Outcomes and effect of treatment according to etiology in HFrEF: an analysis of PARADIGM-HF

Objectives: The purpose of this study was to compare outcomes (and the effect of sacubitril/valsartan) according to etiology in the PARADIGM-HF (Prospective comparison of angiotensin-receptor-neprilysin inhibitor [ARNI] with angiotensin-converting-enzyme inhibitor [ACEI] to Determine Impact on Global Mortality and morbidity in Heart Failure) trial. Background: Etiology of heart failure (HF) has changed over time in more developed countries and is also evolving in non-Western societies. Outcomes may vary according to etiology, as may the effects of therapy. Methods: We examined outcomes and the effect of sacubtril/valsartan according to investigator-reported etiology in PARADIGM-HF. The outcomes analyzed were the primary composite of cardiovascular death or HF hospitalization, and components, and death from any cause. Outcomes were adjusted for known prognostic variables including N terminal pro-B type natriuretic peptide. Results: Among the 8,399 patients randomized, 5,036 patients (60.0%) had an ischemic etiology. Among the 3,363 patients (40.0%) with a nonischemic etiology, 1,595 (19.0% of all patients; 47% of nonischemic patients) had idiopathic dilated cardiomyopathy, 968 (11.5% of all patients; 28.8% of nonischemic patients) had a hypertensive cause, and 800 (9.5% of all patients, 23.8% of nonischemic patients) another cause (185 infective/viral, 158 alcoholic, 110 valvular, 66 diabetes, 30 drug-related, 14 peripartum–related, and 237 other). Whereas the unadjusted rates of all outcomes were highest in patients with an ischemic etiology, the adjusted hazard ratios (HRs) were not different from patients in the 2 major nonischemic etiology categories; for example, for the primary outcome, compared with ischemic (HR: 1.00), hypertensive 0.87 (95% confidence interval [CI]: 0.75 to 1.02), idiopathic 0.92 (95% CI: 0.82 to 1.04) and other 1.00 (95% CI: 0.85 to 1.17). The benefit of sacubitril/valsartan over enalapril was consistent across etiologic categories (interaction for primary outcome; p = 0.11). Conclusions: Just under one-half of patients in this global trial had nonischemic HF with reduced ejection fraction, with idiopathic and hypertensive the most commonly ascribed etiologies. Adjusted outcomes were similar across etiologic categories, as was the benefit of sacubitril/valsartan over enalapril. (Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure; NCT01035255

Management and outcomes of patients with acute coronary syndromes in Australia and New Zealand, 2000-2007

OBJECTIVES: To describe temporal trends in the use of evidence-based medical therapies and management of patients with acute coronary syndromes (ACS) in Australia and New Zealand. DESIGN, SETTING AND PARTICIPANTS: Our analysis of the Australian and New Zealand cohort of the Global Registry of Acute Coronary Events (GRACE) included patients with ST-segment-elevation myocardial infarction (STEMI) and non-ST-segment-elevation ACS (NSTEACS) enrolled continuously between January 2000 and December 2007 from 11 metropolitan and rural centres in Australia and New Zealand. RESULTS: 5615 patients were included in this analysis (1723 with STEMI; 3892 with NSTEACS). During 2000-2007 there was an increase in the use of statin therapy, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and thienopyridines (P \u3c 0.0001 for each). Among patients with STEMI, there was an increase in emergency revascularisation with PCI (from 11% to 27% [P \u3c 0.0001]), and inhospital coronary angiography (from 61% to 76% [P \u3c 0.0001]). Among patients with NSTEACS, there was an increase in revascularisation with PCI (from 20% to 25% [P = 0.004]). Heart failure rates declined substantially among STEMI and NSTEACS patients (from 21% to 12% [P = 0.0002], and from 13% to 4% [P \u3c 0.0001], respectively) as did rates of hospital readmission for ischaemic heart disease at 6 months (from 23% to 9% [P = 0.0001], and from 24% to 15% [P = 0.0001], respectively). CONCLUSIONS: From 2000 to 2007 in Australia and New Zealand, there was a fall in inhospital events and 6-month readmissions among patients admitted with ACS. This showed an association with improved uptake of guideline-recommended medical and interventional therapies. These data suggest an overall improvement in the quality of care offered to contemporary ACS patients in Australia and New Zealand

β-arrestin- but not G protein-mediated signaling by the “decoy” receptor CXCR7

Ubiquitously expressed seven-transmembrane receptors (7TMRs) classically signal through heterotrimeric G proteins and are commonly referred to as G protein-coupled receptors. It is now recognized that 7TMRs also signal through β-arrestins, which act as versatile adapters controlling receptor signaling, desensitization, and trafficking. Most endogenous receptors appear to signal in a balanced fashion using both β-arrestin and G protein-mediated pathways. Some 7TMRs are thought to be nonsignaling “decoys” because of their inability to activate typical G protein signaling pathways; it has been proposed that these receptors act to scavenge ligands or function as coreceptors. Here we demonstrate that ligand binding to the decoy receptor CXCR7 does not result in activation of signaling pathways typical of G proteins but does activate MAP kinases through β-arrestins in transiently transfected cells. Furthermore, we observe that vascular smooth muscle cells that endogenously express CXCR7 migrate to its ligand interferon-inducible T-cell alpha chemoattractant (ITAC), an effect that is significantly attenuated by treatment with either a CXCR7 antagonist or β-arrestin depletion by siRNA. This example of an endogenous “β-arrestin-biased” 7TMR that signals through β-arrestin in the absence of G protein activation demonstrates that some 7TMRs encoded in the genome have evolved to signal through β-arrestin exclusively and suggests that other receptors that are currently thought to be orphans or decoys may also signal through such nonclassical pathways