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Despite the increasing use and success of interventional coronary reperfusion strategies, morbidity and mortality from acute myocardial infarction are still substantial. Myocardial infarct size is a major determinant of prognosis in these patients. Therefore, cardioprotective strategies aim to reduce infarct size. However, a perplexing gap exists between the many preclinical studies reporting infarct size reduction with mechanical and pharmacological interventions and the poor translation into better clinical outcomes in patients. This Review revisits the pathophysiology of myocardial ischaemia–reperfusion injury, including the role of autophagy and forms of cell death such as necrosis, apoptosis, necroptosis and pyroptosis. Other cellular compartments in addition to cardiomyocytes are addressed, notably the coronary microcirculation. Preclinical and clinical research developments in mechanical and pharmacological approaches to induce cardioprotection, and their signal transduction pathways, are discussed. Additive cardioprotective interventions are advocated. For clinical translation into treatments for patients with acute myocardial infarction, who typically are of advanced age, have comorbidities and are receiving several medications, not only infarct size reduction but also attenuation of coronary microvascular obstruction, as well as longer-term targets including infarct repair and reverse remodelling, must be considered to improve patient outcomes. Future clinical trials must focus on patients who really need adjunct cardioprotection, that is, those with severe haemodynamic alterations.In this Review, Gerd Heusch revisits the pathophysiology of myocardial ischaemia–reperfusion injury, discusses the latest developments in cardioprotective interventions and the signalling pathways involved, identifies the challenges for their clinical translation and advocates the use of additive cardioprotective interventions and a focus on patients with severe haemodynamic alterations.

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.In this Review, Heusch summarizes the pathophysiology of myocardial stunning and hibernation and highlights potential treatments and clinical implications. A better understanding of these characteristic reperfusion phenomena is important for the potential indication for revascularization and its consequences in patients with chronic coronary syndromes.

Myocardial infarct size is a major determinant of prognosis. Ischaemic preconditioning with brief coronary occlusion and reperfusion before a sustained period of coronary occlusion with reperfusion delays infarct development. Ischaemic postconditioning uses repetitive brief coronary occlusion during early reperfusion of myocardial infarction and reduces infarct size. Remote ischaemic preconditioning uses brief ischaemia and reperfusion of a distant organ to protect the myocardium. These conditioning protocols recruit a complex signal cascade of sarcolemmal receptor activation, intracellular enzyme activation, and ultimately mitochondrial stabilisation and inhibition of death signalling. Conditioning protocols have been successfully used in patients undergoing elective coronary revascularisation and reperfusion after acute myocardial infarction. Pharmacological recruitment of cardioprotective signalling has also been used to reduce infarct size, but so far without prognostic benefit. Outcomes of cardioprotection are affected by age, sex, comorbidities, and drugs, but also by technical issues related to determination of infarct size and revascularisation procedure.

Heart failure is a clinical syndrome where cardiac output is not sufficient to sustain adequate perfusion and normal bodily functions, initially during exercise and in more severe forms also at rest. The two most frequent forms are heart failure of ischemic origin and of non-ischemic origin. In heart failure of ischemic origin, reduced coronary blood flow is causal to cardiac contractile dysfunction, and this is true for stunned and hibernating myocardium, coronary microembolization, myocardial infarction and post-infarct remodeling, possibly also for the takotsubo syndrome. The most frequent form of non-ischemic heart failure is dilated cardiomyopathy, caused by genetic mutations, myocarditis, toxic agents or sustained tachyarrhythmias, where alterations in coronary blood flow result from and contribute to cardiac contractile dysfunction. Hypertrophic cardiomyopathy is caused by genetic mutations but can also result from increased pressure and volume overload (hypertension, valve disease). Heart failure with preserved ejection fraction is characterized by pronounced coronary microvascular dysfunction, the causal contribution of which is however not clear. The present review characterizes the alterations of coronary blood flow which are causes or consequences of heart failure in its different manifestations. Apart from any potentially accompanying coronary atherosclerosis, all heart failure entities share common features of impaired coronary blood flow, but to a different extent: enhanced extravascular compression, impaired nitric oxide-mediated, endothelium-dependent vasodilation and enhanced vasoconstriction to mediators of neurohumoral activation. Impaired coronary blood flow contributes to the progression of heart failure and is thus a valid target for established and novel treatment regimens.

Cardioprotection aims at infarct size reduction and improvement of clinical outcome from myocardial infarction. The translation of cardioprotection from preclinical and promising proof-of-concept studies to clinical benefit for patients has been largely disappointing. Almost all of these studies which did not translate into clinical benefit had infarct size reduction as the primary endpoint and used protocols selected to achieve infarct size reduction. The present review puts forward the hypothesis that the coronary circulation is a so far neglected target of cardioprotection. Mechanisms of ischemia–reperfusion injury to the coronary circulation are detailed. Clinical methods and measures to assess coronary microvascular impairment in reperfused acute myocardial infarction are presented. A comparison of magnetic resonance imaging data on infarct size vs. coronary microvascular obstruction is made. Finally, the design of studies which are optimized not only for infarct size reduction but also for salvage of the coronary microcirculation is advocated.

