Model Of Sudden Cardiac Death Research Articles

Ent-Verticilide B1 Inhibits Type 2 Ryanodine Receptor Channels and is Antiarrhythmic in Casq2 -/- Mice.

Intracellular Ca2+ leak from cardiac ryanodine receptor (RyR2) is an established mechanism of sudden cardiac death (SCD), whereby dysregulated Ca2+ handling causes ventricular arrhythmias. We previously discovered the RyR2-selective inhibitor ent-(+)-verticilide (ent-1), a 24-membered cyclooligomeric depsipeptide that is the enantiomeric form of a natural product (nat-(-)-verticilide). Here, we examined its 18-membered ring-size oligomer (ent-verticilide B1; "ent-B1") in RyR2 single channel and [3H]ryanodine binding assays, and in Casq2 -/- cardiomyocytes and mice, a gene-targeted model of SCD. ent-B1 inhibited RyR2 single channels and RyR2-mediated spontaneous Ca2+ release in Casq2 -/- cardiomyocytes with sub-micromolar potency. ent-B1 was a partial RyR2 inhibitor, with maximal inhibitory efficacy of less than 50%. ent-B1 was stable in plasma, with a peak plasma concentration of 1460 ng/ml at 10 minutes and half-life of 45 minutes after intraperitoneal administration of 3 mg/kg in mice. In vivo, ent-B1 significantly reduced catecholamine-induced ventricular arrhythmias in Casq2 -/- mice in a dose-dependent manner. Hence, we have identified a novel chemical entity - ent-B1 - that preserves the mechanism of action of a hit compound and shows therapeutic efficacy. These findings strengthen RyR2 as an antiarrhythmic drug target and highlight the potential of investigating the mirror-image isomers of natural products to discover new therapeutics. SIGNIFICANCE STATEMENT: The cardiac ryanodine receptor (RyR2) is an untapped target in the stagnant field of antiarrhythmic drug development. We have confirmed RyR2 as an antiarrhythmic target in a mouse model of sudden cardiac death and shown the therapeutic efficacy of a second enantiomeric natural product.

Abstract 347: Artificial Intelligence for Targeted and Personalized Prediction of Sudden Cardiac Death in the General Population: A Machine Learning Study Based on Electronic Health Records

Background: Identification of subjects from the general population with an increased risk of Sudden Cardiac Death (SCD) remains highly challenging, particularly at an individual level. Methods: Every case of SCD + 18 y.o. that occurred since 2011 in Paris and its inner suburbs was prospectively included in the Paris Sudden Death Expertise Center (SDEC) registry (6.7M inhabitants). SCD cases were matched by age, sex, and residence area with a control group (70000) sampled from the general population. All data from the French National Health Insurance database (SNDS) were collected: prescribed drugs, examinations and diagnoses that occurred up to 10 y. before the event, including cardiovascular and non-cardiovascular variables (10000). We provide a detailed explanation of the prediction at the individual level. For each subject, we computed the Shapley scores from the supervised learning model (CatBoost) to evaluate the contribution of variables to its predicted risk. The model used was derived from 12338 SCD cases and matched controls cohort (2011-15) and validated on 11620 cases cohort (2016-20). Results: A total of 23958 equations have been built with personalized variables and coefficients, achieving an AUC of 0.80 in the derivation cohort (with a PPV=77%, sensitivity=68%). One example is shown below, with an individual predicted risk of SCD at 3 months (89.3%), and the most important factors that increase (red) or decrease (blue) the risk of SCD. Conclusions: For the first time, we provide a personalized prediction model of SCD, which explains the predicted risk at the individual level. These findings offer a new step toward personalized prevention and global public health interventions

Exploring the Risk Factors of Sudden Cardiac Death Using an Electrocardiography and Medical Ultrasonography for the General Population Without a History of Coronary Artery Disease or Left Ventricular Ejection Fraction 35 Years - A Novel Point-Based Prediction Model Based on the Chin-Shan Community Cardiovascular Cohort.

