Coronary Microcirculation – A Neglected Target of Cardioprotection –

by and close-ly related to infarction. 6 Particulate debris and soluble vasoconstrictor, proinflammatory and prothrombotic factors which are released from the culprit lesion, contribute to microvascular obstruction 7 – 9 as do leukocyte-platelet aggregates, tissue edema and capillary destruction. 6 Embolizing particles, which cause patchy microinfarcts, contribute to aggregate infarct size before 10 , 11 and after 12 myocardial ischemia-reperfusion, but do not interfere with the protection by ischemic pre- or postconditioning per se. 11 , 12 In fact, ischemic preconditioning in pigs 13 and postconditioning in humans 14 reduce microvascular obstruction after myocardial ischemia-reperfusion.

ical confounding risk factors and comorbidities is largely responsible for the less than perfect translation of the promising experimental cardioprotective strategies to the clinical area. It is the unequivocal merit of the present study to highlight the importance of these confounding risk factors and comorbidities for the protection of the coronary microcirculation by preconditioning/pre-infarction angina in humans. The present study by Niccoli et al 15 thus extends a prior study by Uchida et al 16 who reported both larger infarct size, as reflected by serum creatine kinase levels, and greater coronary microvascular dysfunction, as reflected by TIMI count and ST-segment elevation resolution, in patients with reperfused acute myocardial infarction when confounded by metabolic syndrome.
In future studies, the exact site and mechanisms of such attenuation of protection remain to be identified: is the protective stimulus weaker in the presence of risk factors/comorbidities or is the target tissue less responsive to the stimulus? Is there possibly a specificity of a given risk factor/comorbidity and/or target tissue (myocardium vs. microcirculation) in the attenuation of protection? In fact, a certain specificity both for the given risk factors/comorbidities and the endpoints is suggested by the present study, because hypertension, smoking and dyslipidemia confounded protection of the coronary microcirculation by pre-infarction angina with the angiographic endpoint, but diabetes, body mass index and positive family history did not; however, then again, a positive family history confounded protection with ECG ST segment elevation resolution as the endpoint. Answers to these questions might help to overcome the impediment of protection by risk factors/ comorbidities and improve the translation of protective strategies for the myocardium and coronary microcirculation to the clinical setting.
ardioprotection aims at the salvage of myocardium from infarction, 1 whereas the atherosclerotic epicardial coronary artery as the primary culprit of coronary occlusion and reperfusion and the coronary microcirculation, as both a confounder and target of cardioprotection are often neglected. 2 Ischemic preconditioning is the original experimental paradigm of cardioprotection and refers to the reduction of infarct size from sustained myocardial ischemia with reperfusion by prior brief episodes of myocardial ischemia and reperfusion. 3 Pre-infarction angina is the natural clinical counterpart of ischemic preconditioning and associated with a better outcome from infarction, in terms of reduced infarct size, less arrhythmias, better LV function and prognosis. 4,5

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Microvascular obstruction is another consequence of myocardial ischemia-reperfusion injury beyond that by and closely related to infarction. 6 Particulate debris and soluble vasoconstrictor, proinflammatory and prothrombotic factors which are released from the culprit lesion, contribute to microvascular obstruction 7-9 as do leukocyte-platelet aggregates, tissue edema and capillary destruction. 6 Embolizing particles, which cause patchy microinfarcts, contribute to aggregate infarct size before 10,11 and after 12 myocardial ischemia-reperfusion, but do not interfere with the protection by ischemic pre-or postconditioning per se. 11, 12 In fact, ischemic preconditioning in pigs 13 and postconditioning in humans 14 reduce microvascular obstruction after myocardial ischemia-reperfusion.
In this issue of the Journal, Niccoli et al 15 recruited 200 patients with acute ST-segment elevation myocardial infarction undergoing primary PCI and reported less angiographic (TIMI flow <2) and ECG (ST segment elevation resolution <70%) evidence of microvascular obstruction in patients with pre-infarction angina within 48 h before infarct onset, confirming protection of the coronary microcirculation by pre-infarction angina. Importantly, such microvascular coronary protection was attenuated in the presence of hypertension, smoking and dyslipidemia, but not confounded by diabetes, body mass index or a positive family history of cardiovascular diseases, which probably reflects the genetic burden. Such attenuation of cardioprotection by typical risk factors and confounders, which are frequently found in patients suffering an acute myocardial infarction, is well established for infarct size as an endpoint. 1 In fact, such attenuation of cardioprotection by typ-