Asleh, Rabea

Abstract Background Renal dysfunction is a major determinant of outcomes after heart transplantation (HT). While baseline renal impairment and post-HT dialysis are known predictors of mortality, the prognostic impact of sustained pre-HT renal decline in patients bridged with durable left ventricular assist devices (LVADs) remains unclear. Methods We conducted a retrospective, multicenter cohort study using the United Network for Organ Sharing (UNOS) registry to identify adult patients who underwent HT following durable LVAD support between 2009 and 2024. Sustained renal decline was defined as a ≥40% reduction in estimated glomerular filtration rate (eGFR) from listing to HT. Multivariable logistic regression identified predictors of renal decline and post-HT dialysis,while Cox proportional hazards models assessed the impact on post-HT mortality. Results Among 10,454 eligible patients, 624 (6.0%) experienced sustained renal decline during LVAD bridging. Compared with patients without renal decline, affected patients had longer waitlist durations (median 297 vs. 197 days; p<0.001), lower eGFR at HT (42.0 vs. 70.6 mL/min/1.73 m²; p<0.001), and higher rates of post-HT dialysis (23.7% vs. 12.8%; p<0.001). Independent predictors of sustained renal decline included longer waitlist time, perioperative blood transfusions, while the use of HeartMate 3 LVAD was protective. Sustained renal decline was independently associated with increased risk of post-HT dialysis (adjusted odds ratio [aOR] 2.64) and all-cause mortality (adjusted hazard ratio [aHR] 1.16),with post-HT dialysis strongly predicting mortality (aHR 3.48). Conclusions Sustained renal deterioration while awaiting HT is a significant predictor of post-HT dialysis and mortality in LVAD-bridged patients. Incorporating renal trajectory into risk stratification may enhance candidate selection and promote perioperative renal protection strategies.

Background Pulmonary hypertension (PH) and sensitization adversely affect heart transplant outcomes. Although left ventricular assist devices may reduce PH, they can increase sensitization. We examined the impact of sensitization on heart transplant outcomes in left ventricular assist device‐bridged patients and whether precapillary PH modifies this effect. Methods Adults bridged to heart transplant with an left ventricular assist device between 2005 and 2020 were identified from the United Network for Organ Sharing database. Patients with available panel‐reactive antibody (PRA) and hemodynamic data were included. Associations between PRA and survival and treated rejection were analyzed. Results Among 2469 patients, 1053 had precapillary PH (pulmonary vascular resistance [PVR] >2 Wood units [WU]) and 1416 had PVR ≤2 WU. Elevated PRA (>10%) occurred in 566 patients (24.8% with PVR >2 WU; 21.5% with PVR ≤2 WU). Overall, PRA >10% was associated with increased mortality (adjusted hazard ratio [aHR], 1.28 [95% CI, 1.04–1.58], P =0.022), driven by patients with PVR >2 WU (aHR, 1.82 [95% CI, 1.34–2.50], P <0.001), with no association in those with PVR ≤2 WU (aHR, 0.99 [95% CI, 0.47–1.32], P =0.92). PRA >10% was also associated with treated rejection overall (adjusted odds ratio [aOR], 1.41 [95% CI, 1.09–1.82], P =0.008), confined to the PVR >2 WU group (aOR, 1.87 [95% CI, 1.26–2.76], P =0.002) and absent in the PVR ≤2 WU group (aOR, 1.13 [95% CI, 0.80–1.59], P =0.49). Conclusions Elevated PRA predicts worse outcomes in LVAD‐bridged transplant recepients with precapillary PH, but not in those without precapillary PH.

