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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.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.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.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.

Continuous-flow left ventricular assist devices (CF-LVAD) have been shown to enhance reverse remodeling and myocardial recovery in certain patients allowing for device removal. We sought to analyze the characteristics and describe outcomes of patients who underwent CF-LVAD explantation at a large academic center. We retrospectively identified all patients who underwent CF-LVAD explants due to recovery from 2006 to 2019. Patient baseline characteristics and data on pre- and postexplant evaluation were collected and analyzed. Of 421 patients who underwent CF-LVAD implantation, 13 underwent explantation (3.1%). Twelve HeartMate II and one HeartWare LVAD were explanted. All patients had nonischemic cardiomyopathy. Median time from heart failure diagnosis to LVAD implant was 12 months (interquartile range [IQR], 2-44) and the median time supported on LVAD was 22 months (IQR, 11-28). Two patients died within 30 days of explant. Three additional patients died during the follow-up period and all were noted to be nonadherent to medical therapy. After a mean follow-up duration of 5 years, overall survival was 52%. Mean pre-explant ejection fraction was 49%, which decreased at most recent follow-up to 32%. Mean pre-explant left ventricular internal diameter in diastole (LVIDD) was 4.37 cm and increased to 5.52 cm at most recent follow-up. Continuous-flow left ventricular assist device explantation is feasible and safe in select patients.

Background: Several factors affect heart (HTx) and lung (LTx) transplant program outcomes. Variability in institutional and community characteristics have been shown to influence survival. At present, currently, half of HTx centers in the United States do not possess a concomitant LTx program. This study sought to better understand the relationship 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 one year was 16 (IQR: 2-29). Number of HL centers (n=67, 57.3%) were comparable to H0 centers (n=50, 42.7%) (p= 0.14). The HTx volume at HL centers [28 (IQR: 17-41)] exceeded HTx volume at H0 centers [13 (IQR: 9-23)], (p

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.

We present 3 cases of superior vena cava (SVC) syndrome following percutaneous right ventricular assist device (RVAD) placement. Each case underscores the importance of early recognition of SVC syndrome in patients with percutaneous RVAD insertion via the internal jugular vein and calls for heightened awareness of device-associated complications. (Level of Difficulty: Advanced.), Central Illustration

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.

Background Thoracic transplantation is considered for patients with Eisenmenger syndrome (ES) who have refractory right ventricular failure despite optimal therapy for pulmonary arterial hypertension. This study compared the outcomes of bilateral lung transplantation (BLT) with cardiac defect repair vs combined heart-lung transplantation (HLT). Research Question This study presents an updated analysis using a US national registry to evaluate the outcomes of patients diagnosed with ES who underwent HLT or BLT with repair of cardiac defects. Study Design and Methods This study identified patients with ES who underwent thoracic transplantation from 1987 to 2018 from the United Network for Organ Sharing database. Survival curves were estimated by using the Kaplan-Meier method and were compared by using the log-rank test. Results During the study period, 442 adults with ES underwent thoracic transplantation (316 HLTs and 126 BLTs). Following BLT, overall survival 1, 5, and 10 years’ posttransplant was 63.1%, 38.5%, and 30.2%, respectively. Following HLT, overall survival 1, 5, and 10 years’ posttransplant was 68.0%, 47.3%, and 30.5% (P = .6). When survival analysis was stratified according to type of defect, patients with an atrial septal defect had better survival following BLT than following HLT (88.3% vs 63.2% 1 year posttransplant, P Interpretation This study suggests that the best transplant option for patients with VSD remains HLT, which prevents subsequent development of ventricular failure. BLT with cardiac defect repair should be considered as the first-line treatment option in patients with ES due to an uncorrected atrial septal defect. These patients can be considered to have isolated and reversible right ventricular failure akin to patients with advanced pulmonary arterial hypertension.

