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

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.

Melatonin Prevents Early but Not Delayed Ventricular Fibrillation in the Experimental Porcine Model of Acute Ischemia

“…Activation of sympathetic system predisposes to ischemia-induced VF [ 22 , 23 ] that can be based on several mechanisms mediated by catecholamine-related [ 24 ] as well as neuropeptide Y-related [ 25 ] signaling. The proarrhythmic effects of sympathetic activation include facilitation of ectopic activity by abnormal automaticity and afterdepolarizations [ 26 , 27 , 28 , 29 ], increase in DOR [ 30 ] and inhomogeneous conduction [ 31 ].…”

Low-Frequency Oscillations in Cardiac Sympathetic Neuronal Activity

“…Alternatively, we speculate that in post-MI subjects with high mortality risk, increased amplitude of PRD oscillations might reflect a higher degree of synchronization among cardiac presympathetic and preganglionic neurons which would allow the recruitment of previously silent postganglionic fibers that innervate specific targets within the heart, such as the myocardium. This would result in the release of copious amounts of norepinephrine from the sympathetic terminals and perhaps the release of arrhythmogenic cotransmitters such as Neuropeptide Y (Kalla et al, 2019) which may ultimately precipitate profound periodic changes in ventricular repolarization.…”

Brain-Heart Afferent-Efferent Traffic

“…Optical mapping experiments in rats showed that NPY steepens the action potential duration restitution curve [86]. Very recently, in Langendorff-perfused rat hearts with intact innervation, Y1 receptor activation was associated with a significant reduction in ventricular fibrillation threshold despite metoprolol that was accompanied by increased amplitude and decreased duration of intracellular calcium transients [93]. Finally, NPY is also a potent vasoconstrictor [94].…”