Rapid fall in circulating non-classical monocytes in ST elevation myocardial infarction patients correlates with cardiac injury

ObjectiveMyocardial infarction leads to a rapid innate immune response that is ultimately required for repair of damaged heart tissue. We therefore examined circulating monocyte dynamics immediately after reperfusion of the culprit coronary vessel in STEMI patients to determine whether this correlated with level of cardiac injury. A mouse model of cardiac ischaemia/reperfusion injury was subsequently used to establish the degree of monocyte margination to the coronary vasculature that could potentially contribute to the drop in circulating monocytes.Approach and ResultsWe retrospectively analysed blood samples from 51 STEMI patients to assess the number of non-classical (NC), classical and intermediate monocytes immediately following primary percutaneous coronary intervention. Classical and intermediate monocytes showed minimal change. On the other hand circulating numbers of NC monocytes fell by approximately 50% at 90 minutes post-reperfusion. This rapid decrease in NC monocytes was greatest in patients with the largest infarct size (p<0.05) and correlated inversely with left ventricular function (r=0.41, p=0.04). The early fall in NC monocytes post reperfusion was confirmed in a second prospective study of 13 STEMI patients. Furthermore, in a mouse cardiac ischaemia model, there was significant monocyte adhesion to coronary vessel endothelium at 2 hours post-reperfusion pointing to a specific and rapid vessel margination response to cardiac injury.ConclusionsRapid depletion of NC monocytes from the circulation in STEMI patients following coronary artery reperfusion correlates with the level of acute cardiac injury and involves rapid margination to the coronary vasculature.Graphical AbstractHighlights3-5 bullet points that summarize the major findings of the study.Circulating non classical monocytes show a rapid fall in STEMI patients within 90 minutes of re-opening the culprit coronary artery.The extent of the drop in non classical monocytes correlates with loss of cardiac function and increased infarct size.A mouse model of cardiac ischaemia and reperfusion shows rapid margination of monocytes to the coronary vasculature

Prognostic benefit of nonemergent revascularization on ischaemic dilated cardiomyopathy depending on patient symptoms

Funding Acknowledgements Type of funding sources: None. INTRODUCTION Both angina and dyspnea symptoms are the most common clinical manifestations of cardiac ischaemia. Nevertheless, cardiac ischaemia may be detected on control functional tests of patients with ischaemic dilated cardiomyopathy despite being asymptomatic. The aim of this study was to assess the effect of elective myocardial revascularization on patient’s prognosis depending on baseline clinical symptoms. METHODS All consecutive patients with ischaemic left ventricular dysfunction (LVEF &lt;40% determined by gated-SPECT) who underwent stress-rest SPECT in our hospital between January 2010 and February 2018 were included. Baseline patients’ clinical presentation (angor pectoris, dyspnea or asymptomatic) and major adverse events (myocardial infarction, heart failure hospitalization and cardiovascular death) were retrospective recorded. RESULTS A total of 748 patients with multiple comorbid conditions (smoking habit 69%, hypertension 78,7%, diabetes mellitus 49,5%, atrial fibrillation 22,1%, previous myocardial infarction 69% and previous heart failure hospitalization 24,9%) were included. Nonemergent coronary intervention during the first year (17,9% of patients) was associated with a reduction in the composite event (HR 0.69 [0.5-0.95]) but the multivariate analysis showed a prognostic benefit of revascularization in symptomatic patients (HR = 0.59 [0.37 - 0.94]) that was not observed among asymptomatic patients. The relative risk of the composite endpoint was RR = 0.63 (p &lt;0.001) for asymptomatic vs. symptomatic non-revascularized patients and RR = 1.09 (p = 0.60) for asymptomatic vs. symptomatic revascularized patients. Finally, asymptomatic patients presented more necrosis (17.3 vs. 20.2%, p &lt;0.01) and less ischemia (9.7 vs. 5.7%, p &lt;0.001) than symptomatic patients. CONCLUSION Patients with ischaemic dilated cardiomyopathy without symptoms of dyspnea or angina present less ischaemia and more necrosis in stress-rest SPECT than symptomatic patients. Moreover, unlike symptomatic patients, asymptomatic patients do not benefit from elective revascularization. Therefore, the clinical presentation should be considered when deciding revascularization of patients with ischaemic dilated cardiomyopathy and a positive SPECT test. Abstract Figure. Kaplan-Meyer curves

Melatonin membrane receptor 2 activation is a key determinant for melatonin-mediated cardioprotection in cardiac ischaemia-reperfusion injury

