IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria: guidelines of the EU-CARDIOPROTECTION COST Action

September 13, 2021

Sandrine Lecour, Ioanna Andreadou, Hans Erik Bøtker, Sean M Davidson, Gerd Heusch, Marisol Ruiz-Meana, Rainer Schulz, Coert J Zuurbier, Péter Ferdinandy, Derek J Hausenloy, on behalf of the European Union-CARDIOPROTECTION COST ACTION CA16225

Acute myocardial infarction (AMI) and the heart failure (HF) which may follow are among the leading causes of death and disability worldwide. As such, new therapeutic interventions are still needed to protect the heart against acute ischemia/reperfusion injury to reduce myocardial infarct size and prevent the onset of HF in patients presenting with AMI. However, the clinical translation of cardioprotective interventions that have proven to be beneficial in preclinical animal studies, has been challenging. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic in vivo preclinical assessment of the efficacy of promising cardioprotective interventions prior to their clinical evaluation. To address this, we propose an in vivo set of step-by-step criteria for IMproving Preclinical Assessment of Cardioprotective Therapies (‘IMPACT’), for investigators to consider adopting before embarking on clinical studies, the aim of which is to improve the likelihood of translating novel cardioprotective interventions into the clinical setting for patient benefit.

Implications of oxidative stress and redox biochemistry for heart disease and cardioprotection – Free Radical Biology and Medicine Special Issue with EU-CARDIOPROTECTION COST Action CA16225

July 12, 2021

Edited by Andreas Daiber, Rainer Schulz, Derek Hausenloy, Ioanne Andreadou

In this Special Issue, which is a collaboration with the EU-CARDIOPROTECTION COST Action (CA16225, we aim to highlight the redox biochemistry and oxidative stress underlying heart disease and cardioprotection as well as the existing research gaps. We will also emphasize emerging mechanisms impacting cardiac health and disease such as the circadian clock, the microbiome, epigenetic and neuronal/central pathways. Also therapeutic approaches and their impact on the redox biochemistry and oxidative stress of heart disease will be discussed in detail, including pre- and post- conditioning or physical exercise as non-drug-based therapies as well as modern cardiovascular drugs with pleiotropic antioxidant/anti-inflammatory properties. Special emphasis, although not exclusively, will be laid on the following points and how they are related to oxidative stress and redox biochemistry of heart disease:

(1) redox signalling in ischemia/reperfusion injury and heart failure
(2) discovery of new therapeutic targets and innovative strategies for cardioprotection against ischemia/reperfusion injury and heart failure
(3) testing the effects of combination therapy to target multiple signalling pathways both within and outside the cardiomyocyte
(4) investigating the effects of confounders (co-morbidities and co-medications) on cardioprotection.

Myocardial stunning and hibernation revisited

February 2, 2021

Gerd Heusch

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

Ioanna Andreadou

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

Ioanna Andreadou

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.

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