Joyce, Lyle D.

Abstract Abstract 1122 Background: Continuous flow left ventricular assist device (CF-LVAD) recipients have increased tendency of post-surgical bleeding. We have previously described a universal loss of high molecular weight VWF multimers (HMWM), likely due to enhanced cleavage of the HMWM in CF-LVAD recipients. Among various VWF laboratory tests, VWF multimer analysis remains the reference method for detecting such an acquired VWF abnormality (AVWA). We hypothesize that the severity of AVWA is a predictor for bleeding tendency. In this study, using our in-gel VWF multimer electrophoresis method, we measured the severity of HMWM loss in CF-LVAD recipients by infra-red densitometry analysis and examined its association with other VWF activity test results and patients' bleeding tendency. Design: As part of an on-going prospective multicenter study, pre- and/or post-CF-LVAD implantation (7, 30 days and 5–7 months) blood samples were collected from 20 LVAD recipients during 2008 and 2009. Their clinically significant bleeding episodes were recorded. Plasma VWF antigen (VWF:Ag), VWF:Lx activity [Chen D, et al. J Thromb Haemost. 2011;9(10):1993–2002] and plasma VWF multimer analyses [Pruthi RK, et al. Thromb Res. 2010;126(6):543–9] were performed on all available plasma samples. VWF multimers were quantified by infra-red fluorescent densitometry analysis using Odyssey Infrared Imager version 2.0. VWF:multi ratio defined by density ratio between the high molecular weight multimer (HMWM, bands 11 and above) and low and intermediate molecular weight multimer (band 2 to 9) was calculated. Normal range of VWF:multi ratio was determined from 16 normal donor plasma and 4 pooled normal plasma. Statistical analyses including t-test and kappa test were employed. Result: The normal range of VWF:multi ratio is 0.4–0.76. The CV of VWF:multi ratio of a pooled normal plasma tested in 21 gel runs is 12%. Loss of VWF HMWM is present in three patients before CF-LVAD implantation and all patients after implantation. All samples with loss of HMWM show decreased VWF:multi ratio (<0.4). At a cut-off value of 0.4, the sensitivity and specificity of VWF:multi ratio for detecting HMWM loss are 100% and 95.5% respectively (n=67). Decrease of VWF:multi ratio is observed after implantation (0.41±0.07 pre- vs. 0.29±0.07 post-implantation, P<0.00001). In four patients who received heart transplantation, normalization of VWF multimer pattern and VWF:multi ratio (0.54±0.06) is observed. Ten patients had significant post-implantation bleeding episodes that are associated with significantly decreased VWF:multi ratio (0.26±0.04 bleeding vs. 0.32±0.09 non-bleeding, P=0.002) and VWF Lx/Ag ratio (0.72±0.10 bleeding vs 0.80±0.09 non-bleeding, P=0.001). At a cut-off of 0.26, VWF:multi ratio demonstrates a sensitivity of 64% and specificity of 85.7% for predicting clinically significant bleeding. The VWF:multi ratio shows moderate agreement with VWF:Lx/Ag ratio (Kappa value 0.42). Conclusions: Severity of VWF HMWM losses can be quantitatively measured by the new in-gel infra-red densitometry method (VWF:multi ratio). Severity of VWF HMWM losses defined by the VWF:multi ratios, along with VWF:Lx/Ag ratios are significantly associated with bleeding tendency in LVAD recipients. Disclosures: Milano: Thoratec: Consultancy.

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 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.

The gold standard for noninvasive blood pressure (BP) measurement, the Doppler technique, does not provide systolic blood pressure (SBP) and diastolic blood pressure (DBP) and may limit therapy outcomes. To improve patient care, we tested specifically designed experimental BP (ExpBP) monitor and the Doppler technique by comparing noninvasive measures to the intraarterial (I-A) BP in 31 patients with end-stage heart failure (4 females) 2.6 ± 3.4 days post-LVAD implantation (20 HeartMate II and 11 HeartWare). Bland–Altman plots revealed that the ExpBP monitor overestimated mean arterial pressure (MAP) by 1.2 (4.8) mm Hg (mean difference [standard deviation]), whereas the Doppler by 6.7 (5.8) mm Hg. The ExpBP SBP was overestimated by 0.8 (6.1) mm Hg and DBP by 1.9 (5.3) mm Hg compared with the respective I-A pressures. Both techniques achieved similar measurement reliability. In the measurement “success rate” expressed as a frequency (percent) of readable BP values per measurement attempts, Doppler accomplished 100% vs. 97%, 97%, and 94% of successful detections of MAP, SBP, and DBP provided by the ExpBP monitor. The ExpBP monitor demonstrated higher accuracy in the MAP assessment than the Doppler in addition to providing SBP and DBP in majority of subjects. Improved BP control may help to mitigate related neurologic adverse event rates.

