High Incidence Of Sudden Cardiac Death Research Articles

Sudden Cardiac Death in National Collegiate Athletic Association Athletes: A 20-Year Study.

Understanding the incidence, causes, and trends of sudden cardiac death (SCD) among young competitive athletes is critical to inform preventive policies. This study included National Collegiate Athletic Association athlete deaths during a 20-year time frame (July 1, 2002, through June 30, 2022). Athlete deaths were identified through 4 separate independent databases and search strategies (National Collegiate Athletic Association resolutions list, Parent Heart Watch database and media reports, National Center for Catastrophic Sports Injury Research database, and insurance claims). Autopsy reports and medical history were reviewed by an expert panel to adjudicate causes of SCD. A total of 143 SCD cases in National Collegiate Athletic Association athletes were identified from 1102 total deaths. The National Collegiate Athletic Association resolutions list identified 117 of 143 (82%), the Parent Heart Watch database or media reports identified 89 of 143 (62%), the National Center for Catastrophic Sports Injury Research database identified 63 of 143 (44%), and insurance claims identified 27 of 143 (19%) SCD cases. The overall incidence of SCD was 1:63 682 athlete-years (95% CI, 1:54 065-1:75 010). Incidence was higher in male athletes than in female athletes (1:43 348 [95% CI, 1:36 228-1:51 867] versus 1:164 504 [95% CI, 1:110 552-1:244 787] athlete-years, respectively) and Black athletes compared with White athletes (1:26 704 [1:20 417-1:34 925] versus 1:74 581 [1:60 247-1:92 326] athlete-years, respectively). The highest incidence of SCD was among Division I male basketball players (1:8188 [White, 1:5848; Black, 1:7696 athlete-years]). The incidence rate for SCD decreased over the study period (5-year incidence rate ratio, 0.71 [95% CI, 0.61-0.82]), whereas the rate of noncardiovascular deaths remained stable (5-year incidence rate ratio, 0.98 [95% CI, 0.94-1.04]). Autopsy-negative sudden unexplained death (19.5%) was the most common postmortem examination finding, followed by idiopathic left ventricular hypertrophy or possible cardiomyopathy (16.9%) and hypertrophic cardiomyopathy (12.7%), in cases with enough information for adjudication (118 of 143). Eight cases of death were attributable to myocarditis over the study period (1 case from January 1, 2020, through June 30, 2022), with none attributed to COVID-19 infection. SCD events were exertional in 50% of cases. Exertional SCD was more common among those with coronary artery anomalies (100%) and arrhythmogenic cardiomyopathy (83%). The incidence of SCD in college athletes has decreased. Male sex, Black race, and basketball are associated with a higher incidence of SCD.

Abstract 13427: Incidence and Causes of Sudden Cardiac Death in National Collegiate Athletic Association Athletes: A 20-year Study

Background: The incidence and causes of sudden cardiac death (SCD) among young competitive athletes impact prevention strategies yet remain incompletely understood. Methods: National Collegiate Athletic Association (NCAA) athlete deaths from 7/1/2002-6/30/2022 were identified through 4 independent databases/search strategies. Autopsy reports and medical history were reviewed by an expert panel to adjudicate causes of SCD. Poisson regression was used to calculate incidence rate ratios (IRR) for 5-year intervals over the 20-year study. Results: A total of 143 SCD cases were identified among 1102 athlete deaths and 9,106,516 athlete-years (AYs). The incidence of SCD among NCAA athletes was 1:63,682 AYs [95% CI 1:54,065, 1:75,010]. Incidence was higher in males compared to females (1:43,348 vs. 1:164,504 AYs) and Black compared to White athletes (1:27,217 vs. 1:74,581 AYs). The highest incidence of SCD was among Division 1 male basketball players (1:8,188; White 1:5,848; Black 1:7,696 AYs). The incidence rate for SCD decreased over the study period (5-year IRR 0.71 [95% CI 0.61,0.82]), whereas the rate of non-cardiovascular deaths remained stable (5-year IRR 0.98 [95% CI 0.94,1.04]; Figure 1A ). Autopsy-negative sudden unexplained death (AN-SUD, 19.5%) was the most common post-mortem exam finding, followed by idiopathic left ventricular hypertrophy/possible cardiomyopathy (CM, 16.9%) and hypertrophic CM (12.7%) in cases with enough information for adjudication (118/143, Figure 1B ). There were 8 cases of myocarditis, with none attributed to COVID-19 infection. SCD events occurred most commonly during exertion among athletes with coronary artery anomalies (100%) and arrhythmogenic CM (83%), whereas AN-SUD and hypertrophic CM had a higher proportion of non-exertional SCD (44% and 40%, respectively). Conclusions: The incidence of SCD in college athletes has decreased. Male sex, Black race, and basketball are associated with a higher incidence of SCD.

