Neuronal Nitric Oxide Synthase Protects Against Myocardial Infarction–Induced Ventricular Arrhythmia and Mortality in Mice

Ventricular arrhythmia is a common cause of death after myocardial infarction (MI). Cardiomyocyte Ca 2 (cid:1) overload and diastolic Ca 2 (cid:1) leak are important mechanisms responsible for afterdepolarization and triggered activity leading to ventricular arrhythmia after MI. Emerging evidence suggests that neuronal nitric oxide synthase (nNOS) may inhibit arrhythmogenesis by maintaining intracellular Ca 2 (cid:1) homeostasis in cardiomyocytes. However, the role of nNOS in ventricular arrhythmia after MI in vivo is not clear. In the present study, we demonstrated that nNOS deletion was associated with increased mortality, reactive oxygen species production, and apopto-sis after MI. A novel finding from our study is that ventricular arrhythmias were significantly higher in nNOS (cid:2) / (cid:2) compared with wild-type mice after MI. Deficiency in nNOS increased Ca 2 (cid:1) transient amplitude and L-type Ca 2 (cid:1) channel activity and increased diastolic Ca 2 (cid:1) levels in cardiomyocytes. Lack of nNOS decreased S -nitrosylation of the L-type Ca 2 (cid:1) channel, ryanodine receptor Ca 2 (cid:1) release channel, and SERCA2 in the myocardium after MI. Thus, nNOS has a beneficial role in Ca 2 (cid:1) homeostasis via S -nitrosylation of Ca 2 (cid:1) handling proteins, leading to reductions in ventricular arrhythmias and death after MI. Our study provides new insights into the protective role of nNOS in arrhythmogenesis and may have therapeutic implications after MI. See p 1345. diabetes mellitus, the effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on left ventricular (LV) hypertrophy (LVH) is unknown. In the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET), patients at high vascular risk and tolerant of angiotensin-converting enzyme inhibitors were randomly assigned to ramipril, telmisartan, or their combination. In the Telmisartan Randomized Assessment Study in that RevPD and LGE imaging in a single CMR study can provide complementary prognostic values for major adverse events, including cardiac death or nonfatal myocardial infarction (MI). Although RevPD and LGE both demonstrated strong unadjusted association with death/MI (hazard ratio, 6.88 and 5.32, respectively; both P (cid:4) 0.0001), robust association with death/MI by RevPD and LGE was maintained when the effects of these variables were adjusted for each other and for patient age and gender. In patients without a history of MI who were found to have no RevPD, the presence of LGE portended a (cid:5) 11-fold hazards increase in death/MI. We found that patients with both RevPD and LGE absent had the most favorable annual negative event rate for death/MI at (cid:5) 98%. We therefore conclude that CMR stress myocardial perfusion and LGE imaging performed in a CMR study provide complementary prognostic implication for cardiac death or acute nonfatal MI. See p 1390. neurologically intact survival. Most of the out-of-hospital cardiac arrests are due to ischemic complications of coronary artery disease. We investigated the effects of intra–cardiopulmonary resuscitation hypothermia with and without volume loading on resuscitation rates and infarction size in a porcine ischemia/reperfusion model (left anterior descending artery occlusion) of cardiac arrest and resuscitation. The findings of this study suggest that intra–cardiopulmonary resuscitation hypothermia can limit the size of myocardial infarction and improve postresuscitation cardiac function. Compared with hypothermia achieved with infusion of cold saline, application of hypothermia with an intravascular device without loading improved resuscitation rates and postresuscitation LV function and further limited the size of myocardial infarction. It also appears that faster cooling improves protection against myocardial infarction. An intravascular device that can be readily in the field does not currently exist. On the basis of this study, methods to achieve fast and effective hypothermia without volume loading should improve the effect of early application of this therapy during cardiopulmonary resuscitation and warrant further investigation. p 1426.