Our results demonstrate that hypoxia increases LRP1 expression through HIF-1α and that LRP1 overexpression mediates hypoxia-induced VLDL-CE uptake and accumulation in cardiomyocytes.

Objectives. This work aims to evaluate the association between antigen carbohydrate 125 (CA125) and the risk of 1-year clinical outcomes in patients with worsening heart failure (HF). Background. CA125 is a widely available biomarker that is up-regulated in patients with acute HF and has been postulated as a useful marker of congestion and risk stratification. Methods. In a large multicenter cohort of patients with worsening HF, either in-hospital or in the outpatient setting, the independent associations between CA125 and 1-year death and the composite of death/HF-readmission (adjusted for BIOSTAT risk score) were determined with the Royston-Parmar method (n=2356). In a sensitivity analysis, the prognostic implications of CA125 were also adjusted for a clinical congestion score (CCS). Data were validated in the BIOSTAT-CHF validation cohort (n=1630). Results. Surrogates of congestion, such as NT-proBNP and a CCS, emerged as independent predictors of CA125. In multivariable survival analyses, higher CA125 was associated with an increased risk of mortality and the composite of death/HF-readmission (p<0.001 for both comparisons), even after adjustment for the CCS (p<0.010 for both comparisons). The addition of CA125 to the BIOSTAT score led to a significant risk reclassification for both outcomes (category-free net reclassification improvement=0.137, p<0.001 and 0.104, p=0.003, respectively). All outcomes were confirmed in an independent validation cohort. Conclusions. In patients with worsening HF, higher levels of CA125 were positively associated with parameters of congestion. Furthermore, CA125 remained independently associated with a higher risk of clinical outcomes, even beyond a predefined risk model and clinical surrogates of congestion.

Using in vitro, in vivo and patient-based approaches, we investigated the potential of circulating microRNAs (miRNAs) as surrogate biomarkers of myocardial steatosis, a hallmark of diabetic cardiomyopathy. We analysed the cardiomyocyte-enriched miRNA signature in serum from patients with well-controlled type 2 diabetes and with verified absence of structural heart disease or inducible ischemia, and control volunteers of the same age range and BMI (N = 86), in serum from a high-fat diet-fed murine model, and in exosomes from lipid-loaded HL-1 cardiomyocytes. Circulating miR-1 and miR-133a levels were robustly associated with myocardial steatosis in type 2 diabetes patients, independently of confounding factors in both linear and logistic regression analyses (P < 0.050 for all models). Similar to myocardial steatosis, miR-133a levels were increased in type 2 diabetes patients as compared with healthy subjects (P < 0.050). Circulating miR-1 and miR-133a levels were significantly elevated in high-fat diet-fed mice (P < 0.050), which showed higher myocardial steatosis, as compared with control animals. miR-1 and miR-133a levels were higher in exosomes released from lipid-loaded HL-1 cardiomyocytes (P < 0.050). Circulating miR-1 and miR-133a are independent predictors of myocardial steatosis. Our results highlight the value of circulating miRNAs as diagnostic tools for subclinical diabetic cardiomyopathy.In asymptomatic patients with type 2 diabetes, cardiac function, structure, and dimension are often altered, even in the absence of coronary artery disease or hypertension, due to diabetic cardiomyopathy 1 . The pathophysiology of non-ischemic diabetic cardiomyopathy is complex, and the precise underlying mechanisms are not fully understood. Several groups, including ours, have proposed abnormal regulation of lipid uptake or its intracellular metabolism in cardiomyocytes as one of the mechanisms underlying diabetic cardiomyopathy [2][3][4] . Myocardial steatosis, defined as the accumulation of neutral lipids in the myocardium, has been previously observed in diabetic patients with end-stage non-ischemic cardiomyopathy 5 . Myocardial steatosis is independently associated with impaired contractile function in both type 2 diabetes patients and animal models [6][7][8][9][10] . A causal relationship has been established between myocardial neutral lipid content and contractile function 11,12 . Importantly, myocardial steatosis is an early manifestation in the pathogenesis of cardiac-related complications; this process precedes the onset of both diastolic and systolic dysfunction and is evident in the absence of heart failure 8,10 . Thus, myocardial steatosis is clinically useful for the early identification and stratification of high-risk type 2 diabetes patients. However, clinical application of the gold standard for the evaluation of myocardial neutral lipid content, proton magnetic resonance spectroscopy ( 1 H-MRS), is currently impractical for large-scale population screening. This technique is complex, expensive, cause...