Stulak, John M.

Background: The FOXO3a (forkhead box O3a)-BNIP3 (B-cell lymphoma 2/adenovirus E1B 19kDa interacting protein 3) pathway modulates mitochondrial dynamics and function and contributes to myocardial remodeling in rodent models of heart failure. We sought to investigate the expression of this pathway along with the expression of mitochondrial biogenesis (PGC-1α [peroxisome proliferator-activated receptor-γ coactivator-1α]), dynamics (DRP-1 [dynamin-related protein 1], OPA-1 [optic atrophy 1], and MFN 2 [mitofusin 2]), and oxidative phosphorylation (citrate synthase and electron transport chain complexes) markers and COX IV (cytochrome C oxidase) activity in myocardium from patients with valvular or ischemic heart disease and heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF). Methods and Results: Subepicardial left ventricular biopsies (10×1×1 mm 3 ) were obtained at aortic valve replacement (HFpEF AVR , n=5; and HFrEF AVR , n=4), coronary artery bypass grafting (HFpEF CABG , n=5; and HFrEF CABG , n=5), or left ventricular assist device implantation (HFrEF LVAD , n=4). Subepicardial biopsies from patients with normal left ventricular function (n=2) and from donor hearts (n=3) served as controls (normal). Relative to normal, mitochondrial fragmentation and cristae destruction were evident, and mitochondrial area was decreased in HFpEF; 1.00±0.09 versus 0.71±0.08; P =0.016. These mitochondrial morphological changes were more pronounced in HFrEF (0.54±0.06); P =0.002 HFpEF versus HFrEF. BNIP3 (monomer+dimer) expression was increased in HFpEF (3.99±2.44) and in HFrEF (5.19±1.70) relative to normal; P =0.004 and P <0.001, respectively. However, BNIP3 monomer was increased in HFrEF (4.32±1.43) compared with normal (0.99±0.06) and HFpEF (1.97±0.90); P =0.001 and 0.004, respectively. The HFrEF group uniquely showed increase in DRP-1 expression (1.94±0.38) and decreases in PGC-1α expression (0.61±0.07) and COX IV activity (0.70±0.10) relative to normal; P =0.013, P <0.001, and P <0.001, respectively, with no significant change in electron transport chain complexes expression. Conclusions: These findings in human myocardium confirm studies in rodents where contractile dysfunction is associated with activation of the FOXO3a-BNIP3 pathway and altered mitochondrial dynamics, biogenesis, and function.

Abstract Various risk models with differing discriminatory power and predictive accuracy have been used to predict right ventricular failure (RVF) after left ventricular assist device (LVAD) placement. There remains an unmet need for a contemporary risk score for continuous flow (CF)‐LVADs. We sought to independently validate and compare existing risk models in a large cohort of patients and develop a simple, yet highly predictive risk score for acute, severe RVF. Data from the Mechanical Circulatory Support Research Network (MCSRN) registry, consisting of patients who underwent CF‐LVAD implantation, were randomly divided into equal‐sized derivation and validation samples. RVF scores were calculated for the entire sample, and the need for a right ventricular assist device (RVAD) was the primary endpoint. Candidate predictors from the derivation sample were subjected to backward stepwise logistic regression until the model with lowest Akaike information criterion value was identified. A risk score was developed based on the identified variables and their respective regression coefficients. Between May 2004 and September 2014, 734 patients underwent implantation of CF‐LVADs [HeartMate II LVAD, 76% ( n = 560), HeartWare HVAD, 24% ( n = 174)]. A RVAD was required in 4.5% ( n = 33) of the patients [Derivation cohort, n = 15 (4.3%); Validation cohort, n = 18 (5.2%); P = 0.68)]. 19.5% of the patients ( n = 143) were female, median age at implant was 59 years (IQR, 49.4–65.3), and median INTERMACS profile was 3 (IQR, 2–3). RVAD was required in 4.5% ( n = 33) of the patients. Correlates of acute, severe RVF in the final model included heart rate, albumin, BUN, WBC, cardiac index, and TR severity. Areas under the curves (AUC) for most commonly used risk predictors ranged from 0.61 to 0.78. The AUC for the new model was 0.89 in the derivation and 0.92 in the validation cohort. Proposed risk model provides very high discriminatory power predicting acute severe right ventricular failure and can be reliably applied to patients undergoing placement of contemporary continuous flow left ventricular assist devices.

