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Background Concerns regarding long-term durability of surgical repair for functional mitral regurgitation are based on short-term data, with few comparisons of ischemic (IMR) versus non-ischemic (NIFMR) etiology. Methods 788 consecutive patients receiving mitral repair for functional mitral regurgitation were evaluated from a prospectively maintained database. Patients with other surgical procedures were included. Propensity score matching was used to compare outcomes in IMR versus NIFMR. Results Unmatched IMR patients tended to be older men with greater comorbidities. 198 matched pairs of IMR versus NIFMR patients had similar demographics with relatively preserved ejection fraction 40±13% and end-systolic diameter 4.3±1.1cm. Concomitant coronary revascularization occurred in 70% of matched IMR patients. All patients received an annuloplasty ring, usually 24-26 mm. Heart failure class improved from 2.8 preop to 1.5 at 5 years (P =2+) mitral regurgitation (27±4% v 26±4%, P=0.4), severe regurgitation (10±3% v 8±2%, P=0.5), and mitral reoperation (3±1% v 3±1%, P=0.4) were not different between IMR v NIFMR. Recurrent moderate regurgitation was associated with heart failure readmission but not with mortality. Conclusions In propensity-matched patients, IMR versus NIFMR had worse survival but similar repair durability, with moderate regurgitation in 27% at 10 years and rare severe regurgitation or mitral reoperation. In selected patients with relatively preserved function, mitral repair for IMR or NIFMR can improve symptoms with durable mild regurgitation in most patients out to 10 years.

PURPOSE: Clinical models to identify patients at high risk of primary graft dysfunction (PGD) after heart transplantation (HT) are limited, and the underlying pathophysiology of this common post-transplant complication remains poorly understood. We sought to identify whether pre-transplant levels of circulating proteins reporting on immune activation and inflammation are associated with incident PGD. METHODS: The study population consisted of 219 adult heart transplant recipients identified between 2016 and 2020 at Duke University Medical Center, randomly divided into derivation (n = 131) and validation (n = 88) sets. PGD was defined using modified ISHLT criteria. Proteomic profiling was performed using Olink panels (n = 354 proteins) with serum samples collected immediately prior to transplantation. Association between normalized relative protein expression and PGD was tested using univariate and multivariable (recipient age, creatinine, mechanical circulatory support, and sex; donor age; ischemic time) models. Significant proteins identified in the derivation set (p < 0.05 in univariate models), were then tested in the validation set. Pathway enrichment analysis was used to test candidate biological processes. The predictive performance of proteins was compared to that of the RADIAL score. RESULTS: Nine proteins were associated with PGD in univariate models in the derivation set. Of these, only CLEC4C remained associated with PGD in the validation set after Bonferroni correction (OR [95% CI] = 3.04 [1.74,5.82], p = 2.8×10(−4)). Patterns of association were consistent for CLEC4C in analyses stratified by biventricular/left ventricular and isolated right ventricular PGD. Pathway analysis identified interferon-alpha response and C-type lectin signaling as significantly enriched biologic processes. The RADIAL score was a poor predictor of PGD (AUC = 0.55). CLEC4C alone (AUC = 0.66, p = 0.048) and in combination with the clinical covariates from the multivariable model (AUC = 0.69, p = 0.018) improved discrimination for the primary outcome. CONCLUSIONS: Pre-transplantation circulating levels of CLEC4C, a protein marker of plasmacytoid dendritic cells (pDCs), may identify HT recipients at risk for PGD. Further studies are needed to better understand the potential role pDCs and the innate immune response in PGD.

The durability of surgical repair for degenerative versus ischemic mitral regurgitation (MR) is thought to be markedly different. We, therefore, examined late outcomes and durability for mitral repair in a large cohort of patients receiving a single annuloplasty device.A total of 749 consecutive patients receiving mitral repair for degenerative mitral regurgitation (DMR) or ischemic mitral regurgitation (IMR) were evaluated from a prospective database. Patients with tricuspid or maze surgery were included. Papillary muscle rupture and mixed valve etiologies were excluded. Outcomes were compared for IMR versus DMR.Patients with DMR were younger and less urgent. Patients with IMR had mean end-systolic diameter 4.5 ± 1.1 cm. All patients received the same complete semirigid annuloplasty device with median ring size 32 mm for DMR and 24 mm for IMR. New York Heart Association failure class improved from 2.8 to 1.5 (p .001). Patients with DMR had lower operative mortality (1/384 [0.3%] vs. 26/365 [7%], p .0001) and shorter length of stay. A 15-year survival was better with DMR (63% ± 3% vs. 13% ± 2%, p .001). At 10 years, the incidence of recurrent ≥2+ MR (10% ± 2% vs. 16% ± 2%, p = .16) was not significantly different. Predictors of recurrent ≥2+ MR were female gender (odds ratio [OR]: 3.0 (1.9-4.8, p .0001), and prior operation (OR: 2.4 [1.3-4.5], p = .02) but not IMR (OR: 1.4 [0.9-2.3], p = .15).In this series, where patients with IMR had relatively preserved ventricular dimensions, the primary determinants of late recurrent MR were female gender and prior operation but not IMR versus DMR. Selected patients with IMR can obtain relatively durable mitral repair despite higher operative risk and lower survival compared to DMR.

Supplemental Digital Content is available in the text., The study aim was to examine the impact time in therapeutic range (TTR, International Normalized Ratio [INR] 2.0–3.0) has on survival and adverse events in patients receiving the HeartWare HVAD System in the ENDURANCE and ENDURANCE Supplemental Trials. Evaluable subjects (n = 495) had >1 INR value recorded 1–24 months postimplant and were categorized as: low TTR (10–39%), moderate TTR (40–69%), and high TTR (≥70%). Baseline characteristics, adverse events, and survival were analyzed. Low TTR patients experienced higher rates of major bleeding (1.69 vs. 0.54 events per patient year [EPPY]; p < 0.001), GI bleeding (1.22 vs. 0.38 EPPY; p < 0.001), stroke (0.47 vs. 0.17 EPPY; p < 0.001), thrombus requiring exchange (0.05 vs. 0.01 EPPY; p = 0.02), infection (1.44 vs. 0.69 EPPY; p < 0.001), and renal dysfunction (0.23 vs. 0.05 EPPY; p < 0.001) compared with high TTR. Moderate TTR had higher rates of major bleeding (0.75 vs. 0.54 EPPY; p < 0.001), thrombus requiring exchange (0.05 vs. 0.01 EPPY; p = 0.007), cardiac arrhythmia (0.32 vs. 0.24 EPPY; p = 0.04), and infection (0.90 vs. 0.69 EPPY; p = 0.001) compared with high TTR. Two year survival was greater among moderate and high versus low cohorts (Log-rank p = 0.001). The significant reduction in morbidity and mortality in destination therapy (DT) HVAD patients with well-controlled TTR (≥70%) emphasizes the importance of vigilant anticoagulation management.

Background Left ventricular assist devices (LVAD) are increasingly used for durable mechanical circulatory support in advanced heart failure. While LVAD therapy provides substantial improvement in mortality and quality of life, long-term therapy confers increased risk for device complications. We evaluated if cardiac computed tomography (CCT) improves the detection of cardiomechanical complications among patients with LVAD and suspected device malfunction. Methods In this study, we compared the diagnostic performance of CCT and transthoracic echocardiography (TTE) for the identification of cardiomechanical LVAD complications, including thrombus or neointimal hyperplasia, inflow cannula malposition with dynamic obstruction, fixed outflow obstruction, device infection, and severe aortic regurgitation. Complications were confirmed with surgical evaluation, pathologic assessment, or response to therapeutic intervention. Results Among 58 LVAD patients, who underwent CCT and TTE for suspected LVAD dysfunction, there were 49 confirmed cardiomechanical LVAD complications among 43 (74.1%) patients. The most common LVAD complication was thrombus or neointimal hyperplasia (65.3%), followed by dynamic obstruction (26.5%). Individually, CCT identified 29 of the 49 (59.2%) confirmed LVAD cardiomechanical complications, whereas TTE alone identified a complication in 11 cases (22.4%). However, diagnostic performance was greatest when the two modalities were used in combination, yielding a sensitivity of 67%, specificity of 93%, PPV of 97%, NPV of 47% and diagnostic accuracy of 73%. Conclusion The novel and complementary use of CCT with TTE for the evaluation of suspected device malfunction improves the accurate identification of cardiomechanical LVAD complication compared to either modality alone.