Background Diabetes mellitus (DM) is a risk factor for morbidity and mortality in patients with heart failure. The effect of DM on post–left ventricular assist device (LVAD) implantation outcomes is unclear. This study sought to investigate whether patients with DM had worse outcomes than patients without DM after LVAD implantation and whether LVAD support resulted in a better control of DM. Methods and Results We retrospectively reviewed 341 consecutive adults who underwent implantation of LVAD from 2007 to 2016. Patient characteristics and adverse events were studied and compared between patients with and without DM. One hundred thirty-one patients (38%) had DM. Compared with patients without DM, those with DM had higher rates of ischemic cardiomyopathy, LVAD implantation as destination therapy, and increased baseline body mass index. In a proportional hazards (Cox) model with adjustment for relevant covariates and median follow-up of 16.1 months, DM was associated with increased risk of all-cause mortality (hazard ratio, 1.73; 95% confidence interval: 1.18–2.53; P =0.005) and increased risk of nonfatal LVAD-related complications, including a composite of stroke, pump thrombosis, and device infection (hazard ratio, 2.1; 95% confidence interval: 1.35–3.18; P =0.001). Preoperative hemoglobin A1c was not significantly associated with mortality or adverse events among patients with DM. LVAD implantation resulted in a remarkable decrease in hemoglobin A1c levels (7.4±1.9 pre-LVAD versus 6.0±1.5 and 6.3±1.4 after 3 and 12 months post-LVAD, respectively; P <0.0001) and a significant reduction in requirements of DM medications. Conclusions DM is associated with increased rates of all-cause mortality and major adverse events despite favorable glycemic control after LVAD implantation.

Atrial fibrillation (AF) and tricuspid regurgitation (TR) are common in patients undergoing left ventricular assist device (LVAD) implantation. TR progression is associated with the presence of AF, and questions remain as to who benefits from tricuspid valve procedures (TVPs). We examined the impact of preoperative AF on TR progression after LVAD implantation. From February 2007 to May 2014, 250 patients underwent LVAD implantation at our institution. Patients with concomitant TVP were excluded from this analysis (113 patients). The indication for LVAD was destination therapy in 80 patients (58%) and the etiology of heart failure was ischemic in 73 (53%). Follow-up was available in all early survivors for a total of 393 patient-years of support. Of the 137 non-TVP patients, 52 (38%) had AF preoperatively. Observed overall survival at 1, 3, and 5 years was 82%, 67%, and 55%, respectively. Median grade of TR increased from 2 preoperatively to 3 (p = 0.04) in the AF group and 2.2 (p = 0.75) in the non-AF group at 5 years of follow-up. We also observed a significant difference in the degree of TR between groups at 3 months (p = 0.03) and 12 months (p = 0.01) postimplantation, and a trend toward significance at 18 (p = 0.06) and 24 (p = 0.07) months. The presence of AF is associated with early progression of TR after LVAD implantation. Addition of concomitant TVP in patients with preoperative AF may be considered in patients with less than severe TR. The impact of these findings on right ventricular failure/remodeling remains to be evaluated.

Wait times have increased for patients approved for heart transplants. We reviewed United Network for Organ Sharing (UNOS) data for 14,242 patients listed for isolated heart transplant (2009–2013) to develop a risk score model for timing left ventricular assist device (LVAD) implantation in bridge-to-transplant patients. We used a multivariable Cox proportional hazards regression model with subsequent bootstrap resampling for internal validation to develop a scoring system that combined risk factors, weighted by the corresponding regression coefficients, to define an individual’s risk score. Four risk factors were identified (body mass index, blood type, region, and urgency status) to be significantly and independently associated with wait time (p < 0.001), showing adequate model discrimination (C = 0.704) and calibration. Higher risk scores correlated with shorter wait times. Our model corresponded closely with observed transplant rates, predicting longer wait times for lower status, larger size, certain blood groups, and some UNOS regions. This tool has the potential to more accurately describe the wait-time duration for an individual patient, which may influence care decisions. The wait-time discrepancies (blood types/regions) reinforce the need to reevaluate the geographic-allocation policy. The proposed review of the UNOS heart allocation policy may make this model especially relevant.

Although improvement in cardiac output and hemodynamic parameters is routinely demonstrated in patients implanted with continuous-flow left ventricular assist devices (CF-LVADs), improvement in exercise capacity is inconsistently seen. Our purpose was to determine whether native cardiac factors, LVAD factors, or comorbid factors were associated with lack of improvement. Review of all patients undergoing preimplant cardiopulmonary exercise testing (CPET) and CPET on LVAD therapy at one institution was performed between 2007 and 2014 (n = 49). Comprehensive assessment of echocardiographic parameters, right heart catheterization data, medications, and comorbid illness was undertaken. There was no mean improvement in peak oxygen consumption (VO2; 11.8–12.4 ml/kg/min; p = 0.26), although exercise time (5.1 [46% predicted] to 5.8 min [56% predicted]; p = 0.02) and nadir of the ratio of minute ventilation to carbon dioxide production slope (VE/VCO2; 39–36; p = 0.001) improved. Factors most strongly associated with improvement in VO2 were Heartmate II pulsatility index (PI; R = 0.48; p = 0.001), power (R = −0.40; p = 0.009), pump flow (R = −0.40; p = 0.008), and pump speed (R = −0.32; p = 0.04). Peak heart rate (HR) was also associated with improvement in VO2 (R = 0.41; p = 0.004). Left ventricular ejection fraction (LVEF; R = 0.004; p = 0.77), right ventricular (RV) function (R = 0.22; p = 0.28), and aortic valve opening (R = 0.20; p = 0.57) were not associated with improvement in VO2. Our data suggest that less reliance on LVAD support was modestly associated with improvement in exercise capacity. Further studies should seek to determine the optimal level of device support prospectively in relation to exercise capacity.