Background Impella (Abiomed Inc, Danvers, MA) is a temporary mechanical support device positioned across the aortic valve, and can be used to support patient before LVAD implantation. There are no data on the incidence of aortic insufficiency (AI) in patients supported with Impella as a bridge to durable LVAD implantation. We sought to assess the incidence of AI in patients with Impella support as a bridge to durable left ventricular assist device (LVAD) implantation. Methods We reviewed all patients undergoing primary LVAD implantation at the University of Pennsylvania from January 2015 onward, comparing those supported with Impella as temporary mechanical support with those supported by either venoarterial extracorporeal life support or an intra-aortic balloon pump. We reviewed transthoracic echocardiography preoperatively, as well as at 1 week, 1, 3, 6, 9, and 12 months after LVAD implantation. Results A total of 215 echocardiograms were analyzed in 41 patients. Eleven patients were supported with Impella before LVAD implant—6 patients with Impella alone (5 with Impella CP, 1 with Impella 5.0) and 5 with Impella in conjunction with venoarterial extracorporeal life support (2 with Impella 2.5, 2 with Impella CP, and 1 with Impella 5.0). After LVAD implant, mild or moderate AI developed in 82% of patients supported with Impella (9 of 11) compared with 43% of those without Impella (13 of 30) (P = .038). Conclusions Patients supported by Impella as a bridge to durable LVAD have a higher risk of developing AI. Further studies are needed to assess this risk as the use of the Impella increases.

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 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.

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.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.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).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.

Heparin-induced thrombocytopenia (HIT) presents a unique challenge in patients requiring orthotopic heart transplantation (OHT). We sought to pool the existing evidence in a systematic review.Electronic search was performed to identify all relevant studies on OHT in patients with HIT. Patient-level data for 33 patients from 21 studies were extracted for statistical analysis.Median patient age was 51 [IQR 41, 55] years, with 75.8% (25/33) males. All patients had a clinical diagnosis of HIT, and anti-PF4/Heparin antibodies were positive in 87.9% (29/33). Median lowest reported platelet count was 46 × 10Heparin use during OHT may be associated with less adverse effects compared to use of other anticoagulants with no difference in 30-day mortality.

A subset of patients with coronavirus disease 2019 (COVID-19) develop profound respiratory failure and are treated via invasive mechanical ventilation (IMV). Of these, a smaller subset has severe gas exchange abnormalities that are refractory to maximal levels of IMV support. Extracorporeal membrane oxygenation (ECMO) has been used successfully in these circumstances. However, using ECMO only after failure of IMV exposes patients to the risks of ventilator-induced lung injury. We report a successful outcome using ECMO in the setting of COVID-19 in the absence of IMV failure in an awake, nonintubated patient. This approach may be beneficial for selected patients with COVID-19.

Transcatheter aortic valve implantation (TAVI) is approved for treatment of symptomatic aortic stenosis in patients at increased risk for surgical valve replacement, but outcomes data in patients with severe native aortic regurgitation (AR) treated with TAVI remain limited. The objective of this analysis was to evaluate outcomes among patients identified in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies Registry who underwent TAVI for native AR with a commercially available self-expanding valve system. From January 2014 to December 2017, 230 patients in the TVT Registry underwent TAVI for primary severe native AR using a commercially available self-expanding valve (n = 81, CoreValve; n = 149, Evolut R). For inclusion, AR was either pure or mixed with predominantly moderate/severe AR and mean aortic valve gradient ≤20 mm Hg. Thirty-day outcomes were evaluated using time-to-event methods. Device success was reported in 81.7% of patients (CoreValve, 72.2%; Evolut R, 86.9%; p = 0.0.01). Thirty-day all-cause mortality was 13.3%. All patients presented with moderate/severe AR at baseline; at 30 days, 9.1% of implanted patients with data continued to have moderate and 1.4% severe AR. There was a significant reduction in residual moderate/severe AR from the CoreValve to Evolut R device (19.1% vs 6.3%, p = 0.02). Multivariable analysis revealed factors associated with 30-day all-cause mortality include number of valves used (hazard ratio [HR] 2.361, 1.643 to 3.391, p0.001), albumin3.3 mg/dL (HR 3.358, 1.551 to 7.273, p=0.002), and left ventricular ejection fraction (HR 0.978, 0.957 to 1.000, p = 0.047). Despite higher 30-day all-cause mortality, self-expanding TAVI may be an option in selected patients with AR who have no surgical options.