BACKGROUND: In the era of antiretroviral therapy, HIV-positive patients have reduced mortality from HIV infection and increased morbidity from end stage heart failure. The number of HIV-positive heart transplantation recipients remains scant. Long-term survival has not been rigorously studied. We compared survival outcomes of heart transplantation in HIV-positive recipients to HIV-negative recipients. METHODS: Clinical data from all adult heart transplantations were extracted from the UNOS Dataset. The impact of recipient HIV status was analyzed with Cox proportional hazards modeling, 1:3 propensity score matching and Kaplan-Meier survival analysis. RESULTS: Seventy-five HIV-positive recipients and 29,848 HIV-negative recipients were identified. Race distributions differed between the recipient groups, with Blacks comprising a larger proportion of the HIV-positive recipient group (46.7% versus 20.9%, p

OptiVol (Medtronic PLC, Minneapolis, MN) is a diagnostic feature of some cardiac implantable electronic devices (CIEDs) based on changes in thoracic impedance (TI) over time. Changes in TI can predict heart failure (HF) hospitalizations and mortality in HF populations. However, the utility of this feature is unknown in patients with a left ventricular assist device (LVAD). To determine if OptiVol and TI correlate with clinical HF events in a population of LVAD patients, hospitalization outcomes were collected retrospectively from the electronic health records at a single academic medical center in 80 LVAD patients with an OptiVol-capable CIED. Demographics, medical history, and available clinical data were reviewed and reported. The primary outcomes of interest were TI and OptiVol trends before and after hospitalization, and association of trends before and after these events was evaluated. Most patients had a HeartMate II LVAD and most CIEDs were defibrillators, and 23 (29%) had at least one HF hospitalization during the study period. HF hospitalizations were preceded by signs of volume overload in Optivol (60%) and TI (78%) with recovery of these measures post hospitalization in 33% and 25% of patients, respectively. Monitoring of TI and OptiVol may be one effective component of HF management in LVAD patients as part of a comprehensive program.

Background Sensitized candidates with unacceptable antigens are a group that demands special attention in organ transplantation. Calculated panel reactive antigen (cPRA) is not used to modify allocation priorities in lung transplantation. The impact of cPRA on waiting list time and mortality is unknown. Methods We performed a retrospective review of candidates for lung transplantation listed from May 2005 to 2018. Data from the Organ Procurement and Transplantation Network/United Network for Organ Sharing STAR (Standard Analysis and Research) dataset was paired with additional unacceptable human leukocyte antigen (UA-HLA) data, which were used to calculate the listing cPRA. Candidates were stratified based on the lack of UA-HLAs or cPRA level for candidates with unacceptable antigens reported. Unadjusted competing risks and adjusted subdistribution hazard models were fit. Results A total of 29,085 candidates met inclusion criteria for analysis. Of these, 23,562 (81%) with no UA-HLAs, 3472 (11.9%) with a cPRA less than 50, and 2051 with a cPRA greater than or equal to 50 (7.1%). On adjusted analysis, a cPRA greater than or equal to 50 was independently associated with increased waitlist mortality at 1 year (hazard ratio, 1.71; 95% confidence interval, 1.55-1.88; P Conclusions Further evaluation of organ allocation with consideration of a candidate's cPRA may be warranted in order to optimize equity in access to transplants.

Background Short duration, antimicrobial prophylaxis that includes antistaphylococcal activity is recommended at the time of left ventricular assist device (LVAD) implantation to reduce infection-related complications. There continues to be wide variability in surgical infection prophylaxis (SIP) regimens among implantation centers. The aim of this study is to characterize current SIP regimens at different LVAD centers. Methods A survey study was conducted from 26 September 2017 to 25 October 2017. Surveys were distributed electronically to LVAD coordinators and infectious diseases specialists at 75 US medical centers identified as having an LVAD program. Data collection included information about antimicrobial selection, duration, Staphylococcus aureus screening, and decolonization procedures. Results We received 29 survey responses. The majority of surveys were completed by infectious diseases physicians (72.4% [21 out of 29]). Most responding centers reported LVAD programs established for greater than 10 years (20 out of 29 [69%]). Cardiac transplantation was performed in 28 out of 29 (96%) centers. Of centers reporting a defined SIP regimen for non-penicillin allergic patients (96% [28 out of 29]), 17.9% (5 out of 28) reported a four-drug regimen, 35.7% (10 out of 28) reported a three-drug regimen, and 46.4% (13 out of 28) reported a two-drug regimen, while no centers reported a single-drug regimen. Empiric fluconazole was common (50% [14 out of 28]) and 96.4% (27 out of 28) of regimens included vancomycin. Duration of antimicrobial prophylaxis (24 hours to 5 days), S. aureus screening, decolonization procedures, and alterations due to drug allergies varied across participating centers. Conclusions Our survey results indicate wide variation in SIP regimens among participating LVAD centers. These results highlight the need for studies evaluating the implications of SIP regimens, and whether clinical factors that prolong antimicrobial duration impact postoperative infection rates.

Acute kidney injury (AKI) and primary graft dysfunction (PGD) are serious complications after heart transplantation (HT). The relationship between AKI and PGD is poorly understood. We sought to examine the incidence of AKI and identify risk factors associated with AKI. We hypothesized that PGD is one of the risk factors independently associated with post-HT AKI. We gathered data for all adult patients who underwent HT between 2009 and 2014. AKI was defined by the KDIGO criteria. PGD was categorized using ISHLT criteria. We assessed univariable and multivariable logistic regression to identify risk factors independently associated with post-HT AKI. Out of 316 patients, postoperative AKI occurred in 273 (86%) patients: 188 (68%) stage I, 44 (16%) stage II, and 41 (15%) stage III. Stage II/III AKI was associated with increased risk of mortality at 1 year. There was significant association between severe PGD and stage II/III AKI (P = 0.001, OR 3.63, 95% CI: 1.69-7.94). Other clinical factors significantly associated with stage II/III AKI included longer donor brain death duration and lower recipient baseline creatinine. We found that stage II/III AKI is common and independently associated with severe PGD. Another potentially modifiable risk factor is donor brain death duration.

Introduction Lead dysfunction can lead to serious consequences including failure to treat ventricular tachycardia or fibrillation (VT/VF). The incidence and mechanisms of lead dysfunction following left ventricular assist device (LVAD) implantation are not well-described. We sought to determine the incidence, mechanisms, timing, and complications of right ventricular lead dysfunction requiring revision following LVAD implantation. Methods Retrospective observational chart review of all LVAD recipients with pre-existing implantable cardioverter-defibrillator (ICD) from 2009 to 2018 was performed including device interrogation reports, laboratory and imaging data, procedural reports, and clinical outcomes. Results Among 583 patients with an ICD in situ undergoing LVAD implant, the median (interquartile range) age was 62.5 (15.7) years, 21% were female, and the types of LVADs included HeartWare HVAD (26%), HeartMate II (52%), and HeartMate III (22%). Right ventricular lead revision was performed in 38 patients (6.5%) at a median (25th, 75th) of 16.4 (3.6, 29.2) months following LVAD. Mechanisms of lead dysfunction included macrodislodgement (n = 4), surgical lead injury (n = 4), recall (n = 3), insulation failure (n = 8) or conductor fracture (n = 7), and alterations in the lead-myocardial interface (n = 12). Undersensing requiring revision occurred in 22 (58%) cases. Clinical sequelae of undersensing included failure to detect VT/VF (n = 4) and pacing-induced torsade de pointes (n = 1). Oversensing occurred in 12 (32%) and sequelae included inappropriate antitachycardia pacing ([ATP], n = 8), inappropriate ICD shock (n = 6), and ATP-induced VT (n = 1). Conclusion The incidence of right ventricular lead dysfunction following LVAD implantation is significant and has important clinical sequelae. Physicians should remain vigilant for lead dysfunction after LVAD surgery and test lead function before discharge.