Background There are limited data on the role of temporary mechanical circulatory support ( MCS ) devices for cardiogenic shock before left ventricular assist device ( LVAD ) surgery. This study sought to evaluate the trends of use and outcomes of MCS in cardiogenic shock before LVAD surgery. Methods and Results This was a retrospective cohort study from 2005 to 2014 using the National Inpatient Sample (20% stratified sample of US hospitals). This study identified admissions undergoing LVAD surgery with preoperative cardiogenic shock. Admissions for other cardiac surgery and heart transplant were excluded. Temporary MCS was identified using administrative codes. The primary outcome was hospital mortality and secondary outcomes were hospital costs and lengths of stay in admissions with and without MCS use. In this 10‐year period, 9753 admissions were identified with 40.6% requiring pre‐ LVAD MCS . There was a temporal increase in the frequency of cardiogenic shock associated with an increase in non–intra‐aortic balloon pump MCS devices. The cohort receiving MCS had greater in‐hospital myocardial infarction, ventricular arrhythmias, and use of coronary angiography. On multivariable analysis, older age, myocardial infarction, and need for MCS devices were independently predictive of higher in‐hospital mortality. In 696 propensity‐matched pairs, use of MCS was predictive of higher in‐hospital mortality (odds ratio 1.4 [95% confidence interval 1.1–1.6]; P =0.02) and higher hospital costs, but similar lengths of stay. Conclusions In patients with cardiogenic shock bridged to LVAD therapy, there was a steady increase in preoperative MCS use. Use of MCS identified patients at higher risk for in‐hospital mortality and greater resource utilization.

Abstract Aim The lungs—and particularly the alveolar-capillary membrane—may be sensitive to continuous flow (CF) and pulmonary pressure alterations in heart failure (HF). We aimed to investigate long-term effects of CF pumps on respiratory function. Methods and results We conducted a retrospective study of patients with end-stage HF at our institution. We analysed pulmonary function tests [e.g. forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)] and diffusing capacity of the lung for carbon monoxide (DLCO) from before and after left ventricular assist device (LVAD) implantation and compared them with invasive haemodynamic studies. Of the 274 patients screened, final study analysis involved 44 patients with end-stage HF who had CF LVAD implantation between 1 February 2007 and 31 December 2015 at our institution. These patients [mean (standard deviation, SD) age, 50 (9) years; male sex, n = 33, 75%] received either the HeartMate II (Thoratec Corp.) pump (77%) or the HeartWare (HeartWare International Inc.) pump. The mean (SD) left ventricular ejection fraction was 21% (13%). At a median of 237 days post-LVAD implantation, we observed significant DLCO decrease (−23%) since pre-implantation (P &lt; 0.001). ΔDLCO had an inverse relationship with changes in pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP) from pre-LVAD to post-LVAD implantation: ΔDLCO to ΔPCWP (r = 0.50, P &lt; 0.01) and ΔDLCO to ΔRAP (r = 0.39, P &lt; 0.05). We observed other reductions in FEV1, FVC, and FEV1/FVC between pre-LVAD and post-LVAD implantation. In mean (SD) values, FEV1 changed from 2.3 (0.7) to 2.1 (0.7) (P = 0.005); FVC decreased from 3.2 (0.8) to 2.9 (0.9) (P = 0.01); and FEV1/FVC went from 0.72 (0.1) to 0.72 (0.1) (P = 0.50). Landmark survival analysis revealed that ΔDLCO from 6 months after LVAD implantation was predictive of death for HF patients [hazard ratio (95% confidence interval), 0.60 (0.28–0.98); P = 0.03]. Conclusions Pulmonary function did not improve after LVAD implantation. The degree of DLCO deterioration is related to haemodynamic status post-LVAD implantation. The ΔDLCO within 6 months post-operative was associated with survival.

Despite the growing acceptance of left ventricular assist device (LVAD) therapy to improve survival and quality of life in heart failure (HF) patients, uncertainties persist regarding the definition of a successful implant. We sought to define an innovative approach to assess success and subsequently compare preoperative variables affecting outcomes. From January 2007 to 2015, 278 patients underwent LVAD implantation. Median age at implant was 62 years and 81% patients were males. Indication for support was bridge-to-transplantation in 36% patients and the etiology of HF was ischemic in 49% patients. Based on clinically relevant and accepted standards, we defined successful LVAD implant as someone who was alive or transplanted at 2 years, had two or less readmissions in the first year, had no major adverse events in the first year, and had a New York Heart Association class of ≤ II at 6 months. Follow-up was obtained for a median of 1.7 years for a total of 605 patient-years-of-support. Based on our criteria, 81/278 (29%) patients were defined as having a successful implant. Univariate predictors of LVAD failure included destination therapy indication (hazard ratio [HR] = 2.11 [1.24, 3.58]), ischemic cardiomyopathy (HR = 1.73 [1.02, 2.94]), and a higher left ventricular ejection fraction (HR = 1.54 [1.07, 2.22]). After multivariable analysis, only destination therapy indication (HR = 2.2 [1.28, 3.78]) was found to be independently predictive of success failure. Despite an overall trend toward improved outcomes on device therapy, our criteria classified only one-third of patients as successful. Continued improvements in adverse event profiles, appropriate patient selection, and optimal time of implantation, together hold the key to improve outcomes after LVAD therapy.

