What If the Destination Is Transplant? Outcomes of Destination Therapy Patients Who Were Transplanted

We sought to characterize patients who underwent heart transplant (HTx) following destination therapy (DT) implant in the combined ENDURANCE/ENDURANCE Supplemental Trials (DT/DT2). A post hoc analysis of the DT/DT2 trials was performed. Baseline characteristics and adverse events between the HTx and no-HTx cohorts were analyzed. Reasons for transplant were examined. Time to HTx was compared with contemporaneous HVAD BTT trial patients. Of the 604 DT/DT2 HVAD patients, 80 (13%) underwent HTx. The HTx cohort was younger (53.6 ± 11.1 vs. 65.2 ± 10.8, P \u3c 0.0001) with fewer Caucasians (60.0% vs. 76.5%, P = 0.002), less ischemic cardiomyopathy (42.5% vs. 58.8%, P = 0.01), and atrial fibrillation (38.8% vs. 54.4%, P = 0.01). The HTx cohort had longer 6-minute walk distances (183.6 vs. 38.0 m, P = 0.02). Most HTx in DT/DT2 were categorized as elective (n = 63, 79%) and, of these, 70% were due to modification of behavioral issues and weight loss. Adverse events were the main indication for urgent HTx (n = 17, 21%). Median times to HTx were longer in DT/DT2 (550.0 days) versus BTT/lateral (285.2 days). In this post hoc analysis of the DT/DT2 trials, over 1 in 10 underwent heart transplantation within 3 years of HVAD support. In DT therapy patients, consideration for transplant following DT VAD implant may be feasible

Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients The ROADMAP Study 2-Year Results

OBJECTIVES The authors sought to provide the pre-specified primary endpoint of the ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients) trial at 2 years. BACKGROUND The ROADMAP trial was a prospective nonrandomized observational study of 200 patients (97 with a left ventricular assist device [LVAD], 103 on optimal medical management [OMM]) that showed that survival with improved functional status at 1 year was better with LVADs compared with OMM in a patient population of ambulatory New York Heart Association functional class IIIb/IV patients. METHODS The primary composite endpoint was survival on original therapy with improvement in 6-min walk distance \u3e= 75 m. RESULTS Patients receiving LVAD versus OMM had lower baseline health-related quality of life, reduced Seattle Heart Failure Model 1-year survival (78% vs. 84%; p = 0.012), and were predominantly INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profile 4 (65% vs. 34%; p \u3c 0.001) versus profiles 5 to 7. More LVAD patients met the primary endpoint at 2 years: 30% LVAD versus 12% OMM (odds ratio: 3.2 [95% confidence interval: 1.3 to 7.7]; p = 0.012). Survival as treated on original therapy at 2 years was greater for LVAD versus OMM (70 +/- 5% vs. 41 +/- 5%; p \u3c 0.001), but there was no difference in intent-to-treat survival (70 +/- 5% vs. 63 +/- 5%; p = 0.307). In the OMM arm, 23 of 103 (22%) received delayed LVADs (18 within 12 months; 5 from 12 to 24 months). LVAD adverse events declined after year 1 for bleeding (primarily gastrointestinal) and arrhythmias. CONCLUSIONS Survival on original therapy with improvement in 6-min walk distance was superior with LVAD compared with OMM at 2 years. Reduction in key adverse events beyond 1 year was observed in the LVAD group. The ROADMAP trial provides risk-benefit information to guide patient- and physician-shared decision making for elective LVAD therapy as a treatment for heart failure. (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients [ROADMAP]; NCT01452802

Sudden cardiac death in patients with ischemic heart failure undergoing coronary artery bypass grafting results from the STICH randomized clinical trial (Surgical Treatment for Ischemic Heart Failure)

Background—The risk of sudden cardiac death (SCD) in patients with heart failure following CABG has not been examined in a contemporary clinical trial of surgical revascularization. This analysis describes the incidence, timing and clinical predictors of SCD after CABG. Methods—Patients enrolled in the Surgical Treatment of Ischemic Heart Failure (STICH) trial who underwent CABG with or without surgical ventricular reconstruction (SVR) were included. We excluded patients with prior ICD and those randomized only to medical therapy. The primary outcome was SCD as adjudicated by a blinded committee. A Cox model was used to examine and identify predictors of SCD. The Fine and Gray method was used to estimate the incidence of SCD accounting for the competing risk of other deaths. Results—Over a median follow-up of 46 months, 113 patients of 1411 patients who received CABG without (n = 934) or with SVR (n = 477) had SCD; 311 died of other causes. The mean LVEF at enrollment was 28±9%. The 5-year cumulative incidence of SCD was 8.5%. Patients who had SCD and those who did not die were younger and had fewer comorbid conditions than those who died for reasons other than SCD. In the first 30 days after CABG, SCD (n=5) accounted for 7% of all deaths. The numerically greatest monthly rate of SCD was in the 31-90 day time period. In a multivariable analysis including baseline demographics, risk factors, coronary anatomy and LV function, ESVI and BNP were most strongly associated with SCD. Conclusions—The monthly risk of SCD shortly after CABG among patients with a low LVEF is highest between the first and third month, suggesting that risk stratification for SCD should occur early in the postoperative period, particularly in patients with increased preoperative ESVI and/or BNP