Purpose Infective endocarditis (IE) is a rare but potentially fatal complication following heart transplantation (HTx). There is a lack of literature regarding the patterns and clinical course of IE development following HTx. We sought to pool the existing data in regards to defining characteristics, management options, and outcomes of IE following HTx. Methods An electronic search of Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Ovid Medline, and the Scopus databases were performed to identify all articles in the English literature that report IE following HTx in adult patients. Patient-level data were extracted and analyzed. Results Systematic search yielded 57 patients from 32 articles. Median patient age was 52 [IQR 43, 59] and 75% of patients (43/57) were male. Median time to IE presentation post-HTx was 8.4 [IQR 3.0, 35.8] months. IE of the mitral valve was observed in 36.8% (21/57) of patients, followed by mural IE in 24.6% (14/57), and tricuspid valve IE in 21.1% (12/57). The most common organisms were Staphylococcus aureus in 26.3% (15/57), Aspergillus fumigatus in 19.3% (11/57), Enterococcus faecalis in 12.3% (7/57), and an undetermined or unspecified organism in 14.0% (8/57) patients. Overall case fatality was 44.6% (25/56). Fungal IE was associated with a significantly higher case fatality 75.0% (9/12) than that of bacterial IE 36.1% (13/36) (p = 0.02). Surgical management of post-HTx IE was observed in 35.1% (20/57) of patients. This included valve surgery for 70.0% (14/20), including the mitral valve in 50.0% (7/14), aortic valve in 35.7% (5/14), and the tricuspid valve in 14.3% (2/14) of patients. Conclusion In addition to bacterial organisms, fungi also represent a frequent cause of IE in post-HTx patients. Overall HTx patient survival in the setting of IE is poor and may be worse if caused by A. fumigatus.

Background: Due to the high cost of left ventricular assist device (LVAD) therapy, payer type may be an important factor in determining eligibility. How payer type influences outcomes after LVAD implantation is unclear. We, therefore, aimed to study the association of health insurance payer type with outcomes after durable LVAD implantation. Methods: Using STS-INTERMACS (Society of Thoracic Surgeons-Interagency Registry for Mechanically Assisted Circulatory Support), we studied nonelderly adults receiving a durable LVAD from 2016 to 2018 and compared all-cause mortality and postindex hospitalization adverse event episode rate by payer type. Multivariable Fine-Gray and generalized linear models were used to compare the outcomes. Results: Of the 3251 patients included, 26.0% had Medicaid, 24.9% had Medicare alone, and 49.1% had commercial insurance. Compared with commercially insured patients, mortality did not differ for patients with Medicaid (subdistribution hazard ratio, 1.00 [95% CI, 0.75–1.34], P =0.99) or Medicare (subdistribution hazard ratio, 1.09 [95% CI, 0.84–1.41], P =0.52). Medicaid was associated with a significantly lower adjusted incidence rate (incidence rate ratio, 0.88 [95% CI, 0.78–0.99], P =0.041), and Medicare was associated with a significantly higher adjusted incidence rate (incidence rate ratio, 1.16 [95% CI, 1.03–1.30], P =0.011) of adverse event episodes compared with commercially insured patients. Conclusions: All-cause mortality after durable LVAD implantation did not differ significantly by payer type. Payer type was associated with the rate of adverse events, with Medicaid associated with a significantly lower rate, and Medicare with a significantly higher rate of adverse event episodes compared with commercially insured patients.