Most of the factors and prediction models of sudden cardiac death (SCD) have been developed without considering the Asia population. The purpose of this study is to construct a point-based prediction model for the general population in Asia. Chin-Shan Community Cardiovascular Cohort (CCCC) is a community-based longitudinal cohort initiated between 1990 and 1991, enrolling participants aged ≥35 years and following them up until 2005. Participants with coronary artery disease (CAD) or a left ventricular ejection fraction (LVEF) of 35% were excluded from this study. The Framingham risk score function was used to derive a simple point-based prediction model. Based on bootstrapping, a novel model (CCCC-SCD-Score) was validated. A total of 2,105 participants were analyzed. The incidence rate of SCD was 0.406 per 1,000 person-years. The CCCC-SCD-Score score was calculated using age groups (maximal points=4), left ventricular hypertrophy, hypertension, left ventricular ejection fraction <40%, aortic flow rate >190 cm/s, and carotid plaque scores ≥5 (point=1 for each risk factor). The C-index of the CCCC-SCD-Score in predicting SCD risks was 0.888 (95% confidence interval: 0.807-0.969). For the general Asian population without a history of CAD or a LVEF <35% and who are aged >35 years, the novel model-based scoring system effectively identifies the risk for SCD using the clinical factors, electrocardiographic and echocardiographic data.

The use of untargeted and widely targeted metabolomics to distinguish between asphyxia and sudden cardiac death as the cause of death in rats: A preliminary study

It is important to determine the cause of death in the case of asphyxia. However, it is difficult to conclude death by asphyxia, especially when the deceased has underlying heart disease, because there are often no specific and representative corpse signs for both asphyxia and sudden cardiac death (SCD). The aim of the present work was to investigate the potential of metabolomics to discriminate asphyxia from SCD as the cause of death. A total of thirty male Sprague–Dawley rats were used to construct models of asphyxia, SCD (interfering cause of death), and cervical dislocation (control). Untargeted and widely targeted metabolomics approaches were used to obtain rat pulmonary metabolic profiles in this study. First, the metabolic alterations resulting from asphyxia were explored. There were significant changes found in carbohydrate metabolism, the endocrine system, and the sensory system. Second, we screened potential biomarkers and built classification models to determine the cause of death. Moreover, some biomarkers remained differentiated at 24 h and 48 h postmortem, so the cause of death could still be determined after death. This study showed the application potential of metabolomics to investigate the metabolic changes occurring in the process of death, as well as to determine the cause of death on the basis of metabolic differences even after death.

Abstract 14180: RyR2 Hyperactivity Contributes to Arrhythmogenic Triggers in the ex vivo Human Right Ventricle

Introduction: Sudden cardiac death (SCD) caused by VT/VF is a major cause of mortality and morbidity, accounting for up to 20% of all deaths in the United States. Novel antiarrhythmic targets and relevant translational models of SCD are urgently needed for basic and translational arrhythmia research, and ex vivo donor human hearts are invaluable resources for such pharmacological studies. It was the goal of this study to investigate the occurrence of VT/VF in excised human hearts and to test a novel pharmacological agent to suppress arrhythmias. Hypothesis: We assessed the hypothesis that RyR2 hyperactivity contributes to arrhythmogenic triggers and substrates in the human RV, and we analyzed the antiarrhythmic effects of pharmacological RyR2 suppression. Methods: Adult human hearts (n = 10; 3F, 7M) were procured from the Washington Regional Transplant Community. The entire RV free wall was isolated, coronary perfused, and placed in an oxygenated, 37°C bath of Tyrode’s solution for optical mapping with the addition of Di-4-ANBDQBS and blebbistatin. Pseduo ECGs were recorded, and action potentials (APs) were spatiotemporally mapped using high-speed CMOS cameras. Optical recordings were taken at baseline and after exposure to the adrenergic agonist isoproterenol (ISO, 250 nM) and the adenosine antagonist caffeine (CAF, 200 μM) to elicit RyR2 hyperactivity. We also evaluated pharmacological RyR2 suppression (2 μM dantrolene) on arrhythmia inhibition. Results: ISO and ISO+CAF significantly shortened tissue APDs. ISO+CAF increased the incidence of PVCs at low pacing frequencies as well as increased the incidence of VT/VF at high pacing frequencies. We observed non-sustained arrhythmias in roughly a third of the hearts examined. No significant differences in conduction velocities were observed. While dantrolene did not return APDs to baseline conditions, it did significantly reverse the effect of caffeine on inducing PVCs. Conclusions: In conclusion, caffeine contributes to arrhythmogenic triggers in the ex vivo human right ventricle, and dantrolene may be used as a pharmacological tool to suppress RyR2 hyperactivity and thus prevent SCD.

