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.
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.
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.
Background. Conventional coronary artery bypass surgery is associated with postoperative pulmonary dysfunction. Inflammation due to cardiopulmonary bypass has been regarded as one of the main causes. ...In this study, we investigated the effect of coronary revascularization with or without cardiopulmonary bypass on pulmonary function.
Methods. Fifty-two patients (40 male, mean age 60.1 years) were prospectively randomized to undergo coronary revascularization via median sternotomy, with or without normothermic cardiopulmonary bypass. Alveolar-arterial oxygen gradients were measured before and after induction of anesthesia, postoperatively in the intensive care unit during mechanical ventilation and 6 hours after tracheal extubation. The techniques of anesthesia and mechanical ventilation were standardized throughout.
Results. Patient characteristics were similar in the two groups. The alveolar-arterial oxygen gradients increased progressively throughout the perioperative period, with no significant differences in the two groups at any time during the study.
Conclusions. Myocardial revascularization with or without cardiopulmonary bypass caused a similar degree of pulmonary dysfunction, as assessed by alveolar-arterial oxygen gradient. Our study suggests that the deterioration in pulmonary gas exchange associated with cardiac surgery is due to factors other than the use of cardiopulmonary bypass.
Abstract
Aims
Succinate accumulates several-fold in the ischaemic heart and is then rapidly oxidized upon reperfusion, contributing to reactive oxygen species production by mitochondria. In ...addition, a significant amount of the accumulated succinate is released from the heart into the circulation at reperfusion, potentially activating the G-protein-coupled succinate receptor (SUCNR1). However, the factors that determine the proportion of succinate oxidation or release, and the mechanism of this release, are not known.
Methods and results
To address these questions, we assessed the fate of accumulated succinate upon reperfusion of anoxic cardiomyocytes, and of the ischaemic heart both ex vivo and in vivo. The release of accumulated succinate was selective and was enhanced by acidification of the intracellular milieu. Furthermore, pharmacological inhibition, or haploinsufficiency of the monocarboxylate transporter 1 (MCT1) significantly decreased succinate efflux from the reperfused heart.
Conclusion
Succinate release upon reperfusion of the ischaemic heart is mediated by MCT1 and is facilitated by the acidification of the myocardium during ischaemia. These findings will allow the signalling interaction between succinate released from reperfused ischaemic myocardium and SUCNR1 to be explored.
Autoregulation is compromised in patients with coronary heart disease. A lack of myogenic reactivity and endothelial dysfunction each contribute to a reduced ability to control blood flow within the ...coronary microcirculation. Little is known how coronary arterial smooth muscle structure and phenotype links to vascular reactivity.
Right atrial appendage biopsies from consented patients undergoing valve replacement surgery, and from pigs were collected at clinical standards under general anesthesia. Human and porcine arteries from right atrial appendage samples were isolated and mounted for pressure myography. Confocal imaging established vasomotor responses, cellular viability, and immunohistochemical localization of proteins. The human study complies with the Helsinki Declaration and the animal study complies with the UK Animal (Scientific Procedures) Act, 1986.
Here, we compared the structural features of human patient intra‐myocardial coronary arteries (IMCAs) with equivalently handled porcine IMCAs, representing healthy, juvenile controls. More than half the human IMCAs failed to develop ≥10% myogenic tone, even those in which constituent smooth muscle cells (SMCs) could adequately mobilize intracellular Ca2+required for contraction. 3D confocal revealed a novel, distinct layer of longitudinally‐arranged sub‐intimal SMCs (l‐SMCs) between the endothelium and the expected circumferentially‐arranged SMCs responsible for radial contraction (r‐SMC) in the majority of human and porcine IMCAs.
Contractile function strongly correlated with SMC phenotype, with the synthetic markers L‐caldesmon and vimentin highly expressed in SMCs with poor contractile function, namely the human r‐SMCs and the porcine l‐SMCs. Thus, we propose that l‐SMCs retain an immature, synthetic phenotype in healthy vessels with functional r‐SMCs but, with loss of r‐SMC function in aged patients, l‐SMCs may play a reparative role and can adopt a contractile phenotype in an attempt to restore function and control myocardial perfusion. The role of l‐SMCs in maintaining the integrity of arterial function warrants further investigation.
Support or Funding Information
This work was supported by the British Heart Foundation (grant numbers FS/08/033/25111, FS/13/16/30199, IG/13/5/30431, PG/18/11/33552) and by the Oxford BHF Centre of Research Excellence (RE/13/1/30181).
This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A new class of nitric oxide donating aspirin (NO-ASA) drugs may increase the therapeutic impact of aspirin in saphenous vein coronary artery bypass grafting (CABG) not only through the inhibition of ...thrombosis but also through a reduction of vasospasm and inhibition of vascular smooth muscle cell (VSMC) proliferation (effects that are inhibited by NO but not ASA). In order to test this proposal the effect of three NO-ASA drugs (NCX 4040, NCX4050, and NCX4060) on in vitro relaxation and cyclic guanosine monophosphate (cGMP) formation in the human isolated saphenous vein and the proliferation of human VSMCs was investigated.
Saphenous vein segments were obtained from 30 patients undergoing CABG (median age, 59 years; range, 49 to 68). The effect of the NO-ASA adducts, ASA alone, and sodium nitroprusside (NO donor) were investigated on (1) relaxation of phenylephrine-stimulated contraction using an organ bath, (2) cyclic guanosine monophosphate (cGMP) formation using an enzyme-linked immunosorbent assay, and (3) the proliferation of VSMCs derived from saphenous vein using bromo-deoxyuridine (BRDU) incorporation.
All three NO-ASA adducts (at concentrations that inhibited responses by 50% IC
50s between 1 μmol/L and 100 μmol/L) and nitroprusside (at IC
50s between 0.5 and 10 μmol/L) elicited relaxation of isolated human saphenous vein, promoted cGMP formation, and inhibited VSMC proliferation whereas ASA alone (up to 100 μmol/L) had no effect on any variable.
These data indicate that the NO-ASA adducts by virtue of their capacity to release NO and stimulate guanylyl cyclase may be useful not only in the prevention of thrombosis following CABG but also the reduction of saphenous vein graft spasm and neointima formation.
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