animals12 Warmblood geldings, age 10.8 ± 4.8 years. MethodsHolter ECGs were performed on days 0, 7 and 14. Measures of RR, QT, QTp, QTc and TpTe intervals and T wave conformation were obtained each hour during the recordings. An ANCOVA analysis was performed to estimate diurnal variation and the sources of variation affecting these intervals. ResultsDifferences between individual horses were the largest source of repolarization variability although the environment had a significant effect on repolarization as well. Diurnal variation affected both the RR interval and the repolarization markers. The QT, QTc and TpTe intervals were prolonged on day 0. Biphasic T waves shortened the TpTe interval approximately 10 ms. Age and BW did not appear to affect repolarization. ConclusionsEquine repolarization markers exhibit significant variation. Factors affecting repolarization measurements include horse-to-horse variation, diurnal variation, the environment, and T wave conformation. These factors must be considered if markers of equine repolarization are used diagnostically.

Reduced Ventricular Arrhythmogeneity and Increased Electrical Complexity in Normal Exercised Rats

BackgroundThe mechanisms whereby aerobic training reduces the occurrence of sudden cardiac death in humans are not clear. We test the hypothesis that exercise-induced increased resistance to ventricular tachycardia and fibrillation (VT/VF) involve an intrinsic remodeling in healthy hearts.Methods and ResultsThirty rats were divided into a sedentary (CTRL, n = 16) and two exercise groups: short- (4 weeks, ST, n = 7) and long-term (8 weeks, LT, n = 7) trained groups. Following the exercise program hearts were isolated and studied in a Langendorff perfusion system. An S1–S2 pacing protocol was applied at the right ventricle to determine inducibility of VT/VF. Fast Fourier transforms were applied on ECG time-series. In-vivo measurements showed training-induced increase in aerobic capacity, heart-to-body weight ratio and a 50% low-to-high frequency ratio reduction in the heart rate variability (p<0.05). In isolated hearts the probability for VF decreased from 26.1±14.4 in CTRL to 13.9±14.1 and 6.7±8.5% in the ST and LT, respectively (p<0.05). Duration of VF also decreased from 19.0±5.7 in CTRL to 8.8±7.1 and 6.0±5.8 sec in ST and LT respectively (p<0.05). Moreover, the pacing current required for VF induction increased following exercise (2.9±1.7 vs. 5.4±2.1 and 8.5±0.9 mA, respectively; p<0.05). Frequency analysis of ECG revealed an exercise-induced VF transition from a narrow single peak spectrum at 17 Hz in CTRL to a broader range of peaks ranging between 8.8 and 22.5 Hz in the LT group (p<0.05).ConclusionExercise in rats leads to reduced VF propensity associated with an intrinsic cardiac remodeling related to a broader spectral range and faster frequency components in the ECG.

Cardiac Na/K-ATPase and Na/Ca Exchange Function is Altered in Ankyrin B Heterozygous Mice

Ankyrin-B (AnkB) is a multivalent “adaptor” protein that targets select membrane proteins to the cytoskeleton. Loss-of-function mutations in AnkB may cause ventricular arrhythmias and sudden cardiac death in humans. Direct interaction with AnkB is required for the membrane targeting and stability of Na/Ca exchanger (NCX) and Na/K-ATPase (NKA), key regulators of cardiac contractility and arrhythmogenesis. However, it is currently unknown how AnkB modulates NCX and NKA function. To investigate this, we used AnkB heterozygous mice (AnkB+/-) and their wild-type (WT) littermates. Cardiac myocytes from AnkB+/- mice show reduced expression (by ∼20%) and altered localization of both NCX and NKA. In agreement with the lower protein level, we found slower decay of the caffeine-induced Ca transient (τ=7.4±0.8 sec vs. 5.2±0.6 sec) and reduced maximum rate of NKA-mediated Na extrusion (5.0±0.5 vs. 6.4±0.4 mM/min) in intact myocytes from AnkB+/- mice vs. WT. Thus, NCX and NKA transport function are reduced in AnkB+/-vs. WT mice. We also measured the voltage-dependence of the currents carried by NCX (INCX) and NKA (Ipump) using whole-cell voltage-clamp. INCX and Ipump were recorded during descending voltage ramps, as Cd-sensitive and K-activated currents, respectively. INCX reflected the lower NCX expression in AnkB+/- myocytes, with no difference in the voltage-dependence vs. WT. In contrast, Ipump had a significantly (p<0.001) steeper voltage-dependence in AnkB+/-vs. WT myocytes. Thus, at −80 mV, close to the resting membrane potential, Ipump was reduced by ∼35% in AnkB+/- mice, whereas at +30 mV, close to the peak of the action potential, AnkB+/- Ipump was elevated by ∼18% vs. WT. Thus, in addition to reducing NKA protein expression, AnkB also directly modulates NKA function in cardiac myocytes, by reducing the voltage-dependent Ipump inactivation. This could significantly affect myocyte [Na]i and [Ca]i regulation.

