Differential gene expression and genomic patient stratification following left ventricular assist device support

AbstractObjectivesWe sought to determine whether mechanical unloading of the failing human heart with a left ventricular assist device (LVAD) results in significant changes in overall left ventricular gene expression.BackgroundMechanical circulatory support by LVAD in end-stage human heart failure (HF) can result in beneficial reverse remodeling of myocardial structure and function. The molecular mechanisms behind this salutary process are not well understood.MethodsLeft ventricular samples from six male patients were harvested during LVAD placement and subsequently at the time of explantation. Cardiac gene expression was determined using oligonucleotide microarrays.ResultsPaired ttest analysis revealed numerous genes that were regulated in a statistically significant fashion, including the downregulation of several previously studied genes. Further statistical analysis revealed that the overall gene expression profiles could significantly distinguish pre- and post-LVAD status. Interestingly, the data also identified two distinct groups among the pre-LVAD failing hearts, in which there was blind segregation of patients based on HF etiology. In addition to the substantial divergence in genomic profiles for these two HF groups, there were significant differences in their corresponding LVAD-mediated regulation of gene expression.ConclusionsSupport with an LVAD in HF induces significant changes in myocardial gene expression, as pre- and post-LVAD hearts demonstrate significantly distinct genomic footprints. Thus, reverse remodeling is associated with a specific pattern of gene expression. Moreover, we found that deoxyribonucleic acid microarray technology could distinguish, in a blind manner, patients with different HF etiologies. Expansion of this study and further development of these statistical methods may facilitate prognostic prediction of the individual patient response to LVAD support

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

Natural history and clinical effect of aortic valve regurgitation after left ventricular assist device implantation

ObjectivesAortic valve regurgitation reduces left ventricular assist device mechanical efficiency. Evidence has also suggested that left ventricular assist device implantation can induce or exacerbate aortic valve regurgitation. However, this has not been compared with aortic valve regurgitation progression in a nonsurgical end-stage heart failure population. Furthermore, its clinical effect is unclear. We sought to characterize the development and progression of aortic valve regurgitation in left ventricular assist device recipients and to identify its clinical effect.MethodsA review of all consecutive patients who received an intracorporeal left ventricular assist device at Duke University Medical Center from January 2004 to January 2011 was conducted. Cases of previous or concomitant aortic valve surgery were excluded. Data from the remaining implants (n = 184) and a control group of contemporaneous nonsurgical patients with end-stage heart failure (n = 132) were analyzed. Serial transthoracic echocardiography was used to characterize aortic valve regurgitation as a function of time.ResultsLeft ventricular assist device implantation was associated with worsening aortic valve regurgitation, defined as an increase in aortic valve regurgitation grade, relative to the nonsurgical patients with end-stage heart failure (P < .0001). The recipients of continuous flow left ventricular assist devices were more likely than recipients of pulsatile left ventricular assist devices to develop worsening aortic valve regurgitation (P = .0348). Moderate or severe aortic valve regurgitation developed in 21 left ventricular assist device recipients; this was unrelated to the type of device implanted (continuous vs pulsatile; P = .754) or aortic valve regurgitation grade before left ventricular assist device implantation (P = .42). Five patients developed severe aortic valve regurgitation; all of whom underwent aortic valve procedures.ConclusionsNative aortic valve regurgitation developed and/or progressed after left ventricular assist device implantation, with this effect being more pronounced in continuous flow left ventricular assist device recipients. However, the preoperative aortic valve regurgitation grade failed to correlate with the development of substantial aortic valve regurgitation after left ventricular assist device implantation. After left ventricular assist device implantation, aortic valve regurgitation had a small, but discernible, clinical effect, with some patients developing severe aortic valve regurgitation and requiring aortic valve procedures. These data have implications for the long-term management of left ventricular assist device recipients, in particular as the durability of implantable continuous flow left ventricular assist device therapy improves

Reproducibility of left atrial ablation with high-intensity focused ultrasound energy in a calf model

ObjectiveAchieving transmural tissue ablation might be necessary for successful treatment of atrial fibrillation. The purpose of this study was to evaluate the reproducibility of transmural left atrial ablation using a high-intensity focused ultrasound energy system in a calf model.MethodsNine heparinized bovines underwent a beating-heart left atrial ablation with a single application of the high-intensity focused ultrasound device. All animals were acutely killed, and the left atrium was fixed in formalin. Protocolized histological sections (5 μm) were obtained throughout each lesion and prepared with Masson trichrome and hematoxylin and eosin staining. Measurements were performed on a total of 359 slides from the 9 lesions. In addition, fresh left atrial tissues from 18 unused human donor hearts that did not meet the criteria for cardiac transplantation were measured at the site where the high-intensity focused ultrasound device is normally applied.ResultsCalf left atrial thickness ranged between 2.5 and 20.1 mm, with a mean of 9.10 mm. High-intensity focused ultrasound ablation consistently produced a 100% transmural lesion in left atrial thickness up to 6 mm. In addition, a transmural lesion was observed in 91% of tissues that were up to 10 mm thick and in 85% that were up to 15 mm thick. Human left atrial thickness ranged between 1.2 to 6 mm, with a mean of 3.7 mm.ConclusionsCalf left atrial thickness in this study was greater than human left atrial thickness. Human left atrial thickness is generally less than 6 mm, and in this range high-intensity focused ultrasound ablation achieved 100% transmurality. These histological results might correlate with a high success rate of atrial fibrillation ablation by using the high-intensity focused ultrasound system