The impact of preoperative end-diastolic left ventricular dimension (preLVEDD) on long-term outcomes with centrifugal continuous-flow left ventricular assist device (CF-LVAD) is not well established. Accordingly, we performed an analysis of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) registry to study this relationship. All patients with centrifugal CF-LVAD in the INTERMACS registry from June 2006 to December 2017 were screened. The final study group consisted of 3,304 patients. After a median follow-up of 9.0 months (interquartile range [IQR], 4.2-18.8 months), 2,596 (79%) patients were alive. After adjusting for significant covariates, increased preLVEDD was associated with lower mortality (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.84-0.98; p = 0.01), stroke (HR, 0.85; 95% CI, 0.77-0.93; p < 0.001), and gastrointestinal bleeding (HR, 0.88; 95% CI, 0.80-0.97; p = 0.01), although there were more arrhythmias (HR, 1.14; 95% CI, 1.05-1.24; p = 0.003). Our study suggests that preLVEDD is an independent predictor of mortality and adverse events in patients treated with centrifugal CF-LVAD. preLVEDD should be considered an important preimplant variable for risk stratification when considering a CF-LVAD.

Quantitative sub-cellular metabolomic measurements can yield crucial insights into 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 - Sub-cellular Fractionation (SILEC-SF), which uses isotope labeled internal standard controls that are present throughout fractionation and processing to quantify acyl-Coenzyme A thioesters in sub-cellular 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 (BCAA) 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.

Treatment of giant cell myocarditis (GCM) can require bridging to orthotopic heart transplantation (OHT) or recovery with mechanical circulatory support (MCS). Since the roles of MCS and immunotherapy are not well-defined in GCM, we sought to analyze outcomes of patients with GCM who required MCS. A systematic search was performed in June 2019 to identify all studies of biopsy-proven GCM requiring MCS after 2009. We identified 27 studies with 43 patients. Patient-level data were extracted for analysis. Median patient age was 45 (interquartile range (IQR): 32&ndash, 57) years. 42.1% (16/38) were female. 34.9% (15/43) presented in acute heart failure. 20.9% (9/43) presented in cardiogenic shock. Biventricular (BiVAD) MCS was required in 76.7% (33/43) of cases. Of the 62.8% (27/43) of patients who received immunotherapy, 81.5% (22/27) used steroids combined with at least one other immunosuppressant. Cyclosporine was the most common non-steroidal agent, used in 40.7% (11/27) of regimens. Immunosuppression was initiated before MCS in 59.3% (16/27) of cases, after MCS in 29.6% (8/27), and not specified in 11.1% (3/27). Immunosuppression started prior to MCS was associated with significantly better survival than MCS alone (p = 0.006), 60.5% (26/43) of patients received bridge-to-transplant MCS, 39.5% (17/43) received bridge-to-recovery MCS, 58.5% (24/41) underwent OHT a median of 104 (58&ndash, 255) days from diagnosis. GCM recurrence after OHT was reported in 8.3% (2/24) of transplanted cases. BiVAD predominates in mechanically supported patients with GCM. Survival and bridge to recovery appear better in patients on immunosuppression, especially if initiated before MCS.

Introduction: Heart failure patients with severe obesity endure significant morbidity and frequent hospitalizations. Bariatric surgery is proven to provide durable weight loss for those with severe obesity, but the clinical impact and safety of these procedures among patients with heart failure has not been well-demonstrated. Methods: We conducted a medical record query of patients who have a previous diagnosis of heart failure (HFpEF and HFrEF) and underwent subsequent Roux-En-Y gastric bypass or laparoscopic sleeve gastrectomy at a high-volume metabolic and bariatric surgery center. We compared clinical, demographic, and echocardiographic data captured just prior to the bariatric procedure to the most recent data available in the medical record for each patient. Results: There were 50 patients (88% had HFpEF) included in this study. Time from HF diagnosis to most recent follow-up ranged from 0.2 to 20.3 years (median 6.7 years) and there was no recorded mortality. The median time from HF diagnosis to surgery was 2.3 years and median time from surgery to recent follow-up was 2.9 years. Post-operative median decrease in BMI was 8.8 kg/m 2 , HF hospitalizations were 0.4 per patient year (PPY) to 0.15 PPY, p=0.008, and median NYHA Class was II pre-op and I post-op, p=0.048). LVEF, LVESD, and LVEDD were not significantly changed post-operatively (Table 1). Conclusion: Weight loss following bariatric surgery for patients with HF led to improvements in NYHA Class, fewer hospitalizations for HF, and was not associated with perioperative mortality. It is reasonable to consider bariatric surgery for this patient population, but further prospective investigation is warranted.