Regression of pressure-induced left ventricular hypertrophy is characterized by a distinct gene expression profile

Left ventricular hypertrophy (LVH) is a highly prevalent and robust predictor of cardiovascular morbidity and mortality. Existing studies have finely detailed mechanisms involved with its development, yet clinical translation of these findings remains unsatisfactory. We propose an alternative strategy focusing on mechanisms of LVH regression rather than its progression and hypothesize that LVH regression is associated with a distinct genomic profil

Inhibitory kappa B kinase-β is a target for specific nuclear factor kappa B-mediated delayed cardioprotection

Myocardial ischemia/reperfusion injury remains a vexing problem. Translating experimental strategies that deliver protective agents before the ischemic insult limits clinical applicability. We targeted 2 proteins in the nuclear factor-κB pathway, inhibitory kappa B kinase-β, and 26S cardiac proteasome to determine their cardioprotective effects when delivered during reperfusion.C57BL/6 mice underwent left anterior descending artery occlusion for 30 minutes. An inhibitory kappa B kinase-β inhibitor (Compound A), a proteasome inhibitor (PS-519), or vehicle was administered at left anterior descending artery release or 2 hours afterward. Infarct size was analyzed 24 hours later. Pressure-volume loops were performed at 72 hours. Serum and left ventricular tissue were collected 1 hour after injury to examine protein expression by enzyme-linked immunosorbent assay and Western blot.Inhibitory kappa B kinase-β and proteasome inhibition significantly attenuated infarct size and preserved ejection fraction compared with the vehicle groups. When delivered even 2 hours after reperfusion, Compound A, but not PS-519, still decreased infarct size in mice. Finally, when delivered at reperfusion, successful inhibition of phosphorylated-p65 and decreased interleukin-6 and tumor necrosis factor-α levels occurred in mice given the inhibitory kappa B kinase-β inhibitor, but not in mice with proteasome inhibition.Although inhibitory kappa B kinase-β and proteasome inhibition at reperfusion attenuated infarct size after acute ischemia/reperfusion, only inhibitory kappa B kinase-β inhibition provided cardioprotection through specific suppression of nuclear factor-κB signaling. This feature of highly targeted nuclear factor-κB inhibition might account for its delayed protective effects, providing a clinically relevant option for treating myocardial ischemia/reperfusion associated with unknown periods of ischemia and reperfusion as seen in cardiac surgery and acute coronary syndromes

Inhibitory kappa B kinase-β is a target for specific nuclear factor kappa B-mediated delayed cardioprotection

Myocardial ischemia/reperfusion injury remains a vexing problem. Translating experimental strategies that deliver protective agents before the ischemic insult limits clinical applicability. We targeted 2 proteins in the nuclear factor-κB pathway, inhibitory kappa B kinase-β, and 26S cardiac proteasome to determine their cardioprotective effects when delivered during reperfusion.C57BL/6 mice underwent left anterior descending artery occlusion for 30 minutes. An inhibitory kappa B kinase-β inhibitor (Compound A), a proteasome inhibitor (PS-519), or vehicle was administered at left anterior descending artery release or 2 hours afterward. Infarct size was analyzed 24 hours later. Pressure-volume loops were performed at 72 hours. Serum and left ventricular tissue were collected 1 hour after injury to examine protein expression by enzyme-linked immunosorbent assay and Western blot.Inhibitory kappa B kinase-β and proteasome inhibition significantly attenuated infarct size and preserved ejection fraction compared with the vehicle groups. When delivered even 2 hours after reperfusion, Compound A, but not PS-519, still decreased infarct size in mice. Finally, when delivered at reperfusion, successful inhibition of phosphorylated-p65 and decreased interleukin-6 and tumor necrosis factor-α levels occurred in mice given the inhibitory kappa B kinase-β inhibitor, but not in mice with proteasome inhibition.Although inhibitory kappa B kinase-β and proteasome inhibition at reperfusion attenuated infarct size after acute ischemia/reperfusion, only inhibitory kappa B kinase-β inhibition provided cardioprotection through specific suppression of nuclear factor-κB signaling. This feature of highly targeted nuclear factor-κB inhibition might account for its delayed protective effects, providing a clinically relevant option for treating myocardial ischemia/reperfusion associated with unknown periods of ischemia and reperfusion as seen in cardiac surgery and acute coronary syndromes

Myocardin inhibits cellular proliferation by inhibiting NF- B(p65)-dependent cell cycle progression