Left ventricular assist devices are (LVAD) used for circulatory support in patients with end-stage heart failure. Hemolysis/pump dysfunction is a well-known complication of this therapy with various etiologic causes. A small proportion of these complications are caused by outflow graft obstructions; this complication has received little attention in the scientific literature. Herein, we provide a comprehensive overview of the role of the LVAD outflow graft obstruction and its treatment options.

Stroke remains a significant complication of left ventricular assist device (LVAD) therapy. We performed a single-center retrospective study evaluating patients undergoing first-time HeartWare HVAD (Medtronic Inc) or HeartMate 3 (Abbott Inc) implantation from September 2009-February 2018.Exclusion criteria were age18 and preoperative ECMO. The primary endpoint was stroke-free survival. Stroke was defined as new neurological deficits persisting24 hours with corresponding radiographic evidence. Risk factors evaluated included demographics, medical comorbidities, heart failure etiology, LVAD indication, INTERMACS profile, and device type. Univariate predictors (P .15) and variables clinically suspected to raise stroke risk were entered in a multivariate hazard regression model, specified using backward selection of covariates and accounting for competing risks of transplant/LVAD exchange.A total of 163 HVAD and 84 HM3 patients were analyzed. Median follow up (until death, censoring for transplant/LVAD removal, or end of follow up) was 1.2 years in HVAD patients and 1.4 years in HM3 patients. Stroke occurred in 24 HVAD patients (15 ischemic, 9 hemorrhagic) and 6 HM3 patients (4 ischemic, 2 hemorrhagic). One-year stroke-free survival was 76.8% for HVAD and 84.3% for HM3. Thirty-day mortality following stroke was 41.7% for HVAD and 66.7% for HM3; 54.2% of HVAD strokes were disabling compared to 83.3% of HM3 strokes. Age, LVAD indication, and device type were associated (P .15) with stroke on univariate analysis. On multivariate analysis, the HVAD was associated with significantly higher stroke risk (hazard ratio, 2.57; 95% confidence interval, 1.02-6.44; P = .045).Different LVAD models appear to be associated with significantly different stroke risks.

We describe a case of inherited restrictive cardiomyopathy in a patient presenting with severe biatrial enlargement. We review the evaluation and management of restrictive cardiomyopathy with a focus on genetic etiologies. (Level of Difficulty: Intermediate.), Graphical abstract, We describe a case of inherited restrictive cardiomyopathy in a patient presenting with severe biatrial enlargement. We review the evaluation and…

The CARMAT-Total Artificial Heart (C-TAH) is designed to provide heart replacement therapy for patients with end-stage biventricular failure. This report details the reliability and efficacy of the autoregulation device control mechanism (auto-mode), designed to mimic normal physiologic responses to changing patient needs. Hemodynamic data from a continuous cohort of 10 patients implanted with the device, recorded over 1,842 support days in auto-mode, were analyzed with respect to daily changing physiologic needs. The C-TAH uses embedded pressure sensors to regulate the pump output. Right and left ventricular outputs are automatically balanced. The operator sets target values and the inbuilt algorithm adjusts the stroke volume and beat rate, and hence cardiac output, automatically. Auto-mode is set perioperatively after initial postcardiopulmonary bypass hemodynamic stabilization. All patients showed a range of average inflow pressures of between 5 and 20 mm Hg during their daily activities, resulting in cardiac output responses of between 4.3 and 7.3 L/min. Operator adjustments were cumulatively only required on 20 occasions. This report demonstrates that the C-TAH auto-mode effectively produces appropriate physiologic responses reflective of changing patients’ daily needs and represents one of the unique characteristics of this device in providing almost physiologic heart replacement therapy.

In two interim analyses of this trial, patients with advanced heart failure who were treated with a fully magnetically levitated centrifugal-flow left ventricular assist device were less likely to have pump thrombosis or nondisabling stroke than were patients treated with a mechanical-bearing axial-flow left ventricular assist device.We randomly assigned patients with advanced heart failure to receive either the centrifugal-flow pump or the axial-flow pump irrespective of the intended goal of use (bridge to transplantation or destination therapy). The composite primary end point was survival at 2 years free of disabling stroke or reoperation to replace or remove a malfunctioning device. The principal secondary end point was pump replacement at 2 years.This final analysis included 1028 enrolled patients: 516 in the centrifugal-flow pump group and 512 in the axial-flow pump group. In the analysis of the primary end point, 397 patients (76.9%) in the centrifugal-flow pump group, as compared with 332 (64.8%) in the axial-flow pump group, remained alive and free of disabling stroke or reoperation to replace or remove a malfunctioning device at 2 years (relative risk, 0.84; 95% confidence interval [CI], 0.78 to 0.91; P0.001 for superiority). Pump replacement was less common in the centrifugal-flow pump group than in the axial-flow pump group (12 patients [2.3%] vs. 57 patients [11.3%]; relative risk, 0.21; 95% CI, 0.11 to 0.38; P0.001). The numbers of events per patient-year for stroke of any severity, major bleeding, and gastrointestinal hemorrhage were lower in the centrifugal-flow pump group than in the axial-flow pump group.Among patients with advanced heart failure, a fully magnetically levitated centrifugal-flow left ventricular assist device was associated with less frequent need for pump replacement than an axial-flow device and was superior with respect to survival free of disabling stroke or reoperation to replace or remove a malfunctioning device. (Funded by Abbott; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755.).

Intra-aortic balloon pump (IABP) is often used to support patients in decompensated heart failure. Placement of the IABP via the axillary artery facilitates long-term support with the device and may allow for the conversion of an acute heart failure (HF) patient into a chronic HF patient using a modified weaning protocol; allowing for medical symptom management and removal of mechanical support. We will discuss strategies for supporting these complicated patients.

Background Postoperative atrial fibrillation (POAF) frequently complicates cardiac surgery and is associated with worse outcomes. The cardiac autonomic nervous system is implicated in the pathogenesis of POAF. Objective The purpose of this study was to determine the efficacy and safety of selective cardiac autonomic modulation in preventing POAF. Methods In this randomized, double-blind, placebo-controlled trial, adults undergoing cardiac surgery were randomized 1:1 to intraoperative injection of 250 units onabotulinumtoxinA (botulinum toxin type A [BoNTA]) or placebo into epicardial fat pads. The study was powered to detect a 40% reduction in relative risk of POAF. Time to first episode of in-hospital POAF was the primary outcome, evaluated in patients receiving injection. Additionally, incidence of POAF, length of stay (LOS), and adverse events were examined. Results The trial assigned 145 patients to injection, 15 of whom were dropped before treatment, leaving 130 patients for analysis. Overall, 36.5% (23/63) of BoNTA-treated patients developed POAF compared with 47.8% (32/67) of placebo-treated patients. The time-to-event analysis revealed a hazard ratio of 0.69 (95% confidence interval 0.41–1.19; P = .18) for the BoNTA vs placebo arm. There were no significant differences in postoperative hospital LOS (median [interquartile range] 6.0 [3.4] vs 6.2 [3.7] days; P = .51) or adverse events prolonging LOS (27/63 [42.9%] vs 30/67 [44.8%]; P = .83) in patients receiving BoNTA vs placebo. Conclusion Epicardial injection of onabotulinumtoxinA was without discernible adverse effects, but we failed to detect a significant difference in risk of POAF. Future large-scale studies of epicardial onabotulinumtoxinA injection as a potential POAF prevention strategy should be designed to study smaller, but clinically meaningful, treatment effects.

