Myocardial stunning and hibernation revisited
February 2, 2021
Unlike acute myocardial infarction with reperfusion, in which infarct size is the end point reflecting irreversible injury, myocardial stunning and hibernation result from reversible myocardial ischaemia-reperfusion injury, and contractile dysfunction is the obvious end point. Stunned myocardium is characterized by a disproportionately long-lasting, yet fully reversible, contractile dysfunction that follows brief bouts of myocardial ischaemia. Reperfusion precipitates a burst of reactive oxygen species formation and alterations in excitation-contraction coupling, which interact and cause the contractile dysfunction. Hibernating myocardium is characterized by reduced regional contractile function and blood flow, which both recover after reperfusion or revascularization. Short-term myocardial hibernation is an adaptation of contractile function to the reduced blood flow such that energy and substrate metabolism recover during the ongoing ischaemia. Chronic myocardial hibernation is characterized by severe morphological alterations and altered expression of metabolic and pro-survival proteins. Myocardial stunning is observed clinically and must be recognized but is rarely haemodynamically compromising and does not require treatment. Myocardial hibernation is clinically identified with the use of imaging techniques, and the myocardium recovers after revascularization. Several trials in the past two decades have challenged the superiority of revascularization over medical therapy for symptomatic relief and prognosis in patients with chronic coronary syndromes. A better understanding of the pathophysiology of myocardial stunning and hibernation is important for a more precise indication of revascularization and its consequences. Therefore, this Review summarizes the current knowledge of the pathophysiology of these characteristic reperfusion phenomena and highlights their clinical implications.
Chronic Empaglifozin treatment reduces myocardial infarct size in non-diabetic mice through STAT-3 mediated protection on microvascular endothelial cells and reduction of oxidative stress.
April 16, 2020
Empagliflozin (EMPA) demonstrates cardioprotective effects on diabetic myocardium but its infarct sparing effects in normoglyceamia remain unspecified. We investigated the acute and chronic effect of EMPA on infarct size (IS) after ischemia-reperfusion injury (I/R) and the mechanisms of cardioprotection in non-diabetic mice.
Chronic oral administration of EMPA (6 weeks) reduced myocardial IS after 30min/2h I/R (29.5%±3.0 vs 45.8%±3.2 in the control group, p<0.01). Body weight, blood pressure, glucose levels and cardiac function remained unchanged between groups. Acute administration of EMPA 24h or 4h before I/R did not affect IS. Chronic EMPA treatment led to a significant reduction of oxidative stress biomarkers. STAT-3 was activated by Y(705) phosphorylation at the 10th min of R, but remained unchanged at 2h of R and in the acute administration protocols. Proteomic analysis was employed to investigate signaling intermediates and revealed that chronic EMPA treatment regulates several pathways at reperfusion including oxidative stress and integrin related proteins which were further evaluated. Superoxide dismutase and vascular endothelial growth factor were increased throughout reperfusion. EMPA pre-treatment (24h) increased the viability of Human Microvascular Endothelial Cells in normoxia and upon 3h hypoxia/1h reoxygenation and reduced reactive oxygen species production. In EMPA treated murine hearts, CD31/VEGFR2 positive endothelial cells and the pSTAT-3(Y705) signal derived from endothelial cells were boosted at early reperfusion. INNOVATION: Chronic EMPA administration reduces IS in healthy mice via STAT-3 pathway and increased survival of endothelial cells. CONCLUSION: Chronic but not acute administration of EMPA reduces IS through STAT-3 activation independently of diabetes mellitus.
SGLT2 inhibitors reduce infarct size in reperfused ischemic heart and improve cardiac function during ischemic episodes in preclinical models.
March 17, 2020
The sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of effective drugs managing patients, who suffer from type 2 diabetes (T2D): Landmark clinical trials including EMPA-REG, CANVAS and Declare-TIMI have demonstrated that SGLT2 inhibitors reduce cardiovascular mortality and re-hospitalization for heart failure (HF) in patients with T2D. It is well established that there is a strong independent relationship among infarct size measured within 1 month after reperfusion and all-cause death and hospitalization for HF: The fact that cardiovascular mortality was significantly reduced with the SGLT2 inhibitors, fuels the assumption that this class of therapies may attenuate myocardial infarct size. Experimental evidence demonstrates that SGLT2 inhibitors exert cardioprotective effects in animal models of acute myocardial infarction through improved function during the ischemic episode, reduction of infarct size and a subsequent attenuation of heart failure development. The aim of the present review is to outline the current state of preclinical research in terms of myocardial ischemia/reperfusion injury (I/R) and infarct size for clinically available SGLT2 inhibitors and summarize some of the proposed mechanisms of action (lowering intracellular Na+ and Ca2+, NHE inhibition, STAT3 and AMPK activation, CamKII inhibition, reduced inflammation and oxidative stress) that may contribute to the unexpected beneficial cardiovascular effects of this class of compounds.
Different signalling in infarcted and non-infarcted areas of rat failing hearts: A role of necroptosis and inflammation.
July 21, 2019
Necroptosis has been recognized in heart failure (HF). In this study, we investigated detailed necroptotic signalling in infarcted and non-infarcted areas separately and its mechanistic link with main features of HF. Post-infarction HF in rats was induced by left coronary occlusion (60 minutes) followed by 42-day reperfusion. Heart function was assessed echocardiographically. Molecular signalling and proposed mechanisms (oxidative stress, collagen deposition and inflammation) were investigated in whole hearts and in subcellular fractions when appropriate. In post-infarction failing hearts, TNF and pSer229-RIP3 levels were comparably increased in both infarcted and non-infarcted areas. Its cytotoxic downstream molecule p-MLKL, indicating necroptosis execution, was detected in infarcted area. In non-infarcted area, despite increased pSer229-RIP3, p-MLKL was present in neither whole cells nor the cell membrane known to be associated with necroptosis execution. Likewise, increased membrane lipoperoxidation and NOX2 levels unlikely promoted pro-necroptotic environment in non-infarcted area. Collagen deposition and the inflammatory csp-1-IL-1β axis were active in both areas of failing hearts, while being more pronounced in infarcted tissue. Although apoptotic proteins were differently expressed in infarcted and non-infarcted tissue, apoptosis was found to play an insignificant role. p-MLKL-driven necroptosis and inflammation while inflammation only (without necroptotic cell death) seem to underlie fibrotic healing and progressive injury in infarcted and non-infarcted areas of failing hearts, respectively. Upregulation of pSer229-RIP3 in both HF areas suggests that this kinase, associated with both necroptosis and inflammation, is likely to play a dual role in HF progression.
Translating Cardioprotection for Patient Benefit
April 15, 2019
Derek J. Hausenloy , Gerd Heusch
Acute myocardial infarction and the subsequent development of heart failure are among the leading causes of death and disability globally. The most effective treatment for limiting infarct size and preventing subsequent heart failure is timely interventional or surgical reperfusion, but even then, mortality and morbidity remain significant (1). Accordingly, new treatments are required, but the translation of adjunct cardioprotection to clinical practice has been largely disappointing so far (2). Reasons for such poor translation and novel strategies are addressed in the ongoing European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action (CA16225).