Calcineurin is a Ca2؉ /calmodulin-activated protein phosphatase that transduces hypertrophic stimuli to regulate transcriptional control of myocyte transformation. It is not known whether overexpression of MCIP1, a recently described endogenous inhibitor of calcineurin, impacts the hypertrophic response to pathophysiologically relevant pressure overload. Further, the functional consequences of calcineurin inhibition by MCIP1 under conditions of hemodynamic stress are unknown. Transgenic mice expressing a human cDNA encoding hMCIP1 in the myocardium were subjected to thoracic aortic banding. Transgenic mice and wild type littermates tolerated pressure overload equally well. Wild type mice developed left ventricular hypertrophy, but the hypertrophic response in transgenics was significantly blunted. An isoform of MCIP1 transcript was up-regulated by pressure stress, whereas MCIP2 transcript was not. Expression patterns of fetal genes were differentially regulated in banded MCIP1 hearts compared with wild type. Echocardiography performed at 3 weeks and 3 months revealed preservation of both left ventricular size and systolic function in banded MCIP1 mice despite the attenuated hypertrophic response. These data demonstrate attenuation of hypertrophic transformation when calcineurin is inhibited by MCIP1. Further, these data suggest that activation of hypertrophic marker genes may not be directly dependent on calcineurin activity. Finally, they demonstrate that ventricular performance is preserved despite attenuation of compensatory hypertrophy.Terminally differentiated cardiac myocytes develop hypertrophy in response to stressful stimuli. The resulting increases in left ventricular (LV) 1 wall thickness serve to normalize wall stress and diminish myocardial oxygen consumption. Salutary effects on energy metabolism, however, are counterbalanced by heightened risk of cardiovascular morbidity and mortality (1). Prominent among these is increased risk of heart failure. Calcineurin is a Ca 2ϩ /calmodulin-activated cytoplasmic protein phosphatase (PP2B) that transduces hypertrophic stimuli to regulate transcriptional control of myocyte transformation (2). A number of groups have investigated the importance of calcineurin signaling in models of in vivo hypertrophy (reviewed in Ref. 2). Although results have been varied, most reports relied on pharmacological inhibition of calcineurin using either cyclosporin A (CsA) or FK-506. Although CsA is a specific inhibitor of calcineurin, CsA has multiple effects on cellular signaling, including altered expression of the cardiac Na ϩ -Ca 2ϩ exchanger (3) and increased concentrations of intracellular Ca 2ϩ (4). Calcineurin is a ubiquitous protein, and systemic CsA has effects on other, noncardiac organ systems.MCIP1 (myocyte-enriched calcineurin-interacting protein) is a recently described (5, 6) protein that is preferentially expressed in striated muscle and that directly binds to the catalytic subunit (CnA) of the calcineurin holoenzyme. MCIP1 binding to CnA inhibits activating eff...

Hypertrophic growth of the myocardium occurs in most forms of heart failure and may contribute to the pathogenesis of the failure state. Little is known about the regulatory mechanisms governing the often-coexisting phenotypes of hypertrophy, systolic failure, and diastolic stiffness that characterize clinical disease. We hypothesized that intracellular signaling pathways are differentially activated by graded degrees of hemodynamic stress. To test this, we developed models of graded pressure stress in mice and used them to directly compare compensated hypertrophy and pressure-overload heart failure. Surgical interventions were designed to be similar, on either side of a threshold separating compensated from decompensated responses. Our findings revealed two dramatically different hypertrophic phenotypes with only modest differences in the activation of relevant intracellular signaling pathways. Furthermore, we uncovered a functional requirement of calcineurin signaling in each model such that calcineurin suppression blunted hypertrophic growth. Remarkably, in each case, suppression of calcineurin signaling was not associated with clinical deterioration or increased mortality. Profiles of stress-response signaling and Ca2+ handling differ between the steady-state, maintenance phases of load-induced cardiac hypertrophy and failure. This information may be useful in identifying novel targets of therapy in chronic disease.

BackgroundWe investigated the association between severe hypoglycemia (SH) and the risk of cardiovascular (CV) or all-cause mortality in patients with type 2 diabetes.MethodsThe study included 1,260 patients aged 25 to 75 years with type 2 diabetes from the Vincent Type 2 Diabetes Resgistry (VDR), who consecutively enrolled (n=1,260) from January 2000 to December 2010 and were followed up until May 2015 with a median follow-up time of 10.4 years. Primary outcomes were death from any cause or CV death. We investigated the association between the CV or all-cause mortality and various covariates using Cox proportional hazards regression analysis.ResultsAmong the 906 participants (71.9%) who completed follow-up, 85 patients (9.4%) had at least one episode of SH, and 86 patients (9.5%) died (9.1 per 1,000 patient-years). Patients who had died were older, had a longer duration of diabetes and hypertension, received more insulin, and had more diabetic microvascular complications at baseline, as compared with surviving patients. The experience of SH was significantly associated with an increased risk of all-cause mortality (hazard ratio [HR], 2.64; 95% confidence interval [CI], 1.39 to 5.02; P=0.003) and CV mortality (HR, 6.34; 95% CI, 2.02 to 19.87; P=0.002) after adjusting for sex, age, diabetic duration, hypertension, mean glycosylated hemoglobin levels, diabetic nephropathy, lipid profiles, and insulin use.ConclusionWe found a strong association between SH and increased risk of all-cause and CV mortality in patients with type 2 diabetes.

Fixed-dose combinations of ezetimibe/rosuvastatin significantly improved lipid profiles in patients with hypercholesterolemia compared with rosuvastatin monotherapy. All groups treated with rosuvastatin and ezetimibe reported a decrease in mean LDL-C level >50%. The safety and tolerability of ezetimibe/rosuvastatin therapy were comparable with those of rosuvastatin monotherapy. ClinicalTrials.gov identifier: NCT02749994.

I ntermediate coronary stenosis is frequently encountered during diagnostic angiography. It is well known that the decision to perform revascularization should be guided by evidence of myocardial ischemia.1 Fractional flow reserve (FFR) is a lesion-specific physiological index to evaluate the functional significance of coronary stenosis and can be easily measured in a cardiac catheterization laboratory. Although its benefit has been proven by many clinical studies, 1-6 the use of FFR-guided revascularization is still low and there is still some room to apply FFR in more patients. . Routine-DES group underwent DES implantation without FFR measurement (n=115). The primary end point was the incidence of major adverse cardiac events, a composite of cardiac death, myocardial infarction, and target lesion revascularization. Of lesions assigned to FFR-guided strategy, only one quarter had functional significance (FFR<0.75). At 2-year follow-up, the cumulative incidence of major adverse cardiac events was 7.9±2.5% in the FFR-guided group and 8.8±2.7% in Routine-DES group (P=0.80). At 5-year follow-up, the cumulative incidence of major adverse cardiac events was 11.6±3.0% and 14.2±3.3% for the FFR-guided group and the Routine-DES group (P=0.55). There was no difference in major adverse cardiac events rates between the 2 groups ≤5-year follow-up (hazard ratio, 1.25; 95% confidence interval, 0.60-2.60). Conclusions-In lesions with angiographically intermediate stenosis, FFR guidance provides a tailored approach, which is at least as good as an angiography-guided routine-DES implantation strategy and avoids unnecessary DES-stenting in a considerable part of the patients. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00592228.(Circ Cardiovasc Interv. 2015;8:e002442.