Sudden cardiac death in dialysis patients: different causes and management strategies.

Sudden cardiac death (SCD) represents a major cause of death in end-stage kidney disease (ESKD). The precise estimate of its incidence is difficult to establish because studies on the incidence of SCD in ESKD are often combined with those related to sudden cardiac arrest (SCA) occurring during a haemodialysis (HD) session. The aim of the European Dialysis Working Group of ERA-EDTA was to critically review the current literature examining the causes of extradialysis SCD and intradialysis SCA in ESKD patients and potential management strategies to reduce the incidence of such events. Extradialysis SCD and intradialysis SCA represent different clinical situations and should be kept distinct. Regarding the problem, numerically less relevant, of patients affected by intradialysis SCA, some modifiable risk factors have been identified, such as a low concentration of potassium and calcium in the dialysate, and some advantages linked to the presence of automated external defibrillators in dialysis units have been documented. The problem of extra-dialysis SCD is more complex. A reduced left ventricular ejection fraction associated with SCD is present only in a minority of cases occurring in HD patients. This is the proof that SCD occurring in ESKD has different characteristics compared with SCD occurring in patients with ischaemic heart disease and/or heart failure and not affected by ESKD. Recent evidence suggests that the fatal arrhythmia in this population may be due more frequently to bradyarrhythmias than to tachyarrhythmias. This fact may partly explain why several studies could not demonstrate an advantage of implantable cardioverter defibrillators in preventing SCD in ESKD patients. Electrolyte imbalances, frequently present in HD patients, could explain part of the arrhythmic phenomena, as suggested by the relationship between SCD and timing of the HD session. However, the high incidence of SCD in patients on peritoneal dialysis suggests that other risk factors due to cardiac comorbidities and uraemia per se may contribute to sudden mortality in ESKD patients.

Abstract 390: Mitochondrial ROS Drive Sudden Cardiac Death and Chronic Proteome Remodeling in Heart Failure

Intro: Sudden cardiac death (SCD) from ventricular arrhythmias (VT/VF) claims more lives each year than all other disease-related causes of death combined. The underlying links between HF and SCD remain unclear. Reactive oxygen species (ROS) are central to SCD pathophysiology, but their effects depend on where and how ROS are generated. Employing innovative approaches, we hypothesized that mitochondrial ROS (mROS) is a principal source of oxidative stress in HF and in vivo reduction of mROS mitigates SCD. Methods: In a unique guinea pig model that mimics human non-ischemic HF with a high incidence of SCD, we performed a randomized 2x2 crossover study with MitoTEMPO therapy. We employed novel, genetically encoded ratiometric redox sensors for quantitative measurement of cytosol (cROS) or mROS of cardiomyocytes. Results: We show for the first time that mROS is elevated in failing hearts and that a mitochondrially targeted antioxidant (MitoTEMPO) normalizes cellular ROS, while NADPH oxidase inhibition is effective in correcting only the cROS component. in vivo mitoTEMPO treatment can prevent or reverse HF while eliminating SCD by decreasing T-wave dispersion and suppressing premature ventricular complexes (PVCs). Scavenging mROS suppressed chronic HF-induced remodeling of the expression proteome and prevented specific phosphoproteome alterations. Pathway analysis of mROS-sensitive networks indicated that, in HF, increased mROS disrupts the normal coupling between cytosolic signals and the nuclear gene programs driving mitochondrial function, antioxidant enzymes, Ca2+ handling and action potential repolarization. Conclusions: mROS drive both acute emergent events, such as electrical instability leading to SCD, and mediates chronic HF remodeling, characterized by suppression or altered phosphorylation of metabolic, antioxidant and ion transport protein networks. Impaired mROS scavenging cause failing hearts to become more vulnerable to demand-induced oxidative stress and promote arrhythmic SCD. Maintaining global redox balance by enhanced mROS scavenging may be an effective strategy for SCD therapy in HF.

