Notch-activated signaling cascade interacts with mitochondrial remodeling proteins to regulate cell survival

Survival of differentiated cells is one of several processes regulated by Notch activity, although the general principles underlying this function remain to be characterized. Here, we probe the mechanism underlying Notch-mediated survival, building on emerging evidence that apoptotic responses coordinated by specialized intermediates converge on mitochondria, identifying a core event in death pathways. The Bcl-2 family protein Bax is one such intermediate, which in a unifying response to diverse apoptotic stimuli nucleates multiprotein assemblies on mitochondria, committing cells to irrevocable damage. Using Bax as the prototype stimulus, we analyze Notch signaling for potential interactions with mitochondria, probe intrinsic properties of the Notch receptor, and describe key intermediates in the Notch-activated signaling cascade. Ligand-dependent processing was necessary to generate the Notch intracellular domain (NIC) although signaling was independent of canonical interactions with nuclear factors. Notably, antiapoptotic activity was recapitulated by NIC recombinants, localized outside the nucleus, and compromised by enforced nuclear sequestration. NIC signaled via the kinase Akt to prevent the loss of mitochondrial function, contiguity, and consequent nuclear damage, outcomes critically depend on mitochondrial remodeling proteins Mitofusins-(Mfn)-1 and 2. Thus, the NIC-Akt-Mfn signaling cascade identifies a pathway regulating cell-survival, independent of canonical functions associated with NIC activity.     

Effect of alcohol-induced septal ablation on left atrial volume and ejection fraction assessed by real time three-dimensional transthoracic echocardiography in patients with hypertrophic cardiomyopathy

Alcohol-induced septal ablation (AISA) is an accepted treatment for hypertrophic cardiomyopathy (HCM) patients with left ventricular (LV) outflow obstruction who are unresponsive to medical therapy. As left atrial (LA) enlargement has been correlated with increased morbidity and mortality in HCM, we assessed LA volumes and ejection fraction (EF) prior to and after AISA using real time three-dimensional (3D) transthoracic echocardiography (TTE) in 12 patients (9 women; mean age 52 ± 15 years; 11 Caucasian). All patients underwent successful AISA with no complications and their resting left ventricular outflow gradients decreased from 40.5 ± 22.2 to 9.1 ± 17.6 mmHg (P < 0.001) while their gradients with provocation decreased from 126.2 ± 31.7 to 21.8 ± 28.0 mmHg (P < 0.001). All patients showed improvements in their New York Heart Association (NYHA) functional class. Both the LA end-systolic (45.2 ± 12.9 to 37.2 ± 13.7 ml, P < 0.0001) and end-diastolic (79.6 ± 18.9 to 77.1 ± 18.6 ml, P = 0.001) volumes decreased after AISA. The LA EF increased from 43.1 ± 9.0 to 52.5 ± 8.8% (P = 0.001). The increase in LA EF correlated with the decrease in the resting left ventricular outflow gradient (R =−0.647, P = 0.03). In conclusion, 3D echocardiography can be utilized to follow LA function after AISA for HCM. AISA results in clinical improvement in patients with HCM and in improvement of LA EF that is correlated with the decrease in the left ventricular outflow gradient.     

Nondisease-Specific Problems and All-Cause Mortality among Older Adults with CKD: The REGARDS Study

Background and objectives

The term “nondisease-specific” has been used to describe problems that cross multiple domains of health and are not necessarily the result of a single underlying disease. Although individuals with reduced eGFR and elevated albumin-to-creatinine ratio have many comorbidities, the prevalence of and outcomes associated with nondisease-specific problems have not been well studied.

Design, setting, participants, & measurements

Participants included 3557 black and white United States adults ≥75 years of age from the Reasons for Geographic and Racial Differences in Stroke Study. Nondisease-specific problems included cognitive impairment, depressive symptoms, exhaustion, falls, impaired mobility, and polypharmacy. Hazard ratios for mortality over a median (interquartile range) of 5.4 (4.2–6.9) years of follow-up associated with one, two, or three to six nondisease-specific problems were calculated and stratified by eGFR (≥60, 45–59, and <45 ml/min per 1.73 m²) and separately, albumin-to-creatinine ratio (<30, 30–299, and ≥300 mg/g). Secondary outcomes included hospitalizations and emergency department visits over 1.8 (0.7–4.0) and 2.3 (0.9–4.7) years of follow-up, respectively.

Results

The prevalence of nondisease-specific problems was more common at lower eGFR and higher albumin-to-creatinine ratio levels. Within each eGFR and albumin-to-creatinine ratio strata, the risk for mortality was higher among those with a greater number of nondisease-specific problems. For example, among those with an eGFR=45–59 ml/min per 1.73 m², the multivariable adjusted hazard ratios (95% confidence intervals) for mortality associated with one, two, or three to six nondisease-specific problems were 1.17 (0.78 to 1.76), 1.95 (1.24 to 3.07), and 2.44 (1.39 to 4.27; P trend <0.001). Risk for hospitalization and emergency department visits was higher among those with more nondisease-specific problems within eGFR and albumin-to-creatinine ratio strata.