Remodelling is a response of the myocardium and vasculature to a range of potentially noxious haemodynamic, metabolic, and inflammatory stimuli. Remodelling is initially functional, compensatory, and adaptive but, when sustained, progresses to structural changes that become self-perpetuating and pathogenic. Remodelling involves responses not only of the cardiomyocytes, endothelium, and vascular smooth muscle cells, but also of interstitial cells and matrix. In this Review we characterise the remodelling processes in atherosclerosis, vascular and myocardial ischaemia–reperfusion injury, and heart failure, and we draw attention to potential avenues for innovative therapeutic approaches, including conditioning and metabolic strategies.

Myocardial ischaemia results from coronary macrovascular or microvascular dysfunction compromising the supply of oxygen and nutrients to the myocardium. The underlying pathophysiological processes are manifold and encompass atherosclerosis of epicardial coronary arteries, vasospasm of large or small vessels and microvascular dysfunction — the clinical relevance of which is increasingly being appreciated. Myocardial ischaemia can have a broad spectrum of clinical manifestations, together denoted as chronic coronary syndromes. The most common antianginal medications relieve symptoms by eliciting coronary vasodilatation and modulating the determinants of myocardial oxygen consumption, that is, heart rate, myocardial wall stress and ventricular contractility. In addition, cardiac substrate metabolism can be altered to alleviate ischaemia by modulating the efficiency of myocardial oxygen use. Although a universal agreement exists on the prognostic importance of lifestyle interventions and event prevention with aspirin and statin therapy, the optimal antianginal treatment for patients with chronic coronary syndromes is less well defined. The 2019 guidelines of the ESC recommend a personalized approach, in which antianginal medications are tailored towards an individual patient’s comorbidities and haemodynamic profile. Although no antianginal medication improves survival, their efficacy for reducing symptoms profoundly depends on the underlying mechanism of the angina. In this Review, we provide clinicians with a rationale for when to use which compound or combination of drugs on the basis of the pathophysiology of the angina and the mode of action of antianginal medications.In this Review, Maack and colleagues discuss the pathophysiology of angina in the context of the underlying cardiovascular condition as well as the modes of action of antianginal drugs to provide the clinician with a rationale and compass of when to use which compound or combination of drugs.

The signal transducer and activator of transcription 3 (STAT3) contributes to cardioprotection by ischemic pre- and postconditioning. Mitochondria are central elements of cardioprotective signaling, most likely by delaying mitochondrial permeability transition pore (MPTP) opening, and STAT3 has recently been identified in mitochondria. We now characterized the mitochondrial localization of STAT3 and its impact on respiration and MPTP opening. STAT3 was mainly present in the matrix of subsarcolemmal and interfibrillar cardiomyocyte mitochondria. STAT1, but not STAT5 was also detected in mitochondria under physiological conditions. ADP-stimulated respiration was reduced in mitochondria from mice with a cardiomyocyte-specific deletion of STAT3 (STAT3-KO) versus wildtypes and in rat mitochondria treated with the STAT3 inhibitor Stattic (STAT3 inhibitory compound, 6-Nitrobenzo[b]thiophene 1,1-dioxide). Mitochondria from STAT3-KO mice and Stattic-treated rat mitochondria tolerated less calcium until MPTP opening occurred. STAT3 co-immunoprecipitated with cyclophilin D, the target of the cardioprotective agent and MPTP inhibitor cyclosporine A (CsA). However, CsA reduced infarct size to a similar extent in wildtype and STAT3-KO mice in vivo. Thus, STAT3 possibly contributes to cardioprotection by stimulation of respiration and inhibition of MPTP opening.

Ischemic conditioning before (ischemic preconditioning, IPC) or after (ischemic postconditioning, POCO) sustained myocardial ischemia/reperfusion (I/R), induced locally or remotely from the heart (remote IPC, RIPC), reduces infarct size. However, none of the identified signaling steps of ischemic conditioning was robust across models and species to be successfully translated to humans. In prior separate studies in pigs, activation of signal transducer and activator of transcription 3 (STAT3) was causal for infarct size reduction by IPC, POCO, and RIPC but it remains unclear whether or not STAT3 is truly a common denominator of cardioprotective signaling. We therefore, now analyzed the phosphorylation of STAT3 and other signaling proteins in left ventricular biopsies from our prior studies on IPC, POCO and RIPC in one approach. We developed a strategy for the quantification of protein phosphorylation in multiple samples from many experiments on different gels/membranes by Western blot. Along with reduced infarct size, the ratio of STAT3tyr705 phosphorylation/total STAT3 protein at early reperfusion was significantly increased by IPC (IPC 2.0 ± 0.3 vs. I/R 1.2 ± 0.2 arbitrary units), but only trendwise by POCO and RIPC (1.3 ± 0.2; 1.4 ± 0.2 arbitrary units); storage time for IPC samples was shorter than for POCO and RIPC samples. No other signaling protein phosphorylation was associated with reduced infarct size. We confirmed STAT3 phosphorylation with IPC. For POCO and RIPC we could not reproduce the findings from our earlier more focused studies. At this point, we can not distinguish between lack of robustness of the biological signal and methodological issues of our retrospective approach.