A novel LMNA nonsense mutation causes two distinct phenotypes of cardiomyopathy with high risk of sudden cardiac death in a large five-generation family.

Characterization of the cardiac phenotype associated with the novel LMNA nonsense mutation c.544C>T, p.Q182*, which we have identified in a large five-generation family. A family tree was constructed. Clinical data [arrhythmia, syncope, sudden cardiac death (SCD), New York Heart Association (NYHA) class] were collected from living and deceased family members. DNA of 23 living family members was analysed for mutations in LMNA. Additionally, dilated cardiomyopathy multi-gene-panel testing and whole exome sequencing were performed in some family members to identify potential phenotype-modifiers. In this five-generation family (n = 65), 17 SCDs occurred at 49.3 ± 10.0 years. Furthermore, we identified eight additional mutation-carriers, seven symptomatic (44 ± 13 years), and one asymptomatic (44 years). First signs of disease [sinus bradycardia with atrioventricular (AV)-block I°] occurred at 36.5 ± 8.1 years. Paroxysmal atrial fibrillation (AF) (onset at 41.8 ± 5.7 years) rapidly progressed to permanent AF (46.2 ± 9.8 years). Subsequently, AV-conduction worsened, syncope, pacemaker-dependence, and non-sustained ventricular tachycardia (43.3 ± 8.2 years) followed. Ventricular arrhythmia caused SCD in patients without implantable cardioverter-defibrillator (ICD). Patients protected by ICD developed rapidly progressive heart failure (45.2 ± 10.6 years). A different phenotype was seen in a sub-family in three patients with early onset of rapidly decompensating heart failure and only minor prior arrhythmia-related symptoms. One patient received high-urgency heart transplantation (HTX) at 32 years, while two died prior to HTX. One of them developed lethal peripartum-associated heart failure. Possible disease-modifiers were identified in this 'heart failure sub-family'. The novel LMNA nonsense mutation c.544C>T causes a severe arrhythmogenic phenotype manifesting with high incidence of SCD in most patients; and in one sub-family, a distinct phenotype with fast progressing heart failure, indicating the need for early consideration of ICD-implantation and listing for heart-transplantation.

Current Perspectives on Sudden Cardiac Death in Hemodialysis Patients.

Recent lines of evidence suggest that, as in other countries, sudden cardiac death (SCD) is more common in the Japanese dialysis clinical setting than we previously thought. Three specific important findings may underlie the increased incidence of SCD in dialysis patients. Even after successful coronary revascularization, hemodialysis (HD) patients continue to have a higher incidence of SCD than the general population. Second, about 70% or more of end-stage kidney disease patients have concentric and eccentric left ventricular hypertrophy, which predisposes many dialysis patients to interstitial fibrosis, decreased coronary perfusion reserve, and decreased ischemia tolerance. Third, mildly impaired left ventricular dysfunction, with an ejection fraction <50%, is associated with a greater risk of SCD in dialysis patients. We have believed and accepted a common sense theory that paroxysmal ventricular tachycardia and fibrillation are the central cause of SCD in HD patients, because such cardiac functional morphological abnormalities were observed, and there are many chances for ventricular arrhythmia triggers, such as volume expansion and electrolyte shift, to develop. However, the type of fatal arrhythmia responsible for SCD differs between before and after HD. Sudden cardiac arrest (SCA) from ventricular fibrillation (VF) was more often seen in the post-HD setting, while SCA from non-VF, which may be bradyarrhythmia, was more often seen in the pre-HD setting. This may imply that the causes of SCA are bradyarrhythmia due to hyperkalemia in the pre-HD setting on the day after a long interval, and fatal ventricular arrhythmia due to a prolonged QT interval in the post-HD setting, because some recent evidence suggests that shifts of electrolytes, such as potassium and calcium, during HD cause rapid prolongation of the QT interval after HD, which may lead to the onset of ventricular arrhythmia and SCD. In fact, a higher calcium gradient, defined as the difference between the pre-HD corrected total serum calcium level and the dialysate calcium level, was associated with a higher risk of SCD in HD patients. Key Messages: Further study is needed to determine which combination of calcium, potassium, and bicarbonate concentrations in dialysate is optimal to avoid SCD in high-risk HD patients.

