Alnsasra, Hilmi

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.

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 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.

Left ventricular assist devices (LVADs) have been increasingly used in patients with advanced heart failure, either as a destination therapy or as a bridge to heart transplant. Continuous flow (CF) LVADs have revolutionized advanced heart failure treatment. However, significant vascular pathology and complications have been linked to their use. While the newer CF-LVAD generations have led to a reduction in some vascular complications such as stroke, no major improvement was noticed in the rate of other vascular complications such as gastrointestinal bleeding. This review attempts to provide a comprehensive summary of the effects of CF-LVAD on vasculature, including pathophysiology, clinical implications, and future directions.

Introduction: The number of patients with sarcoidosis requiring heart transplantation (HT) is on the rise. Hypothesis: The aim of this study was to evaluate outcomes of isolated HT in patients with sarcoid cardiomyopathy. Methods: Adult HT recipients were identified in the UNOS Registry between 1990 and 2020. Patients were grouped according to diagnosis. The cumulative incidences for the all-cause mortality and rejection were compared using Fine and Gray model analysis, accounting for re-transplantation as a competing risk. Moreover, we reviewed characteristics and outcomes of all HT recipients with previous diagnosis of sarcoid cardiomyopathy from a single-center. Results: A total of 30,874 HT recipients were included in the present study (n=240 sarcoidosis, n=1,431 non-ischemic restrictive cardiomyopathy, and n=29,203 non-ischemic dilated cardiomyopathy). During a total of 196,985 patient-years, all-cause mortality at the latest follow-up was not significantly different when comparing sarcoidosis to non-ischemic dilated cardiomyopathy (adjusted subhazard ratio [aSHR] 1.4, 95% confidence intervals [CI]: 0.88-2.3, p=0.15) or restrictive cardiomyopathy (aSHR 1.12, 95% CI: 0.65-1.95, p=0.67). Accordingly, multivariable analysis suggested that 1-year mortality was not significantly different between sarcoidosis and non-ischemic dilated cardiomyopathy (aSHR 1.56, 95% CI: 0.9-2.7, p=0.12) or restrictive (aSHR 1.15, 95% CI: 0.61-2.18, p=0.66) cardiomyopathy. Additionally, no differences were observed regarding 30-day mortality after HT. Data from the single-center case review showed excellent long-term outcomes with sirolimus-based immunosuppression. Conclusions: Short- and long-term outcomes after isolated HT do not seem to be inferior in sarcoid cardiomyopathy when compared to common types of non-ischemic cardiomyopathy.

Background Myocardial fibrosis is an important contributor for development of diastolic dysfunction. We investigated the impact of sirolimus as primary immunosuppression on diastolic dysfunction and fibrosis progression among heart transplantation recipients. Methods and Results In 100 heart transplantation recipients who were either treated with a calcineurin inhibitor (CNI) (n=51) or converted from CNI to sirolimus (n=49), diastolic function parameters were assessed using serial echocardiograms and right heart catheterizations. Myocardial fibrosis was quantified on serial myocardial biopsies. After 3 years, lateral e′ increased within the sirolimus group but decreased in the CNI group (0.02±0.04 versus −0.02±0.04 m/s delta change; P =0.003, respectively). Both pulmonary capillary wedge pressure and diastolic pulmonary artery pressure significantly decreased in the sirolimus group but remained unchanged in the CNI group (−1.50±2.59 versus 0.20±2.20 mm Hg/year; P =0.02; and −1.72±3.39 versus 0.82±2.59 mm Hg/year; P =0.005, respectively). A trend for increased percentage of fibrosis was seen in the sirolimus group (8.48±3.17 to 10.10±3.0%; P =0.07) as compared with marginally significant progression in the CNI group (8.76±3.87 to 10.56±4.34%; P =0.04). The percent change in fibrosis did not differ significantly between the groups (1.62±4.67 versus 1.80±5.31%, respectively; P =0.88). Conclusions Early conversion to sirolimus is associated with improvement in diastolic dysfunction and filling pressures as compared with CNI therapy. Whether this could be attributed to attenuation of myocardial fibrosis progression with sirolimus treatment warrants further investigation.