Ankyrin-B reduction enhances Ca spark-mediated SR Ca release promoting cardiac myocyte arrhythmic activity

Ankyrin-B (AnkB) loss-of-function may cause ventricular arrhythmias and sudden cardiac death in humans. Cardiac myocytes from AnkB heterozygous mice (AnkB(+/-)) show reduced expression and altered localization of Na/Ca exchanger (NCX) and Na/K-ATPase (NKA), key players in regulating [Na](i) and [Ca](i). Here we investigate how AnkB reduction affects cardiac [Na](i), [Ca](i) and SR Ca release. We found reduced NCX and NKA transport function but unaltered [Na](i) and diastolic [Ca](i) in myocytes from AnkB(+/-) vs. wild-type (WT) mice. Ca transients, SR Ca content and fractional SR Ca release were larger in AnkB(+/-) myocytes. The frequency of spontaneous, diastolic Ca sparks (CaSpF) was significantly higher in intact myocytes from AnkB(+/-) vs. WT myocytes (with and without isoproterenol), even when normalized for SR Ca load. However, total ryanodine receptor (RyR)-mediated SR Ca leak (tetracaine-sensitive) was not different between groups. Thus, in AnkB(+/-) mice SR Ca leak is biased towards more Ca sparks (vs. smaller release events), suggesting more coordinated openings of RyRs in a cluster. This is due to local cytosolic RyR regulation, rather than intrinsic RyR differences, since CaSpF was similar in saponin-permeabilized myocytes from WT and AnkB(+/-) mice. The more coordinated RyRs openings resulted in an increased propensity of pro-arrhythmic Ca waves in AnkB(+/-) myocytes. In conclusion, AnkB reduction alters cardiac Na and Ca transport and enhances the coupled RyR openings, resulting in more frequent Ca sparks and waves although the total SR Ca leak is unaffected. This could enhance the propensity for triggered arrhythmias in AnkB(+/-) mice.

Action potential voltage alternans: An indicator of calcium handling dysfunction during heart failure?

Action potential voltage alternans, which leads to T-wave alternans (TWA) on the surface ECG, has been linked to risk for recurrent ventricular arrhythmias and sudden cardiac death in humans.1 In addition, several studies have demonstrated that alternans can trigger cardiac reentry,2–5 at least experimentally. The rate-dependent occurrence of TWA has been used to classify whether a patient will benefit from placement of an implantable cardioverter-defibrillator, although the ability of TWA to predict occurrences of ventricular arrhythmias has been mixed.

Fish consumption and risk of sudden cardiac death.

Studies show conflicting results regarding the protective effect of dietary fish and fish oil on certain types of cardiovascular disease. A recent epidemiologic study supports the hypothesis that moderate consumption (1-2 meals/week) of fish lowers the risk of sudden cardiac death in humans.