Conclusions

Among older adults, nondisease-specific problems commonly co-occur with reduced eGFR and elevated albumin-to-creatinine ratio. Identification of nondisease-specific problems may provide mortality risk information independent of measures of kidney function.     

Autophagy and oxidative stress in gliomas with IDH1 mutations

IDH1 mutations in gliomas associate with longer survival. Prooxidant and antiproliferative effects of IDH1 mutations and its d-2-hydroxyglutarate (2-HG) product have been described in vitro, but inconsistently observed. It is also unclear whether overexpression of mutant IDH1 in wild-type cells accurately phenocopies the effects of endogenous IDH1-mutations on tumor apoptosis and autophagy. Herein we investigated the effects of 2-HG and mutant IDH1 overexpression on proliferation, apoptosis, oxidative stress, and autophagy in IDH1 wild-type glioma cells, and compared those results with patient-derived tumors. 2-HG reduced viability and proliferation of U87MG and LN18 cells, triggered apoptosis in LN18 cells, and autophagy in U87MG cells. In vitro studies and flank xenografts of U87MG cells overexpressing R132H IDH1 exhibited increased oxidative stress, including increases of both manganese superoxide dismutase (MnSOD) and p62. Patient-derived IDH1-mutant tumors showed no significant differences in apoptosis or autophagy, but showed p62 accumulation and actually trended toward reduced MnSOD expression. These data indicate that mutant IDH1 and 2-HG can induce oxidative stress, autophagy, and apoptosis, but these effects vary greatly according to cell type.     

One-year hemodynamic comparison of Perimount Magna with St Jude Epic aortic bioprostheses

Introduction

Cardiac surgeons are using more bioprosthetic valves due to the ageing population as well as to improvements that have been made to these implants. We sought to compare the 1-year hemodynamics of two commercially available valves by echocardiographic parameters.

Material and methods

Retrospective review of our institutional database revealed 69 patients who received either Perimount Magna (n = 33) or St Jude Epic (n = 36) valves in the aortic position with no other valve surgery between June 2004 and March 2006. All patients received transthoracic echocardiography at 1 year. Comparisons between groups were made at baseline and at 1-year follow-up. In addition, a pairwise comparison was performed in each patient to determine the change in echocardiographic parameters between baseline and follow-up.

Results

Mean implanted valve size was similar (Magna 24.3 ±2.0 mm vs. Epic 24.1 ±2.2 mm). Pre- and intraoperative patient variables were similar between the two groups. There were lower peak and mean pressure gradients in the Magna group, both at discharge and one year after surgery. This correlated with a larger indexed effective orifice area (Magna 0.8 ±0.2 cm²/m² vs. Epic 0.67 ±0.2 cm²/m², p = 0.02). In spite of these findings, left ventricular mass regression was not different.

Conclusions

These findings suggest that in a series with relatively low indexed effective orifice areas, the peak and mean gradients obtained were acceptable. More clinical follow-up of these patients is required to assess the true impact of prosthesis patient mismatch.     

Risk modeling for ventricular assist device support in post-cardiotomy shock

BackgroundPost-cardiotomy shock (PCS) has a complex etiology. Although treatment with inotrops and intra-aortic balloon pump (IABP) support improves cardiac performance, end-organ injuries are common and lead to prolonged ICU stay, extended hospitalization and increased mortality. Early consideration of mechanical circulatory support may prevent such complications and improve outcome.MethodsBetween January 1997 and January 2002, 321 patients required IABP and inotropic support for PCS following coronary artery bypass grafting (CABG) at our institution. Perioperative variables including age, mixed venous saturation (MVO₂), inotropic requirements and LV function were analyzed using multivariate statistical methods. All explanatory variables with a univariate p value <0.10 were entered into a stepwise logistic regression model to predict hospital mortality. Odds ratios from significant variables (p < 0.05) in the regression model were used to compose a risk score.ResultsOverall hospital mortality was 16%. The independent risk factors for mortality in this population were: MVO₂ < 60% (OR = 3.2), milrinone > 0.5 μg/kg/min (OR = 3.2), age > 75 (OR = 2.7), adrenaline > 0.1 μg/kg/min (OR = 1.5). A 15-point risk score was developed based on the regression model. Hospital mortality in patients with a score >6 was 46% (n = 13/28), 3–6 was 31% (n = 9/29) and <3 was 11% (n = 29/264).ConclusionsA significant proportion of patients with PCS continue to face high mortality despite IABP and inotropic support. Advanced age, heavy inotropic dependency and poor oxygen delivery all predicted increased risk for death. Further investigation is needed to assess whether early institution of VAD support could improve outcome in this high-risk group of patients.