Characterizing Adaptive Changes and Patient Survival After 2018 Donor Allocation Restructuring: A UNOS Database Analysis.

PURPOSE: We sought to characterize adaptive changes to the revised United Network for Organ Sharing donor heart allocation policy and estimate long-term survival trends for heart transplant (HTx) recipients. METHODS: Patients listed for HTx between October 17, 2013 and September 30, 2021 were identified from the United Network for Organ Sharing database, and stratified into pre- and postpolicy revision groups. Subanalyses were performed to examine trends in device utilization for extracorporeal membranous oxygenation (ECMO), durable left ventricular assist device (LVAD), intra-aortic balloon pump (IABP), microaxial support (Impella), and no mechanical circulatory support (non-MCS). Survival data post-HTx were fitted to parametric distributions and extrapolated to 5 years. RESULTS: We identified 27,523 HTx waitlist candidates during the study period, most of whom (n = 16,376) were waitlisted in the prepolicy change period. Overall, 19,554 patients underwent HTx during the study period (pre: 12,037 and post: 7517). Listings increased after the policy change for ECMO ( P < 0.01), Impella ( P < 0.01), and IABP ( P < 0.01) patients. Listings for LVAD ( P < 0.01) and non-MCS ( P < 0.01) patients decreased. HTx increased for ECMO ( P < 0.01), Impella ( P < 0.01), and IABP ( P < 0.01) patients after the policy change and decreased for LVAD ( P < 0.01) and non-MCS ( P < 0.01) patients. Waitlist survival increased for the overall ( P < 0.01), ECMO ( P < 0.01), IABP ( P < 0.01), and non-MCS ( P < 0.01) groups. Waitlist survival did not differ for the LVAD ( P = 0.8) and Impella ( P = 0.1) groups. Post-transplant survival decreased for the overall ( P < 0.01), LVAD ( P < 0.01), and non-MCS ( P < 0.01) populations. CONCLUSIONS: Allocation policy revisions have contributed to greater utilization of ECMO, Impella, and IABP, decreased utilization of LVADs and non-MCS, increased waitlist survival, and decreased post-HTx survival.

The impact of the OPTN policy change on patients with a durable left ventricular assist device and chronic kidney disease: Analysis of the UNOS database.

BACKGROUND: The Organ Procurement and Transplantation Network (OPTN) implemented modifications in 2018 to the adult heart transplant allocation system to better stratify the most medically urgent transplant candidates. We evaluated the impact of these changes on patients supported by a durable left ventricular assist device (LVAD) with chronic kidney disease (CKD). OBJECTIVE: To evaluate the impact of the OPTN policy change on patients supported by durable left ventricular assist devices (LVAD) with chronic kidney disease (CKD). METHODS: We performed an analysis of patients from the United Network of Organ Sharing Database supported by durable LVAD listed for a heart transplant (HT) between October 17, 2016 and September 30, 2021. Patients were divided into two groups: pre- and postpolicy, depending on whether they were listed on or prior to October 17, 2018. Patients who were on dialysis prior to surgery or discharge were excluded from the analysis. Patients with simultaneous heart and kidney transplants were excluded. Patients who were listed for transplant prepolicy change but transplanted postpolicy change were excluded. This cohort was then subdivided into degrees of CKD based on estimated glomerular filtration rate (eGFR), which resulted in 678 patients (23.7%) in Stage 1 (GFR ≥89.499) (Prepolicy: 345, Postpolicy: 333), 1233 (43.1%) in Stage 2 (89.499 > GFR ≥ 59.499) (Prepolicy: 618, Postpolicy: 615), 613 (21.4%) in Stage 3a (59.499 > GFR ≥ 44.499) (Prepolicy: 291, Postpolicy: 322), 294 (10.3%) in Stage 3b (44.499 > GFR ≥ 29.499) (Prepolicy: 143, Postpolicy: 151), 36 (1.3%) in Stage 4 (29.499 > GFR ≥ 15) (Prepolicy: 21, Postpolicy: 15), and 9 (0.3%) in Stage 5 (15 > GFR) (Prepolicy: 4, Postpolicy: 5). The primary outcome was 1-year and 2-year post-HT survival. RESULTS: There were 2863 patients who met the study criteria (1422 prepolicy, 1441 postpolicy). Overall survival, regardless of CKD stage, was lower following the policy change (p < 0.01). There was a similar risk of primary graft failure (PGF) in the pre- and postpolicy period (1.8% vs. 1.2%, p = 0.26). 1-year overall survival was 93% (91, 94) and 89% (87, 91) in the pre- and postpolicy periods, respectively. 2-year overall survival was 89% (88, 91) and 85% (82, 87) in the pre- and postpolicy periods, respectively. For CKD Stages 1, 2, 3a, 3b, 4, and 5, 1 -year survival was 93% (91, 95), 92% (90,93), 89% (86, 91), 89% (86, 93), 80% (68, 94), and 100% (100, 100), respectively. For CKD Stages 1, 2, 3a, 3b, 4, and 5, 2-year survival was 91% (88, 93), 88% (86, 90), 84% (81, 88), 84% (80, 89), 73% (59, 90), and 100% (100, 100), respectively. Patients with CKD 1 and 2 had better survival compared to those with CKD 3 (p < 0.01) and CKD 4 and 5 (p = 0.03) in the pre- and postpolicy periods. Patients with CKD 3 did not have a survival advantage over those with CKD 4 and 5 (p = 0.25). On cox regression analysis, advancing degrees of CKD were associated with an increased risk of mortality. CONCLUSIONS: Patients with LVAD support had decreased overall survival after the OPTN policy change. Patients with more advanced CKD had lower survival than patients without advanced CKD, though they were not impacted by the OPTN policy change.

