Regular exercise training is known to affect the action potential duration (APD) and improve heart function, but involvement of β-adrenergic receptor (β-AR) subtypes and/or the ATP-sensitive K (K) channel is unknown. To address this, female and male Sprague-Dawley rats were randomly assigned to voluntary wheel-running or control groups; they were anesthetized after 6-8 wk of training, and myocytes were isolated. Exercise training significantly increased APD of apex and base myocytes at 1 Hz and decreased APD at 10 Hz. Ca transient durations reflected the changes in APD, while Ca transient amplitudes were unaffected by wheel running. The nonselective β-AR agonist isoproterenol shortened the myocyte APD, an effect reduced by wheel running. The isoproterenol-induced shortening of APD was largely reversed by the selective β-AR blocker atenolol, but not the β-AR blocker ICI 118,551, providing evidence that wheel running reduced the sensitivity of the β-AR. At 10 Hz, the K channel inhibitor glibenclamide prolonged the myocyte APD more in exercise-trained than control rats, implicating a role for this channel in the exercise-induced APD shortening at 10 Hz. A novel finding of this work was the dual importance of altered β-AR responsiveness and K channel function in the training-induced regulation of APD. Of physiological importance to the beating heart, the reduced response to adrenergic agonists would enhance cardiac contractility at resting rates, where sympathetic drive is low, by prolonging APD and Ca influx; during exercise, an increase in K channel activity would shorten APD and, thus, protect the heart against Ca overload or inadequate filling. Our data demonstrated that regular exercise prolonged the action potential and Ca transient durations in myocytes isolated from apex and base regions at 1-Hz and shortened both at 10-Hz stimulation. Novel findings were that wheel running shifted the β-adrenergic receptor agonist dose-response curve rightward compared with controls by reducing β-adrenergic receptor responsiveness and that, at the high activation rate, myocytes from trained animals showed higher K channel function.

Results demonstrate that exercise training (TRN) downregulates ventricular IKs channel current and the channel’s responsiveness to β-agonist factors mediated by TRN-induced decline in channel subunits KCNQ1 and KCNE1 and the A-kinase anchoring protein yotiao. The reduced IKs current helps explain the TRN-induced prolongation of the action potential in basal conditions and, coupled with previously reported upregulation of the KATP channel, results in a more efficient heart that is better able to respond to beat-by-beat changes in metabolism.

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Exercise training is known to protect the heart from ischemia and improve function during exercise by reducing cardiomyocyte action potential duration (APD) and increasing contractility. The cellular mechanisms involve β-adrenergic regulation and the ATP-sensitive K (K) channel, but how each alters function of the left ventricle and sex specificity is unknown. To address this, female and male Sprague-Dawley rats were randomly assigned to wheel-running (TRN) or sedentary (SED) groups. After 6-8 wk of training, myocytes were isolated from the left ventricle and field stimulated at 1, 2, and 5 Hz. TRN significantly increased cardiomyocyte contractility, the kinetics of the Ca transient, and responsiveness to the adrenergic receptor agonist isoproterenol (ISO), as reflected by an increased sarcomere shortening. Importantly, we demonstrated a TRN-induced upregulation of K channels, which was reflected by elevated content, current density, and the channel's contribution to APD shortening at high activation rates and in the presence of the activator pinacidil. TRN induced increase in K current occurred throughout the left ventricle, but channel subunit content showed regional specificity with increases in Kir6.2 in the apex and SUR2A in base regions. In summary, TRN elevated cardiomyocyte cross-bridge kinetics, Ca sensitivity, and the responsiveness of contractile function to β-adrenergic receptor stimulation in both sexes. Importantly, upregulation of the K channel accelerates repolarization and shortens APD during stress and exercise. These adaptations have clinical importance, as increased contractility and reduced APD would help protect cardiac output and reduce intracellular Ca overload during stresses such as regional ischemia. NEW & NOTEWORTHY Our results demonstrate that regular exercise significantly increased ventricular myocyte shortening and relaxation velocity and the rate of rise in intracellular Ca transient and enhanced the response of biomechanics and Ca reuptake to β-adrenergic stimulation. Importantly, exercise training upregulated the cardiomyocyte sarcolemma ATP-sensitive K channel across the left ventricle in both sexes, as reflected by elevated channel subunit content, current density, and the channel's contribution to reduced action potential duration at high activation rates.

