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Torsade de Pointes (TdP), a rare but lethal ventricular arrhythmia, is a toxic side effect of many drugs. To assess TdP risk, safety regulatory guidelines require quantification of hERG channel block in vitro and QT interval prolongation in vivo for all new therapeutic compounds. Unfortunately, these have proven to be poor predictors of torsadogenic risk, and are likely to have prevented safe compounds from reaching clinical phases. While this has stimulated numerous efforts to define new paradigms for cardiac safety, none of the recently developed strategies accounts for patient conditions. In particular, despite being a well-established independent risk factor for TdP, female sex is vastly underrepresented in both basic research and clinical studies, and thus current TdP metrics are likely biased toward the male sex. Here, we apply statistical learning to synthetic data, generated by simulating drug effects on cardiac myocyte models capturing male and female electrophysiology, to develop new sex-specific classification frameworks for TdP risk. We show that (1) TdP classifiers require different features in females vs. males; (2) malebased classifiers perform more poorly when applied to female data; (3) female-based classifier performance is largely unaffected by acute effects of hormones (i.e., during various phases of the menstrual cycle). Notably, when predicting TdP risk of intermediate drugs on female simulated data, male-biased predictive models consistently underestimate TdP risk in women. Therefore, we conclude that pipelines for preclinical cardiotoxicity risk assessment should consider sex as a key variable to avoid potentially lifethreatening consequences for the female population..

In this large population-based study of hospitalized patients with nonvalvular AF, ablation was associated with lower mortality, ischemic stroke, and hemorrhagic stroke compared with controls.

BV pacing attenuates TWA in tandem with reduced T-wave magnitude. In these patients with baseline QRS prolongation, RV-TWA predicted events more effectively than BV-TWA and RA-TWA. Further studies are required to understand how altered ventricular activation influences repolarization dynamics and arrhythmic tendency.

Heat-shock proteins (HSPs) are members of a highly conserved group of proteins that are induced in response to stress and injury. These proteins have protective properties, and can protect the heart from injury. HSP60 is found in the mitochondria and cytosol, and has essential intracellular functions including folding key proteins after their import into the mitochondria. In the cytosol, HSP60 binds to proapoptotic proteins, sequestering them. HSPs are highly conserved and, thus, are similar to bacterial proteins. Many individuals have antibodies to HSP60, possibly from prior infections. HSP60 can be found in the plasma membrane and in the serum in disease states. Serum HSP60 may be a marker for coronary artery disease. Once extracellular, HSP60 can cause cell injury. Thus, this protein has dichotomous functions for which the role in disease remains to be fully elucidated.

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BackgroundSudden cardiac death (SCD) is a major cause of mortality secondary to coronary artery disease (CAD) in the industrialized societies. Although South Asians have a high prevalence of CAD, the frequency and underlying pathology of SCD among this population are unknown.MethodsMedical records of consecutive patients presenting with unexplained sudden death (USD) in a tertiary care center were reviewed. Patients with trauma, violent deaths, positive toxicology and non-cardiac pathology were excluded to determine sudden cardiac death (SCD). Cardiac pathological findings were analyzed by autopsy. SCD rate was estimated based on census and government vital statistics for the years studied.ResultsDuring a two year period, 223 patients (mean age 55 + 10 yrs, 78.9% male, body mass index 26 + 4, 60% smokers, 39% known CAD, 46% hypertension, 43% diabetes) presented to hospital with USD. SCD was attributed to myocardial infarction (MI) in 87% of cases; 69% were acute (96% anterior MI); 76% were small/moderate infarct and 9.9% of the cohort had normal hearts. Based on official municipal vital statistics, the SCD rate in those >35 yrs of age was estimated as 39.7/100,000 with male/female ratio of 4.6.ConclusionsSCD in this south Indian city occurred predominantly in men of relatively young age and was most frequently associated with small or moderate-sized acute MI. Improved health care access, preventive measures and enhanced emergency management may reduce SCD from acute MI in this locale.