Outcomes of outflow graft stenting in HeartMate 3 left ventricular assist devices: A systematic review and individual patient data meta-analysis.

PURPOSE: LVAD outflow graft stenosis continues to remain prevalent with a high complication rate. We sought to pool the existing evidence on indications, utilization patterns, and outcomes of transcatheter interventions for outflow graft stenosis in the HeartMate 3 LVAD. METHODS: An electronic search was performed to identify all studies in the English literature reporting on HeartMate 3 LVAD outflow graft stenting. Patient-level data were extracted for analysis. RESULTS: Thirteen published reports and one unpublished case comprising a total of 28 patients were included. Median patient age was 68.5 years [Interquartile range: 58, 71] and 25.9% (7/27) were female. Dyspnea [60.7% (17/28)] was the most common presenting symptom. Low flow alarms were present in 60% (15/25) of patients. Findings included external compression [35.7% (10/28)], graft twist [21.4% (6/28)], graft twist and external compression [14.3% (4.28)], intraluminal thrombus [10.7% (3/28)], graft twist and intraluminal thrombus [3.6% (1/28)], and pseudoaneurysm of outflow graft [3.6% (1/28)]. Median time from LVAD implantation to stenting was 2.1 years [1.4, 3]. Immediate flow normalization after stenting was observed in 85.7% (24/28). The 30-day mortality was 12% (3/25). Overall mortality was 12% (3/25) at a median follow-up of 3.9 months [1, 17]. CONCLUSION: Outflow graft stenting in the HeartMate 3 LVAD appears to be a reasonable treatment option for outflow graft stenosis, with low overall rates of complications and mortality. Further refinement of indications and approaches may improve outcomes.

Patient-specific severity of von Willebrand factor degradation identifies patients with a left ventricular assist device at high risk for bleeding.

BACKGROUND: Continuous-flow left ventricular assist devices (LVADs) cause an acquired von Willebrand factor (VWF) deficiency and bleeding. Models to risk-stratify for bleeding are urgently needed. We developed a model of continuous-flow LVAD bleeding risk from patient-specific severity of VWF degradation. METHODS: In a prospective, longitudinal cohort study, paired blood samples were obtained from patients (n = 67) with a continuous-flow LVAD before and during support. After 640 ± 395 days, patients were categorized as all-cause bleeders, gastrointestinal (GI) bleeders, or nonbleeders. VWF multimers and VWF clotting function were evaluated to determine bleeding risk. RESULTS: Of 67 patients, 34 (51%) experienced bleeding, 26 (39%) experienced GI bleeding, and 33 (49%) did not bleed. In all patients, LVAD support significantly reduced high-molecular-weight VWF multimers (P < .001). Bleeders exhibited greater loss of high-molecular-weight VWF multimers (mean ± standard deviation, -10 ± 5% vs -7 ± 4%, P = .008) and reduced VWF clotting function versus nonbleeders (median [interquartile range], -12% [-31% to 4%] vs 0% [-9 to 26%], P = .01). A combined metric of VWF multimers and VWF function generated the All-Cause Bleeding Risk Score, which stratified bleeders versus nonbleeders (86 ± 56% vs 41 ± 48%, P < .001) with a positive predictive value of 86% (95% confidence interval, 66%-95%) and diagnostic odds ratio of 11 (95% confidence interval, 2.9-44). A separate GI Bleeding Risk Score stratified GI bleeders versus nonbleeders (202 ± 114 vs 120 ± 86, P = .003) with a positive predictive value of 88% (64%-97%) and diagnostic odds ratio of 18 (3.1-140). CONCLUSIONS: The severity of loss of VWF multimers and VWF clotting function generated Bleeding Risk Scores with high predictive value for LVAD-associated bleeding. This model may guide personalized antithrombotic therapy and patient surveillance.

