Multilayer control of cardiac electrophysiology by microRNAs.

The electrophysiological properties of the heart include cardiac automaticity, excitation (i.e., depolarization and repolarization of action potential) of individual cardiomyocytes, and highly coordinated electrical propagation through the whole heart. An abnormality in any of these properties can cause arrhythmias. MicroRNAs (miRs) have been recognized as essential regulators of gene expression through the conventional RNA interference (RNAi) mechanism and are involved in a variety of biological events. Recent evidence has demonstrated that miRs regulate the electrophysiology of the heart through fine regulation by the conventional RNAi mechanism of the expression of ion channels, transporters, intracellular Ca2+-handling proteins, and other relevant factors. Recently, a direct interaction between miRs and ion channels has also been reported in the heart, revealing a biophysical modulation by miRs of cardiac electrophysiology. These advanced discoveries suggest that miR controls cardiac electrophysiology through two distinct mechanisms: immediate action through biophysical modulation and long-term conventional RNAi regulation. Here, we review the recent research progress and summarize the current understanding of how miR manipulates the function of ion channels to maintain the homeostasis of cardiac electrophysiology.

Human Cardiac Mesenchymal Stem Cells Remodel in Disease and Can Regulate Arrhythmia Substrates.

BACKGROUND: The mesenchymal stem cell (MSC), known to remodel in disease and have an extensive secretome, has recently been isolated from the human heart. However, the effects of normal and diseased cardiac MSCs on myocyte electrophysiology remain unclear. We hypothesize that in disease the inflammatory secretome of cardiac human MSCs (hMSCs) remodels and can regulate arrhythmia substrates. METHODS: hMSCs were isolated from patients with or without heart failure from tissue attached to extracted device leads and from samples taken from explanted/donor hearts. Failing hMSCs or nonfailing hMSCs were cocultured with normal human cardiac myocytes derived from induced pluripotent stem cells. Using fluorescent indicators, action potential duration, Ca2+ alternans, and spontaneous calcium release (SCR) incidence were determined. RESULTS: Failing and nonfailing hMSCs from both sources exhibited similar trilineage differentiation potential and cell surface marker expression as bone marrow hMSCs. Compared with nonfailing hMSCs, failing hMSCs prolonged action potential duration by 24% (P<0.001, n=15), increased Ca2+ alternans by 300% (P<0.001, n=18), and promoted spontaneous calcium release activity (n=14, P<0.013) in human cardiac myocytes derived from induced pluripotent stem cells. Failing hMSCs exhibited increased secretion of inflammatory cytokines IL (interleukin)-1ß (98%, P<0.0001) and IL-6 (460%, P<0.02) compared with nonfailing hMSCs. IL-1ß or IL-6 in the absence of hMSCs prolonged action potential duration but only IL-6 increased Ca2+ alternans and promoted spontaneous calcium release activity in human cardiac myocytes derived from induced pluripotent stem cells, replicating the effects of failing hMSCs. In contrast, nonfailing hMSCs prevented Ca2+ alternans in human cardiac myocytes derived from induced pluripotent stem cells during oxidative stress. Finally, nonfailing hMSCs exhibited >25× higher secretion of IGF (insulin-like growth factor)-1 compared with failing hMSCs. Importantly, IGF-1 supplementation or anti-IL-6 treatment rescued the arrhythmia substrates induced by failing hMSCs. CONCLUSIONS: We identified device leads as a novel source of cardiac hMSCs. Our findings show that cardiac hMSCs can regulate arrhythmia substrates by remodeling their secretome in disease. Importantly, therapy inhibiting (anti-IL-6) or mimicking (IGF-1) the cardiac hMSC secretome can rescue arrhythmia substrates.