Abstract 302: Prevalence of Acquired Long QT Syndrome in Patients with Aortic Valve Stenosis

Introduction: QT prolongation is associated with an increased risk of sudden cardiac death (SCD). Patients (pts) with aortic valve stenosis (AVS), in particular, have a higher incidence of SCD. We hypothesized that cardiac remodeling in the structural heart abnormalities may result in secondary QT prolongation in AVS. Methods: Electronic medical records in AVS pts prior to valve repairs/replacement in a single center from 2005-2015 were retrieved. ECGs showing QRS duration (QRSD) &gt; 120 ms or non-sinus rhythm were excluded for QT evaluations. Information regarding concomitant hypertension (HTN), dyslipidemia, diabetes, coronary artery disease, heart failure and presence of QT-prolonging factors (electrolytes imbalance and using QT prolonging drugs) was also evaluated. Results: Among 419 AVS pts [median age 75 (13) yrs, male 56%] with normal QRSD [94 (16) ms], the prevalence of acquired long QT syndrome with and without known QT-prolonging factors is shown in Table 1. More pts with heart failure had QTc ≥ 450 ms than those without HF (64% vs. 48%, p &lt;0.01). Conclusions: Regardless of the known QT prolonging factors, the prevalence of QT prolongation is high in AVS and may serve as a pathogenetic factor for sudden death in patients with aortic valve stenosis.

Sudden cardiac death in diabetes mellitus

Sudden cardiac death (SCD) represents one of the most frequent causes of death in patients with diabetes. In contrast to patients without diabetes it has not been significantly reduced despite improvements in the treatment of acute myocardial infarction and long-term treatment of cardiovascular diseases as well as diabetes mellitus. Several mechanisms can be responsible for the high incidence of SCD in diabetics: 1. arrhythmogenic effects mediated via cardiac autonomic neuropathy, repolarization disturbances or sympathetic tone activation (hypoglycemia), 2. myocardial ischemia due to atherosclerosis, endothelial dysfunction, platelet aggregation or thrombophilic effects, 3. myocardial disease due to inflammation, fibrosis, associated hypertension or uremia and 4. potassium imbalance due to diabetic nephropathy or hypoglycemia. This review introduces concepts of mechanisms that are responsible for SCD in patients with diabetes. Treatment of patients with diabetes should primarily consider a systematic assessment of any deterioration of this chronic disease and of complications at an early stage. Cardiovascular drug treatment corresponds to that of non-diabetics. In antidiabetic treatment drugs with a low risk of hypoglycemia should be preferred. Treatment with implantable cardioverter defibrillators (ICD) also combined with cardiac resynchronization therapy () demonstrated a high life-saving potential particularly in patients with diabetes.

QT/RR and T-peak-to-end/RR curvatures and slopes in chronic heart failure: Relation to sudden cardiac death

BackgroundPrevious studies investigated the QT/RR relationship by linear regressions of QT and RR intervals. However, the pattern of the QT/RR relationship is not necessarily linear. This study investigated the QT/RR and T-peak-to-end (Tpe)/RR curvatures and corresponding slopes in chronic heart failure (CHF) patients, and studied their differences between sudden cardiac death (SCD) victims and others. MethodsHolter ECG recordings of 650 CHF patients were analyzed. RR, QT and Tpe series were obtained and for each patient, the data of each subject were fitted with a non-linear regression function of the form: QT=χ+ϕ(1−RRγ), where γ is the QT/RR curvature. The same regression formula was applied to the Tpe interval series. The slopes (dimensionless units) were calculated at the averaged RR intervals and at RR of 1 second. ResultsThe median (difference between 75th and 25th percentile) of the curvature parameter was 0.226 (2.39) for QT/RR and −0.002 (3.64) for Tpe/RR in the overall sample. For the QT/RR slope, these values were 0.170 (0.12) and 0.190 (0.10) when evaluated at RR=1 and at the averaged RR, respectively, while for the Tpe/RR slope the values were 0.016 (0.04) and 0.020 (0.04), respectively. The Tpe/RR slope showed high statistical significance for separation of SCD victims and others, particularly when evaluated at the averaged RR (median values of 0.040 vs 0.020, p=0.002), but also when evaluated at RR=1 second (0.026 vs 0.015, p=0.023). Patients with values of Tpe/RR slope above 0.042 had double incidence of SCD, for the case of the slope being evaluated at RR=1 second, and triple incidence for the case of the slope being evaluated at the averaged RR. The QT/RR slope and curvature, as well as the Tpe/RR curvature, were not different in SCD victims and in others. ConclusionsNon-linear regression models based on curvature and slope characteristics, individually obtained for each patient, were used to characterize the QT/RR and Tpe/RR relationships. Steeper Tpe/RR slopes, obtained after adjusting for the curvature parameter, were associated with higher incidence of SCD. The curvature parameter itself did not show SCD predictive value.