BACKGROUND: Previous studies on readmissions after left ventricular assist device (LVAD) implantation have focused on hospital readmissions after dismissal from the index hospitalization. Because few data exist, the purpose of this study was to examine intensive care unit (ICU) readmissions in patients during their initial hospitalization for LVAD implantation to determine reasons for, factors associated with, and incidence of mortality after ICU readmission. METHODS: A retrospective analysis was performed from February 2007 to March 2015 of patients at our institution receiving first-time LVAD implantation. After LVAD implantation, patients dismissed from the ICU who then required ICU readmission before hospital dismissal were compared to those not requiring ICU readmission before hospital dismissal with respect to preoperative, intraoperative, and postoperative factors. RESULTS: Among 287 LVAD patients, 266 survived their initial ICU admission, of which 49 (18.4%) required ICU readmission. The most common reasons for readmission were bleeding and respiratory failure. Factors found to be univariably associated with ICU readmission were preoperative hemoglobin, preoperative aspartate aminotransferase, preoperative atrial fibrillation, preoperative dialysis, longer cardiopulmonary bypass times, and higher intraoperative allogeneic blood transfusion requirements. Multivariable analysis revealed ICU readmission to be independently associated with preoperative dialysis (odds ratio, 12.86; 95% confidence interval, 3.16–52.28; P < .001). Overall mortality at 1 year was 22.6%. Survival after hospital dismissal was worse for patients who required ICU readmission during the index hospitalization (adjusted hazard ratio, 2.35; 95% confidence interval, 1.15–4.81; P = .019). CONCLUSIONS: ICU readmission after LVAD implantation occurred relatively frequently and was significantly associated with 1-year mortality after hospital dismissal. These data can perhaps be used to identify subsets of LVAD patients at risk for ICU readmission and may lead to implementation of practice changes to mitigate ICU readmissions. Future larger and prospective studies are warranted.

Background: There are contrasting reports on the effectiveness of a concomitant intra-aortic balloon pump (IABP) in cardiogenic shock patients treated with veno-arterial extracorporeal membrane oxygenation (VA-ECMO). This study sought to compare short-term mortality in patients with cardiogenic shock treated with VA-ECMO with and without IABP. Methods and Results: We reviewed the published literature from 2000 to 2018 for studies evaluating adult patients requiring VA-ECMO for cardiogenic shock with concomitant IABP. Studies reporting short-term mortality were included. Meta-analysis of the association of IABP with mortality was performed using Mantel-Haenszel models. Subgroup analyses were performed in patients with cardiogenic shock complicating acute myocardial infarction (AMI) and postcardiotomy cardiogenic shock. Twenty-two observational studies with 4653 patients were included. These studies showed high heterogeneity for the total and postcardiotomy cardiogenic shock cohorts and low heterogeneity for the AMI cohort. Short-term mortality was not significantly different in patients with and without IABP 42.1% versus 57.8%; risk ratio, 0.80; 95% CI, 0.52–1.22; P =0.30. However, concomitant IABP with VA-ECMO was associated with lower mortality in patients with AMI (50.8% versus 62.4%; risk ratio, 0.56; 95% CI, 0.46–0.67; P <0.001). There was no difference in mortality in postcardiotomy cardiogenic shock and mixed causes for cardiogenic shock. Conclusions: In cardiogenic shock patients requiring VA-ECMO support, the use of IABP did not influence mortality in the total cohort. In patients with AMI, use of IABP with VA-ECMO was associated with 18.5% lower mortality in comparison to patients on VA-ECMO alone. Further randomized studies are warranted to corroborate these observational data.

International normalized ratio (INR) measurements manage risks of bleeding and clotting sequelae in the population with left ventricular assist device (LVAD). Studies suggest that point-of-care (POC) INR does not significantly differ from plasma INR (P-INR) values in other patient populations, although this has not been validated in a multicenter LVAD study. We sought to determine whether POC-INR and P-INR values differ significantly in the LVAD population and reviewed patients with permanent LVAD implantation at seven institutions internationally. Our cohort comprised of 279 paired POC-INR and P-INR checks in patients supported on average 630 ± 598 days postimplant with predominately HeartWare, HeartMate II, and HeartMate III devices. The population averaged 57.9 years of age, and there were 86.7% male. We found no statistically significant difference between POC-INR and P-INR values. International normalized ratio accuracy correlated weakly with the time between INR measurements (p < 0.001). When the time difference was less than 4 hours, the difference between INR pairs was significantly lower than measurements greater than 8 hours (p = 0.006). There was no statistically significant difference when comparing paired INR values and time after implant to INR check (p = 0.43), age (p = 0.12), known coagulopathy (p = 0.12), bleeding history (p = 0.22), or thrombosis history (p = 0.34). This is the first large multicenter international study comparing POC-INR and P-INR measurements in patients with LVAD and found no statistically significant difference between either methods, particularly when measured within less than 4 hours of each other.