Left ventricular assist devices (LVADs) improve quality of life (QoL) and functional capacity (FC) for patients with advanced heart failure. The association between adverse events (AEs) and changes in QoL and FC are unknown. Patients treated with the HeartWare ventricular assist device (HVAD) with paired 6-minute walk distance (6MWD, n = 263) and Kansas City Cardiomyopathy Questionnaires (KCCQ, n = 272) at baseline and 24 months in the ENDURANCE and ENDURANCE Supplemental Trial databases were included. Patients were stratified based upon occurrence of clinically significant AEs during the first 24 months of support and analyzed for the mean change in 6MWD and KCCQ. The impact of AE frequency on change in 6MWD and KCCQ from baseline to 24 months was evaluated. Of the AEs examined, only sepsis was associated with an improvement in 6MWD (109 m vs. 16 m, p = 0.002). Patients without improvement in 6MWD test from baseline to 24 months had significantly more AEs than those with FC improvement (p = 0.0002). Adverse events did not affect the KCCQ overall summary score. In this analysis, patients with fewer AEs had greater improvement in FC during the 24-month follow up. The frequency of AEs did not have a significant impact on QoL after LVAD implantation.

Stroke is a devastating complication of left ventricular assist device (LVAD) therapy. Understanding the characteristics, risk factors and outcomes of strokes associated with the centrifugal flow LVADs is important to devise better strategies for management and prevention. This is a retrospective cohort study at a single US academic medical center. The cohort includes patients who received a first time Heartmate 3 (HM3) or Heartware (HVAD) LVAD between September 2009 through February 2018 and had a stroke while the LVAD was in place. Descriptive statistics were used when appropriate. A logistic regression analysis was used to determine predictors of poor outcome. Out of a total of 247 patients, 12.1% (N = 30, 24 HVAD and 6 HM3) had a stroke (63% ischemic) and 3 of these patients had pump thrombosis. Events per patient year (EPPY) were similar for HVAD and HM3 patients (0.3 ± 0.1). INR was subtherapeutic in 47.4% of ischemic stroke patients and supratherapeutic in 18.2% of hemorrhagic stroke patients. Concurrent infections were more common in the setting of hemorrhagic stroke than ischemic stroke (45.4% vs 5.3%, p = 0.008). Strokes were severe in most cases, with initial NIH stroke scale (NIHSS) higher in HM3 patients compared to HVAD patients (mean 24.6 vs 16) and associated with high in-patient mortality (21.1% of ischemic stroke vs. 88.8% of hemorrhagic stroke). Predictors of death within 30 days and disability at 90 days included creatinine at stroke onset, concurrent infection, hemorrhaghic stroke, and initial stroke severity (NIHSS). A score derived from these variables predicted with 100% certainty mortality at 30 days and mRS ≥ 4 at 90 days. For patients with centrifugal flow LVADs, ischemic strokes were more common but hemorrhagic strokes were associated with higher in-patient mortality and more frequently seen in the setting of concurrent infections. Infections, sub or supratherapeutic INR range, and comorbid cardiovascular risk factors may all be contributing to the stroke burden. These findings may inform future strategies for stroke prevention in this population.

Introduction: There is a complex epidemiologic relationship between type two diabetes mellitus (DM) and heart failure (HF), and it is unclear whether the biochemical basis of HF differs in patients with and without DM. Hypothesis: Proteomic profiling of myocardial tissue from patients with and without DM will identify unique signatures of diabetic HF. Methods: Using the Olink aptamer-based platform, we performed proteomic profiling of 552 proteins on 37 myocardial tissue samples: 9 controls, 10 with HF, 7 with DM, and 11 with HF+DM. One-way ANOVA was first used to identify proteins that differed across the four groups. Associated proteins were then tested for differences between HF+DM and each other group independently; we retained proteins with the same direction of effect for each comparison. Each analysis was controlled for false discovery rate (q Results: We identified 12 proteins that differed significantly between HF+DM and all three other groups. Among these, six proteins were significant after FDR adjusted ANOVA and had the same direction of effect. These included 5’-NT (q=5.35E-07), a regulator of intracellular energy utilization, and carboxypeptidase A2, a metalloprotease that cleaves peptides during digestion (q=0.0003). Expression of myocardial leptin receptors (q=0.001), complement factor H related protein (q=0.003), and carbonic anhydrase (q=0.006) were also upregulated in diabetic HF, and have previously been linked to myocyte hypertrophy. Markers of endothelial dysfunction - ESM-1 (q=5.62E-06) and VEGFR-3 (q=0.024) - were also increased in HF+DM myocardium as compared to other groups (Figure 1). Conclusions: Proteomic profiling of HF, DM, and HF+DM myocardial tissue suggest alterations in intracellular energy substrate utilization as well as increased expression of tissue biomarkers previously associated with ventricular hypertrophy and myocardial remodeling.

Background Ventricular arrhythmias (VAs) and electrical storm (ES) are recognized complications following left ventricular assist device (LVAD) implantation; however, their association with long term-outcomes remains poorly understood. Objective The purpose of this study was to describe the clinical impact of ES in a population of patients undergoing LVAD implantation at a quaternary care center in the United States. Methods This was an observational retrospective study of patients undergoing LVAD implantation from 2009 to 2020 at Duke University Hospital. The incidence of ES (≥3 sustained VA episodes over a 24-hour period without an identifiable reversible cause) was determined from patient records. Risk factors for ES were identified using multivariable Cox proportional hazards modeling. Results Among 730 patients undergoing LVAD implant, 78 (10.7%) developed ES at a median of 269 (interquartile range [IQR] 7–766) days following surgery. Twenty-seven patients (34.6%) developed ES within 30 days, while 51 (65.4%) presented with ES at a median 639 (IQR 281–1017) days after implant. Following ES, 41% of patients died within 1 year. Patients who developed ES were more likely to have a history of VAs, ventricular tachycardia ablation, antiarrhythmic drug use, and perioperative mechanical circulatory support around the time of LVAD implant than patients without ES. Conclusion ES occurs in 1 in 10 patients after LVAD and is associated with higher mortality. Risk factors for ES include a history of VAs, VT ablation, antiarrhythmic drug use, and perioperative mechanical circulatory support. Optimal management of ES surrounding LVAD implant, including escalation of medical therapy, catheter ablation, or adjunctive sympatholytic therapies, remains uncertain.

Background: The NuPulseCV intravascular ventricular assist system (iVAS) provides extended duration ambulatory counterpulsation via a durable pump placed through the distal subclavian artery. Methods: We performed a prospective, single-arm, multicenter, US Food and Drug Administration-approved feasibility trial of iVAS therapy as a bridge to transplant or decision following the FIH (First-In-Human) trial. Results: Forty-seven patients were enrolled, and 45 patients (median 61 years old, 37 males, and 30 listed on United Network of Organ Sharing) received iVAS support for median 44 (25–87) days. There were no intraoperative complications. Success was defined as survival or transplant on iVAS therapy free from disabling stroke. Outcome success at 30 days (the primary end point of this study) and at 6 months was 89% and 80%, respectively. During 6 months of iVAS support, 2 patients died and 2 patients experienced disabling neurological dysfunction. Six-minute walk distance, 2-minute step test, and Kansas City Cardiomyopathy Questionnaire score improved during 4-week iVAS support. Conclusions: This feasibility trial demonstrated promising short-term outcomes of iVAS therapy with improved functional capacity and quality of life during the therapy. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02645539.

Introduction: Stroke is a devastating complication of left ventricular assist device (LVAD) therapy and a leading cause of mortality in this group. The newer HeartMate (HVAD, 2012) and HeartMate 3 (HM3, 2017) devices use a continuous flow centrifugal pump with a magnetically levitated rotor that may cause less thrombosis and stroke. We aim to compare the rate and severity of strokes in the setting of the new generation LVADs. Methods: This was a single-center retrospective cohort study at a single US academic medical center. The cohort includes all subjects at Duke University Medical Center who received either an HM3 or HVAD LVAD between September 2009 through February 2018 and had a cerebrovascular accident while the LVAD was in place. Descriptive statistics were calculated to compare the clinical variables for individuals receiving either the HVAD or HM3 device. 95% confidence intervals were calculated when appropriate. Results: A total of 163 HVAD patients and 84 HM3 patients were included in the analysis. Strokes occurred more commonly among those with HVAD (14.7%, 9.7%-21.1%) compared to those with HM3 (6.0%, 2.0%-13.3%). About 62.1% of strokes were ischemic. Patients with HM3 were older and had a higher rate of cardiovascular risk factors. The initial mean NIHSS was higher in HM3 patients (24.6, 11.9-37.3) compared to those with HVADs (16, 10.9-21.1). Mortality within 30 days was higher in HM3 patients (60.0%, 14.7%-94.7%) compared to HVAD patients (45.8%, 25.6%-67.2%). Patients were more likely to be disabled (mRs> 3) at 3 months if they had an HM3 (80%, 28.4%-99.5%) compared to those who had an HVAD (54.2%, 32.8%-74.4%). Conclusion: Strokes occurred more commonly among those with HVAD compared to HM3, but the strokes in those with HM3 tended to be more severe at onset compared to HVAD with a higher 30 days mortality and more disability at 3 months. The difference in stroke frequency may suggest that the HM3 is less prone to thrombosis. The difference in mortality may have been secondary to patients with HM3 being older and with more cardiovascular risk factors or could be related to a reduction in minor strokes causing a shift to worse outcomes. Additional studies are needed to understand the predictors of stroke in the setting of the new generation LVADs.

