Revascularization Strategies for Calcified Lesions in Patients Presenting With Acute Coronary Syndromes (From the Acute Catheterization and Urgent Intervention Triage StrategY [ACUITY] Trial).

BACKGROUND: Revascularization of calcified coronary lesions has been shown to be associated with suboptimal outcomes. The optimal revascularization strategy for calcified lesions in patients presenting with non-ST segment elevation acute coronary syndromes (NSTEACS) has yet to be defined. METHODS: Outcomes in patients presenting with NSTEACS and moderately or severely calcified target lesions in native coronary vessels, as assessed by an independent angiographic core lab, were examined according to revascularization strategy (percutaneous coronary intervention [PCI] vs coronary artery bypass graft [CABG] surgery) from the large-scale, prospective ACUITY trial. Propensity-adjusted multivariable analysis was used to identify the independent predictors of events at 30 days. RESULTS: Of 1315 NSTEACS patients with moderately and severely calcified lesions in whom revascularization was performed, a total of 334 (25%) and 981 (75%) underwent CABG and PCI, respectively. CABG patients had more severe baseline comorbidities and coronary artery disease. By propensity-adjusted multivariable analysis, the CABG group had higher 30-day rates of reinfarction, composite death or reinfarction, major bleeding, and thrombocytopenia. CONCLUSIONS: In this large-scale study of patients presenting for NSTEACS, 30-day adverse events were more frequent after revascularization of calcified coronary lesions with CABG rather than PCI. Further studies are warranted to evaluate means of improving early safety outcomes in this high-risk patient group with complex coronary disease.

Cardiac myosin light chain phosphorylation and inotropic effects of a biased ligand, TRV120023, in a dilated cardiomyopathy model.

AIMS: Therapeutic approaches to treat familial dilated cardiomyopathy (DCM), which is characterized by depressed sarcomeric tension and susceptibility to Ca(2+)-related arrhythmias, have been generally unsuccessful. Our objective in the present work was to determine the effect of the angiotensin II type 1 receptor (AT1R) biased ligand, TRV120023, on contractility of hearts of a transgenic mouse model of familial DCM with mutation in tropomyosin at position 54 (TG-E54K). Our rationale is based on previous studies, which have supported the hypothesis that biased G-protein-coupled receptor ligands, signalling via ß-arrestin, increase cardiac contractility with no effect on Ca(2+) transients. Our previous work demonstrated that the biased ligand TRV120023 is able to block angiotensin-induced hypertrophy, while promoting an increase in sarcomere Ca(2+) response. METHODS AND RESULTS: We tested the hypothesis that the depression in cardiac function associated with DCM can be offset by infusion of the AT1R biased ligand, TRV120023. We intravenously infused saline, TRV120023, or the unbiased ligand, losartan, for 15 min in TG-E54K and non-transgenic mice to obtain left ventricular pressure-volume relations. Hearts were analysed for sarcomeric protein phosphorylation. Results showed that the AT1R biased ligand increases cardiac performance in TG-E54K mice in association with increased myosin light chain-2 phosphorylation. CONCLUSION: Treatment of mice with an AT1R biased ligand, acting via ß-arrestin signalling, is able to induce an increase in cardiac contractility associated with an increase in ventricular myosin light chain-2 phosphorylation. AT1R biased ligands may prove to be a novel inotropic approach in familial DCM.

Coronary artery calcification: pathogenesis and prognostic implications.

Coronary artery calcification (CAC) is a risk factor for adverse outcomes in the general population and in patients with coronary artery disease. The pathogenesis of CAC and bone formation share common pathways, and risk factors have been identified that contribute to the initiation and progression of CAC. Efforts to control CAC with medical therapy have not been successful. Event-free survival is also reduced in patients with coronary calcification after both percutaneous coronary intervention (PCI) and bypass graft surgery. Although drug-eluting stents and devices for plaque modification have modestly improved outcomes in calcified vessels, adverse event rates are still high. Innovative pharmacologic and device-based approaches are needed to improve the poor prognosis of patients with CAC.

Relation between coronary calcium and major bleeding after percutaneous coronary intervention in acute coronary syndromes (from the Acute Catheterization and Urgent Intervention Triage Strategy and Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction Trials).

Percutaneous coronary intervention (PCI) of calcified coronary lesions has been associated with increased rates of adverse ischemic events. However, the potential association between the presence and severity of calcific deposits and bleeding complications has yet to be investigated. Data from 6,855 patients with non-ST-segment elevation acute coronary syndrome (NSTEACS) or ST-segment elevation myocardial infarction (STEMI) treated with PCI were pooled from 2 large-scale randomized controlled trials-Acute Catheterization and Urgent Intervention Triage Strategy and Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction. Patients were stratified into 3 groups according the grade of target PCI lesion calcium (none to mild, moderate, and severe) as assessed by an independent angiographic core laboratory. Thirty-day bleeding event rates were assessed and compared among groups. In the total cohort undergoing PCI, none-to-mild target lesion calcium was found in 4,665 patients (68.1%), moderate target lesion calcium in 1,788 patients (26.1%), and severe target lesion calcium in 402 patients (5.9%). The 30-day rates of non-coronary artery bypass graft surgery major bleeding increased significantly with each degree of coronary calcium (none to mild = 5.9%, moderate = 7.2%, and severe = 11.2%, p = 0.0003). By multivariable analysis, presence of severe calcium was an independent predictor of non-coronary artery bypass graft major bleeding after PCI (hazard ratio 1.54, 95% confidence interval 1.09 to 2.17, p = 0.01). In conclusion, in patients undergoing PCI for non-ST-segment elevation acute coronary syndrome and ST-segment elevation myocardial infarction, target lesion coronary calcium was an independent predictor of major bleeding events. Further studies are needed to elucidate mechanisms underlying this finding and to optimize treatment of this high-risk population.