Predicted heart mass based on ideal body weight for donor-to-recipient size matching.

BACKGROUND: Predicted heart mass (PHM) is a commonly used tool for donor-to-recipient size matching. However, incorporating body weight as part of PHM can be considered problematic given its high variability, and low metabolic nature of fat. We sought to assess whether substituting the actual donor and recipient weight with the ideal body weight (IBW) would affect the association of donor-to-recipient PHM ratio with 1-year and overall survival after heart transplantation. METHODS: The United Network for Organ Sharing (UNOS) database was queried for adult patients who received a primary heart transplant between January 2000 and September 2021. RESULTS: Both PHM and ideal PHM (IPHM) ratios were associated with one-year (PHM: p = .003; IPHM: p = .0007) and overall (PHM: p = .02; IPHM: p = .02) survival. In the continuous analysis with restricted cubic splines, both PHM (p = .0003) and IPHM (p = .00001) were associated with relative hazards of death. CONCLUSION: IPHM is significantly associated with post-transplant survival and may be a useful compliment to PHM.

Utilization and outcomes of V-AV ECMO: A systematic review and meta-analysis.

BACKGROUND: Veno-arterial-venous extracorporeal membrane oxygenation (V-AV ECMO) is a less commonly used configuration of ECMO. We sought to understand the indications, utilization patterns, and outcomes of V-AV ECMO by quantitatively pooling the existing evidence from the literature. METHODS: Electronic search was performed to identify all relevant studies reporting V-AV ECMO usage. Five studies comprising 77 patients were selected and cohort-level data were extracted for further analysis. RESULTS: Mean patient age was 61 (95% CI: 55.2, 66.5) years and 30% (23/77) were female. The majority of cases [91% (70/77)] were transitioned to V-AV ECMO from another pre-existing ECMO configuration: V-A ECMO in 55% (42/77) vs. V-V ECMO in 36% (28/77), p = 0.04. Only 9% (7/77) of cases were directly placed on V-AV ECMO. The mean duration of hospital stay was 42.3 (95% CI: 10.5, 74.2) days, while ICU mortality was 46% (29, 64). Transition to durable left ventricular assist device was performed in 3% (2/64) of patients, while 3% (2/64) underwent heart transplantation. V-AV ECMO was successfully weaned to explantation in 33% (21/64) of patients. CONCLUSION: V-AV ECMO is a viable option for optimizing cardiopulmonary support in selected patients. Survival to weaning or bridging therapy appears comparable to more common ECMO configurations.

Effect of Anesthesia Induction on Cardiac Hemodynamics in Patients Undergoing Durable Left Ventricular Assist Device Implantation: The EACH-LVAD Study.

Right ventricular (RV) dysfunction is common after left ventricular assist device (LVAD) implantation leading to clinical right heart failure (RHF) associated with worsened survival and quality of life. It is likely that intraoperative events such as anesthesia induction play a role in the development or unmasking of RV dysfunction in addition to known effects from hemodynamic changes that occur after LVAD implantation. The EACH-LVAD Study is a prospective, single-center, single-arm, observational cohort study of adult patients with advanced heart failure undergoing durable LVAD implantation with standard anesthesia induction. Intraoperative RV hemodynamics via central venous pressure, mean pulmonary artery pressure, pulmonary artery pulsatility index, and vasoactive-inotropic score (a simple weighted summation of standardized drug doses) and echocardiographic parameters (RV fractional area change, RV area in diastole, RV basal diameter, septum position, RV function, tricuspid regurgitation) were measured and compared at prespecified timepoints, including postinduction. Postoperative clinical RHF was determined based on published definitions. Forty-two patients receiving a first-time LVAD were included between September 2017 and March 2019. Propofol-based induction was used in 31 patients and etomidate-based induction in eight patients. A significant increase in central venous pressure (CVP; p < 0.001), mean pulmonary artery pressure (mPAP; p < 0.001), and vasoactive inotropic score (VIS; p < 0.001) with associated decrease in pulmonary artery pulsatility index (PAPi; p < 0.001) was observed. Right ventricular function worsened throughout. Right heart failure occurred in 70% of patients. Propofol-based induction was not associated with a higher risk of RHF (relative risk [RR], 1.01 [95% confidence interval {CI}, 0.64-1.61]). The EACH-LVAD study demonstrates an effect of anesthesia induction on worsened RV hemodynamics and echocardiographic changes which may have an effect on the development of RHF.

