Cardiac myofilament Caa2+ sensitization disturbs regulation of coronary flow and leads to focal myocardial ischemia and arrhythmias during stress (1079.25)

Abstract

Myofilament Ca2+ sensitization has been linked to increased arrhythmia susceptibility, but the underlying mechanism is not completely understood. Mice with the Ca2+ sensitizing TnT‐I79N mutation develop arrhythmias during stress, despite the absence of an overt anatomical substrate. Stress by fast pacing of isolated perfused TnT‐I79N hearts for 16 min elicited arrhythmias (63%) and caused the formation of hypoxic regions (14.1% of total tissue in I79N vs 2.6% in control, Hypoxyprobe) associated with focal cellular energy depletion (Connexin isoforms P0 and pT172‐AMP kinase both increased). The cause for the local energetic supply‐and‐demand mismatch is unclear and we tested if insufficient perfusion is at least in part responsible. Global coronary flow was not decreased in isolated TnT‐I79N hearts. To test if flow distribution was altered, we infused fluorescent 15 µm microspheres and compared the fraction of microspheres inside hypoxic areas with the fraction of hypoxic tissue. Microspheres inside hypoxic regions were drastically reduced, suggesting regional ischemia. These results were reproduced in control hearts treated with the Ca2+ sensitizing drug EMD57033. Next we tested if hypoxia also occurs naturally in TnT‐I79N mice in vivo. Despite expecting low sensitivity due to localized effects, the mRNA expression levels of genes up‐regulated by hypoxia (GLUT1, TUBB3) were increased (0.3fold, 3fold).We conclude that myofilament Ca2+ sensitization disturbs regulation of coronary flow and leads to focal ischemia and arrhythmias during stress. This suggests that myofilament properties of cardiomyocytes importantly contribute to local regulation of coronary flow.Grant Funding Source: supported by AHA 10SDG2640109 and NIH HL71670