Abstract P122: Plasma Fatty Acid Binding Protein 4 is Associated with the Incidence of Sudden Cardiac Death in Non-Diabetic Adults in the Cardiovascular Health Study

Background: Fatty acid binding protein 4 (FABP4) is an adipokine that plays a role in lipid transport. Previous studies have reported that FABP4 may increase the risk of diabetes and exert negative inotropy on the myocardium. It is unknown whether plasma FABP4 is associated with the risk of sudden cardiac death (SCD). Objective: To test the hypothesis that plasma FABP4 is associated with a higher incidence of SCD in older adults and determine if diabetes status modifies this association. Methods: We prospectively analyzed data on 4,564 men and women aged 65+ years from the Cardiovascular Health Study. FABP4 was measured at baseline using ELISA and SCD events were adjudicated through review of medical records (inter-reviewer agreement of 88% and kappa of 0.74). We used Cox proportional hazards model to examine the association between FABP4 and SCD. Results: During a median follow up of 11.8 years, 146 new cases of SCD occurred. In a multivariable model adjusting for age, sex, race, clinic, education, glomerular filtration rate based on cystatin C, high-sensitive C-reactive protein, leisure time physical activity, hormone replacement therapy, alcohol intake, self-reported general health status, smoking, prevalent coronary heart disease, and prevalent heart failure, each higher standard deviation (SD) of plasma FABP4 was associated with a non-significant 14% (95% CI: -5% to 37%) higher risk of SCD. When stratified by prevalent diabetes status, FABP4 was associated with a higher risk of SCD in non-diabetic participants, [HR per SD of FABP4: 1.37 (95% CI: 1.11-1.67)] but not in diabetic participants [HR per SD of FABP4: 0.77 (95% CI: 0.52-1.15)], p for diabetes-FABP4 interaction was 0.026. Conclusion: A single measure of plasma FABP4 obtained later in life was associated with a higher risk of SCD among older adults without diabetes but not among those with diabetes. If confirmed in other studies, these data may point to novel mechanisms and opportunities for SCD prevention.

Cardiac implantable electronic devices in end-stage renal disease patients: preservation of central venous circulation

Cardiovascular disease is the leading cause of death in patients with end-stage renal disease (ESRD). In the United States Renal Data System database, 25–29.7% of cardiac deaths are attributable to arrhythmic mechanisms [1, 2]. Ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) likely remain the most common initiating and potentially reversible mechanisms of outof-hospital sudden cardiac death (SCD). Defibrillation is the only predictably effective therapy for reverting VF and pulseless VT to an effective rhythm for restoration of blood flow [3]. The expanding indications of implantable cardioverter-defibrillator (ICD) therapy for primary and secondary prevention of SCD have significantly increased the patient population with cardiac implantable electronic devices (CIEDs) [4]. A meta-analysis of secondary prevention trials showed a 28% relative risk reduction (RRR) in all-cause mortality (p0 0.0006) with ICD therapy that was due almost entirely to a 50% RRR in arrhythmic death (p<0.0001); similarly, primary prevention trials showed a 28% reduction in the risk of death in the ICD-treated patients as compared with the conventionally treated patients and an overall absolute 2year mortality reduction of 3% [3]. Despite the high incidence of SCD among patients with ESRD and the proven survival benefits of ICD therapy, the benefit of ICD therapy in this patient population has been questioned. This is probably due to the fact that all major ICD trials excluded patients with advanced renal dysfunction and transvenous ICD therapy is associated with higher complications rates in this patient group; especially, on hemodialysis (HD) patients. Our current knowledge regarding the efficacy of ICD therapy in this population relies on observational data and secondary post hoc analyses of major ICD trials [5–11]. Initially, ICDs were implanted via thoracotomy, which was associated with mortality rates of 3% to 5.4%. The development of transvenous ICD systems in the early 1990s was associated with an operative mortality of <1%, lower costs, and shorter hospital stays [12–14]. For these reasons, the transvenous route has become the most frequently used method for implantation of CIEDs. However, the use of the transvenous CIEDs can be associated with significant complications in chronic HD patients including central venous stenosis, tricuspid regurgitation (TR), and device infection [15–31]. Varies degrees of central venous stenosis have been reported in 23% to 67% patients with transvenous CIEDs [15–17]. This complication is asymptomatic in most patients. However, the situation is different in patients on G. Lopera : R. Carrillo Division of Cardiology, University of Miami, Miller School of Medicine, Miami, FL, USA