Summary Metabolism is highly compartmentalized within cells, and the sub-cellular distribution of metabolites determines their use. Quantitative sub-cellular metabolomic measurements can yield crucial insights into the roles of metabolites in cellular processes. Yet, these analyses are subject to multiple confounding factors in sample preparation. We developed Stable Isotope Labeling of Essential nutrients in cell Culture - Sub-cellular Fractionation (SILEC-SF), which uses rigorous internal standard controls that are present throughout fractionation and processing to quantify metabolites in sub-cellular compartments by liquid chromatography-mass spectrometry (LC-MS). Focusing on the analysis of acyl-Coenzyme A thioester metabolites (acyl-CoAs), SILEC-SF was tested in a range of sample types from cell lines to mouse and human tissues. Its utility was further validated by analysis of mitochondrial versus cytosolic acyl-CoAs in the well-defined compartmentalized metabolic response to hypoxia. We then applied the method to investigate metabolic responses in the cytosol and nucleus. Within the cytosol, we found that the mevalonate pathway intermediate 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) is exquisitely sensitive to acetyl-CoA supply. The nucleus has been an exceptionally challenging compartment in which to quantify metabolites, due in part to its permeability. We applied the SILEC-SF method to nuclei, identifying that the nuclear acyl-CoA profile is distinct from the cytosolic compartment, with notable nuclear enrichment of propionyl-CoA. Altogether, we present the SILEC-SF method as a flexible approach for quantitative sub-cellular metabolic analyses.

Early right heart failure (ERHF) remains a common complication after continuous-flow left ventricular assist device (cf-LVAD) and has been associated with increased mortality. The specific criteria used to define ERHF remain somewhat arbitrary. Correlating the degree of ERHF with outcomes after LVAD could inform a more clinically relevant definition. We identified 196 patients who underwent first durable cf-LVAD between 2008 and 2015 at a single center. Postimplant ERHF was graded as absent, mild (requiring inotropic support for 14-20 days), moderate (inotropes for ≥ 21 days), or severe (requiring unplanned RVAD at any time during the index hospitalization). ERHF was associated with clinical outcomes including 1 year survival and New York Heart Association (NYHA) class and 6 minute walk distance (6MWD) at 3 and 6 months. Survival was assessed using the Kaplan-Meier method with log-rank testing and multivariate Cox proportional-hazards modeling. Compared to patients without ERHF, those with mild ERHF had similar 1 year survival (hazard ratio [HR] 0.69, 95% confidence interval [CI]: 0.26-1.80, p = 0.45), while mortality was substantially increased in patients with moderate (HR 2.65, 95% CI: 1.27-5.54, p = 0.009) and severe ERHF (HR 8.16, 95% CI: 3.97-16.76, p < 0.0001). The severity of ERHF was associated with 6MWD at both 3 months (p = 0.001) and 6 months (p = 0.013). The relationship between ERHF and postimplant survival and functional status persisted in multivariate modeling. A simple, modified grading system for ERHF severity is strongly associated with 1 year survival and functional capacity after cf-LVAD. These results argue against using a binary definition for ERHF and suggest the need to modify definition of ERHF severity.