ABSTRACT Background and Aim This study aimed to provide updated nationwide data on outcomes in heart transplantation for amyloid cardiomyopathy (ACM) compared with other cardiomyopathy etiologies. Methods United Network for Organ Sharing data for patients over 18 who underwent heart transplant for ACM, and other cardiomyopathies including DCM, ICM, RCM, and CHD were reviewed from 2001 through 2022. The data were analyzed with a propensity score‐matched analysis comparing ACM patients with transplant for the cardiomyopathies to measure primary outcomes, including 5‐year, 10‐year, and all‐cause mortality accounting for differences at baseline. Results Of 21 457 heart transplant recipients who met eligibility criteria, there was a 100% increase in the number of heart transplants for ACM from 2010 to 2020 ( p < 0.001). The unadjusted mortality did not differ significantly among ACM, DCM, ICM, RCM, and CHD groups, and 5‐year mortality was comparable between ACM and DCM patients. ACM patients had a significantly lower incidence of postoperative stroke ( p = 0.044), and risk factors for ACM transplant mortality were identified as mechanical ventilation at the time of transplant (HR: 3.8, p = 0.023) and older donor age (HR: 1.1, p = 0.015). Conclusions The number of heart transplants for ACM has increased in recent years, and overall outcomes in these ACM transplants have been similar compared to those for other cardiomyopathies. Despite historical concerns regarding poor prognosis and amyloid recurrence, carefully screened ACM patients can benefit from heart transplantation. Further research and optimization of ACM patient eligibility criteria alongside investigation of concurrent adjunctive therapies could optimize treatment of ACM with heart transplantation.

Background: Despite its use in patients awaiting heart transplant (HT), the impact of continuous inotropic support on short-term complications and long-term transplant outcomes remains unclear. This study evaluated inotrope use at the time of HT on perioperative complications and post-transplant survival, comparing outcomes at 30 days, 1 year, and 10 years with mechanical circulatory support (MCS) strategies including ECMO, IABP, and VADs. Methods: A retrospective analysis of the United Network for Organ sharing (UNOS) registry was performed, stratifying patients based on bridge strategy at the time of transplant: inotropes, ECMO, IABP, or VADs. Baseline characteristics, perioperative complications, and 30-day, 1-year, and 10-year post-transplant survival outcomes were analyzed across groups. Survival was assessed using Kaplan–Meier and Cox proportional hazards models. Results: Among the 11,801 heart transplant patients included, 9330 were on inotropes, 372 were on ECMO, 1072 received an IABP, and 1027 had VADs. Inotrope-bridged patients had significantly lower 30-day and 1-year mortality rates compared to the ECMO, IABP, and VAD groups. They also experienced reduced incidences of post-transplant dialysis and stroke. At 10 years, the inotrope group demonstrated superior long-term survival, with significantly lower mortality risk compared to ECMO (HR: 1.81; CI: 1.49–2.20, p < 0.001), IABP (HR: 1.19; CI: 1.06–1.32, p = 0.005), and VAD (HR: 1.18; CI: 1.10–1.27, p < 0.001). Conclusions: Continuous use of inotropes after waitlisting is associated with lower short, intermediate, and long-term mortality and does not lead to worse outcomes compared to ECMO, IABP, and VAD support. When mechanical support is not an option, inotropic therapy remains a viable and effective strategy.