BACKGROUND: Patients with end stage heart failure are increasingly being bridged to heart transplant (BTT) with mechanical circulatory support (MCS), however the association between a left ventricular assist device (LVAD) BTT strategy and post-transplant renal outcomes is unclear. The aim of this study was to analyze the association of LVAD BTT with the development of post-transplant renal failure using a large national registry. METHODS: We queried the 2009-2018 United Network for Organ Sharing (UNOS) registry for all adults undergoing first-time heart or heart-kidney transplantation and stratified patients by use of pre-transplant durable LVAD. The primary outcome of interest was post-transplant renal failure, which was evaluated with multivariable logistic regression. RESULTS: 18,307 patients met inclusion criteria including 7,887 (43%) and 10,420 (57%) that were and were not bridged to transplant with an LVAD, respectively. BTT patients had slightly better baseline renal function (eGFR 68.7 vs 65.8 mL/min, p

Objectives The aim of this study was to prospectively evaluate the impact of blood pressure management on stroke rates in patients receiving the HeartWare HVAD System. Background The ENDURANCE trial demonstrated noninferiority of the HeartWare HVAD System versus control (HeartMate II) in patients with advanced heart failure ineligible for heart transplantation. However, stroke was more common in HVAD subjects. Post hoc analyses demonstrated increased mean arterial blood pressure as a significant independent risk factor for stroke. Methods The ENDURANCE Supplemental Trial was a prospective, multicenter evaluation of 465 patients with advanced heart failure ineligible for transplantation, randomized 2:1 to HVAD (n = 308) or control (n = 157). The primary endpoint was the 12-month incidence of transient ischemic attack or stroke with residual deficit 24 weeks post-event. Secondary endpoints included the composite of freedom from death, disabling stroke, and need for device replacement or urgent transplantation, as well as comparisons of stroke or transient ischemic attack rates in HVAD cohorts in ENDURANCE Supplemental and ENDURANCE. Results The enhanced blood pressure protocol significantly reduced mean arterial blood pressure. The primary endpoint was not achieved (14.7% with HVAD vs. 12.1% with control, noninferiority [margin 6%] p = 0.14). However, the secondary composite endpoint demonstrated superiority of HVAD (76.1%) versus control (66.9%) (p = 0.04). The incidence of stroke in HVAD subjects was reduced 24.2% in ENDURANCE Supplemental compared with ENDURANCE (p = 0.10), and hemorrhagic cerebrovascular accident was reduced by 50.5% (p = 0.02). Conclusions The ENDURANCE Supplemental Trial failed to demonstrate noninferiority of HVAD versus control regarding the pre-specified primary endpoint. However, the trial confirmed that BP management is associated with reduced stroke rates in HVAD subjects. HVAD subjects, relative to control subjects, more commonly achieved the composite endpoint (freedom from death, disabling stroke, and device replacement or urgent transplantation). (A Clinical Trial to Evaluate the HeartWare™ Ventricular Assist System [ENDURANCE SUPPLEMENTAL TRIAL] [DT2]; NCT01966458)

Objectives This study sought to determine the durability of tricuspid valve repair (TVr) performed concurrently with left ventricular assist device (LVAD) implantation and its association with the development of late right heart failure (RHF). Background Surgical management of tricuspid regurgitation (TR) at the time of LVAD implantation is performed in an attempt to reduce the occurrence of postoperative RHF. Limited data exist regarding the durability of TVr in patients with LVAD as well as its impact on development of late RHF. Methods A retrospective review was conducted of consecutive adult patients who underwent durable LVAD implantation and concurrent TVr at the authors’ institution between 2009 and 2017. Late RHF was defined as readmission for HF requiring inotropic or diuretic therapy. TVr failure was defined as moderate or severe TR at any follow-up echocardiographic examination after LVAD implantation. Results A total of 156 patients underwent LVAD and concurrent TVr during the study. Of the total, 59 patients (37.8%) had a failed TVr. The mean duration of echocardiographic follow-up was 23 ± 22 months. Of the 146 patients who were discharged after the index hospitalization, 53 patients (36.3%) developed late RHF. Multivariate Cox proportional hazard analysis demonstrated that TVr failure was an independent predictor of late RHF development (hazard ratio: 2.62; 95% confidence interval: 1.38 to 4.96; p = 0.003). Conclusions Failure of TVr in this cohort occurred at a significant rate. Failure of TVr is an independent risk factor for development of late RHF. Future studies should investigate strategies to reduce recurrence of significant TR.

Changes in heart transplantation (HT) donor and recipient demographics may influence the incidence of primary graft dysfunction (PGD). We conducted a retrospective study to evaluate PGD incidence, trends, and associated risk factors by analyzing consecutive adult patients who underwent HT between January 2009 and December 2014 at our institution. Patients were categorized as having PGD using the International Society for Heart & Lung Transplantation (ISHLT)–defined criteria. Variables, including clinical and demographic characteristics of donors and recipients, were selected to assess their independent association with PGD. A time-trend analysis was performed over the study period. Three-hundred seventeen patients met inclusion criteria. Left ventricular PGD, right ventricular PGD, or both, were observed in 99 patients (31%). Risk factors independently associated with PGD included ischemic time, recipient African American race, and recipient amiodarone treatment. Over the study period, there was no change in the PGD incidence; however, there was an increase in the recipient pretransplantation use of amiodarone. The rate of 30-day mortality was significantly elevated in those with PGD versus those without PGD (6.06% vs 0.92%, P = .01). Despite recent advancements, incidence of PGD remains high. Understanding associated risk factors may allow for implementation of targeted therapeutic interventions.

Background Outcome of mitral valve replacement in extreme scenarios of small mitral annulus with the use of the Regent mechanical aortic valve is not well documented. Methods Records were examined in 31 consecutive patients who underwent mitral valve replacement with the use of the aortic Regent valve because of a small mitral annulus. Results Mean age was 60 ± 14 years. Mitral stenosis or mitral annulus calcification was present in 30 of 31 patients (97%). Concurrent procedures were performed in 17 of 31 patients (55%). Median valve size was 23 mm. Mean mitral gradient coming out of the operating room was 4.2 ± 1.5 mm Hg and at follow-up echocardiogram performed at a median of 32 months after the procedure was 5.8 ± 2.4 mm Hg. Conclusions A Regent aortic mechanical valve can be a viable option with a larger orifice area than the regular mechanical mitral valve in a problematic situation of a small mitral valve annulus. Moreover, the pressure gradients over the valve are acceptable intraoperatively and over time.