Extracorporeal membrane oxygenation (ECMO) as a bridge to left ventricular assist device (LVAD) implantation has shown promise in improving end-organ function and optimizing outcomes in some critically ill patients, but the practice remains controversial. Retrospective review of patients who received LVADs from May 2008 to September 2016 at a high-volume, tertiary care cardiovascular center was performed. Subjects were Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) class 1 patients divided into ECMO bridge and non-ECMO bridge cohorts. Patient demographics, adverse events, and survival at immediate and 1 year postoperative time points were compared between groups. In total, 235 patients received a HeartMate II or HVAD during the study period. Among INTERMACS 1 patients, 18 were ECMO bridge and 17 were non-ECMO bridge. Age, gender and bridge-to-transplant proportions (50% vs. 53%) were similar between groups. The ECMO bridge group had lower hemoglobin (7.9 ± 1.1 vs. 10.2 ± 2.2; p < 0.01), platelet (101 [70] vs. 176 [115]; p < 0.05), and prealbumin levels (10.6 ± 4.3 vs. 17.3 ± 7.7; p < 0.01). Nearly half (n = 8; 44%) of the ECMO bridge patients required packed red blood cell transfusions before VAD and were more likely to be on an epinephrine drip (78% vs. 12%; p < 0.01). However, along with these adjunctive measures, the ECMO bridge did effectively improve hemodynamic profiles by the time of VAD implant resulting in lower central venous pressure (7.7 ± 2.5 vs. 10.4 ± 4.8; p < 0.01) and mean pulmonary arterial pressure (18 ± 9 vs. 32 ± 8; p < 0.01). It also allowed for restoration of end-organ function as noted by comparable creatinine (1.0 [1.2] vs. 1.4 [0.6]) and total bilirubin levels (1.6 ± 1 vs.1.5 ± 1.7) between the two groups. There was no difference in rates of adverse events. Survival at 30 days postoperative and at 1 year (77% vs. 88%; p = 0.6) was similar. This study demonstrates that ECMO bridge is a central component of a multifaceted strategy for stabilization of select patients with severe hemodynamic instability before LVAD implantation. Further studies to optimize patient selection should be further explored.

Summary 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.

Background Heart failure (HF) is the leading cause of death in adults with congenital heart disease (ACHD). Identification of disease progression and timing of referral for advanced therapies is often delayed. However, increased awareness and understanding of ACHD and improvements in the approach to treatment have led to improved outcomes. Pulmonary hypertension (PH) is a common barrier to HT. In ACHD, the approach to PH and HT is quite complicated, given the anatomic heterogeneity and lower prevalence and experience. However, in some cases, PH is a result of elevated systemic filling pressures and low output. Methods We describe the approach used to successfully transplant an ACHD patient with severe pre-HT PH performing HT alone. We review the literature and describe the one patient's journey from primarily palliative, to a combined heart-lung transplant candidate, to successful HT patient. Results We discuss the methodology used to successfully transplant a patient, with significantly elevated pulmonary pressures and an initial pulmonary vascular resistance (PVR) > 13 Wood units. Conclusions There are a number of complexities associated with the ACHD population and it is of utmost importance to carefully identify the underlying hemodynamic milieu and inform the appropriate treatment course in order to have successful transplant outcomes.

Background In patients with ventricular tachycardia or ventricular fibrillation (VT/VF) electrical storm (ES) undergoing catheter ablation (CA), hypotension due to refractory VT/VF, use of anesthesia, and cardiac stunning due to repeated implantable cardioverter-defibrillator shocks might precipitate acute hemodynamic decompensation (AHD). Objective We evaluated the outcomes of emergent cardiopulmonary support with extracorporeal membrane oxygenation (ECMO) to rescue AHD in patients undergoing CA of ES. Methods Between January 1, 2010 and December 31, 2016, 21 patients with ES (VT in 11 and premature ventricular complex–triggered VF in 10) were referred for CA and had periprocedural AHD requiring emergent ECMO support. Results In 14 patients, AHD occurred a mean of 1.5 ± 1.7 days before the procedure. In the remaining 7 patients, AHD occurred during or shortly after the procedure. ECMO was started successfully in all patients. Ablation was performed in 18 patients (9 with VF and 9 with VT). In patients with VF, premature ventricular complex suppression was achieved in 8 of 9 (89%). In those with VT, noninducibility was achieved in 7 of 9 (78%). After a median follow-up of 10 days, 16 patients died (13 during the index admission). Death was due to refractory VT/VF in 4 patients, heart failure in 11, and noncardiac cause in 1 patient. Seven patients survived beyond 6 months postablation; 5 remained free of VT/VF and 3 ultimately received a destination therapy (heart transplantation in 2 and left ventricular [LV] assist device in 1). Conclusion In patients with ES undergoing CA, the outcomes of ECMO support as rescue intervention for AHD are poor. The majority of these patients die of refractory heart failure in the short-term. Strategies to prevent AHD including preemptive use of hemodynamic support may improve survival.