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Objective: Previous studies on the efficacy and safety of genotype-guided antiplatelet therapy in patients with coronary artery disease (CAD) or undergoing percutaneous coronary intervention (PCI) have been inconclusive. Aim: We conducted a meta-analysis to evaluate if the genotype-guided antiplatelet strategy is superior to the standard therapy in patients with CAD or undergoing PCI. Method: PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials databases were searched up to October 1st, 2021. Studies reporting efficacy and safety outcomes in the genotype-guided treatment and standard treatment groups were included. The two groups were statistically compared. Result: Eleven randomized controlled trials (RCTs) involving 11740 patients were included in this meta-analysis. Compared with the standard treatment group, the genotype-guided group had significant lower risks of all efficacy outcomes, including major adverse cardiovascular events (MACEs) (RR 0.60, 95%, CI 0.44-0.82, P=0.001), all-cause death (RR 0.70, 95% CI 0.51-0.95, P=0.02), cardiovascular death (RR 0.71, 95% CI 0.53-0.95, P=0.02), myocardial infarction (RR 0.53, 95% CI 0.42-0.67, P<0.0001), stroke (RR 0.64, 95% CI 0.41-0.98, P=0.04), stent thrombosis (RR 0.63, 95% CI 0.43-0.91, P=0.01) and targeted vessel revascularization (RR 0.79, 95% CI 0.67-0.92, P=0.003). There was no significant difference in any bleeding events between the two groups. As a result of the subgroup analyses, the genotype-guided treatment was more likely to reduce the incidence of MACEs in the subgroup where the proportion of patients with ACS was ≥ 90%, and subgroup of the Chinese population. Conclusion: Genotype-guided antiplatelet treatment could reduce the risk of MACEs without increasing the risk of bleeding events as compared with the standard treatment in patients with CAD or those undergoing PCI. In addition, Genotype-guided antiplatelet treatment might benefit Chinese population or patients with ACS.

Pharmacologic strategies that target factors with both pro-apoptotic and anti-proliferative functions in cardiomyocytes (CMs) may be useful for the treatment of ischemic heart disease. One such multifunctional candidate for drug targeting is the acetyltransferase Tip60, which is known to acetylate both histone and non-histone protein targets that have been shown in cancer cells to promote apoptosis and to initiate the DNA damage response, thereby limiting cellular expansion. Using a murine model, we recently published findings demonstrating that CM-specific disruption of the Kat5 gene encoding Tip60 markedly protects against the damaging effects of myocardial infarction (MI). In the experiments described here, in lieu of genetic targeting, we administered TH1834, an experimental drug designed to specifically inhibit the acetyltransferase domain of Tip60. We report that, similar to the effect of disrupting the Kat5 gene, daily systemic administration of TH1834 beginning 3 days after induction of MI and continuing for 2 weeks of a 4-week timeline resulted in improved systolic function, reduced apoptosis and scarring, and increased activation of the CM cell cycle, effects accompanied by reduced expression of genes that promote apoptosis and inhibit the cell cycle and reduced levels of CMs exhibiting phosphorylated Atm. These results support the possibility that drugs that inhibit the acetyltransferase activity of Tip60 may be useful agents for the treatment of ischemic heart disease.

Regeneration of muscle in the damaged myocardium is a major objective of cardiovascular research, for which purpose many investigators utilize mice containing transgenes encoding Cre-recombinase to recombine loxP-flanked target genes. An unfortunate side-effect of the Cre-loxP model is the propensity of Cre-recombinase to inflict off-target DNA damage, which has been documented in various eukaryotic cell-types including cardiomyocytes (CMs). In the heart, reported effects of Cre-recombinase include contractile dysfunction, fibrosis, cellular infiltration, and induction of the DNA damage response (DDR). During experiments on adult mice containing a widely used Myh6-merCremer transgene, the protein product of which is activated by tamoxifen, we observed large, transient off-target effects of merCremer, some of which have not been previously reported. On Day 3 after the first of three daily tamoxifen injections, immunofluorescent microscopy of heart sections revealed that the presence of merCremer protein in myonuclei was nearly uniform, thereafter diminishing to near extinction by Day 6; during this time, cardiac function was depressed as determined by echocardiography. On Day 5, peaks of apoptosis and expression of DDR regulatory genes were observed, highlighted by >25-fold increased expression of Brca1; concomitantly, the expression of genes encoding Cyclin A2, Cyclin B1 and Cdk1, which regulate the G2/S cell-cycle transition, were dramatically increased (>50-100-fold). Importantly, immunofluorescent staining revealed that this was accompanied by peaks of Ki67, 5’-bromodeoxyuridine, and phosphohistone H3 labeling in non-CMs, as well as CMs. We further document that tamoxifen-induced activation of merCremer exacerbates cardiac dysfunction following MI. These findings, when considered in the context of previous reports, indicate that the presence of merCremer in the nucleus induces DNA damage and unscheduled cell-cycle activation. Although these effects are transient, the inclusion of appropriate controls, coupled with an awareness of defects caused by Cre-recombinase, are required to avoid misinterpreting results when using Cre-loxP models for cardiac regeneration studies.