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TRPM4 is a broadly expressed, calcium-activated, monovalent cation channel that regulates immune cell function in mice and cell lines. Clinically, however, partial loss- or gain-of-function mutations in TRPM4 lead to arrhythmia and heart disease, with no documentation of immunologic disorders. To characterize functional cellular mechanisms underlying the immune dysregulation phenotype in a proband with a mutated TRPM4 gene. We employed a combination of biochemical, cell biological, imaging, omics analyses, flow cytometry, and gene editing approaches. We report the first human cases to our knowledge with complete loss of the TRPM4 channel, leading to immune dysregulation with frequent bacterial and fungal infections. Single-cell and bulk RNA sequencing point to altered expression of genes affecting cell migration, specifically in monocytes. Inhibition of TRPM4 in T cells and the THP-1 monocyte cell line reduces migration. More importantly, primary T cells and monocytes from TRPM4 patients migrate poorly. Finally, CRISPR knockout of TRPM4 in THP-1 cells greatly reduces their migration potential. Our results demonstrate that TRPM4 plays a critical role in regulating immune cell migration, leading to increased susceptibility to infections. [ABSTRACT FROM AUTHOR]

We describe the successful use of the Impella LP 5.0 intracardiac microaxial pump (Abiomed, Danvers, MA) in a 13-year-old boy with fulminant biopsy-proven viral myocarditis. The patient, who previously was in refractory cardiogenic shock despite increasing inotropic and vasopressor support, immediately stabilized after Impella LP 5.0 implantation and was successfully bridged to a full recovery. Months later, he remains completely well, with no intracardiac or peripheral vascular sequelae of the procedure. In carefully selected pediatric patients the Impella may be a beneficial form of temporary mechanical circulatory support for fulminant cardiogenic shock. [Copyright &y& Elsevier]

We sought to determine whether childhood obesity is associated with increased aortic stiffness by measuring the biophysical properties of the aorta in obese children using a noninvasive echocardiographic Doppler method. Increased aortic stiffness is a strong predictor of future cardiovascular events and mortality in adults. Obesity is known to be associated with increased aortic stiffness and arterial disease in adults. We prospectively evaluated a cohort of obese children (n = 61) and compared them to normal-weight controls (n = 55). The anthropometric data were recorded. The pulsewave velocity (PWV), aortic input impedance (Zi), characteristic impedance (Zc), arterial pressure-strain elastic modulus (Ep), arterial wall stiffness index (B index), and peak aortic velocity were calculated. We correlated our echocardiographic Doppler findings with the lipid levels. We assessed the left ventricular (LV) dimensions and standard measures of cardiac function. Cardiopulmonary exercise testing was performed on all obese children. Compared to normal-weight children, obese children had a greater PWV, Zc, B index, Ep, and peak aortic velocity. Obese children had greater systolic blood pressure than normal-weight children but no difference in diastolic blood pressure. The LV dimensions and standard measures of cardiac systolic function were similar in the 2 groups, but the obese children had altered diastolic properties. The LV mass was greater in the obese children. No association was found between the lipid levels and the biophysical properties of the aorta. The relative oxygen consumption was 68% predicted in obese children. In conclusion, measures of the biophysical properties of the aorta are already abnormal in obese children, reflecting increased aortic stiffness at this early stage of disease. Obese children also had an increased LV mass, altered diastolic properties, and an abnormal exercise capacity. PWV might be useful in monitoring the progression of arterial disease or the effect of therapeutic interventions. [ABSTRACT FROM AUTHOR]