Abstract
Background: The pathological heart contractions, called arrhythmias, especially ventricular fibrillation (VF), are a prominent feature of many cardiovascular diseases leading to sudden cardiac death. The present investigation evaluates the effect of electrically stimulated VF on cardiac functions related to autophagy and apoptotic mechanisms in isolated working rat hearts. Methods: Each group of hearts was subjected to 0 (Control), 1, 3, or 10 min of spacing-induced VF, followed by 120 min of recovery period and evaluated for cardiac functions, including aortic flow (AF), coronary flow (CF), cardiac output (CO), stroke volume (SV), and heart rate (HR). Hearts were also evaluated for VF effects on infarcted zone magnitude and Western blot analysis was conducted on heart tissue for expression of the apoptotic biomarker cleaved-caspase-3 and the autophagy proteins: p62, P-mTOR/mTOR, LC3BII/LC3BI ratio, and Atg5-12 complexes. Results: Data revealed that VF induced degradation in AF, CF, CO, and SV, which prominently included-variable post-VF capacity for recovery of normal heart rhythm; increased extent of infarcted heart tissue; altered expression of cleaved-caspase-3 suggesting potential for VF-mediated amplification of apoptosis. VF influence on expression of p62, LC3BII/LC3BI, and Atg5-12 proteins was complex, possibly due to differential effects of VF-induced expression on proteins comprising the autophagic program. Conclusions: VF was observed to cause time-dependent changes in autophagy processes, which with additional analysis under ongoing investigations, likely to yield novel therapeutic targets for the prevention of VF and sudden cardiac death.
Highlights
Several pathological processes to cardiovascular tissue occur as a result of sudden restoration of blood flow and cardiac function to tissues, and such an event may result in characteristic deleterious effects and symptoms that include impairment of physiological functions
The major hypothesis of the present investigation is that the occurrence of ventricular fibrillation (VF), which is one of the most clinically significant arrhythmic disorders leading to sudden cardiac death, directly influences apoptotic and autophagic processes and signal transductions to an extent that arrhythmias may act as major inducers of alterations in basic cellular, tissue, and organ processes that underlie myocardial diseases
Outcomes of cardiac output (CO) assessment shown in Figure 1C. indicates a significantly reduced CO magnitude after a 1, 3, and 10 min period of VF followed by 30, 60, and 120 min of aerobic perfusion at each time point, respectively, (p = 0.0432)
Summary
Several pathological processes to cardiovascular tissue occur as a result of sudden restoration of blood flow and cardiac function to tissues, and such an event may result in characteristic deleterious effects and symptoms that include impairment of physiological functions These outcomes are due to oxidation of myocardial membrane lipids, perturbed ion homeostasis, and reactive oxygen species [1,2,3,4], which lead to various cell deaths, including necrosis, apoptosis, and autophagy. It has previously been demonstrated that alterations in the principle cardiac functions, including aortic flow (AF), coronary flow (CF), cardiac output (CO), stroke volume (SV), and heart rate (HR) correlate with occurrence of arrhythmias in ways that clearly demonstrate common underlying regulatory processes for both cardiac functions and arrhythmogenesis [17,18,19] It is presently unknown whether various pathologic processes, which result in disruption of physiological heart function and contributing cellular processes, such as apoptosis and autophagy, may be promoted by the occurrence of arrhythmias. Conclusions: VF was observed to cause time-dependent changes in autophagy processes, which with additional analysis under ongoing investigations, likely to yield novel therapeutic targets for the prevention of VF and sudden cardiac death
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