The Role of Neuropeptide Y in Human Cardiac Hypertrophy after Myocardial Infarction

Background High levels of neuropeptide Y (NPY), a molecule co-released from cardiac sympathetic neurons, are associated with poor outcomes in myocardial infarction and heart failure. One possible reason for this might be cardiac remodelling triggered by NPY-induced changes in calcium handling—a mechanism which has not yet been explored in human models. Purpose To explore the link between NPY exposure and cardiac hypertrophy as well as the underlying cellular mechanisms in humans. Methods The relationship between peripheral venous NPY concentration and left ventricular (LV) mass was investigated in 35 patients recruited to the Oxford Acute Myocardial Infarction (OxAMI) study following ST-elevated myocardial infarction (STEMI). To isolate the effects of NPY on cardiomyocytes, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) were incubated with NPY for 48 hours. Some cells were additionally incubated with antagonists of the Y1 (1 μM BIBO3004), Y2 (1 μM BIIE0246) or Y5 (1 μM CGP71683) NPY receptors, or with inhibitors of CAMKII (1 μM KN93) or calcineurin (1 μM FK506). Cell size was assessed using confocal microscopy and pathological relevance by brain natriuretic peptide (BNP) immunoblotting. Optical mapping with Rhod-2 fluorescent dye was used to visualise hiPSC-CM calcium transients in response to NPY. Results In patients with STEMI, peripheral venous NPY levels were significantly correlated with the percentage increase in LV mass between 2 days and 6 months post-infarct (r = 0.35, p = 0.04) and with the absolute LV mass at 6 months, independent of age, sex, blood pressure and infarct size on multiple linear regression (p < 0.05). In vitro, NPY exposure produced a significant increase in hiPSC-CM size (at 1, 10 and 100 nM, p < 0.0001) as well as BNP expression, a marker of cardiac hypertrophy. This could be prevented by antagonists of NPY receptors. Inhibition of both CAMKII and calcineurin prevented hiPSC-CM enlargement in response to NPY (100 nM). A direct effect of NPY (100 nM) on calcium transient kinetics was observed in optical mapping experiments. Calcium entry and extrusion time—quantified by rise time, CTD-30 and CTD-90 (calcium transient duration at 30% and 90% decay of peak amplitude)—were significantly shortened (p < 0.01) which, again, could be reversed by antagonists of NPY receptors. Conclusions This study is the first to demonstrate an association between venous NPY levels and left ventricular hypertrophy after myocardial infarction independent of infarct size. Elevated intracellular calcium and subsequent activation of CAMKII and calcineurin might be driving cardiomyocyte enlargement secondary to NPY receptor activation. NPY receptor antagonists may therefore be potential targets to treat cardiac remodelling in patients after MI.