Invasive versus medically managed acute coronary syndromes with prior bypass (CABG-ACS): insights into the registry versus randomised trial populations.

BACKGROUND: Coronary artery bypass graft (CABG) patients are under-represented in acute coronary syndrome (ACS) trials. We compared characteristics and outcomes for patients who did and did not participate in a randomised trial of invasive versus non-invasive management (CABG-ACS). METHODS: ACS patients with prior CABG in four hospitals were randomised to invasive or non-invasive management. Non-randomised patients entered a registry. Primary efficacy (composite of all-cause mortality, rehospitalisation for refractory ischaemia/angina, myocardial infarction (MI), heart failure) and safety outcomes (composite of bleeding, stroke, procedure-related MI, worsening renal function) were independently adjudicated. RESULTS: Of 217 patients screened, 84 (39%) screenfailed, of whom 24 (29%) did not consent and 60 (71%) were ineligible. Of 133 (61%) eligible, 60 (mean±SD age, 71±9 years, 72% male) entered the trial and 73 (age, 72±10 years, 73% male) entered a registry (preferences: physician (79%), patient (38%), both (21%)).Compared with trial participants, registry patients had more valve disease, lower haemoglobin, worse New York Heart Association class and higher frailty.At baseline, invasive management was performed in 52% and 49% trial and registry patients, respectively, of whom 32% and 36% had percutaneous coronary intervention at baseline, respectively (p=0.800). After 2 years follow-up (694 (median, IQR 558-841) days), primary efficacy (43% trial vs 49% registry (HR 1.14, 95% CI 0.69 to 1.89)) and safety outcomes (28% trial vs 22% registry (HR 0.74, 95% CI 0.37 to 1.46)) were similar. EuroQol was lower in registry patients at 1 year. CONCLUSIONS: Compared with trial participants, registry participants had excess morbidity, but longer-term outcomes were similar. TRIAL REGISTRATION NUMBER: NCT01895751.

DDR1 autophosphorylation is a result of aggregation into dense clusters.

The collagen receptor DDR1 is a receptor tyrosine kinase that promotes progression of a wide range of human disorders. Little is known about how ligand binding triggers DDR1 kinase activity. We previously reported that collagen induces DDR1 activation through lateral dimer association and phosphorylation between dimers, a process that requires specific transmembrane association. Here we demonstrate ligand-induced DDR1 clustering by widefield and super-resolution imaging and provide evidence for a mechanism whereby DDR1 kinase activity is determined by its molecular density. Ligand binding resulted in initial DDR1 reorganisation into morphologically distinct clusters with unphosphorylated DDR1. Further compaction over time led to clusters with highly aggregated and phosphorylated DDR1. Ligand-induced DDR1 clustering was abolished by transmembrane mutations but did not require kinase activity. Our results significantly advance our understanding of the molecular events underpinning ligand-induced DDR1 kinase activity and provide an explanation for the unusually slow DDR1 activation kinetics.

Invasive Versus Medical Management in Patients With Prior Coronary Artery Bypass Surgery With a Non-ST Segment Elevation Acute Coronary Syndrome.

BACKGROUND: The benefits of routine invasive management in patients with prior coronary artery bypass grafts presenting with non-ST elevation acute coronary syndromes are uncertain because these patients were excluded from pivotal trials. METHODS: In a multicenter trial, non-ST elevation acute coronary syndromes patients with prior coronary artery bypass graft were prospectively screened in 4 acute hospitals. Medically stabilized patients were randomized to invasive management (invasive group) or noninvasive management (medical group). The primary outcome was adherence with the randomized strategy by 30 days. A blinded, independent Clinical Event Committee adjudicated predefined composite outcomes for efficacy (all-cause mortality, rehospitalization for refractory ischemia/angina, myocardial infarction, hospitalization because of heart failure) and safety (major bleeding, stroke, procedure-related myocardial infarction, and worsening renal function). RESULTS: Two hundred seventeen patients were screened and 60 (mean±SD age, 71±9 years, 72% male) were randomized (invasive group, n=31; medical group, n=29). One-third (n=10) of the participants in the invasive group initially received percutaneous coronary intervention. In the medical group, 1 participant crossed over to invasive management on day 30 but percutaneous coronary intervention was not performed. During 2-years' follow-up (median [interquartile range], 744 [570-853] days), the composite outcome for efficacy occurred in 13 (42%) subjects in the invasive group and 13 (45%) subjects in the medical group. The composite safety outcome occurred in 8 (26%) subjects in the invasive group and 9 (31%) subjects in the medical group. An efficacy or safety outcome occurred in 17 (55%) subjects in the invasive group and 16 (55%) subjects in the medical group. Health status (EuroQol 5 Dimensions) and angina class in each group were similar at 12 months. CONCLUSIONS: More than half of the population experienced a serious adverse event. An initial noninvasive management strategy is feasible. A substantive health outcomes trial of invasive versus noninvasive management in non-ST elevation acute coronary syndromes patients with prior coronary artery bypass grafts appears warranted. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01895751.

The right ventricular response to lung resection.