Sex-specific differences in outcome and risk stratification of ventricular arrhythmias in implantable cardioverter defibrillator patients.

AimsRisk stratification models of sudden cardiac death (SCD) are based on the assumption that risk factors of SCD affect risk to a similar extent in both sexes. The aim of the study is to evaluate differences in clinical outcomes between sexes and evaluate whether risk factors associated with appropriate device therapy (ADT) differ between men and women.Methods and resultsWe performed a cohort study of implantable cardioverter defibrillator (ICD) patients referred for primary or secondary prevention of SCD between 2009 and 2018. Multivariable Cox regression models for prediction of ADT were constructed for men and women separately. Of 2300 included patients, 571 (25%) were women. Median follow‐up was 4.6 (inter‐quartile range: 4.4–4.9) years. Time to ADT was shorter for men compared with women [hazard ratio (HR) 1.71, P < 0.001], as was time to mortality (HR 1.37, P = 0.003). In women, only secondary prevention ICD therapy (HR 1.82, P < 0.01) was associated with ADT, whereas higher age (HR 1.20, P < 0.001), absence of left bundle branch block (HR 0.72, P = 0.01), and secondary prevention therapy (HR 1.80, P < 0.001) were independently associated with ADT in men. None of the observed parameters showed a distinctive sex‐specific pattern in ADT.ConclusionsMale ICD patients were at higher risk of ADT and death compared with female ICD patients, irrespective of an ischaemic or non‐ischaemic underlying cardiomyopathy. Our study highlights the importance to stratify outcomes of ICD trials by sex, as study results differ between men and women. However, none of the available clinical parameters showed a clear sex‐specific relation to ventricular arrhythmias. As a consequence, sex‐specific risk stratification models of SCD using commonly available clinical parameters could not be derived.

Dynamic changes in cardiovascular and systemic parameters prior to sudden cardiac death in heart failure with reduced ejection fraction: a PARADIGM-HF analysis.

Prognostic models of sudden cardiac death (SCD) typically incorporate data at only a single time-point. We investigated independent predictors of SCD addressing the impact of integrating time-varying covariates to improve prediction assessment. We studied 8399 patients enrolled in the PARADIGM-HF trial and identified independent predictors of SCD (n=561, 36% of total deaths) using time-updated multivariable-adjusted Cox models, classification and regression tree (CART), and logistic regression analysis. Compared with patients who were alive or died from non-sudden cardiovascular deaths, patients who suffered a SCD displayed a distinct temporal profile of New York Heart Association (NYHA) class, heart rate and levels of three biomarkers (albumin, uric acid and total bilirubin), with significant differences observed more than 1year prior to the event (Pinteraction < 0.001). In multivariable models adjusted for baseline covariates, seven time-updated variables independently contributed to SCD risk (incremental likelihood chi-square=46.2). CART analysis identified that baseline variables (implantable cardioverter-defibrillator use and N-terminal prohormone of B-type natriuretic peptide levels) and time-updated covariates (NYHA class, total bilirubin, and total cholesterol) improved risk stratification. CART-defined subgroup of highest risk had nearly an eightfold increment in SCD hazard (hazard ratio 7.7, 95% confidence interval 3.6-16.5; P < 0.001). Finally, changes over time in heart rate, NYHA class, blood urea nitrogen and albumin levels were associated with differential risk of sudden vs. non-sudden cardiovascular deaths (P < 0.05). Beyond single time-point assessments, distinct changes in multiple cardiac-specific and systemic variables improved SCD risk prediction and were helpful in differentiating mode of death in chronic heart failure.

Sex-specific differences in risk stratification of ventricular arrhythmias among implantable cardioverter defibrillator patients: do women differ from men?