Late Right Heart Failure After Left Ventricular Assist Device Implantation: Contemporary Insights and Future Perspectives.

Late right heart failure (RHF) is increasingly recognized in patients with long-term left ventricular assist device (LVAD) support and is associated with decreased survival and increased incidence of adverse events such as gastrointestinal bleeding and stroke. Progression of right ventricular (RV) dysfunction to clinical syndrome of late RHF in patients supported with LVAD is dependent on the severity of pre-existing RV dysfunction, persistent or worsening left- or right-sided valvular heart disease, pulmonary hypertension, inadequate or excessive left ventricular unloading, and/or progression of the underlying cardiac disease. RHF likely represents a continuum of risk with early presentation and progression to late RHF. However, de novo RHF develops in a subset of patients leading to increased diuretic requirement, arrhythmias, renal and hepatic dysfunction, and heart failure hospitalizations. The distinction between isolated late RHF and RHF due to left-sided contributions is lacking in registry studies and should be the focus of future registry data collection. Potential management strategies include optimization of RV preload and afterload, neurohormonal blockade, LVAD speed optimization, and treatment of concomitant valvular disease. In this review, the authors discuss definition, pathophysiology, prevention, and management of late RHF.

Association of Heart Transplant Volume with Presence of Lung Transplant Programs and Heart Transplant's SRTR One-year Survival Rating.

BACKGROUND: Several factors affect heart transplant (HTx) and lung transplant (LTx) program outcomes. Variabilities in institutional and community characteristics have been shown to influence survival. At present, half of HTx centers in the United States do not possess a concomitant LTx program. This study sought to better understand the characteristics of HTx with and without LTx programs. METHODS: Nationwide transplant data were collected from the Scientific Registry of Transplant Recipients (SRTR) in August 2020. SRTR star rating ranges from tier 1 (lowest) to tier 5 (highest). HTx volumes and SRTR star ratings for survival were compared between the centers with heart-only (H0) programs and the centers with heart-lung (HL) programs. RESULTS: SRTR star ratings were available for 117 transplant centers with one or more HTx reported. The median number of HTx performed over 1 year was 16 (interquartile range [IQR]: 2-29). The number of HL centers (n = 67, 57.3%) were comparable to H0 centers (n = 50, 42.7%; p = 0.14). The HTx volume at the HL centers (28 [IQR: 17-41]) exceeded the HTx volume at the H0 centers (13 [IQR: 9-23]; p < 0.01), but were comparable to the LTx volume at the HL centers (31 [IQR: 16-46]; p = 0.25). The median HTx one-year survival rating was 3 (IQR: 2-4) at both the H0 and HL centers (p = 0.85). The HTx and LTx volumes were positively associated with the respective 1-year survivals (p < 0.01). CONCLUSION: While the presence of an LTx program is not directly associated with HTx survival, it has a positive association with the HTx volume. The HTx and LTx volumes are positively associated with the 1-year survival.

Hepatitis B in Heart Transplant Donors and Recipients: A Systematic Review and Meta-Analysis.