Postpacing abnormal repolarization in catecholaminergic polymorphic ventricular tachycardia associated with a mutation in the cardiac ryanodine receptor gene

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic disease for which electrophysiological studies (EPS) have shown to be of limited value. This study presents a CPVT family in which marked postpacing repolarization abnormalities during EPS were the only consistent phenotypic manifestation of ryanodine receptor (RyR2) mutation carriers. The study was prompted by the observation of transient marked QT prolongation preceding initiation of ventricular fibrillation during atrial fibrillation in a boy with a family history of sudden cardiac death (SCD). Family members underwent exercise and pharmacologic electrocardiographic testing with epinephrine, adenosine, and flecainide. Noninvasive clinical test results were normal in 10 patients evaluated, except for both epinephrine- and exercise-induced ventricular arrhythmias in 1. EPS included bursts of ventricular pacing and programmed ventricular extrastimulation reproducing short-long sequences. Genetic screening involved direct sequencing of genes involved in long QT syndrome as well as RyR2. Six patients demonstrated a marked increase in QT interval only in the first beat after cessation of ventricular pacing and/or extrastimulation. All 6 patients were found to have a heterozygous missense mutation (M4109R) in RyR2. Two of them, presenting with aborted SCD, also had a second missense mutation (I406T- RyR2). Four family members without RyR2 mutations did not display prominent postpacing QT changes. M4109R- RyR2 is associated with a high incidence of SCD. The contribution of I406T to the clinical phenotype is unclear. In contrast to exercise testing, marked postpacing repolarization changes in a single beat accurately predicted carriers of M4109R- RyR2 in this family.

Reconciling the Protean Manifestations of Arrhythmogenic Cardiomyopathy

Medical conception of a disease begins with in vivo observation and develops with recognition of cognate findings on gross anatomy, histology, and cellular pathology. It was histopathology that established myocyte disarray as the cardinal feature of hypertrophic cardiomyopathy, present even in cases where left ventricular (LV) hypertrophy is subtle or absent. To this day, clinical-pathological association retains its historical value as the primary means of gaining insight into underlying disease processes. Enhancing its appeal is its accessibility to physicians, most of whom are familiar with histopathology from medical school and attuned to visual diagnosis. Article see p 632 With the advent of molecular genetics, however, the limitations of clinical-pathological association have become apparent and nowhere more so than in the inherited arrhythmia syndromes. In the long-QT and Brugada syndromes and catecholaminergic polymorphic ventricular tachycardia, a structurally normal heart belies the propensity to ventricular arrhythmia and sudden cardiac death (SCD). How this might be possible began to unravel with the isolation of mutations in genes encoding ion channels, transporters, and binding proteins. Genetic studies also have provided fresh insights into diseases with an obvious pathological substrate, such as hypertrophic cardiomyopathy, in which sarcomeric mutations predominate. Families with a high incidence of SCD and myocyte disarray but minimal LV hypertrophy were found to have mutations in troponin T,1 lending further support to the inclusion of this phenotype within the spectrum of hypertrophic cardiomyopathy. Redefining diseases according to their genetic etiology, while attractive, is less straightforward than immediately obvious. Defects in sarcomeric components, for example, have been implicated in both hypertrophic cardiomyopathy and dilated cardiomyopathy. In some heritable disorders, such as dilated cardiomyopathy, marked locus heterogeneity precludes delineation of a single genetic determinant. The ultimate solution to disease classification involves going 1 step further and identifying a unifying molecular mechanism, which may …