Abstract Background Implantable cardioverter defibrillator (ICD) guidelines and risk stratification models of sudden cardiac death (SCD) are applied without differentiation between men and women, based on the assumption that the incidence of ventricular arrhythmias and risk factors of SCD are similar in both sexes. Sex-specific risk factors of SCD may influence studies evaluating the benefit of ICD therapy, for both men and women. Purpose Aim of the study is to assess sex-specific differences in occurrence and predictors of appropriate device therapy (ADT) for ventricular arrhythmias. Methods A multicenter retrospective cohort of 2300 consecutive patients was evaluated, including patients referred for ICD implantation between the years 2009–2018 (age 62±13 years, LVEF 32±12%, 53% ischemic cardiomyopathy [CMP], 28% resynchronization therapy, 65% primary prevention). Exclusion criteria were: (1) patients with hypertrophic CMP, arrhythmogenic right ventricular CMP, systemic infiltrative cardiac disease or channelopathy; (2) lost to follow-up immediately after ICD implantation. Primary endpoint was ADT, defined as anti-tachycardia pacing or shock for ventricular tachyarrhythmia. Secondary endpoints were mortality and inappropriate ICD therapy. Univariable and multivariable Cox regression analyses, stratified by sex, were performed to assess predictors of ADT. Results The cohort primarily consisted of men (75%). After a mean follow-up of 4.8±3.0 years, men experienced more ADT compared to women (25% versus 16%, HR 1.71, p&amp;lt;0.001) and men displayed a higher mortality compared to women (25% versus 19%, HR 1.37, p&amp;lt;0.01). No difference in inappropriate ICD therapy was observed (9% versus 10%, HR 1.01, p=0.94). In the total study cohort, male sex (HR 1.55, p&amp;lt;0.001), higher age (HR 1.15 per 10 years, p&amp;lt;0.0019), left bundle branch block (LBBB, HR 0.74, p=0.01) and secondary prevention indication (HR 1.89, p&amp;lt;0.001) were independently associated with ADT. In male patients, independent predictors of ADT were comparable with the total study cohort: higher age (HR 1.20 per 10 years, p&amp;lt;0.001), LBBB (HR 0.72, p=0.01) and secondary prevention therapy (HR 1.80, p&amp;lt;0.001). In contrast, age (p=0.54) or LBBB (p=0.29) were not associated with ADT in women. In women, only paroxysmal atrial fibrillation (HR 1.76, p=0.03) and secondary prevention therapy (HR 1.78, p&amp;lt;0.01) were independently associated with ADT. Conclusion This study showed that men were at higher risk of ADT compared to women and that risk factors associated with SCD differ between both sexes. The results strongly suggests that SCD risk stratification models are primarily driven by male patients and sex-specific risk models of SCD are needed to identify those women at high risk of SCD. Figure 1 Funding Acknowledgement Type of funding source: None

ECG-based Detection and Prediction Models of Sudden Cardiac Death: Current Performances and New Perspectives on Signal Processing Techniques

Heart disease remains the main leading cause of death globally and around 50% of the patients died due to sudden cardiac death (SCD). Early detection and prediction of SCD have become an important topic of research and it is crucial for cardiac patient’s survival. Electrocardiography (ECG) has always been the first screening method for patient with cardiac complaints and it is proven as an important predictor of SCD. ECG parameters such as RR interval, QT duration, QRS complex curve, J-point elevation and T-wave alternan are found effective in differentiating normal and SCD subjects. The objectives of this paper are to give an overview of SCD and to analyze multiple important ECG-based SCD detection and prediction models in terms of processing techniques and performance wise. Detail discussions are made in four major stages of the models developed including ECG data, signal pre-processing and processing techniques as well as classification methods. Heart rate variability (HRV) is found as an important SCD predictor as it is widely used in detecting or predicting SCD. Studies showed the possibility of SCD to be detected as early as one hour prior to the event using linear and non-linear features of HRV. Currently, up to 3 hours of analysis has been carried out. However, the best prediction models are only able to detect SCD at 6 minutes before the event with acceptable accuracy of 92.77%. A few arguments and recommendation in terms of data preparation, processing and classification techniques, as well as utilizing photoplethysmography with ECG are pointed out in this paper so that future analysis can be done with better accuracy of SCD detection accuracy.