OBJECTIVES: Lung cancer is a leading cause of cancer death and in suitable cases the best chance of cure is offered by surgery. Lung resection is associated with significant postoperative cardiorespiratory morbidity, with dyspnea and reduced functional capacity as dominant features. These changes are poorly associated with deterioration in pulmonary function and a potential role of right ventricular (RV) dysfunction has been hypothesized. Cardiovascular magnetic resonance imaging is a reference method for noninvasive assessment of RV function and has not previously been applied to this population. METHODS: We used cardiovascular magnetic resonance imaging to assess the RV response to lung resection. Cardiovascular magnetic resonance imaging with volume and flow analysis was performed on 27 patients preoperatively, on postoperative day 2 and at 2 months. Left ventricular ejection fraction and RV ejection fraction, the ratio of stroke volume to end systolic volume, pulmonary artery acceleration time, and distensibility of main and branch pulmonary arteries were studied. RESULTS: Mean ± standard deviation RV ejection fraction deteriorated from 50.5% ± 6.9% preoperatively to 45.6% ± 4.5% on postoperative day 2 and remained depressed at 44.9% ± 7.7% by 2 months (P = .003). The ratio of stroke volume to end systolic volume deteriorated from median 1.0 (quartile 1, quartile 3: 0.9, 1.2) preoperatively to median 0.8 (quartile 1, quartile 3: 0.7, 1.0) on postoperative day 2 (P = .011). On postoperative day 2 there was a decrease in pulmonary artery acceleration time and operative pulmonary artery distensibility (P < .030 for both). There were no changes in left ventricular ejection fraction during the study period (P = .621). CONCLUSIONS: These findings suggest RV dysfunction occurs following lung resection and persists 2 months after surgery. The deterioration in the ratio of stroke volume to end systolic volume suggests a mismatch between afterload and contractility. There is an increase in indices of pulsatile afterload resulting from the operative pulmonary artery.

Collagen induces activation of DDR1 through lateral dimer association and phosphorylation between dimers.

The collagen-binding receptor tyrosine kinase DDR1 (discoidin domain receptor 1) is a drug target for a wide range of human diseases, but the molecular mechanism of DDR1 activation is poorly defined. Here we co-expressed different types of signalling-incompetent DDR1 mutants ('receiver') with functional DDR1 ('donor') and demonstrate phosphorylation of receiver DDR1 by donor DDR1 in response to collagen. Making use of enforced covalent DDR1 dimerisation, which does not affect receptor function, we show that receiver dimers are phosphorylated in trans by the donor; this process requires the kinase activity of the donor but not that of the receiver. The receiver ectodomain is not required, but phosphorylation in trans is abolished by mutation of the transmembrane domain. Finally, we show that mutant DDR1 that cannot bind collagen is recruited into DDR1 signalling clusters. Our results support an activation mechanism whereby collagen induces lateral association of DDR1 dimers and phosphorylation between dimers.

Myocardial strain in healthy adults across a broad age range as revealed by cardiac magnetic resonance imaging at 1.5 and 3.0T: Associations of myocardial strain with myocardial region, age, and sex.

PURPOSE: To assess myocardial strain using cine displacement encoding with stimulated echoes (DENSE) using 1.5T and 3.0T MRI in healthy adults. MATERIALS AND METHODS: Healthy adults without any history of cardiovascular disease underwent magnetic resonance imaging (MRI) at 1.5T and 3.0T within 2 days. The MRI protocol included balanced steady-state free-precession (b-SSFP), 2D cine-echo planar imaging (EPI)-DENSE, and late gadolinium enhancement in subjects >45 years. Acquisitions were divided into six segments; global and segmental peak longitudinal and circumferential strain were derived and analyzed by field strength, age, and gender. RESULTS: In all, 89 volunteers (mean age 44.8 ± 18.0 years, range: 18-87 years) underwent MRI at 1.5T, and 88 of these subjects underwent MRI at 3.0T (1.4 ± 1.4 days between the scans). Compared with 3.0T, the magnitudes of global circumferential (-19.5 ± 2.6% vs. -18.47 ± 2.6%; P = 0.001) and longitudinal (-12.47 ± 3.2% vs. -10.53 ± 3.1%; P = 0.004) strain were greater at 1.5T. At 1.5T, longitudinal strain was greater in females than in males: -10.17 ± 3.4% vs. -13.67 ± 2.4%; P = 0.001. Similar observations occurred for circumferential strain at 1.5T (-18.72 ± 2.2% vs. -20.10 ± 2.7%; P = 0.014) and at 3.0T (-17.92 ± 1.8% vs. -19.1 ± 3.1%; P = 0.047). At 1.5T, longitudinal and circumferential strain were not associated with age after accounting for sex (longitudinal strain P = 0.178, circumferential strain P = 0.733). At 3.0T, longitudinal and circumferential strain were associated with age (P < 0.05). Longitudinal strain values were greater in the apico-septal, basal-lateral, and mid-lateral segments and circumferential strain in the inferior, infero-lateral, and antero-lateral LV segments. CONCLUSION: Myocardial strain parameters as revealed by cine-DENSE at different MRI field strengths were associated with myocardial region, age, and sex. J. Magn. Reson. Imaging 2016;44:1197-1205.