Abstract Heart transplantation (HT) is one of the prodigious achievements in modern medicine and remains the cornerstone in the treatment of patients with advanced heart failure. Advances in surgical techniques, immunosuppression, organ preservation, infection control, and allograft surveillance have improved short‐ and long‐term outcomes thereby contributing to greater clinical success of HT. However, prolonged allograft and patient survival following HT are still largely restricted by the development of late complications, including allograft rejection, infection, cardiac allograft vasculopathy (CAV), and malignancy. The introduction of mTOR inhibitors early after HT has demonstrated multiple protective effects against CAV progression, renal dysfunction, and tumorigenesis. Therefore, several HT programs increasingly use mTOR inhibitors with partial or complete withdrawal of calcineurin inhibitor (CNI) in stable HT patients to reduce complications risk and improve long‐term outcomes. Furthermore, despite a substantial improvement in exercise capacity and health‐related quality of life after HT as compared to advanced heart failure patients, most HT recipients remain with a 30% to 50% lower peak oxygen consumption (Vo 2 ) than that of age‐matched healthy subjects. Several factors, including alterations in central hemodynamics, HT‐related complications and alterations in the musculoskeletal system, and peripheral physiological abnormalities, presumably contribute to the reduced exercise capacity following HT. Cardiac denervation and subsequent loss of sympathetic and parasympathetic regulation are responsible for various physiological alterations in the cardiovascular system, which contributes to restricted exercise tolerance. Restoration of cardiac innervation may improve exercise capacity and quality of life, but the reinnervation process is only partial even several years after HT. Multiple studies have shown that aerobic and strengthening exercise interventions improve exercise capacity by increasing maximal heart rate, chronotropic response, and peak Vo 2 after HT. Novel exercise modalities, such as high‐intensity interval training (HIT), have been proven as safe and effective for further improvement in exercise capacity, including among de novo HT recipients. Further developments have recently emerged, including donor heart preservation techniques, noninvasive CAV and rejection surveillance methods, and improvements in immunosuppressive therapies, all aiming at increasing donor availability and improving late survival after HT. © 2023 American Physiological Society. Compr Physiol 13:4719‐4765, 2023.

Abstract Background It has been hypothesized that combined heart and kidney transplantation (HKT) may lead to immune modulation and attenuation of cardiac allograft vasculopathy (CAV) progression. Sirolimus (SRL) has been shown to mitigate the progression of CAV and confer renal protection. With the increasing use of SRL as primary immunosuppression in heart transplant (HT) recipients, the effect of HKT on CAV progression compared to HT-only remains undetermined. Purpose We sought to investigate the patterns of conversion from calcineurin inhibitors (CNI) to SRL, and its impact on CAV progression and outcomes in HKT compared to HT-only in a cohort with frequent use of SRL as primary immunosuppression. Methods A cohort of 302 patients who underwent either HT only (n=262) or combined HKT (n=40) was analyzed. CAV progression was assessed by measuring the delta (Δ) annual change in plaque volume (PV) normalized to vessel length (PV/VL in mm3/mm) and plaque index (PI) (%) (calculated as the PV to VV ratio) between baseline and last follow-up coronary intravenous ultrasound (IVUS). Clinical adverse outcomes included all-cause death and CAV-associated events. Secondary outcomes included differences in renal function and incidence of SRL-associated proteinuria (defined as Δ urine protein ≥300 mg/24 h at 1 year after conversion to SRL) between HT-only and HKT recipients. Results Overall, 217 (72%) patients were converted from CNI to SRL as primary immunosuppression. HT recipients were more likely to be converted to SRL than combined HKT recipients (74% vs. 55%, P=0.01). HKT was associated with significantly higher ΔPV/VL (P=0.01) and a trend toward a higher ΔPI (P=0.06) than HT-only, but this association was markedly attenuated after adjustment to SRL conversion. HKT was associated with similar risk of death (adjusted hazard ratio [HR] 0.69, 95%CI: 0.28-1.71, P=0.43) and CAV-related events (adjusted HR 0.83, 95% CI: 0.30-2.31, P=0.72). Conversion to SRL was significantly associated with decreased risk of death and CAV-related events in the overall cohort. This association was not modified by the type of organ transplantation (Pinteraction=NS), and without a significant effect on estimated glomerular filtration rate (eGFR) or proteinuria. Conclusions HKT recipients compared to HT-only were less likely to be converted from CNI to SRL-based immunosuppression and had a greater CAV progression but without significant differences in all-cause mortality or CAV-related events. The clinical benefit and safety of conversion to SRL appeared similar in the HKT and isolated HT cohorts.