Experimental models of spontaneous ventricular arrhythmias and of sudden cardiac death

Sudden cardiac death defined as natural death from cardiac causes occurring within one hour of the onset of acute symptoms is one of the most significant non-injury causes of death in the adult population of industrialised countries. The understanding of the mechanisms leading to sudden cardiac death is so far limited. Recently, a number of experimental animal models with high incidence of sudden cardiac death were developed and are intensively studied to get new insights into the sudden cardiac death mechanisms. In this review the animal models of sudden cardiac death are summarized and their principal properties shortly described.

Risk assessment for sudden cardiac death in dialysis patients: How relevant are conventional cardiac risk factors?

Patients with end stage renal disease on long term dialysis support have a very high risk of sudden cardiac death (SCD) presumably due to serious ventricular arrhythmias. Implantable cardioverter defibrillators (ICD) can be life saving in patients with SCD but their role in dialysis patients is unclear. Much of the current evidence on this important clinical issue limits to retrospective analysis of patients who received an ICD for conventional cardiac indication. It appears that there are certain factors that are unique to patients with renal failure which pre-disposes them to such high incidence of SCD and by applying the conventional risk assessment model on this sub-group of patients we are likely to miss a significant proportion of patients who would not fulfil that criteria but would be at high risk of SCD. In order to clarify this issue, we performed a retrospective screening of patients with end stage renal disease on haemodialysis using conventional risk assessment model and compared the outcome with the known incidence of SCD in this sub-group.

Abstract 1158: Sudden Death in Children with Cardiomyopathy: Long Term Follow-Up from a National Population-Based Study of Childhood Cardiomyopathy

Introduction Better data regarding the incidence and risk factors for sudden cardiac death (SCD) in children with cardiomyopathy (CM) is critical in defining appropriate primary prevention strategies. Methods The National Australian Childhood Cardiomyopathy Study is a prospective cohort study, including all children in Australia with primary CM diagnosed at 0 – 10 years of age, between 1987–1997. SCD was defined as sudden and unexpected death in children who were not hospitalized and not in congestive heart failure at the time of death. Nine subjects with sudden death as presenting symptom were excluded. Indexed echocardiographic measurements at latest follow-up were compared between subjects with SCD and survivors. Results Study criteria were met by 291 children. Mean duration of follow-up was 9.2 years. The incidence of sudden death relative to each CM type, for all cases and as a proportion of deaths, is shown in the Table : Incidence of SCD by CM type. SCD incidence was significantly associated with CM type, for all cases ( p = 0.006) and when only those subjects who died were considered ( p = 0.005), with LVNC and RCM having up to 4 times the risk of other CM types. Children with familial DCM had a significantly higher rate of SCD than subjects with non-familial CM (12% vs 3%; p = 0.028), however, familial CM was not a risk factor in other CM types. DCM SCD subjects had larger LVEDd Z score than survivors (median 5.53 vs 1.16; p &lt;0.0001) and lower FS Z score (median −9.23 vs −0.51; p = 0.0025). HCM SCD subjects had thicker LVPW dimension Z scores than survivors (median 4.63 vs 1.18; p = 0.007). Twelve subjects (2 DCM, 8 HCM and 2 LVNC) underwent ICD implantation (8/12 for primary prevention). Conclusions: This population based study defines new risk factors for sudden death in children with CM. RCM is well known to have a high incidence of SCD. In addition, children with LVNC and those with DCM who have severe dilatation, systolic dysfunction or familial DCM are at increased risk of sudden death.

