Pro-arrhythmic effects of the cardiac sympathetic co-transmitter, neuropeptide-Y, during ischemia-reperfusion and ST elevation myocardial infarction

Beta-blockers are the only anti-arrhythmic drugs that improve mortality post myocardial infarction (MI), but a significant risk of ventricular arrhythmia remains. We have shown that ventricular fibrillation threshold is reduced following high-level sympathetic stimulation even in the presence of a beta-blocker due to release of the sympathetic co-transmitter neuropeptide-Y (NPY). We hypothesized that exogenous NPY would increase the prevalence of ventricular arrhythmias following ischemia reperfusion in the isolated rat heart. Moreover, we hypothesized that plasma NPY levels would correlate with ventricular arrhythmias following primary percutaneous intervention (PPCI) in patients being treated for ST-elevation MI (STEMI). In the isolated Langendorff perfused (10ml/min) rat heart NPY (250nM, n=10) significantly increased the prevalence of ventricular arrhythmias (90% v’s 20%, p<0.01) following 7 minutes of no flow ischemia compared to control (n=10), and also their severity as measured by arrhythmia scoring (2.0±0.4 v’s 0.3±0.2, mean±SEM, p<0.01). In 55 patients presenting with left coronary artery STEMI for PPCI, those with venous plasma NPY levels taken immediately post PPCI above the median (>19 pg/ml) were significantly older (68.0±2.2 v’s 58.2±2.5 year old, p<0.01) but had similar cardiovascular risk factors, peak troponin rise and beta-blocker usage. There was no difference in ejection fraction measured on cardiac MRI after 24 hours (45.3±2.1 v’s 46.3±1.9%, n=39) and 6 months (51.8±2.6 v’s 55.0±2.9%, n=34) post STEMI between the two groups, and no difference in infarct size (20.4±2.8 v’s 17.2±2.6% late Gd enhancement at 6 months). However, over the course of the coronary care unit admission following PPCI, those with NPY levels above the median had a higher prevalence (53.6% v’s 25.9%, p=0.03) and a higher severity of ventricular arrhythmias (score: 0.96±0.23 v’s 0.33±0.12, p=0.02). NPY may be a novel arrhythmic trigger during ischemia reperfusion and drugs inhibiting NPY or NPY receptors may offer a potential therapeutic opportunity.