Repolarization gradients and arrhythmogenicity in the murine heart

Repolarization gradients and arrhythmogenicity in the murine heart

β2-Adrenergic Receptor Genetic Variants and Risk of Sudden Cardiac Death

Sympathetic activation influences the risk of ventricular arrhythmias and sudden cardiac death (SCD), mediated in part by the beta2-adrenergic receptor (B2AR). We investigated whether variation in the B2AR gene is associated with SCD risk. In this study, 4441 white and 808 black Cardiovascular Health Study (CHS) participants were followed up prospectively for SCD and genotyped for B2AR Gly16Arg and Gln27Glu polymorphisms. The study was replicated in 155 case and 144 control white subjects in a population-based case-control study of SCD, the Cardiac Arrest Blood Study (CABS). In CHS, Gly16 and Gln27 allele frequencies were 62.4% and 57.1% among white and 50.1% and 81.4% among black participants. Over a median follow-up of 11.1 years, 156 and 39 SCD events occurred in white and black participants, respectively. The Gln27Glu variant was associated with SCD risk (P=0.008 for general model). SCD risk was higher in Gln27 homozygous participants than in Glu27 carriers (ethnicity-adjusted hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.17 to 2.09; P=0.003). The increased risk did not differ significantly between white (HR, 1.62; 95% CI, 1.18 to 2.23) and black (HR, 1.23; 95% CI, 0.61 to 2.48) participants, although the confidence interval was wide in blacks. In the CABS replication study, Gln27 homozygous participants similarly had higher SCD risk than Glu27 carriers (odds ratio, 1.64; 95% CI, 1.02 to 2.63; P=0.040). Gly16Arg was not associated with SCD risk in either study. Gln27 homozygous individuals have an increased risk of SCD in 2 study populations. Our findings suggest that B2AR plays a role in SCD in humans. Study of genetic variation within the B2AR gene may help identify those at increased SCD risk.

Blockers of the ATP-sensitive potassium channel SUR2A/Kir6.2: a new approach to prevent sudden cardiac death.

The cardiac ATP sensitive potassium channel (K(ATP) channel) SUR2A/Kir6.2 is an emerging target for antiarrhythmic intervention. This channel accounts for known electrophysiological derangements soon after the onset of myocardial ischemia. Consequently, blockers of this channel have the potential to prevent ischemic malignant arrhythmias and sudden cardiac death in humans. Since cardiac K(ATP) channels are closed at physiological intracellular ATP concentrations (ATP(i)) and open only when ATP(i) falls below a critical value, these agents do not affect the normal cardiac action potential and should be devoid of proarrhythmic side effects. Due to the existence of isoforms of this channel, mainly in vascular smooth muscle cells, pancreatic beta-cells and cardiac mitochondria, only specific blockers of SUR2A/Kir6.2 will offer a reasonable option for the treatment of cardiovascular patients at risk of sudden cardiac death. Presently known K(ATP) blockers are derived from diverse classes of compounds with antidiabetic sulfonylureas being their most prominent members. Retrospective evaluations of clinical studies with the sulfonylurea glibenclamide in diabetics revealed antifibrillatory activity to be an important additional effect of this class of compounds. However, for the safe treatment of arrhythmias nearly all presently known blockers lack sufficient selectivity, either within the target family or with respect to other ion channels modulating the cardiac action potential. The present article illustrates the new principle in terms of molecular biology and electrophysiology and summarizes all presently known K(ATP) blockers. As a highlight, first strategies to come to selective SUR2A/Kir6.2 blockers, such as HMR 1883, are reviewed.

Partitioning of polyunsaturated fatty acids, which prevent cardiac arrhythmias, into phospholipid cell membranes

