Structural and functional cardiac profile after prolonged duration of mechanical unloading: potential implications for myocardial recovery.

Clinical and experimental studies have suggested that the duration of left ventricular assist device (LVAD) support may affect remodeling of the failing heart. We aimed to 1) characterize the changes in Ca2+/calmodulin-dependent protein kinase type-IIδ (CaMKIIδ), growth signaling, structural proteins, fibrosis, apoptosis, and gene expression before and after LVAD support and 2) assess whether the duration of support correlated with improvement or worsening of reverse remodeling. Left ventricular apex tissue and serum pairs were collected in patients with dilated cardiomyopathy ( n = 25, 23 men and 2 women) at LVAD implantation and after LVAD support at cardiac transplantation/LVAD explantation. Normal cardiac tissue was obtained from healthy hearts ( n = 4) and normal serum from age-matched control hearts ( n = 4). The duration of LVAD support ranged from 48 to 1,170 days (median duration: 270 days). LVAD support was associated with CaMKIIδ activation, increased nuclear myocyte enhancer factor 2, sustained histone deacetylase-4 phosphorylation, increased circulating and cardiac myostatin (MSTN) and MSTN signaling mediated by SMAD2, ongoing structural protein dysregulation and sustained fibrosis and apoptosis (all P < 0.05). Increased CaMKIIδ phosphorylation, nuclear myocyte enhancer factor 2, and cardiac MSTN significantly correlated with the duration of support. Phosphorylation of SMAD2 and apoptosis decreased with a shorter duration of LVAD support but increased with a longer duration of LVAD support. Further study is needed to define the optimal duration of LVAD support in patients with dilated cardiomyopathy. NEW & NOTEWORTHY A long duration of left ventricular assist device support may be detrimental for myocardial recovery, based on myocardial tissue experiments in patients with prolonged support showing significantly worsened activation of Ca2+/calmodulin-dependent protein kinase-IIδ, increased nuclear myocyte enhancer factor 2, increased myostatin and its signaling by SMAD2, and apoptosis as well as sustained histone deacetylase-4 phosphorylation, structural protein dysregulation, and fibrosis.

Current or recent pregnancy is associated with adverse pathologic features but not impaired survival in early breast cancer.

BACKGROUND: Pregnancy-associated breast cancer (PABC) may be defined as breast cancer diagnosed during pregnancy or within 1 year of giving birth. Conflicting data exist regarding the impact of pregnancy on clinical features and prognosis of breast cancer. METHODS: A single-institution retrospective chart review was performed of 99 patients identified with PABC between 1992 and 2007. Non-PABC controls were matched 2:1 to PABC cases by year of diagnosis and age. The differences in clinical features were compared between cases and controls using chi-square tests. Univariate and multivariate analyses were performed to assess the effect of PABC on survival. RESULTS: Of the 99 PABC cases, breast cancer was diagnosed during pregnancy in 36 patients, and after delivery in 63. PABC cases were more likely than controls to be negative for estrogen receptor (59% vs 31%, P < .0001) and negative for progesterone receptor (72% vs 40%, P < .0001). Cases were also more likely to have advanced T class (P = .0271) and N class (P = .0104) and higher grade tumors (P = .0115). With a median follow-up of 6.3 years for cases and 4.7 years for controls, overall survival did not differ between cases and controls (P = .0787). On multivariate analysis, the independent prognostic factors for overall survival were estrogen receptor status (P = .0031) and N class (P = .0003). The diagnosis of PABC was not an independent prognostic factor (P = .1317). CONCLUSIONS: PABC is associated with more adverse tumor features than non-PABC matched for age and year of diagnosis. After correcting for pathologic features, the diagnosis of PABC is not in itself an adverse prognostic factor for survival.

om92 , a glp-1 enhancer mutation, is an allele of ekl-1.

