Neuropeptide-Y causes coronary microvascular constriction and is associated with reduced ejection fraction following ST-elevation myocardial infarction

Aims: The co-transmitter neuropeptide-Y (NPY) is released during high sympathetic drive, including ST-elevation myocardial infarction (STEMI), and can be a potent vasoconstrictor. We hypothesized that myocardial NPY levels correlate with reperfusion and subsequent recovery following primary percutaneous coronary intervention (PPCI), and sought to determine if and how NPY constricts the coronary microvasculature. Methods and results: Peripheral venous NPY levels were significantly higher in patients with STEMI (n = 45) compared to acute coronary syndromes/stable angina ( n = 48) or with normal coronary arteries (NC, n = 16). Overall coronary sinus (CS) and peripheral venous NPY levels were significantly positively correlated (r = 0.79). STEMI patients with the highest CS NPY levels had significantly lower coronary flow reserve, and higher index of microvascular resistance measured with a coronary flow wire. After 2 days they also had significantly higher levels of myocardial oedema and microvascular obstruction on cardiac magnetic resonance imaging, and significantly lower ejection fractions and ventricular dilatation 6 months later. NPY (100–250 nM) caused significant vasoconstriction of rat microvascular coronary arteries via increasing vascular smooth muscle calcium waves, and also significantly increased coronary vascular resistance and infarct size in Langendorff hearts. These effects were blocked by the Y1 receptor antagonist BIBO3304 (1 μM). Immunohistochemistry of the human coronary microvasculature demonstrated the presence of vascular smooth muscle Y1 receptors. Conclusion: High CS NPY levels immediately after reperfusion correlate with microvascular dysfunction, greater myocardial injury, and reduced ejection fraction 6 months after STEMI. NPY constricts the coronary microcirculation via the Y1 receptor, and antagonists may be a useful PPCI adjunct therapy

The role of neuropeptide Y in cardiovascular health and disease

Neuropeptide Y (NPY) is an abundant sympathetic co-transmitter, widely found in the central and peripheral nervous systems and with diverse roles in multiple physiological processes. In the cardiovascular system it is found in neurons supplying the vasculature, cardiomyocytes and endocardium, and is involved in physiological processes including vasoconstriction, cardiac remodeling, and angiogenesis. It is increasingly also implicated in cardiovascular disease pathogenesis, including hypertension, atherosclerosis, ischemia/infarction, arrhythmia, and heart failure. This review will focus on the physiological and pathogenic role of NPY in the cardiovascular system. After summarizing the NPY receptors which predominantly mediate cardiovascular actions, along with their signaling pathways, individual disease processes will be considered. A thorough understanding of these roles may allow therapeutic targeting of NPY and its receptors

The cardiac sympathetic co-transmitter neuropeptide Y is pro-arrhythmic following ST-elevation myocardial infarction despite beta-blockade

AIMS:ST-elevation myocardial infarction is associated with high levels of cardiac sympathetic drive and release of the co-transmitter neuropeptide Y (NPY). We hypothesized that despite beta-blockade, NPY promotes arrhythmogenesis via ventricular myocyte receptors. METHODS AND RESULTS:In 78 patients treated with primary percutaneous coronary intervention, sustained ventricular tachycardia (VT) or fibrillation (VF) occurred in 6 (7.7%) within 48 h. These patients had significantly (P < 0.05) higher venous NPY levels despite the absence of classical risk factors including late presentation, larger infarct size, and beta-blocker usage. Receiver operating curve identified an NPY threshold of 27.3 pg/mL with a sensitivity of 0.83 and a specificity of 0.71. RT-qPCR demonstrated the presence of NPY mRNA in both human and rat stellate ganglia. In the isolated Langendorff perfused rat heart, prolonged (10 Hz, 2 min) stimulation of the stellate ganglia caused significant NPY release. Despite maximal beta-blockade with metoprolol (10 μmol/L), optical mapping of ventricular voltage and calcium (using RH237 and Rhod2) demonstrated an increase in magnitude and shortening in duration of the calcium transient and a significant lowering of ventricular fibrillation threshold. These effects were prevented by the Y1 receptor antagonist BIBO3304 (1 μmol/L). Neuropeptide Y (250 nmol/L) significantly increased the incidence of VT/VF (60% vs. 10%) during experimental ST-elevation ischaemia and reperfusion compared to control, and this could also be prevented by BIBO3304. CONCLUSIONS:The co-transmitter NPY is released during sympathetic stimulation and acts as a novel arrhythmic trigger. Drugs inhibiting the Y1 receptor work synergistically with beta-blockade as a new anti-arrhythmic therapy