It has been demonstrated in animal studies that polyunsaturated fatty acids (PUFA) prevent ischemia-induced malignant ventricular arrhythmias, a major cause of sudden cardiac death in humans. To learn how these PUFA, at low micromolar concentrations, exert their antiarrhythmic activity, we studied their effects in vitro on the contractions of isolated cardiac myocytes and the conductances of their sarcolemmal ion channels. These fatty acids directly stabilize electrically every cardiac myocyte by modulating the conductances of specific ion channels in their sarcolemma. In this study, we determined the molar ratio of PUFA to the moles of phospholipid (PL) in cell membranes to learn if the ratio is so low as to preclude the possibility that the primary site of action of PUFA is on the packing of the membrane PL. [3H]-arachidonic acid (AA) was used to measure the incorporation of PUFA, and the inorganic phosphorous of the PL was determined as a measure of the moles of PL in the cell membrane. Our results indicate that the mole percent of AA to moles of phospolipid is very low (≤1.0) at the concentrations that affect myocyte contraction and the conductance of voltage-dependent Na+ and L-type Ca2+ channels in rat cardiomyocytes and in α-subunits of human myocardial Na+ channels. In conclusion, it seems highly unlikely that these fatty acids are affecting the packing of PL within cell membranes as their way of modulating changes in cell membrane ion currents and in preventing arrhythmias in our contractility studies. —Pound, E. M., J. X. Kang, and A. Leaf. Partitioning of polyunsaturated fatty acids, which prevent cardiac arrhythmias, into phospholipid cell membranes.

Rate-dependent electrical, contractile and restitution properties of isolated left ventricular myocytes in guinea-pig hypertrophy.

Left ventricular hypertrophy predisposes to sudden cardiac death (SCD) and studies of human SCD suggest that the antecedent heart rate (HR) is usually < 100 beats min(-1). This is surprising in view of the known association between adrenergic receptor stimulation and SCD which by itself would suggest that it is more likely to occur from high rather than low HR. We therefore hypothesized that there may be electrical or mechanical abnormalities present in myocytes isolated from animals with left ventricular hypertrophy that predispose to SCD at low stimulation frequencies but which may not be present at high HR. Mild left ventricular hypertrophy was induced in guinea-pigs by infra-renal aortic banding. Electrical and mechanical properties of isolated myocytes were studied at different stimulation frequencies between 0.1 and 3 Hz. Action potential duration (APD) is prolonged in hypertrophy at stimulation frequencies < 1 Hz but not at faster rates. Contraction size, time-to-peak contraction (TTPC) and half-relaxation time are greatly enhanced in hypertrophy at all frequencies between 0.1 and 3 Hz. Electrical (50.3 +/- 5.2 ms in hypertrophy and 78.4 +/- 12.1 ms in control, P < 0.03) and mechanical (205 +/- 16 ms for hypertrophy and 266 +/- 24 ms for control cells, P < 0.03) restitution time constants are quicker in hypertrophy. The finding of APD prolongation at low but not at high frequencies is consistent with the finding that SCD arises from low and not high HR. This data supports the role of abnormal repolarization in SCD.

Prevention of cardiac sudden death by N-3 fatty acids: a review of the evidence.

The essential n-6 and n-3 polyunsaturated fatty acids can prevent ischaemia-induced ventricular fibrillation in rats, dogs and marmosets. In isolated neonatal rat cardiac myocytes, these have been shown to prevent tachyarrhythmias caused by elevated calcium concentrations, toxic levels of ouabain, a beta-adrenergic agent (isoproterenol), lysophosphatidylcholine and acylcarnitine. The antiarrhythmic effect is caused by a reduction in electrical excitability caused by partitioning of the free polyunsaturated fatty acids into the phospholipid cell membranes of the cardiac myocytes, which modulates membrane ion channels. Two clinical trials suggest they could prevent sudden cardiac death in humans.

Ventricular fibrillation in the neonate: elusive or illusive?

Ventricular fibrillation (VF) in mature large mammals is usually a terminal event. It constitutes the most common mode of exitus and the main cause of sudden cardiac death in humans. In neonates, VF is of particular interest because it often reverse spontaneously and promptly to potentially become a non-lethal event. Accordingly, the study of VF and spontaneous defibrillation (SDF) in the neonate is key for the understanding of the developmental anatomical and functional characteristics enabling mammalian myocardium to initiate and sustain this lethal arrhythmia. Such characteristics may include age-related changes of myocardial tissue properties, mass and geometry, autonomic cardiac innervation and myocardial perfusion/hydration. In the human neonate, VF/SDF could provide a plausible framework for explaining and directing the search for the elusive evidence underlying the mechanism and age distribution of the sudden infant death syndrome.