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Atherosclerotic cardiovascular disease is increased on average 2-3-fold in people with diabetes as compared to their non-diabetic counterparts and is the major cause of the increased morbidity and mortality in this disease. There is however heterogeneity in cardiovascular risk between individuals based on demographic, cardiometabolic and clinical risk factors in the setting of hyperglycemia, insulin resistance and obesity that needs to be taken into consideration in planning preventive interventions. Randomized clinical trials of agents or procedures used for amelioration of augmented CVD risk in diabetes have been pivotal in providing evidenced-based treatments. Improvement in hyperglycemia in both type 1 and type 2 diabetes is considered to be central in the prevention of microvascular and macrovascular complications although selected antihyperglycemic agents have demonstrated beneficial as well as possible deleterious off-target effects. Lowering low density lipoprotein cholesterol, treating hypertension and stopping smoking each play important roles in preventing cardiovascular disease in diabetes as they do in the general population and low dose aspirin is overall beneficial in high risk individuals. Hypertriglyceridemia may represent another important marker for augmented cardiovascular risk in diabetes and newer agents targeting dyslipidemia appear promising. The fall in cardiovascular events over the past two decades offers hope that modern intervention strategies as well as novel approaches such as those targeting inflammation may contribute to a continued reduction of cardiovascular disease in people with diabetes.Background No medical therapies exist to treat right ventricular (RV) remodeling and RV failure (RVF), in large part because molecular pathways that are specifically activated in pathologic human RV remodeling remain poorly defined. Selleckchem Plumbagin Murine models have suggested involvement of Wnt signaling, but this has not been well-defined in human RVF. Methods Using a candidate gene approach, we sought to identify genes specifically expressed in human pathologic RV remodeling by assessing the expression of 28 WNT-related genes in the RVs of three groups explanted nonfailing donors (NF, n = 29), explanted dilated and ischemic cardiomyopathy, obtained at the time of cardiac transplantation, either with preserved RV function (pRV, n = 78) or with RVF (n = 35). Results We identified the noncanonical WNT receptor ROR2 as transcriptionally strongly upregulated in RVF compared to pRV and NF (Benjamini-Hochberg adjusted P less then 0.05). ROR2 protein expression correlated linearly to mRNA expression (R2 = 0.41, P = 8.1 × 10-18) among all RVs, and to higher right atrial to pulmonary capillary wedge ratio in RVF (R2 = 0.40, P = 3.0 × 10-5). Utilizing Masson's trichrome and ROR2 immunohistochemistry, we identified preferential ROR2 protein expression in fibrotic regions by both cardiomyocytes and noncardiomyocytes. We compared RVF with high and low ROR2 expression, and found that high ROR2 expression was associated with increased expression of the WNT5A/ROR2/Ca2+ responsive protease calpain-μ, cleavage of its target FLNA, and FLNA phosphorylation, another marker of activation downstream of ROR2. ROR2 protein expression as a continuous variable, correlated strongly to expression of calpain-μ (R2 = 0.25), total FLNA (R2 = 0.67), calpain cleaved FLNA (R2 = 0.32) and FLNA phosphorylation (R2 = 0.62, P less then 0.05 for all). Conclusion We demonstrate robust reactivation of a fetal WNT gene program, specifically its noncanonical arm, in human RVF characterized by activation of ROR2/calpain mediated cytoskeleton protein cleavage.Background Heart failure with preserved ejection fraction (HFpEF) affects women more frequently than men. However, data on sex-specific associations of adverse health outcomes and left ventricular structure and function and with microalbuminuria in patients with HFpEF are scarce. Methods In 1,334 participants enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) Trial, we estimated the sex-specific multivariable-adjusted risk and LV traits with urine microalbumin/creatine ratio (ACR), using Cox or linear regression. Results In total, 604 (45.3%) were women. In multivariable-adjusted analyses, a doubling of ACR in both men and women was associated with higher posterior (+0.014 cm, p = 0.012/+0.012 cm, p = 0.033) wall thickness and left ventricular mass index (+2.55 mg/m2, p = 0.004/+2.45 mg/m2, p = 0.009), whereas was also associated with higher septal (+0.018 cm, p = 0.002) and left atrial volume index (+1.44 mL/m2, p = 0.001) in men. ACR was a key predictor of all-cause (HR, 1.11; p = 0.006) and cardiovascular (HR, 1.17; p = 0.002) death in women, whereas in men ACR was associated with HF hospitalization (HR, 1.23; p less then 0.001), any hospitalization (HR, 1.06; p = 0.006), and myocardial infarction (HR, 1.19; p = 0.017). The interactions of sex with ACR were significant for hospitalization for heart failure and any hospitalization (p ≤ 0.034). Conclusions Outcomes and cardiac structure and function in patients with HFpEF appear to be influenced by ACR that vary according to sex. In men, ACR was significant associated with LV diastolic function, hospitalization, and myocardial infarction, whereas in women was associated with mortality.Premenopausal women generally have a favorable cardiovascular risk profile, owing to young age and the protective effects of estrogen. Rates of hypertension and more advanced cardiovascular disease (CVD) are low in premenopausal women. A large body of epidemiological evidence has shown that lifestyle behaviors in midlife, i.e., cardiorespiratory fitness, physical activity, and healthy diet, are associated with lower risk of overt CVD and adverse cardiovascular outcomes in the future for men and women. Despite differences in future cardiovascular risk, brachial blood pressures might be similar between premenopausal women with favorable vs. unfavorable levels of lifestyle behaviors in early-to-mid-life. Here we make the case for deeper phenotyping by means of vascular function measurements, such as arterial stiffness, augmentation index, and endothelial function, to identify potential mechanistic pathways linking lifestyle behaviors in early-to-mid-adulthood with lifelong CVD risk in women. We describe considerations for vascular function measurement in premenopausal women and opportunities for investigators to fill in knowledge gaps to further our understanding of CVD risk assessment and CVD progression in premenopausal women.