Introduction Limited data are available describing indications for and outcomes of therapeutic plasma exchange (TPE) in cardiac transplantation. Methods In a retrospective study of patients who underwent cardiac transplantation at Duke University Medical Center from 2010 to 2014, we reviewed 3 TPE treatment patterns: a Single TPE procedure within 24 h of transplant; Multiple TPE procedures initiated within 24 h of transplant; and 1 or more TPE procedures beginning >24 h post-transplant. Primary and secondary outcomes were overall survival (OS) and TPE survival (TS), respectively. Results Of 313 patients meeting study criteria, 109 (35%) underwent TPE. TPE was initiated in 82 patients within 24 h, 40 (37%) receiving a single procedure (Single TPE), and 42 (38%) multiple procedures (Multiple TPE). Twenty-seven (25%) began TPE >24 h after transplant (Delayed TPE). The most common TPE indication was elevated/positive panel reactive or human leukocyte antigen antibodies (32%). With a median follow-up of 49 months, the non-TPE treated and Single TPE cohorts had similar OS (HR 1.08 [CI, 0.54, 2.14], P = .84), while the Multiple and Delayed TPE cohorts had worse OS (HR 2.62 [CI, 1.53, 4.49] and HR 1.98 [CI, 1.02, 3.83], respectively). The Multiple and Delayed TPE cohorts also had worse TS (HR 2.59 [CI, 1.31, 5.14] and HR 3.18 [CI, 1.56, 6.50], respectively). Infection rates did not differ between groups but was independently associated with OS (HR 2.31 [CI, 1.50, 3.54]). Conclusions TPE is an important therapeutic modality in cardiac transplant patients. Prospective studies are needed to better define TPE's different roles in this patient population.

Use of durable, continuous-flow left ventricular assist devices (LVADs) has expanded rapidly, although data are limited regarding optimization strategies before LVAD implantation. We examined current use of intra-aortic balloon pumps (IABPs) before LVAD implantation and compared outcomes of patients with IABP use to those without. We analyzed data from the Interagency Registry for Mechanical Assisted Circulatory Support (INTERMACS) on patients who underwent LVAD implantation between 2006 and 2014. We limited the analysis to patients with an admitting diagnosis of LVAD placement. The primary exposure was IABP use within 48 hours before LVAD implantation. We used propensity scores to compare 30 day postoperative outcomes to reduce treatment selection bias. Of 2,446 patients, 433 (18%) received an IABP before LVAD placement. Patients with IABP use, compared with those without, had markers of more advanced disease, including worse renal and liver function, worse right ventricular function, and use of mechanical ventilation (p < 0.05 for all comparisons). A composite outcome of post-operative right heart failure, hepatic dysfunction, renal dysfunction, or death occurred in 83 (19.2%) patients with IABP use, compared with 342 (17.1%) patients without IABP use (unadjusted hazard ratio, 1.13; 95% confidence interval, 0.89-1.44; adjusted hazard ratio, 1.02; 95% confidence interval, 0.78-1.33). IABP use before LVAD placement was common. Despite markers of higher risk in patients with IABP use, we found no significant difference in 30 day outcomes compared to those without. The results suggest that IABP use may mitigate risk of early postoperative adverse outcomes in select patients.

Background Primary outcomes analysis of the Multicenter Study of MagLev Technology in Patients Undergoing MCS Therapy With HeartMate 3 (MOMENTUM 3) trial short-term cohort demonstrated a higher survival rate free of debilitating stroke and reoperation to replace/remove the device (primary end-point) in patients receiving the HeartMate 3 (HM3) compared with the HeartMate (HMII). In this study we sought to evaluate the individual and interactive effects of pre-specified patient subgroups (age, sex, race, therapeutic intent [bridge to transplant/bridge to candidacy/destination therapy] and severity of illness) on primary end-point outcomes in MOMENTUM 3 patients implanted with HM3 and HMII devices. Methods Cox proportional hazard models were used to analyze patients enrolled in the “as-treated cohort” ( n = 289) of the MOMENTUM 3 trial to: (1) determine interaction of various subgroups on primary end-point outcomes; and (2) identify independent variables associated with primary end-point success. Results Baseline characteristics were well balanced among HM3 ( n = 151) and HMII ( n = 138) cohorts. No significant interaction between the sub-groups on primary end-point outcomes was observed. Cox multivariable modeling identified age (≤65 years vs >65 years, hazard ratio 0.42 [95% confidence interval 0.22 to 0.78], p = 0.006]) and pump type (HM3 vs HMII, hazard ratio 0.53 [95% confidence interval 0.30 to 0.96], p = 0.034) to be independent predictors of primary outcomes success. After adjusting for age, no significant impact of sex, race, therapeutic intent and INTERMACS profiles on primary outcomes were observed. Conclusions This analysis of MOMENTUM 3 suggests that younger age (≤65 years) at implant and pump choice are associated with a greater likelihood of primary end-point success. These findings further suggest that characterization of therapeutic intent into discrete bridge-to-transplant and destination therapy categories offers no clear clinical advantage, and should ideally be abandoned.

Purpose Survival and the relative impact of adverse events after mechanical circulatory support may be different amongst white males (WM), black males (BM), white females (WF) and black females (BF). Methods Patients implanted with the HeartWareTM HVADTM System in the BTT/CAP, ENDURANCE and ENDURANCE Supplemental trials were assessed. Baseline characteristics, survival and adverse events were investigated and compared between WM, BM, WF and BF. Results There were 947 patients included: 60% WM, 16% BM, 15% WF and 9% BF. There were no differences in INTERMACS profile at implant. WM were more likely to be older, with more ischemic risk factors (smoking 70.0%, diabetes 46.7%, carotid disease 15.8%, ischemic HF 64.0%, MI 51.6%, CABG 32.9%). BM had a higher mean body mass index (29.2 kg/m2) and renal insufficiency (mean 1.5 mg/dL), while WF were least likely to be hypertensive (48.2%). Implant as DT was highest in WM 66.3% and lowest in WF 51.1%. According to 4-year adverse event rates per patient year (Figure 1A), WM had highest rates of gastrointestinal bleeds, ischemic stroke, and pump thrombosis, but lowest risk of right heart failure. WF had the lowest risk for driveline infection. Mean duration of support (months) was longest in BF 31.7 compared to WM 24.8, BM 29.4, and WF 25.8, p=0.007. However, BF had the best survival at two years and overall; WM had the worst survival. (Figure 1B) Conclusion In a large cohort of HVAD recipients, white men had the highest rates of gastrointestinal bleeding, pump thrombus, ischemic stroke and the worst survival. Black women had a significantly longer duration of support, but the highest survival, particularly in the first two years post-implant.

Left ventricular assist device (LVAD) therapy unloads the failing heart but exposes the human body to unique pathophysiologic demands such as continuous blood flow and complete univentricular support, which are associated with increased risk of adverse clinical outcomes. MicroRNAs (miRNAs) are 22–23 nucleotide RNAs involved in regulation of multiple biologic processes including the pathogenesis of heart failure (HF). Thus, measurement of miRNAs may have potential in both diagnostics as circulating biomarkers and in therapeutics for targeted interventions. We examined 23 distinct miRNAs that have previously been shown to play a role in HF pathogenesis and measured them in 40 individuals both before continuous-flow LVAD implantation and at a median of 96.5 days after implantation. Quantitative real-time polymerase chain reaction was performed for miRNA amplification, and 19 miRs were included in statistical analysis. Wilcoxon signed-rank tests were used to compare within-patient median relative quantification values pre- and post-LVAD placement. The median age of patients was 67 years, and 57.5% were at Interagency Registry for Mechanically Assisted Circulatory Support level 1–2. After LVAD support, only miR-155 was found to be statistically significant (p < 0.002), with an upregulation in plasma expression levels with LVAD support, which persisted regardless of the direction of change in serial HF biomarker levels. MicroRNA-155, which has been shown to play a central role in inflammation and neovascularization, was upregulated with long-term LVAD support. If validated by future studies, miR-155 may help further inform on underlying LVAD physiology and has a role as a therapeutic target in this patient population.

