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).
Mitochondrial integrity during early reperfusion in an isolated rat heart model of donation after circulatory death—consequences of ischemic duration
December 21, 2018
BACKGROUND: Cardioprotection and graft evaluation after ischemia-reperfusion (IR) are essential in facilitating heart transplantation with donation after circulatory death. Given the key role of mitochon- dria in IR, we aimed to investigate the tolerance of cardiac mitochondria to warm, global ischemia and to determine the predictive value of early reperfusion mitochondria-related parameters for post-ische- mic cardiac recovery.
METHODS: Isolated, working rat hearts underwent 0, 21, 24, 27, 30, or 33 minutes of warm, global ischemia, followed by 60 minutes of reperfusion. Functional recovery (developed pressure£heart rate) was determined at 60 minutes of reperfusion, whereas mitochondrial integrity was measured at 10 minutes of reperfusion.
RESULTS: Functional recovery at 60 minutes of reperfusion decreased with ≥ 27 minutes of ischemia vs no ischemia (n = 7−8/group; p < 0.01). Cytochrome c, succinate release, and mitochondrial Ca2+ con- tent increased with ≥ 27 minutes of ischemia vs no ischemia (p < 0.05). Ischemia at ≥ 21 minutes decreased mitochondrial coupling, adenosine 50-triphosphate content, mitochondrial Ca2+ retention capacity, and increased oxidative damage vs no ischemia (p < 0.05). Reactive oxygen species (ROS) from reverse electron transfer increased with 21 and 27 minutes of ischemia vs no ischemia and 33 minutes of ischemia (p < 0.05), whereas ROS from forward electron transfer increased only with 33 minutes of ischemia vs no ischemia (p < 0.05). Mitochondrial coupling and adenosine 50-triphosphate content correlated positively and cytochrome c, succinate, oxidative damage, and mitochondrial Ca2+ content correlated negatively with cardiac functional recovery (p < 0.05). CONCLUSIONS: Mitochondrial dysfunction occurs with shorter periods of ischemia than cardiac dys- function. Mitochondrial coupling, ROS emission from reverse electron transfer, and calcium retention are particularly sensitive to early reperfusion injury, reflecting potential targets for cardioprotection.
The Spleen in Myocardial Infarction
January 4, 2019
In the largely empirical, from a Western perspective nonscientific Traditional Chinese Medicine, spleen and heart are intimately related through meridians. Again on an empirical, observational level, splenectomy increases the mortality from acute myocardial infarction on long-term follow-up, as evidenced in World War II veterans.1 While the latter observation supports a cardioprotective role of the spleen, the disadvantage from splenectomy may also derive from secondary factors, such as increased hematocrit or increased susceptibility to infections.