Acute myocardial infarction is a common condition responsible for heart failure and sudden death. Here, we show that following acute myocardial infarction in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue and release Granzyme B, leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function is confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of GRANZYME B in patients with acute myocardial infarction predict increased risk of death at 1-year follow-up. Our work unravels a deleterious role of CD8+ T lymphocytes following acute ischemia, and suggests potential therapeutic strategies targeting pathogenic CD8+ T lymphocytes in the setting of acute myocardial infarction.

Background-Constitutive bradykinin B 1 receptors have been identified in dogs; however, their physiological implications involving the coronary circulation remain to be determined. This study examined, in conscious dogs, the coronary response to des-Arg 9 -bradykinin (a B 1 receptor agonist) and the mechanisms involved. Methods and Results-Eleven dogs were instrumented with a left ventricular micromanometer, a circumflex coronary catheter, a cuff occluder, a Doppler flow probe, and ultrasonic crystals to measure coronary blood flow velocity (CBFv) and coronary diameter (CD). Intracoronary des-Arg 9 -bradykinin (3 to 100 ng/kg) and bradykinin (0.1 to 10 ng/kg) did not modify systemic hemodynamics but dose-dependently increased CBFv and CD. Des-Arg 9 -bradykinin was less potent than bradykinin. Hoe 140 (a B 2 antagonist, 10 g/kg) abolished the effects of bradykinin but did not influence the effects of des-Arg 9 -bradykinin. When CBFv increase was prevented by the cuff occluder, CD responses to bradykinin and des-Arg 9 -bradykinin were maintained. Intracoronary lisinopril (0.75 mg) increased the CD response to bradykinin, with only minimal effect on CBFv, and extended the duration of the effect. Lisinopril did not alter des-Arg 9 -bradykinin responses. Intracoronary N -nitro-L-arginine (2 mg/kg) decreased the CD effect of bradykinin and prevented the CBFv and CD effects of des-Arg 9 -bradykinin. The relaxing effect of des-Arg 9 -bradykinin on isolated coronary rings was prevented by des-Arg 9 ,[Leu 8 ]-bradykinin. Conclusions-In the conscious dog, B 1 receptors are present in coronary vessels, and their stimulation produces vasodilation in conductance and resistance vessels, which is mediated essentially by NO but not modulated by angiotensin-converting enzyme. However, the coronary vasodilation induced by B 1 receptor stimulation is not as great as that produced by B 2 receptor stimulation.

ObjectivesThe aim of this study was to investigate the potential of coronary ultrafast Doppler angiography (CUDA), a novel vascular imaging technique based on ultrafast ultrasound, to image noninvasively with high sensitivity the intramyocardial coronary vasculature and quantify the coronary blood flow dynamics.BackgroundNoninvasive coronary imaging techniques are currently limited to the observation of the epicardial coronary arteries. However, many studies have highlighted the importance of the coronary microcirculation and microvascular disease.MethodsCUDA was performed in vivo in open-chest procedures in 9 swine. Ultrafast plane-wave imaging at 2,000 frames/s was combined to an adaptive spatiotemporal filtering to achieve ultrahigh-sensitive imaging of the coronary blood flows. Quantification of the flow change was performed during hyperemia after a 30-s left anterior descending (LAD) artery occlusion followed by reperfusion and was compared to gold standard measurements provided by a flowmeter probe placed at a proximal location on the LAD (n = 5). Coronary flow reserve was assessed during intravenous perfusion of adenosine. Vascular damages were evaluated during a second set of experiments in which the LAD was occluded for 90 min, followed by 150 min of reperfusion to induce myocardial infarction (n = 3). Finally, the transthoracic feasibility of CUDA was assessed on 2 adult and 2 pediatric volunteers.ResultsUltrahigh-sensitive cine loops of venous and arterial intramyocardial blood flows were obtained within 1 cardiac cycle. Quantification of the coronary flow changes during hyperemia was in good agreement with gold standard measurements (r2 = 0.89), as well as the assessment of coronary flow reserve (2.35 ± 0.65 vs. 2.28 ± 0.84; p = NS). On the infarcted animals, CUDA images revealed the presence of strong hyperemia and the appearance of abnormal coronary vessel structures in the reperfused LAD territory. Finally, the feasibility of transthoracic coronary vasculature imaging was shown on 4 human volunteers.ConclusionsUltrafast Doppler imaging can map the coronary vasculature with high sensitivity and quantify intramural coronary blood flow changes.