Objectives The authors sought to provide the pre-specified primary endpoint of the ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients) trial at 2 years. Background The ROADMAP trial was a prospective nonrandomized observational study of 200 patients (97 with a left ventricular assist device [LVAD], 103 on optimal medical management [OMM]) that showed that survival with improved functional status at 1 year was better with LVADs compared with OMM in a patient population of ambulatory New York Heart Association functional class IIIb/IV patients. Methods The primary composite endpoint was survival on original therapy with improvement in 6-min walk distance ≥75 m. Results Patients receiving LVAD versus OMM had lower baseline health-related quality of life, reduced Seattle Heart Failure Model 1-year survival (78% vs. 84%; p = 0.012), and were predominantly INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profile 4 (65% vs. 34%; p Conclusions Survival on original therapy with improvement in 6-min walk distance was superior with LVAD compared with OMM at 2 years. Reduction in key adverse events beyond 1 year was observed in the LVAD group. The ROADMAP trial provides risk-benefit information to guide patient- and physician-shared decision making for elective LVAD therapy as a treatment for heart failure. (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients [ROADMAP]; NCT01452802 )

BackgroundMechanical circulatory support with a left ventricular assist device (LVAD) is an established treatment for patients with advanced heart failure. We compared a newer LVAD design (a small intrapericardial centrifugal-flow device) against existing technology (a commercially available axial-flow device) in patients with advanced heart failure who were ineligible for heart transplantation. MethodsWe conducted a multicenter randomized trial involving 446 patients who were assigned, in a 2:1 ratio, to the study (centrifugal-flow) device or the control (axial-flow) device. Adults who met contemporary criteria for LVAD implantation for permanent use were eligible to participate in the trial. The primary end point was survival at 2 years free from disabling stroke or device removal for malfunction or failure. The trial was powered to show noninferiority with a margin of 15 percentage points. ResultsThe intention-to treat-population included 297 participants assigned to the study device and 148 participan...

Systemic right ventricle failure often develops in patients with dextro-transposition of the great arteries who have undergone atrial-level switch procedures. An adult with dextro-transposition of the great arteries with Mustard repair in childhood presented with end-stage heart failure due to systemic right ventricle failure, Mustard baffle leak, and unrepaired partial anomalous pulmonary venous return. She underwent device closure of the baffle leak by catheterization, followed by baffle revision and concomitant systemic ventricular assist device placement by adult and pediatric heart surgeons. This case demonstrates the importance of multidisciplinary collaboration between pediatric and adult heart failure specialists in caring for complex adult congenital heart patients.

Left ventricular assist devices (LVADs) are being used widely to support patients with advanced systolic heart failure. Some of these patients will need more than one LVAD replacement due to pump thrombosis. The Heartmate III LVAD (Abbott Inc, Chicago, IL) recently has been shown to have a very low incidence of pump thrombosis. In this article, we describe cases of patients with multiple pump thrombosis events, who were successfully replaced with the Heartmate III.

Background: Patients with diabetes mellitus (DM) have a higher risk of heart failure (HF). While metabolic dysregulation has been well-established in HF and DM separately, molecular mechanisms associated with diabetic HF are incompletely understood. Thus, we sought to test the overarching hypothesis that cardiac metabolic programming is distinct in diabetic HF compared to DM and HF individually. Methods: RNA-sequencing and targeted metabolomics profiles were completed on human myocardial tissue from 54 unique individuals received from the Duke Human Heart Biorepository and the University of Colorado. Multi-omics profiles of cardiac tissue from 4 groups were compared: a) controls with no clinical evidence of DM or HF (n = 12), b) DM-only (n = 15), c) HF-only (n = 10), and d) HF+DM (n = 17). Results: After using statistical criteria to prioritize genes, we looked for genes that function together or modulate the same activity. Genes encoding producers of reactive oxygen species (ROS), DUOX2, DUOXA2, and DUOXA1, were differentially upregulated in diabetic-HF, compared to DM or HF alone (FDR HF+DM vs DM-only/HF-only = 6.6 x 10 -7 /2.2 x 10 -4 , 7.7 x 10 -3 /6.7 x 10 -3 , and 3.6 x 10 -6 /0.013, respectively). Modulators of mTOR signaling, ERBB3, ERBB4, and PIK3R3, were also differentially regulated in diabetic-HF (FDR HF+DM vs DM-only/HF-only = 1.4 x 10 -3 /0.010, 0.012/7.4 x 10 -3 , and 0.011/9.3 x 10 -3 , respectively). Gene set enrichment analysis supported our focus on these genes; top enriched gene sets included mTOR signaling and processes related to oxidative stress response. In our metabolomics data, long chain acylcarnitines (AC) and ceramides (Cer) are decreased in diabetic-HF. For example, C20:1 AC can be converted to C20:1 Cer and accumulation of both is diminished in diabetic-HF (FDR = 0.0032 and 0.035, respectively). Conclusions: We found that diabetic-HF was characterized by a distinct omics profile consistent with increased ROS production, diminished AC and Cer accumulation, and modulation of mTOR signaling. The fact that ceramide accumulation has been previously associated with oxidative stress and also linked to ERBB and PI3K pathways suggests that these data may reveal a unique regulation of these pathways in diabetic-HF.

Background The transplantation of hearts from traumatically brain‐injured (TBI) donors has been associated with inferior long‐term survival in single‐center analyses. However, in a more recent analysis, death caused by cerebrovascular accident was associated with worse posttransplant survival in recipients. The purpose of this study was to explore the outcomes of heart transplantation in recipients receiving donor hearts from TBI and non‐TBI donors in a large national registry. Methods and Results We performed a retrospective cohort analysis of the UNOS (United Network of Organ Sharing) Registry Organ Procurement and Transplantation Network between 2006 and 2018 for adult candidates wait‐listed for isolated heart transplantation. Recipients were stratified into 2 groups, TBI and non‐TBI donors. Propensity score matching was performed. Kaplan‐Meier analysis was used to estimate survival posttransplant. A total of 24 894 candidates met inclusion criteria. TBI was the leading cause of death in the donor population. Recipients of TBI donor hearts (N=13 07) were younger (median age, 55 versus 57 years; P P P Conclusions In the largest analysis of heart transplants and their survival, according to the type of donor injury (TBI versus non‐TBI), we found similar survival in heart transplant recipients. Future studies should address specific subpopulations (eg, hemorrhagic stroke) in the non‐TBI group to address concerns about reduced posttransplant survival.

Objective The Cardiothoracic Surgical Trials Network reported that left ventricular reverse remodeling at 2 years did not differ between patients with moderate ischemic mitral regurgitation randomized to coronary artery bypass grafting plus mitral valve repair (n = 150) or coronary artery bypass grafting alone (n = 151). To address health resource use implications, we compared costs and quality-adjusted survival. Methods We used individual patient data from the Cardiothoracic Surgical Trials Network trial on survival, hospitalizations, quality of life, and US hospitalization costs to estimate cumulative costs and quality-adjusted life years. A microsimulation model was developed to extrapolate to 10 years. Bootstrap and deterministic sensitivity analyses were performed to address uncertainty. Results In-hospital costs were $59,745 for coronary artery bypass grafting plus mitral valve repair versus $51,326 for coronary artery bypass grafting alone (difference $8419; 95% uncertainty interval, 2259-18,757). Two-year costs were $81,263 versus $67,341 (difference 13,922 [2370 to 28,888]), and quality-adjusted life years were 1.35 versus 1.30 (difference 0.05; −0.04 to 0.14), resulting in an incremental cost-effectiveness ratio of $308,343/quality-adjusted life year for coronary artery bypass grafting plus mitral valve repair. At 10 years, its costs remained higher ($107,733 vs $88,583, difference 19,150 [−3866 to 56,826]) and quality-adjusted life years showed no difference (−0.92 to 0.87), with 5.08 versus 5.08. The likelihood that coronary artery bypass grafting plus mitral valve repair would be considered cost-effective at 10 years based on a cost-effectiveness threshold of $100K/quality-adjusted life year did not exceed 37%. Only when this procedure reduces the death rate by a relative 5% will the incremental cost-effectiveness ratio fall below $100K/quality-adjusted life year. Conclusions: The addition of mitral valve repair to coronary artery bypass grafting for patients with moderate ischemic mitral regurgitation is unlikely to be cost-effective. Only if late mortality benefits can be demonstrated will it meet commonly used cost-effectiveness criteria.