INTRODUCTION: Expanding the heart donor pool to include patients with hepatitis B virus (HBV) could help ameliorate the organ shortage in heart transplantation. We performed a systematic review and meta-analysis to evaluate the management and recipient outcomes of D+/R- and D-/R+ heart transplants. METHODS: An electronic search was performed to identify all relevant studies published on heart transplants involving HBV+ donors and/or HBV+ recipients. A comparison was performed between two groups where heart transplants were performed a) D+/R- (n = 98) versus b) D-/R+ (n = 65). RESULTS: Overall, 13 studies were selected, comprising 163 patients. Mean patient age was 55 y (95% CI: 39, 78) and 79% (69, 86) were male. Active post-transplant HBV infection requiring antiviral treatment occurred in 11% (1, 69) of D+/R- recipients and 33% (9, 71) of D-/R+ recipients. Post-transplant antiviral therapy was given to 80% (6, 100) of D+/R- recipients compared to 72% (42, 90) of D-/R+ recipients (P = 0.84). Hepatitis-related mortality was observed in no D+/R- recipients and 7% (2, 27) of D-/R+ recipients. Survival 1-y post-transplant was comparable between both groups at 83% (83, 92) and 81% (61, 92) for D+/R- and D-/R+ transplants, respectively. CONCLUSIONS: Our review found that HBV D+/R- heart transplantation was associated with fewer active hepatitis infections and lower hepatitis-related mortality than D-/R+ transplantation, with comparable survival at 1 y. Additional studies utilizing HBV nucleic acid testing (NAT) to compare outcomes with HBsAg+ and anti-HBc+ donors are crucial to reach more definitive conclusions about the risk of donor-derived infections in this context.

Utility of Recipient Cardiothoracic Ratio in Predicting Delayed Chest Closure after Heart Transplantation.

BACKGROUND: Predicted cardiac mass (PCM) has been well validated for size matching donor hearts to heart transplantation recipients. We hypothesized that cardiothoracic ratio (CTR) could be reflective of recipient-specific limits of oversizing, and sought to determine the utility of donor to recipient PCM ratio (PCMR) and CTR in predicting delayed chest closure after heart transplantation. METHODS: A retrospective review of prospectively collected data on 38 consecutive heart transplantations performed at our institution from 2017 to 2020 was performed. Donor and recipient PCM were estimated using Multi-Ethnic Study of Atherosclerosis predictive models. Receiver operating characteristic analysis was performed to determine the discriminatory power of the ratio of PCMR to CTR in predicting delayed sternal closure. RESULTS: Of the 38 patients, 71.1% (27/38) were male and the median age at transplantation was 58 (interquartile range [IQR]: 47-62) years. Ischemic cardiomyopathy was present in 31.6% of recipients (12/38). Median recipient CTR was 0.63 [IQR: 0.59-0.66]. Median donor to recipient PCMR was 1.07 [IQR: 0.96-1.19], which indicated 7% oversizing. Thirteen out of 38 (34.2%) underwent delayed sternal closure. Primary graft dysfunction occurred in 15.8% (6/38). PCMR/CTR showed good discriminatory power in predicting delayed sternal closure [area under the curve: 80.4% (65.3-95.6%)]. PCMR/CTR cut-off of 1.7 offered the best trade-off between the sensitivity (69.6%) and specificity (91.7%). CONCLUSION: CTR could be helpful in guiding the recipient-specific extent of oversizing donor hearts. Maintaining the ratio of PCMR to CTR below 1.7 could avoid excessive oversizing of the donor heart.

Microaxial circulatory support for percutaneous coronary intervention: A systematic review and meta-analysis.

BACKGROUND: Microaxial circulatory support devices have been used to support patients treated with percutaneous coronary intervention (PCI) for acute myocardial infarction complicated by cardiogenic shock (AMICS). The purpose of this systematic review and meta-analysis was to pool and analyze the existing evidence on the baseline characteristics, periprocedural data, and outcomes of microaxial support before and after PCI in AMICS. METHODS: An electronic database search was performed to identify all cohort studies on Impella and PCI for cardiogenic shock in the English language. A total of five articles comprising 543 patients were included. These patients received microaxial support either before (pre-PCI) or after (post-PCI) undergoing PCI. Comparative analyses were done between both groups. RESULTS: The mean patient age was 66 years [95% Confidence Interval (58-74)], and 22% (89/396) of patients were female. ST-elevation myocardial infarctions (MI) comprised 64% (44-80) of MIs and 50% (44-56) of MIs involved the left anterior descending artery. The mean number of diseased vessels was 2.21 (1.62-2.80). The mean left ventricular ejection fraction was 31% (23.4-38.6). The mean arterial pressure was 66.3 mm Hg (54.1-78.5). Mean serum lactate [6.1 mmol/L (3.3-8.9)] and serum creatinine [1.4 mg/dl (1.0-1.7)] were similar between groups. 30-day mortality was lower in the pre-PCI group [41% (34%-49%)] compared to the post-PCI group [61% (42%-77%), p < 0.01]. Pooled Kaplan-Meier analysis showed better early survival in the pre-PCI group (p < 0.001). CONCLUSION: Patients presenting with AMICS were similar at baseline in both pre-PCI and post-PCI groups. Nevertheless, pre-PCI group showed better early survival compared to post-PCI group.