Abstract Background In light of the updated lowered threshold for diagnosing pulmonary hypertension (PH), the reversibility of precapillary PH with left ventricular assist device (LVAD) and the associated post heart transplantation (HT) outcomes remain unclear. Purpose and methods Using data from the United Network for Organ Sharing database, we aimed to investigate predictors of persistent precapillary PH in HT recipients bridged with LVAD, and examine the interrelated post-HT survival, using the updated pulmonary vascular resistance (PVR) cutoff of &gt;2 WU for precapillary PH. Results Among 2169 HT recipients bridged with LVAD, 1299 had PVR&gt;2 at baseline; 551 (42.4%) of whom normalized their PVR≤2 and 748 (57.6%) remained with elevated PVR&gt;2 after LVAD implantation. Female sex (adjusted odds ratio [aOR] 2.22, 95% confidence interval [CI]:1.61-3.07, p&lt;0.001) and inotropes-treatment at-listing (aOR 1.31, 95% CI: 1.03-1.66, p=0.028) were associated with persistently elevated PVR post LVAD. Conversely, longer duration of LVAD support (aOR 0.74, 95% CI: 0.65-.84, p&lt;0.001) and use of HeartMate 2 (aOR 0.74, CI: 0.59-0. 93, p=0.011) were protective against persistently elevated PVR post-LVAD. Persistently elevated PVR &gt;2 post-LVAD was associated with increased risk of death compared to those who normalized their PVR (adjusted hazard ratio [aHR] 1.26, 95% CI: 1.01-1.57, p=0.037). However, normalized PVR post-LVAD group had comparable survival to those with PVR≤2 at baseline (aHR 0.76, 95% CI: 0.57-1.02, p=0.07). Conclusions Many HT recipients bridged with LVAD remain with PVR&gt;2 post-LVAD implantation, which is associated with increased risk of death post-HT compared to patients with normalized PVR post-LVAD.

Abstract Background and Aims In the STEP-HFpEF trial programme, treatment with semaglutide resulted in multiple beneficial effects in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Efficacy may vary according to baseline diuretic use, and semaglutide treatment could modify diuretic dose. Methods In this pre-specified analysis of pooled data from the STEP-HFpEF and STEP-HFpEF-DM trials (n = 1145), which randomized participants with HFpEF and body mass index ≥ 30 kg/m2 to once weekly semaglutide 2.4 mg or placebo for 52 weeks, we examined whether efficacy and safety endpoints differed by baseline diuretic use, as well as the effect of semaglutide on loop diuretic use and dose changes over the 52-week treatment period. Results At baseline, across no diuretic (n = 220), non-loop diuretic only (n = 223), and loop diuretic [&lt;40 (n = 219), 40 (n = 309), and &gt;40 (n = 174) mg/day furosemide equivalents] groups, there was progressively higher prevalence of hypertension and atrial fibrillation; and greater severity of obesity and heart failure. Over 52 weeks of treatment, semaglutide had a consistent beneficial effect on change in body weight across diuretic use categories (adjusted mean difference vs. placebo ranged from −8.8% [95% confidence interval (CI) −10.3, −6.3] to −6.9% [95% CI −9.1, −4.7] from no diuretics to the highest loop diuretic dose category; interaction P = .39). Kansas City Cardiomyopathy Questionnaire clinical summary score improvement was greater in patients on loop diuretics compared to those not on loop diuretics (adjusted mean difference vs. placebo: +9.3 [6.5; 12.1] vs. +4.7 points [1.3, 8.2]; P = .042). Semaglutide had consistent beneficial effects on all secondary efficacy endpoints (including 6 min walk distance) across diuretic subgroups (interaction P = .24–.92). Safety also favoured semaglutide vs. placebo across the diuretic subgroups. From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group vs. a 2.4% increase in the placebo group (P &lt; .0001). Semaglutide (vs. placebo) was more likely to result in loop diuretic dose reduction (odds ratio [OR] 2.67 [95% CI 1.70, 4.18]) and less likely dose increase (OR 0.35 [95% CI 0.23, 0.53]; P &lt; .001 for both) from baseline to 52 weeks. Conclusions In patients with obesity-related HFpEF, semaglutide improved heart failure-related symptoms and physical limitations across diuretic use subgroups, with more pronounced benefits among patients receiving loop diuretics at baseline. Reductions in weight and improvements in exercise function with semaglutide vs. placebo were consistent in all diuretic use categories. Semaglutide also led to a reduction in loop diuretic use and dose between baseline and 52 weeks. Clinical Trial Registration NCT04788511 and NCT04916470.