Background Cardiac ischaemia/reperfusion (I/R) injury has been an economic and health burden worldwide. Previous studies have reported the beneficial effects of melatonin when given prior to cardiac ischaemia in animals with cardiac I/R injury. However, the effects of melatonin on the hearts when it is given after ischaemia or at the onset of reperfusion, which is more relevant to the clinical setting, is not known. Moreover, the mechanisms responsible for the potential benefits of melatonin and the roles of melatonin receptors on the heart during cardiac I/R injury have not been fully investigated. Purpose We tested the hypothesis that in rats with cardiac I/R injury, melatonin exerts cardioprotective effects even when it is given after ischaemia via an activation of both melatonin receptors 1 (MT1) and 2 (MT2), leading to decreased mitochondrial dysfunction, mitochondrial dynamics imbalance, excessive mitophagy, cardiomyocyte death and finally resulting in decreased infarct size and improved left ventricular (LV) function. Methods Male Wistar rats were subjected to cardiac I/R (30 min of LAD ligation and 120 min of reperfusion). These rats were divided into 4 interventions (n=12/group) including vehicle, pretreatment with melatonin, melatonin treatment during ischaemia, or at the onset of reperfusion. Melatonin was given to the rats at the dose of 10 mg/kg via intravenous injection. In addition, either a non-specific melatonin receptor blocker (Luzindole) or specific MT2 blocker (4-PPDOT) at 1 mg/kg was given intravenously to 2 additional sets of rats (n=12/set) prior to melatonin and cardiac I/R induction. At the end of cardiac I/R, infarct size, LV function, and molecular mechanisms were determined. Furthermore, in vitro experiment was conducted in MT1 or MT2 silenced H9C2 cell with hypoxia/reoxygenation (H/R) to investigate the mechanism underlying cardioprotective effects of melatonin during cardiac I/R. Results Rats in all melatonin-treated groups had similarly reduced cardiac I/R injury as indicated by reduced infarct size (Fig. 1A), arrhythmia score. Melatonin-treated rats also had decreased mitochondrial ROS production, mitochondrial depolarization and swelling, decreased p-Drp1/Drp1 ratio (Fig. 1B) and increased Mfn1, Mfn2, and OPA1, and decreased apoptosis, leading to increased %LVEF. Luzindole and 4-PPDOT abolished these protective effects of melatonin (Fig. 1A). In in vitro study, melatonin increased %cell viability (Fig. 1C), reduced mitochondrial dynamics imbalance and cardiomyocyte apoptosis in H9C2 cells with H/R. However, these beneficial effects of melatonin were abrogated only in MT2 silenced H9C2 cell with H/R. Conclusion Melatonin exerted both preventive and treatment effects in reducing cardiac I/R injury. Its cardioprotective effects were dependent upon the activation of MT2 receptor. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Science and Technology Development Agency of Thailand

Metformin exerts cardioprotection via attenuating mitochondrial fission in cardiac ischaemia-reperfusion injury in rats

Background Cardiac ischemia/reperfusion (I/R) injury following myocardial infarction reperfusion therapy is a phenomenon that results in further cardiomyocytes death and impaired cardiac contractility. Although metformin has been shown to exert cardioprotection in addition to glycemic control, its effect on cardiac I/R injury are still controversy, and the comparative doses of metformin in cardiac I/R injury have never been investigated. Purpose We hypothesized that metformin given acutely prior to cardiac ischaemia exerts cardioprotection in rats with cardiac I/R injury via attenuating cardiac mitochondrial dysfunction, leading to improved left ventricular (LV) function. Methods Forty Male Wistar rats were subjected to cardiac I/R injury. Four treatment groups were investigated. The first group received saline as a control group. The second to the fourth groups received metformin at 100, 200, and 400 mg/kg intravenously, respectively. During the I/R protocols, the LV function, arrhythmia score, and mortality rate were determined. At the end, the hearts were rapidly removed to determine infarct size, cardiac mitochondrial function, cardiac mitochondrial dynamics, and cardiac apoptosis. Results Metformin 200 mg/kg exerted the highest level of cardioprotection through the attenuated incidence of arrhythmia, decreased infarct size (Fig. 1), improved cardiac mitochondrial function, and decreased mitochondrial fission (Fig. 1) and cardiac apoptotic markers, leading to improved cardiac function during I/R injury. Although Metformin at all doses effectively decreased infarct size, improved cardiac mitochondrial function and LV function, Metformin at 200 mg/kg exerted the best efficacy (Fig. 1). Conclusions Metformin exerts cardioprotection by attenuating mitochondrial dysfunction and decreased mitochondrial fission, leading to decreased infarct size and ultimately improved LV function after acute cardiac I/R injury in rats. These findings also indicate the potential biphasic effects of metformin on infarct size which are dose-dependent. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Science and Technology Development Agency Thailand (NC), and Thailand Research Fund (SCC)