The SHIFT model combines clinical, electrocardiographic and echocardiographic parameters to predict sudden cardiac death in hypertrophic cardiomyopathy

IntroductionLimitations have been pointed out in the clinical risk prediction model for sudden cardiac death (SCD) of the European Society of Cardiology (ESC), which is recommended for hypertrophic cardiomyopathy (HCM) patients. The aim of this study was to determine the SCD risk of the HCM patients enrolled in a Portuguese nationwide registry and to develop a new SCD risk prediction model applicable to our population. Methods and resultsThe cohort consisted of 1022 patients (mean age 53.2±16.4 years, 59% male) enrolled in a Portuguese national HCM registry. During the follow-up period (median five years), 19 patients (1.9%) died suddenly or had aborted SCD or appropriate implantable cardioverter-defibrillator (ICD) shock therapy. Through a Cox proportional hazards model, four variables were independently associated with SCD or equivalent: unexplained Syncope, Heart failure signs, Interventricular septum thickness ≥19 mm and FragmenTed QRS complex. These predictors were included in the SHIFT model and individual risk probabilities of SCD at five years were estimated. This model was internally validated using bootstrapping. The C-index of the SHIFT model was 0.81 (95% CI: 0.77-0.83) and the C-index of the ESC model (performed in a subgroup of 349 HCM patients) was 0.77 (95% CI: 0.73-0.81) (p=0.246). ConclusionThe SHIFT model may potentially provide prognostic value and contribute to the clinical decision-making process for ICD implantation for primary prevention of SCD.

AKT and ERK1/2 activation via remote ischemic preconditioning prevents Kcne2-dependent sudden cardiac death.

Sudden cardiac death (SCD) is the leading global cause of mortality. SCD often arises from cardiac ischemia reperfusion (IR) injury, pathologic sequence variants within ion channel genes, or a combination of the two. Alternative approaches are needed to prevent or ameliorate ventricular arrhythmias linked to SCD. Here, we investigated the efficacy of remote ischemic preconditioning (RIPC) of the limb versus the liver in reducing ventricular arrhythmias in a mouse model of SCD. Mice lacking the Kcne2 gene, which encodes a potassium channel β subunit associated with acquired Long QT syndrome were exposed to IR injury via coronary ligation. This resulted in ventricular arrhythmias in all mice (15/15) and SCD in 5/15 mice during reperfusion. Strikingly, prior RIPC (limb or liver) greatly reduced the incidence and severity of all ventricular arrhythmias and completely prevented SCD. Biochemical and pharmacological analysis demonstrated that RIPC cardioprotection required ERK1/2 and/or AKT phosphorylation. A lack of alteration in GSK‐3β phosphorylation suggested against conventional reperfusion injury salvage kinase (RISK) signaling pathway protection. If replicated in human studies, limb RIPC could represent a noninvasive, nonpharmacological approach to limit dangerous ventricular arrhythmias associated with ischemia and/or channelopathy‐linked SCD.

Chronic Omega-3 Polyunsaturated Fatty Acid Treatment Variably Affects Cellular Repolarization in a Healed Post-MI Arrhythmia Model.

Introduction: Over the last 40 years omega-3 polyunsaturated fatty acids (PUFAs) have been shown to be anti-arrhythmic or pro-arrhythmic depending on the method and duration of administration and model studied. We previously reported that omega-3 PUFAs do not confer anti-arrhythmic properties and are pro-arrhythmic in canine model of sudden cardiac death (SCD). Here, we evaluated the effects of chronic omega-3 PUFA treatment in post-MI animals susceptible (VF+) or resistant (VF−) to ventricular tachyarrhythmias.Methods: Perforated patch clamp techniques were used to measure cardiomyocyte action potential durations (APD) at 50 and 90% repolarization and short term variability of repolarization. The early repolarizing transient outward potassium current Ito was also studied.Results: Omega-3 PUFAs prolonged the action potential in VF− myocytes at both 50 and 90% repolarization. Short term variability of repolarization was increased in both untreated and treated VF− myocytes vs. controls. Ito was unaffected by omega-3 PUFA treatment. Omega-3 PUFA treatment attenuated the action potential prolongation in VF+ myocytes, but did not return repolarization to control values.Conclusions: Omega-3 PUFAs do not confer anti-arrhythmic properties in the setting of healed myocardial infarction in a canine model of SCD. In canines previously resistant to ventricular fibrillation (VF−), omega-3 PUFA treatment prolonged the action potential in VF− myocytes, and may contribute to pro-arrhythmic responses.