Percutaneous Decommissioning 11 Years After Initial CF-LVAD Placement.

An 80-year-old man with severe nonischemic cardiomyopathy status post left ventricular assist device (LVAD) placement 11 years prior presented for recurrent LVAD alarms from internal driveline fracture. Given his partial myocardial recovery and his preference to avoid surgical procedures, percutaneous LVAD decommissioning was performed by occlusion of the outflow graft and subsequently driveline removal. (Level of Difficulty: Advanced.).

Impact of ventricular arrhythmia on LVAD implantation admission outcomes.

INTRODUCTION: Ventricular arrhythmias (VAs) are common after left ventricular assist device (LVAD) implantation though data are mixed on whether these events have an impact on mortality. METHODS: The National Inpatient Sample (NIS) database from 2002-2019 was queried for LVAD implantation admissions. Secondary ICD codes were analyzed to assess for the occurrence of VAs during this admission. Propensity score matching (PSM) was used to control for confounding variables between those with versus without VAs. RESULTS: The NIS database from 2002-2019 contained 43 936 admissions with LVAD implantation. VAs occurred in 19 985 (45.4%) patients. After PSM, the study cohort consisted of 39 989 patients, 19 985 (50.0%) of which had a secondary diagnosis of VA during the admission. When compared to those without VA, those with VA were at no higher risk for in-hospital mortality (adjusted odds ratio 1.011, 99.9% CI 0.956-1.069, p = 0.699). Those with a VA were at higher risk for cardiogenic shock and requiring mechanical ventilation, tracheostomy, and percutaneous endoscopic gastrostomy placement. Patients with a VA were also at lower risk for device thrombosis. Conversely, the VA group was at no higher risk for stroke. In comparing trends from 2002 to 2019, the incidence of VAs has increased, while the mortality rate of those with and without VAs has decreased during this same period. CONCLUSION: In this retrospective study of the NIS database, VAs were common (45.4%) during the LVAD implantation admission. However, the occurrence of VAs during the implantation admission did not alter in-hospital mortality. More longitudinal studies are required to assess the long-term impact of VAs on mortality. In comparing trends from 2002-2019, the incidence of VAs has increased, while the mortality rate of those with and without VAs has decreased.

The Anemia Stress Index-Anemia, Transfusions, and Mortality in Patients with Continuous Flow Ventricular Assist Devices.

We aimed to identify a simple metric accounting for peri-procedural hemoglobin changes, independent of blood product transfusion strategies, and assess its correlation with outcomes in patients undergoing left ventricular assist device (LVAD) implantation We included consecutive patients undergoing LVAD implantation at a single center between 10/1/2008 and 6/1/2014. The anemia stress index (ASI), defined as the sum of number of packed red blood cells transfused and the hemoglobin changes after LVAD implantation, was calculated for each patient at 24 h, discharge, and 3 months after LVAD implantation. Our cohort included 166 patients (80.1% males, mean age 56.3 ± 15.6 years) followed up for a median of 12.3 months. Increases in ASI per unit were associated with a higher hazard for all-cause mortality and early RV failure. The associations between the ASI and all-cause mortality persisted after multivariable adjustment, irrespective of when it was calculated (adjusted HR of 1.11, 95% CI 1.03-1.20 per unit increase in ASI). Similarly, ASI at 24 h after implant was associated with early RV failure despite multivariable adjustment (OR 1.09, 95% CI 1.05-1.14). We present a novel metric, the ASI, that is correlated with an increased risk for all-cause mortality and early RV failure in LVAD recipients.

Direct anabolic metabolism of three-carbon propionate to a six-carbon metabolite occurs in vivo across tissues and species.

