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Background: Lowering of atherogenic lipoproteins, including low-density lipoprotein cholesterol (LDL-C), reduces the risk of ischemic stroke. However, concerns have been raised about very low LDL-C levels and a potential increased risk of hemorrhagic stroke. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, despite intensive statin therapy, targeting LDL-C levels of 25 to 50 mg/dL and avoiding sustained LDL-C <15 mg/dL. This prespecified analysis was designed to assess the effect of alirocumab on ischemic and hemorrhagic stroke. We hypothesized that for patients treated with alirocumab there would be a reduction in risk of ischemic stroke without increasing hemorrhagic stroke, irrespective of baseline LDL-C and of history of cerebrovascular disease. Methods: Patients were randomized to alirocumab or placebo 1 to 12 months after acute coronary syndrome. The risk of nonfatal or fatal ischemic or hemorrhagic stroke was evaluated, stratified by baseline LDL-C concentration and history of cerebrovascular disease. A potential association of very low achieved LDL-C with alirocumab treatment at month 4 and subsequent hemorrhagic stroke was assessed. Results: Median follow-up was 2.8 years. In total, 263 ischemic and 33 hemorrhagic strokes occurred. Alirocumab reduced the risk of any stroke (HR, 0.72 [95% CI, 0.57−0.91]) and ischemic stroke (HR, 0.73 [95% CI, 0.57−0.93]) without increasing hemorrhagic stroke (HR, 0.83 [95% CI, 0.42−1.65]). In total, 7164 (37.9%), 6128 (32.4%), and 5629 (29.7%) patients had a baseline LDL-C of <80, 80 to 100, and >100 mg/dL, respectively. The treatment effect on stroke appeared numerically greater for patients with higher baseline LDL-C, but there was no formal evidence of heterogeneity ( P interaction =0.31). The effect of alirocumab on stroke was similar among 944 patients (5.0%) with a history of previous cerebrovascular disease and among those without a history of cerebrovascular disease ( P interaction =0.37). There was no apparent adverse relation between lower achieved LDL-C and incidence of hemorrhagic stroke in the alirocumab group. Conclusions: In patients with recent acute coronary syndrome and dyslipidemia despite intensive statin therapy, alirocumab decreased the risk of stroke, irrespective of baseline LDL-C and history of cerebrovascular disease, over a median follow-up of 2.8 years. Furthermore, risk of hemorrhagic stroke did not depend on achieved LDL-C levels within the alirocumab group. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01663402.

SummaryOver the past decades donor and recipient characteristics and medical management of heart transplantation (HT) patients have changed markedly. We studied the impact of these changes on long-term clinical outcome. Data of all consecutive HT recipients in our center have been collected prospectively. Cohort A (n = 353) was defined as the adult pts transplanted between 1984 and 1999 and was compared with cohort B (n = 227) transplanted between 2000 and 2013. Compared with cohort A, recipients in cohort B had older donors (mean age 29 vs. 43 years, donors aged >50 year: 2% vs. 33%, respectively). Survival at 1 and 10 years in cohort A vs. B was 89% vs. 86% and 53% vs. 68%, respectively (P = 0.02). Cohort B pts were treated more often with tacrolimus-based immunosuppression (77% vs. 22%; P = <0.0001) and early statins post-HT (88% vs. 18%; P = 0.0001), while renal function was better conserved at 5 and 10 years (P = 0.001 and 0.02). Multivariate analysis showed significant reduction in 10-year mortality with tacrolimus-based immunosuppression (HR 0.27 and 95% CI 0.17-0.42), hypertension post-HT (HR 0.5, 95% CI 0.36-0.72), and revascularization (HR 0.28, 95% CI 0.15-0.52). In spite of the use of much older donors, the long-term outcome after HT has improved considerably in the last decade, probably due to the introduction of newer treatment modalities.

Background The prevalence of end-stage renal disease (ESRD) is increasing worldwide, with the majority of new ESRD cases diagnosed in patients aged &gt;60 years. These older patients are at increased risk for impaired cognitive functioning, potentially through cerebral small vessel disease (SVD). Novel markers of vascular integrity may be of clinical value for identifying patients at high risk for cognitive impairment. Methods We aimed to associate the levels of Angiopoietin-2 (Ang-2), asymmetric dimethylarginine (ADMA), and a selection of eight circulating angiogenic miRNAs with SVD and cognitive impairment in older patients reaching ESRD that did not initiate renal replacement therapy yet (n = 129; mean age 75.3 years; mean eGFR 16.4 mL/min). We assessed brain MRI changes of SVD (white matter hyperintensity volume, microbleeds and presence of lacunes) and measures of cognition in domains of memory, psychomotor speed and executive function, comprised in a neuropsychological test battery. Results Older patients reaching ESRD showed an unfavorable angiogenic profile, as indicated by aberrant levels of Ang-2 and five angiogenic miRNAs (miR-27a, miR-126, miR-132, miR-223, miR-326), compared to healthy persons and patients with diabetic nephropathy. Moreover, Ang-2 associated with SVD and with the domains of psychomotor speed and executive function, while miR-223 and miR-29a associated with memory function. Conclusions Taken together, these novel angiogenic markers might serve to identify older patients with ESRD at risk of cognitive decline, as well as give insight into the underlying (vascular) pathophysiology.