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

• Published in: European heart journal Vol. 41; no. 23; pp. 2168 - 2179
• Main Authors: Kalla, Manish, Hao, Guoliang, Tapoulal, Nidi, Tomek, Jakub, Liu, Kun, Woodward, Lavinia, Dall’Armellina, Erica, Banning, Adrian P, Choudhury, Robin P, Neubauer, Stefan, Kharbanda, Rajesh K, Channon, Keith M, Ajijola, Olujimi A, Shivkumar, Kalyanam, Paterson, David J, Herring, Neil
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 14.06.2020
• Subjects: Animals; Clinical Research; Heart; Humans; Neuropeptide Y; Percutaneous Coronary Intervention; Rats; ST Elevation Myocardial Infarction; Ventricular Fibrillation; Neuropeptide Y; Myocardial infarction; Ventricular tachycardia; Percutaneous coronary intervention; Ventricular fibrillation
• ISSN: 0195-668X; 1522-9645; 1522-9645
• DOI: 10.1093/eurheartj/ehz852

Abstract 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.