Background Heart transplantation is limited by the supply of donor organs. Previous studies have associated female donor to male recipient with decreased posttransplant survival. We wanted to evaluate whether this risk can be mitigated using higher donor than recipient body mass index (BMI). Methods We performed a retrospective analysis of the Organ Procurement and Transplantation Network/United Network of Organ Sharing registry encompassing years 2005 to 2018 for all male adult recipients (>18 years of age) who underwent isolated heart transplantation with grafts from female donors. The association between donor and recipient BMI difference and recipient survival was evaluated using adjusted Cox proportional hazards modeling. Results A total of 3788 male recipients who received female donor hearts met inclusion criteria for analysis. Maximally selected rank statistics identified donor minus recipient BMI of 1.5 kg/m2 as a meaningful cutoff point in the analysis of recipient survival. Multivariable Cox proportional hazards analysis demonstrated that increasing donor BMI relative to recipient BMI up to this cutoff point was associated with improved survival (hazard ratio per 5-unit difference, 0.87; 95% confidence interval, 0.77-0.99). Above this cutoff point, increasing donor BMI relative to the recipient did not improve survival more than what was achieved by adding 1.5 of BMI difference (hazard ratio per 5-unit difference, 0.97; 95% confidence interval, 0.90-1.04). Conclusions Increasing donor BMI relative to recipient BMI up to 1.5 kg/m2 greater than recipient BMI was associated with improved survival. BMI difference may be useful as a simple surrogate for predicted heart mass difference to help mitigate the impact of sex mismatch in heart transplantation.

BACKGROUND: The association of donor and recipient age with survival following adult heart transplantation has not been well characterized. The purpose of this study was to examine the impact of the relationship between donor and recipient age on post-transplant survival. METHODS: We retrospectively reviewed the 2005–2018 UNOS heart transplant database for all adult recipients undergoing first-time isolated heart transplantation. The impact of donor and recipient age on survival was analyzed with Cox proportional hazards modelling using restricted cubic splines. RESULTS: A total of 25,480 heart transplant donor and recipient pairs met inclusion criteria. Unadjusted and adjusted Cox proportional hazards modelling demonstrated a near-linear association between increasing donor age and decreased survival; in addition, older and younger recipient age was associated with decreased survival. After adjustment, there was no significant interaction between donor and recipient age. Older donors decreased survival similarly in both older and younger recipients. CONCLUSION: Increasing donor age as well as both younger and older recipient age are independently associated with worsened post-heart transplant survival. The relationship between donor and recipient age does not significantly affect survival following heart transplant.

OBJECTIVES: We hypothesized that an increased duration of donor brain death may worsen survival following orthotropic heart transplantation. METHODS: The United Network for Organ Sharing (UNOS) registry was queried for first-time, adult recipients of heart transplant from 2006–2018. Cox Proportional Hazards with penalized smooth splines was used to stratify patients based on donor brain death interval: shorter (42 hours). Overall survival was estimated using Kaplan-Meier and Cox Proportional Hazards models. RESULTS: A total of 22,960 patients met study criteria (9.2% shorter, 55.0% reference, 35.8% longer). Longer brain death duration recipients were more likely to have a later year of transplant and have a mechanical bridge to transplant, while longer duration donors were more likely to be Black and die of anoxia compared to shorter duration and reference donors. Compared to reference, neither shorter (Hazard Ratio [HR] 1.02; 95% Confidence Interval [CI] 0.94–1.12) nor longer donor brain death interval (HR 1.01; 95%CI 0.94–1.08) was associated with post-transplant survival in either unadjusted or multivariable analyses (both p>0.6). CONCLUSIONS: Longer duration of brain death was not associated with worse survival following heart transplantation. Donors with prolonged interval of brain death should not necessarily be excluded based on brain death period alone.

Left ventricular assist devices (LVADs) are life-saving, surgically implanted mechanical heart pumps used to treat patients with advanced heart failure (HF). While life-saving, LVAD support is associated with a high incidence of complications, making early recognition and management of LVAD complications a critical need. Blood clot formation within the LVAD, known as LVAD thrombosis, is a catastrophic complication of LVAD therapy that often requires LVAD exchange due to delayed diagnosis and treatment. Using digital stethoscopes, we identified differences in acoustic spectra from two patients presenting with LVAD thrombosis compared with normally functioning LVAD pumps within the same patient. Importantly, these acoustic changes were present even in the absence of typical signs of HF that are often present in LVAD thrombosis patients. Our work suggests that acoustic spectral analysis of digital stethoscope signals could be used for early detection and mitigation of LVAD complications.

Background The incidence of permanent pacemaker (PPM) implantation is higher following mitral valve surgery (MVS) with ablation for atrial fibrillation (AF) compared with MVS alone. Objectives This study identified risk factors and outcomes associated with PPM implantation in a randomized trial that evaluated ablation for AF in patients who underwent MVS. Methods A total of 243 patients with AF and without previous PPM placement were randomly assigned to MVS alone (n = 117) or MVS + ablation (n = 126). Patients in the ablation group were further randomized to pulmonary vein isolation (PVI) (n = 62) or the biatrial maze procedure (n = 64). Using competing risk models, this study examined the association among PPM and baseline and operative risk factors, and the effect of PPM on time to discharge, readmissions, and 1-year mortality. Results Thirty-five patients received a PPM within the first year (14.4%), 29 (83%) underwent implantation during the index hospitalization. The frequency of PPM implantation was 7.7% in patients randomized to MVS alone, 16.1% in MVS + PVI, and 25% in MVS + biatrial maze. The indications for PPM were similar among patients who underwent MVS with and without ablation. Ablation, multivalve surgery, and New York Heart Association functional (NYHA) functional class III/IV were independent risk factors for PPM implantation. Length of stay post-surgery was longer in patients who received PPMs, but it was not significant when adjusted for randomization assignment (MVS vs. ablation) and age (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.61 to 1.08; p = 0.14). PPM implantation did not increase 30-day readmission rate (HR: 1.43; 95% CI: 0.50 to 4.05; p = 0.50). The need for PPM was associated with a higher risk of 1-year mortality (HR: 3.21; 95% CI: 1.01 to 10.17; p = 0.05) after adjustment for randomization assignment, age, and NYHA functional class. Conclusions AF ablation, multivalve surgery, and NYHA functional class III/IV were associated with an increased risk for permanent pacing. PPM implantation following MVS was associated with a significant increase in 1-year mortality. (Surgical Ablation Versus No Surgical Ablation for Patients With Atrial Fibrillation Undergoing Mitral Valve Surgery; NCT00903370)

Purpose Inhaled pulmonary vasodilators (iPVD) are commonly used to lower PVR to modify the risk of acute RV failure in durable LVAD implantation or orthotopic heart transplantation (OHT). While inhaled nitric oxide (iNO) is the iPVD gold standard, inhaled epoprostenol (Veletri®) has been introduced as a cost-conscious alternative without high-grade evidence. Thus, we conducted an investigation to primarily determine if inhaled epoprostenol is equivalent to iNO in the ability to modify acute RVF after advanced heart failure therapies. Methods Our group has enrolled 232 patients (LVAD, N=100; OHT, N=132) in a triple-blinded (clinician, subject, statistician) randomized controlled trial conducted between May 2017-October 2020 (NCT03081052). Participants were grouped into strata according to key clinical prognostic features. Within each stratum, subjects were assigned either iNO or inhaled epoprostenol via 1:1 randomization. To assess equivalency between the two treatment arms for our primary outcome analysis, we will calculate absolute and relative risk estimates and corresponding confidence intervals (CI). If the CI do not contain the margin of difference (15%), then we will conclude there is sufficient evidence that the risk of the primary outcome in each treatment arm is similar. For each secondary outcome, we will construct univariable effect estimates and corresponding CI, which will allow for assessment of difference between treatment arms. In the case that patients have switched to the other treatment arm, we will perform an intent-to-treat (ITT) analysis without reclassifying treatment assignment. To verify ITT results, we will perform a per-protocol analysis. Endpoints Primary. LVAD: Moderate or Severe RVF (defined by INTERMACS, up to 21-days after surgery); OHT: PGD-RV treated with RVAD or VA-ECMO, up to 30-days after surgery. Secondary. Duration of postoperative mechanical ventilation, iPVD duration/cost, ICU and hospital lengths-of-stay, postoperative acute kidney injury, and 30-day mortality.