Abstract 20062: Predicting Sudden Cardiac Death in the General Population: Analysis of the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study

Introduction: Most cases of sudden cardiac death (SCD) in the general population occur primarily among persons who do not have any prior history of clinical heart disease. Hypothesis: After evaluating a comprehensive panel of traditional and novel cardiovascular risk factors in two, large, racially diverse, population-based cohorts, we sought to develop a predictive model of SCD among US adults without a history of cardiovascular disease. Methods: We evaluated a series of 26 demographic, clinical, laboratory and electrocardiographic measures in participants who were free of baseline cardiovascular disease in the Atherosclerosis Risk in Communities (ARIC) Study (n=13,677) and the Cardiovascular Health Study (CHS) (n=3,650). Results: After a median follow-up of approximately 13 years, there were a combined total of 318 adjudicated SCD events for analysis. The following 11 risk factors were significant risk factors for SCD after meta-analyzing the findings from each cohort: age (per 5 years; HR 1.32, 95% CI [1.17 - 1.49]), male sex (HR 2.23; 1.70 - 2.93]), African American race (HR 1.62, 1.19 - 2.20), current smoking (HR 2.19, 1.65 - 2.92), low physical activity (HR 1.42, 1.09 - 1.85), hypertension (HR 1.82, 1.37 - 2.42), diabetes (HR 2.49, 1.86 - 3.34), low serum albumin (per 0.3 g/dL decrease; HR 1.38, 1.20 - 1.59), low HDL (&lt;40 mg/dL in men and &lt;50 mg/dL in women; HR 1.37, 1.05 - 1.80), eGFR&lt;60 ml/min/1.73m2 (HR 1.77, 1.16 - 2.71), and a prolonged QTc interval (≥440 milliseconds in men or ≥460 milliseconds in women; HR 2.08, 1.54 - 2.80). Over a 10-year follow-up period, a model combining these risk factors showed good to excellent discrimination for SCD risk (C statistic 0.831 in ARIC and 0.745 in CHS). Serum biomarkers including C-reactive protein (CRP), NT-pro-brain natriuretic peptide (BNP) and high sensitivity troponin T were not significant risk factors and did not enhance SCD risk prediction when added to the final multivariate model. Conclusions: A prediction model including demographic, clinical, laboratory, and electrocardiographic variables provided accurate information on the future SCD risk in middle-aged and elderly populations.