Anabolic metabolism of carbon in mammals is mediated via the one- and two-carbon carriers S-adenosyl methionine and acetyl-coenzyme A. In contrast, anabolic metabolism of three-carbon units via propionate has not been shown to extensively occur. Mammals are primarily thought to oxidize the three-carbon short chain fatty acid propionate by shunting propionyl-CoA to succinyl-CoA for entry into the TCA cycle. Here, we found that this may not be absolute as, in mammals, one nonoxidative fate of propionyl-CoA is to condense to two three-carbon units into a six-carbon trans-2-methyl-2-pentenoyl-CoA (2M2PE-CoA). We confirmed this reaction pathway using purified protein extracts provided limited substrates and verified the product via LC-MS using a synthetic standard. In whole-body in vivo stable isotope tracing following infusion of 13C-labeled valine at steady state, 2M2PE-CoA was found to form via propionyl-CoA in multiple murine tissues, including heart, kidney, and to a lesser degree, in brown adipose tissue, liver, and tibialis anterior muscle. Using ex vivo isotope tracing, we found that 2M2PE-CoA also formed in human myocardial tissue incubated with propionate to a limited extent. While the complete enzymology of this pathway remains to be elucidated, these results confirm the in vivo existence of at least one anabolic three- to six-carbon reaction conserved in humans and mice that utilizes propionate.

Outcomes With Phosphodiesterase-5 Inhibitor Use After Left Ventricular Assist Device: An STS-INTERMACS Analysis.

BACKGROUND: Elevated right ventricular afterload following continuous-flow left ventricular assist device (CF-LVAD) may contribute to late right heart failure (LRHF). PDE5i (phosphodiesterase-5 inhibitors) are used to treat pulmonary hypertension and right heart dysfunction after CF-LVAD, but their impact on outcomes is uncertain. METHODS: We queried Interagency Registry for Mechanically Assisted Circulatory Support from 2012 to 2017 for adults receiving a primary CF-LVAD and surviving ≥30 days from index discharge. Patients receiving early PDE5i (ePDE5i) at 1 month were propensity-matched 1:1 with controls. The primary outcome was the cumulative incidence of LRHF, defined using prevailing Interagency Registry for Mechanically Assisted Circulatory Support criteria; secondary outcomes included all-cause mortality and major bleeding. RESULTS: Among 9627 CF-LVAD recipients analyzed, 2463 (25.6%) received ePDE5i and 1600 were propensity-matched 1:1 with controls. Before implant, ePDE5i patients had more severe RV dysfunction (13.1% versus 9.6%) and higher pulmonary vascular resistance (2.8±2.7 versus 2.2±2.4 WU), both P<0.001, but clinical factors were well-balanced after propensity-matching. In the unmatched cohort, ePDE5i patients had a higher 3-year cumulative incidence of LRHF, mortality, and major bleeding, but these differences were attenuated in the propensity-matched cohort: LRHF 40.8% versus 35.7% (hazard ratio, 1.14 [95% CI, 0.99-1.32]; P=0.07); mortality 38.6% versus 35.8% (hazard ratio, 0.99 [95% CI, 0.86-1.15]; P=0.93); major bleeding 51.2% versus 46.0% (hazard ratio, 1.12 [95% CI, 0.99-1.27]; P=0.06). CONCLUSIONS: Compared with propensity-matched controls, adult CF-LVAD patients receiving ePDE5i had similar rates of LRHF, mortality, and major bleeding. While intrinsic patient risk factors likely account for more adverse outcomes with ePDE5i in the unmatched cohort, there is no obvious benefit of ePDE5i in the LVAD population.

Quantitative subcellular acyl-CoA analysis reveals distinct nuclear metabolism and isoleucine-dependent histone propionylation.

Quantitative subcellular metabolomic measurements can explain the roles of metabolites in cellular processes but are subject to multiple confounding factors. We developed stable isotope labeling of essential nutrients in cell culture-subcellular fractionation (SILEC-SF), which uses isotope-labeled internal standard controls that are present throughout fractionation and processing to quantify acyl-coenzyme A (acyl-CoA) thioesters in subcellular compartments by liquid chromatography-mass spectrometry. We tested SILEC-SF in a range of sample types and examined the compartmentalized responses to oxygen tension, cellular differentiation, and nutrient availability. Application of SILEC-SF to the challenging analysis of the nuclear compartment revealed a nuclear acyl-CoA profile distinct from that of the cytosol, with notable nuclear enrichment of propionyl-CoA. Using isotope tracing, we identified the branched chain amino acid isoleucine as a major metabolic source of nuclear propionyl-CoA and histone propionylation, thus revealing a new mechanism of crosstalk between metabolism and the epigenome.