Article, see p 1632 Impaired contractile function is the hallmark of systolic heart failure (HF). However, the exact mechanisms are not fully understood, and the resulting morbidity and mortality remain high despite significant advances in pharmacological and device therapies.1,2 Resulting from plasticity of cardiac responses to injury, called pathological remodeling, the human heart changes in size, shape, and function. The culmination of complex, interdependent changes in molecular signatures, gene expression, metabolic adaptations, and cellular structures, the response of the failing heart to pathological insults of mechanical overload, neurohormonal excess, and ischemia has been studied extensively.2 In addition, cardiomyocyte ultrastructural remodeling of subcellular organelles including sarcoplasmic reticulum (SR), sarcolemma (plasma membrane), mitochondria, myofibrils, and extracellular matrix has also been described during the development of HF.3 Communication between subcellular organelles is extensive in eukaryotic cells, involving plasma membrane, endoplasmic reticulum, mitochondria, nucleus, and other organellar structures through specialized membrane domains in close proximity to one another.4 This communication relies on different protein entities, depending on the organelles involved, and controls key cellular processes in a spatial and temporal fashion including cell death, metabolism, and gene expression.4 An example of interorganellar communication in cardiomyocytes is the important interaction of sarcolemma with SR during excitation-contraction (EC) coupling.5,6 In this case, the transverse tubular system (T system) is the specialized membrane penetrating into the cardiomyocyte interior as an extensive network of T tubules which allows a rapid and synchronized transmission of the membrane action potential. Activation of L-type Ca2+ channels in the transverse tubule allows small amounts of Ca2+ into the cytosol, a quantity insufficient by itself to activate a contractile response. Rather, this Ca2+ acts as a messenger to trigger the release of Ca2+ from the SR to reach a …

Advanced heart failure (A-HF) is characterized by progressive symptoms of heart failure despite optimal therapy. In patients with A-HF, ventricular arrhythmias (VAs) are common. Clinical studies evaluating different therapies to prevent VAs had very limited representation of patients with A-HF. Among antiarrhythmic drugs, only amiodarone reduces VAs, although its use may be associated with increased mortality. Catheter ablation with substrate modification is effective to achieve VA suppression in patients with A-HF, including those with left ventricular assist devices. In high-risk cases, temporary mechanical hemodynamic support tailored to the individual patient on the basis of presentation and hemodynamic conditions may be beneficial. Advanced therapies for pump failure or refractory VAs, including heart transplantation and durable mechanical circulatory support, may be required in high-risk patients who are reasonable candidates for these surgical therapies. In this review, the authors discuss important management considerations in patients with VAs and A-HF.

Durable ventricular assist device (VAD) therapy improves survival in patients with refractory heart failure with reduced ejection fraction, but is inaccessible to uninsured patients due to high cost. Medicaid expansion under the Affordable Care Act increased health insurance coverage for low-income

Visual Abstract, Highlights • LVSD is associated with reduced LV systolic function and geometrical changes. • MVR results from LVSD. • Current management strategies address LVSD and secondary MVR separately, even in advanced stages of LVSD. • We describe an implantable soft robotic device that would provide a new paradigm in supporting patients with coexistence of LVSD and concomitant MVR by dynamically augmenting native LV contraction and supporting the mitral valve apparatus to eliminate the associated MVR., Summary Left ventricular failure is strongly associated with secondary mitral valve regurgitation. Implantable soft robotic devices are an emerging technology that enables augmentation of a native function of a target tissue. We demonstrate the ability of a novel soft robotic ventricular assist device to dynamically augment left ventricular contraction, provide native pulsatile flow, simultaneously reshape the mitral valve apparatus, and eliminate the associated regurgitation in an Short-term large animal model of acute left ventricular systolic dysfunction.

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown.\ud \ud Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy.\ud \ud Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response.\ud \ud Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56–0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro–brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil–assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12–60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting.\ud \ud Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.\ud \ud Clinical trial registered with www.clinicaltrials.gov (NCT01560624).