AbstractBackgroundUnited Network for Organ Sharing (UNOS) allocation criteria changed in 2018 to accommodate the increased prevalence of patients on a ventricular assist device as a bridge to heart transplant and prioritize sicker people in anticipation of a heart graft. We aimed to assess the impact of patient age in the new allocation policy on mortality following heart transplantation. Secondary outcomes included the effect of age ≥70 on post‐transplant events, including stroke, dialysis, pacemaker, and rejection requiring treatment.MethodsThe UNOS Registry was queried to identify patients who underwent heart transplants alone in the US between 2000 and 2021. Patients were divided into groups according to their age (over 70 and under 70 years old).ResultsPatients aged over 70 were more likely to require dialysis during follow‐up, but less likely to experience rejection requiring treatment, compared with patients aged <70. Age ≥70 in the new allocation system was a significant predictor of 1‐year mortality (adjusted HR: 1.41; 95% CI: 1.05–1.91; p = .024), but its effect on 5‐year mortality was not significant after adjusting for potential confounders (adjusted HR: 1.27; 95% CI:.97–1.66; p = .077). Undergoing transplantation under the new allocation policy vs the old allocation policy was not a significant predictor of mortality in patients over 70 years old.ConclusionsAge ≥70 is a significant predictor of 1‐year mortality following heart transplantation, but not at 5 and 10 years; however, the new allocation does not seem to have changed the outcomes for this group of patients.

Abstract Aims Graft dysfunction (GD) after heart transplantation (HTx) can develop without evidence of cell- or antibody-mediated rejection. Cardiac magnetic resonance imaging (CMR) has an evolving role in detecting rejection; however, its role in biopsy-negative GD has not been described. This study examines CMR findings, evaluates outcomes based on CMR results, and seeks to identify the possibility of rejection missed through endomyocardial biopsy by using CMR in HTx recipients with biopsy-negative GD. Methods and results HTx recipients with GD [defined as a decrease in left ventricular ejection fraction (LVEF) by &gt;5% and LVEF &lt; 50%] in the absence of rejection by biopsy or allograft vasculopathy and who underwent CMR were included in the study. The primary outcome was a composite of all-cause mortality, re-transplantation, or persistent LVEF &lt; 50%. Overall, 34 HTx recipients developed biopsy-negative GD and underwent CMR. Left ventricular late gadolinium enhancement (LGE) on CMR was observed in 16 patients with two distinct patterns: diffuse epicardial (n = 13) and patchy (n = 3) patterns. Patients with LGE developed GD later after HTx [4 (1.4–6.8) vs. 0.8 (0.3–1.2) years, P &lt; 0.001], were more often symptomatic (88% vs. 56%, P = 0.06), and had greater haemodynamic derangement (pulmonary capillary wedge pressure: 19 ± 7 vs. 13 ± 3 mmHg, P = 0.002) as compared with those without LGE. No significant difference was observed in the primary composite outcome between patients with LGE and those without LGE (50% vs. 38% of patients with events, P = 0.515). During a median follow-up of 3.8 years, mean LVEF improved similarly in the LGE-negative (37–55%) and LGE-positive groups (32–55%) (P = 0.16). Conclusions Biopsy-negative GD occurs with and without LGE when assessed by CMR, indicative of possible rejection/inflammation occurring only in a subset of patients. Irrespective of LGE, LVEF improvement occurs in most GD patients, suggesting that other neurohormonal or immunomodulatory mechanisms may also contribute to GD development.