We previously reported the importance of the serum response factor (SRF) cofactor myocardin in controlling muscle gene expression as well as the fundamental role for the inflammatory transcription factor NF-κB in governing cellular fate. Inactivation of myocardin has been implicated in malignant tumor growth. However, the underlying mechanism of myocardin regulation of cellular growth remains unclear. Here we show that NF-κB(p65) represses myocardin activation of cardiac and smooth muscle genes in a CArG-box-dependent manner. Consistent with their functional interaction, p65 directly interacts with myocardin and inhibits the formation of the myocardin/SRF/CArG ternary complex in vitro and in vivo. Conversely, myocardin decreases p65-mediated target gene activation by interfering with p65 DNA binding and abrogates LPS-induced TNF-α expression. Importantly, myocardin inhibits cellular proliferation by interfering with NF-κB-dependent cell-cycle regulation. Cumulatively, these findings identify a function for myocardin as an SRF-independent transcriptional repressor and cell-cycle regulator and provide a molecular mechanism by which interaction between NF-κB and myocardin plays a central role in modulating cellular proliferation and differentiation

Evidence of Glycolysis Up-Regulation and Pyruvate Mitochondrial Oxidation Mismatch During Mechanical Unloading of the Failing Human Heart: Implications for Cardiac Reloading and Conditioning

This study sought to investigate the effects of mechanical unloading on myocardial energetics and the metabolic perturbation of heart failure (HF) in an effort to identify potential new therapeutic targets that could enhance the unloading-induced cardiac recovery. The authors prospectively examined paired human myocardial tissue procured from 31 advanced HF patients at left ventricular assist device (LVAD) implant and at heart transplant plus tissue from 11 normal donors. They identified increased post-LVAD glycolytic metabolites without a coordinate increase in early, tricarboxylic acid (TCA) cycle intermediates. The increased pyruvate was not directed toward the mitochondria and the TCA cycle for complete oxidation, but instead, was mainly converted to cytosolic lactate. Increased nucleotide concentrations were present, potentially indicating increased flux through the pentose phosphate pathway. Evaluation of mitochondrial function and structure revealed a lack of post-LVAD improvement in mitochondrial oxidative functional capacity, mitochondrial volume density, and deoxyribonucleic acid content. Finally, post-LVAD unloading, amino acid levels were found to be increased and could represent a compensatory mechanism and an alternative energy source that could fuel the TCA cycle by anaplerosis. In summary, the authors report evidence that LVAD unloading induces glycolysis in concert with pyruvate mitochondrial oxidation mismatch, most likely as a result of persistent mitochondrial dysfunction. These findings suggest that interventions known to improve mitochondrial biogenesis, structure, and function, such as controlled cardiac reloading and conditioning, warrant further investigation to enhance unloading-induced reverse remodeling and cardiac recovery

Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure

Cardiovascular disease is the leading cause of human morbidity and mortality. Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy associated with heart failure. Here, we report that cardiac-specific knockout of Dicer, a gene encoding a RNase III endonuclease essential for microRNA (miRNA) processing, leads to rapidly progressive DCM, heart failure, and postnatal lethality. Dicer mutant mice show misexpression of cardiac contractile proteins and profound sarcomere disarray. Functional analyses indicate significantly reduced heart rates and decreased fractional shortening of Dicer mutant hearts. Consistent with the role of Dicer in animal hearts, Dicer expression was decreased in end-stage human DCM and failing hearts and, most importantly, a significant increase of Dicer expression was observed in those hearts after left ventricle assist devices were inserted to improve cardiac function. Together, our studies demonstrate essential roles for Dicer in cardiac contraction and indicate that miRNAs play critical roles in normal cardiac function and under pathological conditions

Lkb1 Deficiency Alters Goblet and Paneth Cell Differentiation in the Small Intestine

The Lkb1 tumour suppressor is a multitasking kinase participating in a range of physiological processes. We have determined the impact of Lkb1 deficiency on intestinal homeostasis, particularly focussing on secretory cell differentiation and development since we observe strong expression of Lkb1 in normal small intestine Paneth and goblet cells. We crossed mice bearing an Lkb1 allele flanked with LoxP sites with those carrying a Cyp1a1-specific inducible Cre recombinase. Lkb1 was efficiently deleted from the epithelial cells of the mouse intestine after intraperitoneal injection of the inducing agent β-naphthoflavone. Bi-allelic loss of Lkb1 led to the perturbed development of Paneth and goblet cell lineages. These changes were characterised by the lack of Delta ligand expression in Lkb1-deficient secretory cells and a significant increase in the levels of the downstream Notch signalling effector Hes5 but not Hes1. Our data show that Lkb1 is required for the normal differentiation of secretory cell lineages within the intestine, and that Lkb1 deficiency modulates Notch signalling modulation in post-mitotic cells