Thoracic transplantation is considered for patients with Eisenmenger syndrome (ES) who have refractory right ventricular failure despite optimal therapy for pulmonary arterial hypertension. This study compared the outcomes of bilateral lung transplantation (BLT) with cardiac defect repair vs combined heart-lung transplantation (HLT).This study presents an updated analysis using a US national registry to evaluate the outcomes of patients diagnosed with ES who underwent HLT or BLT with repair of cardiac defects.This study identified patients with ES who underwent thoracic transplantation from 1987 to 2018 from the United Network for Organ Sharing database. Survival curves were estimated by using the Kaplan-Meier method and were compared by using the log-rank test.During the study period, 442 adults with ES underwent thoracic transplantation (316 HLTs and 126 BLTs). Following BLT, overall survival 1, 5, and 10 years' posttransplant was 63.1%, 38.5%, and 30.2%, respectively. Following HLT, overall survival 1, 5, and 10 years' posttransplant was 68.0%, 47.3%, and 30.5% (P = .6). When survival analysis was stratified according to type of defect, patients with an atrial septal defect had better survival following BLT than following HLT (88.3% vs 63.2% 1 year posttransplant, P .01; 71.1% vs 49.8% 3 years' posttransplant, P .01; and 37.4% vs 29.9% 10 years' posttransplant, P = .08). Patients with a ventricular septal defect (VSD) exhibited better survival following HLT than following BLT (78.2% vs 49.6% 1 year posttransplant, P .01; 55.6% vs 34.3% 5 years' posttransplant, P .01; and 35.7% vs 26.5% 10 years' posttransplant, P = .03). The most common cause of mortality in patients with VSD undergoing BLT was cardiac ventricular failure.This study suggests that the best transplant option for patients with VSD remains HLT, which prevents subsequent development of ventricular failure. BLT with cardiac defect repair should be considered as the first-line treatment option in patients with ES due to an uncorrected atrial septal defect. These patients can be considered to have isolated and reversible right ventricular failure akin to patients with advanced pulmonary arterial hypertension.

Background Initial development of a prominent bariatric surgery mortality risk calculator comprising cases that now account for Objectives To validate and improve a bariatric-surgery-specific mortality calculator with updated case mix and outcomes data. Setting Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program–accredited bariatric surgery programs. Methods The Metabolic and Bariatric Accreditation and Quality Improvement Program Participant Use File from years 2015 to 2017 was used for the analysis. C-statistics were calculated with observed death as the outcome and estimated 30-day mortality risk as the only predictor and receiver operating characteristic curve was plotted. Similar analyses were repeated for each body mass index (BMI) subgroup. Backward selection logistic regression was used to investigate the potential of improving the robustness of the model. Results Patients were predominantly female (n = 446,149, 80.4%) and white (n = 409,350, 73.7%) with a mean (standard deviation) age of 45.4 (12.0) years and BMI of 44.5 (8.4) kg/m2, and the most commonly performed operation was sleeve gastrectomy (n = 338,061, 60.9%). Assessing previous model using present data, area under the curve was .7412. By BMI subgroup, area under the curve for BMI 60 kg/m2 was .6576. Discussion The present study found that the model previously developed maintains discrimination with changing surgical procedures. Though variables in the initial calculator are helpful, additional factors should be considered when weighing risk, such as sex, previous surgery, and renal function. Future studies are needed to determine whether changes in modifiable risk factors will impact mortality rates.

The anatomy and physiology of the right ventricle are unique and need to be considered when planning for left ventricular assist device (LVAD) placement. Many predictive models of right heart failure after LVAD placement are discussed. Several temporary right ventricular assist devices are available, and options for chronic biventricular assist device support is very limited. Delayed right ventricular function and its implications are discussed.

LVAD therapy has traditionally been viewed as a bridge to transplant or destination therapy strategy. However, an exciting new area of research has reopened the door to using these devices as a bridge to recovery. The RESTAGE-HF trial was designed to evaluate the potential for a recovery protocol to achieve successful explantation of the device. The early results from this trial suggest that a protocol including optimal medical therapy in the setting of LVAD therapy may allow for explantation in many cases with durable recovery. This chapter outlines the concepts and data surrounding this important area of study.