Tensor cardiography: A novel ECG analysis of deviations in collective myocardial action potential transitions based on point processes and cumulative distribution functions.

To improve clinical diagnoses, assessments of potential cardiac disease risk, and predictions of lethal arrhythmias, the analysis of electrocardiograms (ECGs) requires a more accurate method of weighting waveforms to efficiently detect abnormalities that appear as minute strains in the waveforms. In addition, the inverse problem of estimating the myocardial action potential from the ECG has been a longstanding challenge. To analyze the variance of the ECG waveforms and to estimate collective myocardial action potentials (APs) from the ECG, we designed a model equation incorporating the probability densities of Gaussian functions of time-series point processes in the cardiac cycle and dipoles of the collective APs in the myocardium. The equation, which involves taking the difference between the cumulative distribution functions (CDFs) that represent positive endocardial and negative epicardial potentials, fits both R and T waves. The mean, standard deviation, weights, and level of each cumulative distribution function (CDF) are metrics for the variance of the transition state of the collective myocardial AP. Clinical ECGs of myocardial ischemia during coronary intervention show abnormalities in the aforementioned specific elements of the tensor associated with repolarization transition variance earlier than in conventional indicators of ischemia. The tensor can be used to evaluate the beat-to-beat dynamic repolarization changes between the ventricular epi and endocardium in terms of the Mahalanobis distance (MD). This tensor-based cardiography that uses the differences between CDFs to show changes in collective myocardial APs has the potential to be a new analysis tool for ECGs.

Autophagy and protein kinase C are required for cardioprotection by sulfaphenazole.

Previously, we showed that sulfaphenazole (SUL), an antimicrobial agent that is a potent inhibitor of cytochrome P4502C9, is protective against ischemia-reperfusion (I/R) injury (Ref. 15). The mechanism, however, underlying this cardioprotection, is largely unknown. With evidence that activation of autophagy is protective against simulated I/R in HL-1 cells, and evidence that autophagy is upregulated in preconditioned hearts, we hypothesized that SUL-mediated cardioprotection might resemble ischemic preconditioning with respect to activation of protein kinase C and autophagy. We used the Langendorff model of global ischemia to assess the role of autophagy and protein kinase C in myocardial protection by SUL during I/R. We show that SUL enhanced recovery of function, reduced creatine kinase release, decreased infarct size, and induced autophagy. SUL also triggered PKC translocation, whereas inhibition of PKC with chelerythrine blocked the activation of autophagy in adult rat cardiomyocytes. In the Langendorff model, chelerythrine suppressed autophagy and abolished the protection mediated by SUL. SUL increased autophagy in adult rat cardiomyocytes infected with GFP-LC3 adenovirus, in isolated perfused rat hearts, and in mCherry-LC3 transgenic mice. To establish the role of autophagy in cardioprotection, we used the cell-permeable dominant-negative inhibitor of autophagy, Tat-Atg5(K130R). Autophagy and cardioprotection were abolished in rat hearts perfused with recombinant Tat-Atg5(K130R). Taken together, these studies indicate that cardioprotection mediated by SUL involves a PKC-dependent induction of autophagy. The findings suggest that autophagy may be a fundamental process that enhances the heart's tolerance to ischemia.