Measurement of Ado-stimulated absolute MBF is superior to relative measurement of myocardial tracer retention for identification of CAD and can be accomplished with a single MBFado measurement.

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 hMSCs remodels and can regulate arrhythmia substrates. Methods - Human cardiac MSCs (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 non-failing hMSCs were co-cultured with normal human myocytes (hCM) derived from induced pluripotent stem cells. Using fluorescent indicators, APD, Ca2+ alternans, and spontaneous calcium release (SCR) incidence were determined. Results - Failing and non-failing hMSCs from both sources exhibited similar tri-lineage differentiation potential and cell surface marker expression as bone marrow hMSCs. Compared to non-failing hMSCs, failing hMSCs prolonged APD by 24% (p<0.001, n=15), increased Ca2+ alternans by 300% (p<0.001, n=18), and promoted SCR activity (n=14, p <0.013) in hCM. Failing hMSCs exhibited increased secretion of inflammatory cytokines IL-1β (98%, p<0.0001) and IL-6 (460%, p <0.02) compared to non-failing hMSCs. IL-1β or IL-6 in the absence of hMSCs prolonged APD but only IL-6 increased Ca2+ alternans and promoted SCR activity in hCM, replicating the effects of failing hMSCs. In contrast, non-failing hMSCs prevented Ca2+ alternans in hCM during oxidative stress. Finally, non-failing hMSCs exhibited >25 times higher secretion of IGF-1 compared to 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.

Introduction: Adult women with LQT2 are at higher risk for clinical events and sudden cardiac death (SCD) than men. We have created transgenic rabbits over-expressing pore mutants of the human KvLQT1 (LQT1) and HERG (LQT2) selectively in the heart. We report the gender differences in cardiac repolarization, incidence of polymorphic VT and SCD in these cohorts. Methods: Adult female and male LQT1, LQT2, and littermate controls (ages 5 to 33 mo were similar in f/m, LQT2 were younger due to higher mortality) underwent telemetric ECG monitoring, surface ECG and in vivo electrophysiological studies under general anaesthesia with isoflurane (2–5%). Results: Monitoring data showed a steeper QT/RR slope in female (0.745 ± 0.05, n=4) than in male (0.513 ± 0.06, n=9; p<0.05) LQT2 rabbits. No significant gender differences were observed in QT/RR slopes in either LQT1 or WT rabbits. QT-, QTpeak-index and Tp-e were significantly longer in female than in male LQT2 rabbits (females, n=6: QT: 129.2% ± 3.9; QTp: 105.9% ± 2.1; Tp-e: 42.9ms ± 4.1 vs. males, n=8: QT: 117.5% ± 4.3; p<0.05; QTp: 93.5% ± 5.6, p<0.05; Tp-e: 29.5ms ± 2.9, p<0.02). EP studies revealed significantly longer atrial (AERP) and ventricular (VERP) refractory periods in LQT2 females compared to males (females, n=4: AERP: 143.3 ± 5.8 ms; VERP: 212.5 ± 22.2 ms vs. males, n=8: AERP: 102.5 ± 7.7 ms, p<0.01; VERP: 178.1 ± 7.8 ms, p<0.05). AERP and VERP were significantly longer in LQT2 females than in LQT1 females (LQT1 females, n=7: AERP: 101.4 ± 7.7 ms, p<0.01, VERP: 156.9 ± 6.2, p<0.001), whereas in male LQT rabbits this genotype difference was only found in VERP but not in AERP. Survival was significantly shorter in female LQT2 rabbits compared to LQT1 or WT controls, with 4 sudden deaths among 10 LQT2, 1 among 19 WT and no SCD in 13 LQT1 females (p<0.02). No gender difference was observed in mortality. All cases of SCD occurred after sexual maturation and two LQT2 females died during lactation. Monitoring revealed the cause of SCD was polymorphic VT. Conclusions: Monitoring of LQT rabbits reveal gender differences in LQT2 rabbits. QT/RR slope is steeper in female than in male adult LQT2 rabbits. AERP and VERP are longer in LQT2 females than in males. Finally, in LQT2 females, SCD was associated with lactation, but not pregnancy.