Hypertrophic cardiomyopathy in a large community-based population: clinical outcome and identification of risk factors for sudden cardiac death and clinical deterioration

ObjectivesThis study evaluates the clinical course and identifies risk factors for sudden cardiac death (SCD) and clinical deterioration in hypertrophic cardiomyopathy (HCM) in a large community-based population. Comparison was made with data from six tertiary referral and six nonreferral institutions. BackgroundHypertrophic cardiomyopathy is a disease with marked heterogeneity in clinical presentation and prognosis. Risk factors for SCD are not well defined in patients free of referral bias. MethodsBetween 1970 and 1999, 225 consecutive patients (mean age [±SD] 41±16 years) were examined and followed at yearly intervals. ResultsForty-four deaths were recorded of which 27 cases were cardiovascular. Fourteen patients died suddenly, six were successfully resuscitated, and seven patients died of congestive heart failure. The annual mortality, annual cardiac mortality, and annual mortality due to sudden death were 1.3%, 0.8%, and 0.6%, respectively. At least one New York Heart Association (NYHA) functional class deterioration was reported in 33% of the patients with a significant (≥50 mm Hg) left ventricular outflow tract (LVOT) gradient in contrast to 7% without obstruction. The presence of syncope was related to SCD (p < 0.05). Younger age and more severe functional limitation distinguishes patients from in hospital-based centers from the ones in community-based centers. ConclusionsHypertrophic cardiomyopathy is a benign disease in an unselected population with a low incidence of cardiac death. Syncope was associated with a higher incidence of SCD and patients with a significant LVOT obstruction were more susceptible to clinical deterioration.

The Molecular Genetic Basis for Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM), a relatively common disease, is diagnosed clinically by unexplained cardiac hypertrophy and pathologically by myocyte hypertrophy, disarray, and interstitial fibrosis. HCM is the most common cause of sudden cardiac death (SCD) in the young and a major cause of morbidity and mortality in elderly. Hypertrophy and fibrosis are the major determinants of morbidity and SCD. More than 100 mutations in nine genes, all encoding sarcomeric proteins have been identified in patients with HCM, which had led to the notion that HCM is a disease of contractile sarcomeric proteins. Theβ -myosin heavy chain (MyHC), cardiac troponin T (cTnT) and myosin binding protein-C (MyBP-C) are the most common genes accounting for approximately 2/3 of all HCM cases. Genotype–phenotype correlation studies suggest that mutations in the β -MyHC gene are associated with more extensive hypertrophy and a higher risk of SCD as compared to mutations in genes coding for other sarcomeric proteins, such as MyBP-C and cTnT. The prognostic significance of mutations is related to their hypertrophic expressivity and penetrance, with the exception of those in the cTnT, which are associated with mild hypertrophic response and a high incidence of SCD. However, there is a significant variability and factors, such as modifier genes and probably the environmental factors affect the phenotypic expression of HCM. The molecular pathogenesis of HCM is not completely understood.In vitro and in vivo studies suggest that mutations impart a diverse array of functional defects including reduced ATPase activity of myosin, acto–myosin interaction, cross-bridging kinetics, myocyte contractility, and altered Ca2+sensitivity. Hypertrophy and other clinical and pathological phenotypes are considered compensatory phenotypes secondary to functional defects. In summary, the molecular genetic basis of HCM has been identified, which affords the opportunity to delineate its pathogenesis. Understanding the pathogenesis of HCM could provide for genetic based diagnosis, risk stratification, treatment and prevention of cardiac phenotypes.

Molecular Genetic Basis of Hypertrophic Cardiomyopathy:

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease caused by mutations in sarcomeric proteins. The disease is characterized by left ventricular hypertrophy in the absence of an increased external load, and myofibrillar disarray. A large number of mutations in genes coding for the beta-myosin heavy chain (beta-MyHC), cardiac troponin T (cTnT), cardiac troponin I, alpha-tropomyosin, myosin binding protein C (MyBP-C), and myosin light chain 1 and 2 in patients with HCM have been identified. Genotype-phenotype correlation studies have shown that mutations carry prognostic significance. The Gly256Glu, Val606Met, and Leu908Val mutations in the beta-MyHC are associated with a benign prognosis. In contrast, Arg403Gln, Arg719Trp, and Arg453Cys mutations are associated with a high incidence of sudden cardiac death (SCD). Mutations in cTnT are associated with a mild degree of hypertrophy, but a high incidence of SCD. Mutations in MyBP-C are associated with mild hypertrophy and a benign prognosis. However, it has become evident that factors other than the underlying mutations, such as genetic background and possibly environmental factors, also modulate phenotypic expression of HCM.