Twenty-five-year outcomes after multiple internal thoracic artery bypass

ObjectiveCoronary artery bypass grafting with multiple internal thoracic artery grafts is currently controversial. This study assessed single institutional outcomes with multiple internal thoracic artery grafting for guidance with future clinical decisions.MethodsIn 19,482 patients undergoing multivessel coronary artery bypass grafting (1984-2009), baseline characteristics were recorded in a prospective databank, and follow-up was obtained by questionnaires, phone contact, or National Death Index. Outcomes examined were subsequent myocardial infarction, percutaneous coronary intervention, reoperative coronary artery bypass grafting, all-cause death, and a composite of the 4. Three groups were defined: (1) no internal thoracic artery graft (1874/19,482 or 9%); (2) single internal thoracic artery grafts and adjunctive venous conduits (single internal thoracic artery; 16,881/19,482 or 87%); and (3) multiple internal thoracic artery grafts (728/19,482 or 4%). Multivariable Cox modeling adjusted for differences in baseline characteristics, and comparisons were performed using area under the curve analysis.ResultsDifferences in baseline characteristics for the no internal thoracic artery graft, single internal thoracic artery, and multiple internal thoracic artery groups were as follows: median age 66, 64, and 59 years, respectively; congestive heart failure 22%, 18%, and 13%, respectively; ejection fraction 0.50, 0.52, and 0.51, respectively; reoperation 10%, 3%, and 7%, respectively; diabetes 27%, 30%, and 15%, respectively; and female gender 33%, 28%, and 20%, respectively. No differences existed in the median number of diseased vessels (3, 3, and 3, respectively) or number of grafts per patient (3, 3, and 3, respectively). Composite outcome improved with increasing internal thoracic artery grafts, whether assessing unadjusted or risk-adjusted data. Compared with no internal thoracic artery graft, the adjusted hazard ratio was 0.79 (confidence interval, 0.74-0.83) for single internal thoracic artery grafting and 0.70 (confidence interval, 0.62-0.80) for multiple internal thoracic artery grafting (both P < .001), reducing risk by 21% and 30%, respectively.ConclusionsThis study confirms improved patient outcomes with multiple internal thoracic artery grafting, achieving half again as much benefit as single internal thoracic artery grafting alone. The data suggest that increasing application of multiple internal thoracic artery grafting should be encouraged to mitigate the inherent risks and costs of long-term cardiac events

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

Hemodynamic Predictors of Heart Failure Morbidity and Mortality: Fluid or Flow?

BACKGROUND: Patients with advanced heart failure may persist for prolonged times with persistent hemodynamic abnormalities; intermediate and long-term outcomes of these patients are unknown. METHODS AND RESULTS: We used ESCAPE trial data to examine characteristics and outcomes of patients with invasive hemodynamic monitoring during an acute heart failure hospitalization. Patients were stratified by final measurement of cardiac index (CI; L/min/m2) and pulmonary capillary wedge pressure (PCWP; mmHg) before catheter removal. The study groups were CI ≥ 2/PCWP <20 (n = 74), CI ≥ 2/PCWP ≥ 20 (n = 37), CI < 2/PCWP < 20 (n = 23), and CI < 2/PCWP ≥ 20 (n = 17). Final CI was not associated with the combined risk of death, cardiovascular hospitalization, and transplantation (HR:1.03, 95% CI:0.96–1.11 per 0.2 L/min/m(2) decrease, p=0.39), but final PCWP ≥ 20mmHg was associated with increased risk of these events (HR:2.03, 95% CI:1.31–3.15, p<0.01), as was higher final right atrial pressure (RAP; HR:1.09, 95% CI:1.06–1.12 per mmHg increase, p<0.01). CONCLUSION: Final PCWP and final RAP were stronger predictors of post-discharge outcomes than CI in patients with advanced heart failure. The ability to lower filling pressures appears to be more prognostically important than improving CI in the management of patients with advanced heart failure. CLINICALTRIALS.GOV IDENTIFIER: NCT0000061