The reduction of infarct size--forty years of research.
Advances in electrocardiography and enzymology in the 1940s and 1950s have provided better knowledge of the clinical evolution of myocardial infarction and recognition of the prognostic relevance of acute phase arrhythmias. This prompted the creation of intensive coronary care units in the subsequent decade. After the successful resolution of acute phase arrhythmias, it became clear that the myocardium necrotic area size was a determining factor in the long-term prognosis. The Killip-Kimball clinical classification in the 60s helped to clarify the role of infarct size on left ventricle (LV) dysfunction, from Class I for small infarcts to Class IV with major necrosis, (involving more than 30% of the LV free wall area, the majority of these being fatal). Along with these advances, a series of experimental studies have shown that myocardial ischemia depends on the oxygen supply-demand imbalance, highlighting the factors affecting oxygen consumption. The study of various physiological, pharmacological or mechanical interventions on these factors became the next step towards optimizing the supply-demand relation. Several animal experiments were conducted in the 1970s, followed by the first clinical studies to reduce infarct size, particularly by increasing the oxygen supply either with fibrinolytic agents or with mechanical coronary angioplasty. The clinical experience of coronary reperfusion showed that left ventricle function did not normalize in 30% of the patients. In spite of unblocking the epicardial vessel, demonstrated hemodynamically, no equivalent myocardial perfusion was observed in these studies. New concepts emerged such as reperfusion injury, microvascular dysfunction, "no-reflow" phenomenon, stunned myocardium, and hibernating myocardium, which have become the target of basic research and clinical investigation. The replication of these phenomena in experimental models has attempted on the one hand to improve characterization with the use of different technologies, e.g. contrast echocardiography, isotopic studies including positron tomography, and magnetic resonance. On the other hand it has tested new therapeutic approaches as adjuvants of coronary reperfusion. Reperfusion injury is responsible for 50% of infarct size, so it became the target of research on cardiac protection. Post-reperfusion arrhythmias, stunned myocardium, microvascular obstruction that translates into the "no-reflow" phenomenon, are reperfusion injury manifestations. Imaging technology developments made it possible to demonstrate that microvascular obstruction occurs in 40% of patients who underwent primary angioplasty. Several therapeutic approaches to prevent microembolization have been studied such as glycoprotein IIb/IIIa receptor blockers. Ischemic myocardium conditioning is one of the new strategies to reduce reperfusion injury. The concept of pre-conditioning, defined experimentally in 1986, establishes that multiple brief episodes of ischemia may protect the heart from a subsequent prolonged infarction. Several observations have proved that pre-conditioning occurs in cardiac patients, for example, during coronary angioplasty and coronary bypass graft surgery, and so it is regarded as a promising approach to reducing infarct size. The concept of pre-conditioning was then enlarged by the demonstration, experimentally, that producing ischemia in a vascular bed could induce pre-conditioning in another vascular bed. Ischemia resulting from repeated successive insufflations of a blood pressure cuff on a lim, reduces myocardial necrosis after coronary angioplasty or coronary bypass graft surgery. This remote pre-conditioning seems to be a safe and effective non-invasive way of reducing the reperfusion injury. In 2002 a hypothesis was tested in studies on dogs that multiple repeated episodes of ischemia, produced in the beginning of reperfusion, would attenuate the reperfusion injury. This technique, called post-conditioning, was first used in patients in 2005, in AMI reperfusion, with beneficial short and long-term results. In the last 15 years, a large number of clinical studies have been carried with different pharmacologic groups to explore association pre- and post-conditioning concepts. Four agents were studied in particular: adenosine, nicorandil, atrial natriuretic peptide, and statins. The most important studies are reviewed, calling attention to disparities in results and discussing possible causes of negative outcomes. Cyclosporine, recently tested, opens a new field of investigation since it inhibits mitochondrial permeability and may directly attenuate the reperfusion injury. Microvascular dysfunction occurs in many patients after coronary angioplasty and is caused, in the first place, by distal embolization. The purpose of thrombectomy is to reduce the probability of distal embolization during angioplasty and stent placement. Available devices for clinical use include thrombus aspiration and thrombectomy catheters. Initial studies did not have the expected impact, but the number of patients studied was limited. A recent series involving more than 1000 AMI patients undergoing coronary angioplasty and thrombus aspiration has shown an improvement of myocardial perfusion indices and a reduction of mortality at 30 days. Distal embolization protection systems aim to prevent the embolic material entering the circulation and causing macro-or microembolization. The present small and controversial experience does not yet recommend the routine use of this technique. Reduction of infarct size has been the main objective of research on ischemic myocardial disease during the last 40 years. Myocardial reperfusion is a major accomplishment in this field. But it is like a double-edged sword because reperfusion injury significantly reduces the potential benefits of reperfusion. The huge amount of research undertaken in the past 20 years constitutes a paradigm of the relationship between experimental work and clinical practice, and has improved the prospects for diminishing infarct size, in both the short and long-term.
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