A thorough assessment of RV-PC coupling and RV contractile function stratify HFpEF phenotypes at different level of risk. These observations shift the interest toward therapeutic strategies that may benefit the right heart as primary unmet need in the complex pathophysiology of the HFpEF syndrome.

Obesity and metabolic syndrome result from excess calorie intake and genetic predisposition and are mechanistically linked to type II diabetes and accelerated body aging; abnormal nutrient and insulin signaling participate in this pathologic process, yet the underlying molecular mechanisms are incompletely understood. Mice lacking the p66 kDa isoform of the Shc adaptor molecule live longer and are leaner than wild-type animals, suggesting that this molecule may have a role in metabolic derangement and premature senescence by overnutrition. We found that p66 deficiency exerts a modest but significant protective effect on fat accumulation and premature death in lep Ob/Ob mice, an established genetic model of obesity and insulin resistance; strikingly, however, p66 inactivation improved glucose tolerance in these animals, without affecting (hyper)insulinaemia and independent of body weight. Protection from insulin resistance was cell autonomous, because isolated p66KO preadipocytes were relatively resistant to insulin desensitization by free fatty acids in vitro. Biochemical studies revealed that p66shc promotes the signal-inhibitory phosphorylation of the major insulin transducer IRS-1, by bridging IRS-1 and the mTOR effector p70S6 kinase, a molecule previously linked to obesity-induced insulin resistance. Importantly, IRS-1 was strongly up-regulated in the adipose tissue of p66KO lep Ob/Ob mice, confirming that effects of p66 on tissue responsiveness to insulin are largely mediated by this molecule. Taken together, these findings identify p66shc as a major mediator of insulin resistance by excess nutrients, and by extension, as a potential molecular target against the spreading epidemic of obesity and type II diabetes.O besity and metabolic syndrome represent ramping public health issues in the Western world, due to overnutrition and reduced physical activity, coupled with genetic susceptibility (1). Although a correct lifestyle remains the mainstream solution to this problem, pharmacological strategies are also being actively seeked; to this end, a better knowledge of the molecular players and biochemical mechanisms linking excess body fat to glucose intolerance and an increased cardiovascular risk is critically needed.Genetic and diet-induced disturbances in insulin and nutrient signaling have been compellingly linked to diabetes, obesity, and accelerated aging (2-4). In particular, deregulated activity of the nutrient-sensitive kinase mTOR (mammalian target of rapamycin) and of its downstream effector S6 kinase (S6K) by high-fat diet or leptin deficiency promotes fat accumulation, induces insulin resistance, and shortens mouse lifespan (5, 6). On the other hand, calorie restriction and hypomorphic mutations or pharmacological blockade within the insulin and mTOR/S6 kinase signaling cascades increase longevity both in lower model organisms and in mammals (7-11), and adipose-specific deletion of the insulin receptor (IR) extends lifespan of FIRKO mice (12).Mice lacking the 66-kDa isoform of the adaptor Shc (Src ...

Aims Heart rate recovery (HRR) appears to be a robust prognostic marker in heart failure (HF). When using the 6 min walk test (6MWT) in HF, distance ambulated is generally the reference prognostic variable. We hypothesized that HRR after the 6MWT would be a better prognostic measure than distance ambulated. Methods and results A 6MWT and cardiopulmonary exercise testing (CPX) were randomly performed in 258 HF patients [216 HF with reduced EF (HFrEF) and 42 HF preserved EF (HFpEF)], after which HRR was measured. HRR was defined as the difference between heart rate at peak exercise and 1 min following test termination. Patients were assessed for major cardiac events during a mean follow‐up period of 22.8 ± 22.1 months. There were 50 major cardiac events during the tracking period. Univariate Cox regression analysis results identified HRR after both the 6MWT and CPX as a significant (P < 0.001) predictor of adverse events. Multivariate Cox regression analysis revealed that dichotomized HRR after the 6MWT and CPX was the strongest predictor of survival (χ2 61.1 and 53.8, respectively; P < 0.001), with LVEF (residual χ2 6.1, P < 0.05) adding significant prognostic value to the 6MWT model and ventilatory efficiency (the VE/VCO2 slope) (residual χ2 6.6, P < 0 .05) adding significant prognostic value to the CPX model. Conclusions HRR after the 6MWT is a powerful prognosticator that performs similarly to HRR after maximal exercise. If confirmed in subsequent studies, 6MWT HRR should replace 6MWT distance as the reference criterion 6MWT measure to consider when grading cardiovascular risk in HF patients.