Germline stem cell proliferation in C. elegans requires activation of the GLP-1/Notch receptor, which is located on the germline plasma membrane and encoded by the glp-1 gene. We previously identified several genes whose products directly or indirectly promote activity of the GLP-1 signaling pathway by finding mutations that enhance the germline phenotype of a glp-1(ts) allele, glp-1(bn18) . Here, we report phenotypic and molecular analysis of a new ekl-1 allele, ekl-1(om92) , that enhances the glp-1(bn18) phenotype. ekl-1(om92) is a 244 bp deletion predicted to generate a frameshift and premature termination codon, yielding a severely truncated protein, suggesting it is a null allele.

The influence of advanced age on venous-arterial extracorporeal membrane oxygenation outcomes.

OBJECTIVES: Ethical and health care economic concerns surround the use of venous-arterial extracorporeal membrane oxygenation (VA-ECMO) in elderly patients. Patients requiring VA-ECMO are often in critical condition and the decision to cannulate is time-sensitive. We investigated the relationship between age and VA-ECMO outcomes to better inform this decision. METHODS: This is a retrospective study of 355 patients placed on VA-ECMO between March 2007 and August 2016 at our institution. Using piecewise modelling, age became associated with in-hospital mortality after 63 years. Based on further analysis with the χ2 statistic maximization, patients were divided into 2 age groups: ≤72 years old [Group Y (Young), n = 310] and >72 years old [Group O (Old), n = 45]. Multivariable logistic regression was performed to identify preoperative predictors of in-hospital mortality. RESULTS: Patients over the age of 72 had a significantly higher prevalence of comorbidities, including coronary disease, previous strokes and chronic kidney disease. Weaning from ECMO was achieved in 76% of Group Y and 47% of Group O (P < 0.001). In-hospital mortality was 52% among Group Y and 69% among Group O (P = 0.037). Multivariable logistic regression using preoperative risk factors identified coronary artery disease, acute decompensated heart failure and an age >72 years as independent predictors of mortality (age >72 years: odds ratio 2.71, 95% confidence interval 1.22-6.00; P = 0.01). CONCLUSIONS: VA-ECMO in-hospital mortality is considerable across all age groups. However, age only becomes associated with mortality after 63 years and rises dramatically after 72 years. This study provides useful insight into these time-sensitive decisions for the development of possible practice guidelines.

Dose-dependent association between amiodarone and severe primary graft dysfunction in orthotopic heart transplantation.

BACKGROUND: There is growing concern regarding the association between pre-transplant amiodarone exposure and post-transplant adverse outcomes. We hypothesized that amiodarone use would be associated with the development of severe primary graft dysfunction (PGD) in a dose-dependent manner. METHODS: This was a retrospective review of 269 adult orthotopic heart transplantation (OHT) recipients at our institution between 2010 and 2014. At the time of OHT, 100 were receiving amiodarone therapy (Group 1) and 169 were not (Group 2). RESULTS: Pre-OHT creatinine was higher in Group 1 (1.49 ± 0.63 vs 1.27 ± 0.68 mg/dl, p = 0.011). At time of listing, Group 1 had higher frequency of status 2 (42.0% vs 29.0%), and Group 2 had higher frequency of status 1A (20.7% vs 8.0%; p = 0.009). Severe PGD (mechanical circulatory support within 24 hours post-OHT) was significantly higher in Group 1 (20.0% vs 5.3%, p < 0.001). Pre-OHT amiodarone use was an independent risk factor for severe PGD (odds ratio [OR], 6.05; 95% confidence interval [CI], 2.47-14.83; p < 0.001) and in-hospital mortality (OR, 2.88; 95% CI, 1.05-7.88; p = 0.039) in multivariable analysis. Each 100-mg increase in the day-of-OHT amiodarone dose (OR, 1.55; 95% CI, 1.26-1.90) and each 18,300-mg increase in the 6-month cumulative dose (OR, 1.67; 95% CI, 1.31-2.15) was associated with increased odds of developing severe PGD (p < 0.001 for both). CONCLUSIONS: Amiodarone use pre-OHT is independently associated with increased incidence of severe PGD and in-hospital mortality and linearly associated with increased incidence of severe PGD in a dose-dependent manner.