Background— There is a paucity of data from large cohort studies examining the prognostic significance of obstructive sleep apnea (OSA) in patients with coronary artery disease. We hypothesized that OSA predicts subsequent major adverse cardiac and cerebrovascular events (MACCEs) in patients undergoing percutaneous coronary intervention. Methods and Results— The Sleep and Stent Study was a prospective, multicenter registry of patients successfully treated with percutaneous coronary intervention in 5 countries. Between December 2011 and April 2014, 1748 eligible patients were prospectively enrolled. The 1311 patients who completed a sleep study within 7 days of percutaneous coronary intervention formed the cohort for this analysis. Drug-eluting stents were used in 80.1% and bioresorbable vascular scaffolds in 6.3% of the patients, and OSA, defined as an apnea-hypopnea index of ≥15 events per hour, was found in 45.3%. MACCEs, a composite of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, and unplanned revascularization, occurred in 141 patients during the median follow-up of 1.9 years (interquartile range, 0.8 years). The crude incidence of an MACCEs was higher in the OSA than the non-OSA group (3-year estimate, 18.9% versus 14.0%; p =0.001). Multivariate Cox regression analysis indicated that OSA was a predictor of MACCEs, with an adjusted hazard ratio of 1.57 (95% confidence interval, 1.10–2.24; P =0.013), independently of age, sex, ethnicity, body mass index, diabetes mellitus, and hypertension. Conclusions— OSA is independently associated with subsequent MACCEs in patients undergoing percutaneous coronary intervention. Evaluation of therapeutic approaches to mitigate OSA-associated risk is warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01306526.

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Background: Heart failure (HF) is the most common long-term complication of acute myocardial infarction (MI). Understanding plasma proteins associated with post-MI HF and their gene expression may identify new candidates for biomarker and drug target discovery. Methods: We employed aptamer-based affinity-capture plasma proteomics to measure 1305 plasma proteins at one month post-MI in a New Zealand cohort (CDCS) including 181 post-MI patients who were subsequently hospitalized for HF compared with 250 post-MI patients who remained event-free over a median follow-up of 4.9 years. We then correlated plasma proteins with left ventricular ejection fraction measured at 4 months post-MI and identified proteins potentially co-regulated in post-MI HF using Weighted Gene Co-expression Network Analysis (WCGNA). A Singapore cohort (IMMACULATE) of 223 post-MI patients, of which 33 patients were hospitalized for HF (median follow-up 2.0 years), was used for further candidate enrichment of plasma proteins using Fisher meta-analysis, resampling-based statistical testing and machine learning. We then cross-referenced differentially-expressed proteins with their differentially-expressed genes from single-cell transcriptomes of non-myocyte cardiac cells isolated from a murine MI model, and single-cell and single-nuclei transcriptomes of cardiac myocytes from murine HF models and human HF patients. Results: In the CDCS cohort, 212 differentially-expressed plasma proteins were significantly associated with subsequent HF events. Of these, 96 correlated with left ventricular ejection fraction measured at 4 months post-MI. WCGNA prioritised 63 of the 212 proteins that demonstrated significantly higher correlations among patients who developed post-MI HF compared with event-free controls (dataset 1). Cross-cohort meta-analysis of the IMMACULATE cohort identified 36 plasma proteins associated with post-MI HF (dataset 2) while single-cell transcriptomes identified 15 gene-protein candidates (dataset 3). The majority of prioritized proteins were of matricellular origin. The 6 most highly-enriched proteins that were common to all 3 datasets included well-established biomarkers of post-MI HF - N-terminal B-type natriuretic peptide and troponin T - as well as newly-emergent biomarkers - angiopoietin-2, thrombospondin-2, latent transforming growth factor-β binding protein-4 and follistatin-related protein-3. Conclusions: Large-scale human plasma proteomics, cross-referenced to unbiased cardiac cell transcriptomics at single-cell resolution, prioritized protein candidates associated with post-MI HF for further mechanistic and clinical validation.