The Third-Generation Beta-Blocker

In this issue of the Journal, Khan et al1 study the third-generation beta-blocker, nebivolol, in a rat model of aldosterone/salt treatment–induced hypertensive heart disease and show that myocyte necrosis is incited by oxidative stress secondary to an increase in cytosolic free calcium and mitochondrial calcium overload—a process that overwhelms the endogenous zinc (Zn)-based antioxidants. Using the first-generation beta-blocker atenolol as a control, treatment with nebivolol induced activation of endothelial nitric oxide synthase, nitric oxide (NO) generation, and a marked increase in intracellular Zn. Conversely, there was a concomitant decrease in intracellular and subsarcolemmal mitochondrial calcium levels. Likewise, there was attenuation of mitochondrial hydrogen peroxide production and lipid peroxidation, inhibition of microscopic myocardial scarring, and a reduction in collagen volume fractions. They postulate an intriguing pathophysiologic phenomenon whereby nebivolol, acting as a β3 agonist, increases NO formation leading to a rise in cytosolic free Zn. This inhibits intracellular and mitochondrial calcium overload, which ameliorates many of the detrimental effects of reactive oxygen species (ROS), lipid peroxidation, and the eventual myocardial scarring. Several important points can be gleaned from this study. First, this animal model of hypertensive cardiomyopathy serves as an effective model of sudden cardiac death as both myocardial fibrosis and adverse remodeling are key features of this disease process. This hypothesis, originally formulated by Weber and others, served as a fundamental basis for the RALES and EPHESUS trials. This concept was recently reviewed and confirmed by Esposito et al2 in a canine model of pacing-induced systolic heart failure, interstitial fibrosis, and myocardial electrical activation delays. They showed that mineralocorticoid receptor antagonism played a key role in preventing the activation of inflammatory pathways and in the development of ventricular arrhythmogenic foci. It is interesting to speculate that nebivolol may also induce similar cardioprotection. Nebivolol is approved for the treatment of hypertension in the United States and is marketed as Bystolic. In Europe, it is approved for the treatment of both hypertension and left ventricular failure. At low doses, it is a selective β1-receptor blocker, and as the dose is up-titrated, it loses its selectivity. It is unique in that unlike carvedilol (Coreg), it has a NO potentiating ability, a property that Khan et al1 have effectively shown in their study. Another plausible mechanism for the drug's efficacy is that it may act primarily within the mitochondria at the site of ROS production or as a ROS scavenger, inhibiting superoxide anion or hydrogen peroxide. Accordingly, the sequelae of pathology associated with excessive ROS production in hypertensive cardiomyopathy can effectively be targeted. Nebivolol is not the first beta-blocker to demonstrate antioxidant properties. Carvedilol, the first of the third-generation beta-blockers, has been shown in a number of studies to be both an antioxidant and free radical scavenger.3 Its antioxidant property resides in its carbazole moiety, a property partly shared by nebivolol. The apparent underlying protective mechanism of carvedilol is through inhibition of lipid peroxidation primarily through free radical scavenging. Khan et al1 showed that nebivolol could similarly protect against lipid peroxidation. This unique property has not received a great deal of attention from our clinical colleagues, except in the burgeoning field of Cardio-Oncology. The chemotherapeutic anthracyclines are known to be one of the most effective anticancer treatments available but produce an excessive amount of free radicals within the myocardium, leading to cardiotoxicity and heart failure. It is of no surprise then that carvedilol is currently considered the “beta-blocker of choice” for patients suffering from anthracycline-induced heart failure. Perhaps, it is time when nebivolol was investigated for its antioxidant properties in oxidative pathological conditions also? The use of the term “third-generation beta-blocker,” is a method we use to explain the hierarchy of beta-blockers in terms of development. Atenolol is a first-generation beta-blocker in terms of age, a drug known to have no antioxidant properties and a characteristic Khan et al1 use for control experiments. The second-generation beta-blockers include metoprolol, which although has cardioprotective effects, does not have any antioxidant effects. The current third-generation beta-blockers include carvedilol, a drug with antioxidant effects and free radical scavenging ability.4 Nebivolol can now be added to this list. It is rather interesting to recall that over the last several decades, both laboratory and clinical research with endogenous antioxidants such as superoxide dismutase, vitamin E, and catalase were all fraught with failure and frustration. Conceivably, the elusive and effective antioxidant has been right in front us for the past 20 years, and we were just a little slow in recognizing the potential expedient effects of these drugs.

Discrete Event Simulation Model of Sudden Cardiac Death Predicts High Impact of Preventive Interventions

Sudden Cardiac Death (SCD) is responsible for at least 180,000 deaths a year and incurs an average cost of $286 billion annually in the United States alone. Herein, we present a novel discrete event simulation model of SCD, which quantifies the chains of events associated with the formation, growth, and rupture of atheroma plaques, and the subsequent formation of clots, thrombosis and on-set of arrhythmias within a population. The predictions generated by the model are in good agreement both with results obtained from pathological examinations on the frequencies of three major types of atheroma, and with epidemiological data on the prevalence and risk of SCD. These model predictions allow for identification of interventions and importantly for the optimal time of intervention leading to high potential impact on SCD risk reduction (up to 8-fold reduction in the number of SCDs in the population) as well as the increase in life expectancy.

Alexander Leaf, MD (1920–2012)—A tribute to a life in physiology and medicine

EDITORIAL article Front. Physiol., 25 January 2013Sec. Cardiac Electrophysiology Volume 4 - 2013 | https://doi.org/10.3389/fphys.2013.00006

Endurance exercise training normalizes repolarization and calcium-handling abnormalities, preventing ventricular fibrillation in a model of sudden cardiac death

