ATP-sensitive K (K) channels uniquely link cellular energy metabolism to membrane excitability and are expressed in diverse cell types that range from the endocrine pancreas to neurons and smooth, skeletal, and cardiac muscle. A decrease in the surface expression of K channels has been linked to various disorders, including dysregulated insulin secretion, abnormal blood pressure, and impaired resistance to cardiac injury. In contrast, up-regulation of K channel surface expression may be protective, for example, by mediating the beneficial effect of ischemic preconditioning. Molecular mechanisms that regulate K channel trafficking are poorly understood. Here, we used cellular assays with immunofluorescence, surface biotinylation, and patch clamping to demonstrate that Eps15 homology domain-containing protein 2 (EHD2) is a novel positive regulator of K channel trafficking to increase surface K channel density. EHD2 had no effect on cardiac Na channels (Nav1.5). The effect is specific to EHD2 as other members of the EHD family-EHD1, EHD3, and EHD4-had no effect on K channel surface expression. EHD2 did not directly affect K channel properties as unitary conductance and ATP sensitivity were unchanged. Instead, we observed that the mechanism by which EHD2 increases surface expression is by stabilizing K channel-containing caveolar structures, which results in a reduced rate of endocytosis. EHD2 also regulated K channel trafficking in isolated cardiomyocytes, which validated the physiologic relevance of these observations. Pathophysiologically, EHD2 may be cardioprotective as a dominant-negative EHD2 mutant sensitized cardiomyocytes to ischemic damage. Our findings highlight EHD2 as a potential pharmacologic target in the treatment of diseases with K channel trafficking defects.-Yang, H. Q., Jana, K., Rindler, M. J., Coetzee, W. A. The trafficking protein, EHD2, positively regulates cardiac sarcolemmal K channel surface expression: role in cardioprotection.

Myocardial ischemia remains the primary cause of morbidity and mortality in the United States. Ischemic preconditioning (IPC) is a powerful form of endogenous protection against myocardial infarction. We studied alterations in KATP channels surface density as a potential mechanism of the protection of IPC. Using cardiac-specific knockout of Kir6.2 subunits, we demonstrated an essential role for sarcolemmal KATP channels in the infarct-limiting effect of IPC in the mouse heart. With biochemical membrane fractionation, we demonstrated that sarcolemmal KATP channel subunits are distributed both to the sarcolemma and intracellular endosomal compartments. Global ischemia causes a loss of sarcolemmal KATP channel subunit distribution and internalization to endosomal compartments. Ischemia-induced internalization of KATP channels was prevented by CaMKII inhibition. KATP channel subcellular redistribution was also observed with immunohistochemistry. Ischemic preconditioning before the index ischemia reduced not only the infarct size but also prevented KATP channel internalization. Furthermore, not only did adenosine mimic IPC by preventing infarct size, but it also prevented ischemia-induced KATP channel internalization via a PKC-mediated pathway. We show that preventing endocytosis with dynasore reduced both KATP channel internalization and strongly mitigated infarct development. Our data demonstrate that plasticity of KATP channel surface expression must be considered as a potentially important mechanism of the protective effects of IPC and adenosine.

These sudden infant death syndrome (SIDS)-related variants caused a severely dysfunctional Nav1.5 channel, which was mainly due to trafficking defects caused by the Q1832E mutation. The decreased current density is likely to be a major contributing factor to arrhythmogenesis in Brugada syndrome and the sudden death of this SIDS victim.

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Background. The SARS-CoV-2 virus caused the global COVID-19 pandemic, with waxing and waning course. This study was conducted to compare outcomes in the first two waves, in mechanically ventilated patients. Methods. This retrospective observational study included all mechanically ventilated COVID-19 patients above 18 years of age, between March 2020 and January 2021. Patients were grouped into first wave from March 2020 to July 2020, and second wave from August 2020 to January 2021. Outcome measures were mortality, the development of acute kidney injury (AKI), and need for renal replacement therapy (RRT). Univariate and multivariate cox regression analysis were used to delineate risk factors for the outcome measures. Results. A total of 426 patients, 285 in the first wave and 185 in the second wave, were included. The incidence of AKI was significantly lower in the second wave (72% vs. 63%; p = 0.04 ). There was no significant difference in mortality (70% vs. 63%; p = 0.16 ) and need for RRT (36% vs. 30%; p = 0.1 ). Risk factors for mortality were increasing age and AKI in both waves, and chronic kidney disease (CKD) (adj. HR 1.7; 95% CI 1.02–2.68; p = 0.04 ) in the second wave. Risk factors for AKI were CKD in both the waves, while it was diabetes (adj. HR 1.4; 95% CI 1.02–1.95; p = 0.04 ) and increasing age in the first wave. Remdesivir (adj. HR 0.5; 95% CI 0.3–0.7; p < 0.01 ) decreased the risk of AKI, and convalescent plasma (adj. HR 0.5; 95% CI 0.3–0.9; p = 0.02 ) decreased the risk of mortality in the first wave, however, such benefit was not observed in the second wave. Conclusions. Our study shows a decrease in the incidence of AKI in critically ill patients, however, the reason for this decrease is still unknown. Studies comparing the waves of the pandemic would not only help in understanding disease evolution but also to develop tailored management strategies.