The risk of sudden cardiac death is increased following myocardial infarction. Exercise training reduces arrhythmia susceptibility, but the mechanism is unknown. We used a canine model of sudden cardiac death (healed infarction, with ventricular tachyarrhythmias induced by an exercise plus ischemia test, VF+); we previously reported that endurance exercise training was antiarrhythmic in this model (Billman GE. Am J Physiol Heart Circ Physiol 297: H1171-H1193, 2009). A total of 41 VF+ animals were studied, after random assignment to 10 wk of endurance exercise training (EET; n = 21) or a matched sedentary period (n = 20). Following (>1 wk) the final attempted arrhythmia induction, isolated myocytes were used to test the hypotheses that the endurance exercise-induced antiarrhythmic effects resulted from normalization of cellular electrophysiology and/or normalization of calcium handling. EET prevented VF and shortened in vivo repolarization (P < 0.05). EET normalized action potential duration and variability compared with the sedentary group. EET resulted in a further decrement in transient outward current compared with the sedentary VF+ group (P < 0.05). Sedentary VF+ dogs had a significant reduction in repolarizing K(+) current, which was restored by exercise training (P < 0.05). Compared with controls, myocytes from the sedentary VF+ group displayed calcium alternans, increased calcium spark frequency, and increased phosphorylation of S2814 on ryanodine receptor 2. These abnormalities in intracellular calcium handling were attenuated by exercise training (P < 0.05). Exercise training prevented ischemically induced VF, in association with a combination of beneficial effects on cellular electrophysiology and calcium handling.

Redox modification of ryanodine receptors underlies calcium alternans in a canine model of sudden cardiac death

Although cardiac alternans is a known predictor of lethal arrhythmias, its underlying causes remain largely undefined in disease settings. The potential role of, and mechanisms responsible for, beat-to-beat alternations in the amplitude of systolic Ca(2+) transients (Ca(2+) alternans) was investigated in a canine post-myocardial infarction (MI) model of sudden cardiac death (SCD). Post-MI dogs had preserved left ventricular (LV) function and susceptibility to ventricular fibrillation (VF) during exercise. LV wedge preparations from VF dogs were more susceptible to action potential (AP) alternans and the frequency-dependence of Ca(2+) alternans was shifted towards slower rates in myocytes isolated from VF dogs relative to controls. In both groups of cells, cytosolic Ca(2+) transients ([Ca(2+)](c)) alternated in phase with changes in diastolic Ca(2+) in sarcoplasmic reticulum ([Ca(2+)](SR)), but the dependence of [Ca(2+)](c) amplitude on [Ca(2+)](SR) was steeper in VF cells. Abnormal ryanodine receptor (RyR) function in VF cells was indicated by increased fractional Ca(2+) release for a given amplitude of Ca(2+) current and elevated diastolic RyR-mediated SR Ca(2+) leak. SR Ca(2+) uptake activity did not differ between VF and control cells. VF myocytes had an increased rate of reactive oxygen species production and increased RyR oxidation. Treatment of VF myocytes with reducing agents normalized parameters of Ca(2+) handling and shifted the threshold of Ca(2+) alternans to higher frequencies. Redox modulation of RyRs promotes generation of Ca(2+) alternans by enhancing the steepness of the Ca(2+) release-load relationship and thereby providing a substrate for post-MI arrhythmias.

Antifibrillatory actions of HBI‐3000 in the conscious canine model of sudden cardiac death

The antifibrillatory actions of HBI‐3000 (sulcardine sulfate) were studied in a conscious canine model of sudden cardiac death (SCD). Female purpose‐bred beagles were anesthetized, and left ventricular anterior wall ischemic injury was induced by a 90 minute occlusion followed by reperfusion of the left anterior descending coronary artery. Three to seven days later, the dogs were randomized into two groups: Group 1 (n = 8) received 0.9% NaCl solution for injection while Group 2 (n = 7) received 15 mg/kg of HBI‐3000 intravenously. The dogs were subjected to anodal current‐induced injury of the circumflex coronary artery, resulting in transient interruptions in coronary artery blood flow and posterolateral myocardial ischemia. The electrocardiogram confirmed the presence of regional myocardial ischemia and ventricular fibrillation (VF). Control animals developed premature ventricular complexes (PVC) followed by ventricular tachycardia, which terminated in VF in four of the eight dogs and one expired overnight. PVC was also observed in HBI‐3000 treated animals, but only one of the seven animals developed VF in SCD (p &lt; 0.05 vs. control). The data indicate that HBI‐3000 is effective in reversing polymorphic ventricular arrhythmias and has favorable antifibrillatory actions in the post‐infarcted canine heart subjected to a remote ischemic event.Supported by HUYA Bioscience International.

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.