Heart Transplantation Research Articles

Clinical impact of genetic testing in a large cohort of pediatric cardiomyopathies.

There are limited data that can explain the earlier penetrance and the different expressivity of pediatric cardiomyopathy (pCM) compared to adult-onset cardiomyopathy (aCM). In addition, the relationship between genotype and pCM results is poorly described. We compared the genotypes between a cohort of aCM and a cohort of pCM to propose hypotheses on the earlier penetrance and expressivity of pCM. Finally, we report how genetic testing was used to guide genetic counseling in pCM. 253 pCM (<18 years old) and 1466 aCM patients were sequenced on a panel of 67 cardiomyopathy genes. Risk factors for death and heart transplantation were analyzed. In pCM, the variant of interest (VOI) yield was 53.7 % including 24.2 % carrying two VOI. De novo variants represented 11 % of VOI in pCM and 50 % in restrictive pCM. An age at diagnosis younger than 1 year (HR = 2.07, p = 0.029), restrictive phenotype (HR = 2.87, p = 0.03) and the presence of two VOI (HR = 2.97, p = 0.001) were independent risk factors for death or heart transplantation. In comparison with aCM, pCM patients harbored more frequently two VOI (p = 0.02), or de novo variants (p = 4.10-13). In addition, the distribution of VOI was different in aCM and pCM. Genotyping of pCM improved genetic counseling in families and led to ten prenatal-diagnosis. Genetic testing provides clues for earlier penetrance of pCM. The presence of two VOI in children with CM is a risk factor for severe and early cardiac events.

Early acute kidney injury after tacrolimus administration in heart transplant recipients receiving basiliximab induction therapy.

In this study, we aimed to analyze the association among the timing of tacrolimus initiation, time required to reach the target blood concentration, and early acute kidney injury (AKI) after tacrolimus administration in heart transplant recipients who received basiliximab induction therapy. 88 patients treated with tacrolimus-based immunosuppressive therapy were retrospectively reviewed. Induction therapy was administered to 52 patients. AKI was evaluated within 7 days of tacrolimus administration. The rate of increase in tacrolimus trough concentration to the target trough concentration of 10 µg/mL early after its administration was set to be similar in the basiliximab induction and non-induction group; 8 and 2 patients developed AKI in the induction and non-induction group, respectively. In the induction group, there was no significant difference in the timing of tacrolimus initiation and the time required to reach the target concentration between patients who developed and did not develop AKI. In contrast, the cumulative incidence of AKI was significantly different between patients with an estimated glomerular filtration rate below and those with an estimated glomerular filtration rate above 43 mL/min/1.73m2 at the start of tacrolimus administration (37.5% and 11.4%, respectively; p=0.045). In patients receiving basiliximab induction therapy, the timing of tacrolimus initiation and the time to reach the target concentration are unlikely to be associated with early AKI after tacrolimus administration. However, the recovery of sufficient renal function after heart transplantation is important for determining the start time of tacrolimus.

Ultrasound-targeted sirolimus-loaded microbubbles improves acute rejection of heart transplantation in rats by inhibiting TGF-β1-Smad signaling pathway, promoting autophagy and reducing inflammation

Acute rejection (AR) remains a pivotal complication and leading cause of mortality within the first year following heart transplantation (HT). In this study, we assessed the impact of ultrasound-targeted microbubbles loaded with sirolimus (SIR-MBs) on AR in a rat HT model and delved into the underlying mechanisms. We established a rat abdominal ectopic HT model, which was stratified into three groups receiveing the PBS, SIR-MBs + ultrasound-targeted microbubble destruction (UTMD), and sirolimus, respectively. The protective effects of each treatments on survival rate, inflammatory response, autophagy and TGF-β1-Smad signaling pathway-related proteins were evaluted. Additionally, rescue experiment was performed via adding the autophagy inhibitor or TGF-β1 agonist in combination therapy. UTMD combined SIR-MBs mediated 15-fold higher local drug concentration compared to direct sirolimus administration. The infiltration of inflammatory cells in the transplanted hearts indicated that SIR-MBs combined with UTMD were effective in mitigating the inflammatory response, achieving levels significantly lower than those observed in the sirolimus group. Furthermore, after SIR-MBs combined with UTMD treatment, the expression levels of TGF-β1-Smad signaling pathway-related proteins in heart tissues also showed a significant decrease compared to the model control group. Conversely, the expressions of autophagy proteins LC3-II, Beclin-1 and β-arrestin showed an up-regulated trend. Rescue experiments also revealed that the enhancement in survival trends was markedly suppressed following the administration of CsA or SRI-011381, respectively. Collectively, our findings suggest that SIR-MBs combined with UTMD augment the local treatment efficacy for AR in rat HT models by inhibiting the TGF-β1-Smad signaling pathway, promoting autophagy, and alleviating inflammation.

Can sinoatrial reinnervation improve survival after heart transplantation?

Can sinoatrial reinnervation improve survival after heart transplantation?

Late gadolinium enhancement on cardiac MRI: A systematic review and meta-analysis of prognosis across cardiomyopathies

BackgroundLate gadolinium enhancement (LGE) on cardiac MRI has been shown to predict adverse outcomes in a range of cardiac diseases. However, no study has systematically reviewed and analyzed the literature across all cardiac pathologies including rare diseases. MethodsPubMed, EMBASE and Web of Science were searched for studies evaluating the relationship between LGE burden and cardiovascular outcomes. Outcomes included all-cause mortality, MACE, sudden cardiac death, sustained VT or VF, appropriate ICD shock, heart transplant, and heart failure hospitalization. Only studies reporting hazards ratios with LGE as a continuous variable were included. ResultsOf the initial 8928 studies, 95 studies (23,313 patients) were included across 19 clinical entities. The studies included ischemic cardiomyopathy (7182 patients, 33 studies), hypertrophic cardiomyopathy (5080 patients, 17 studies), non-ischemic cardiomyopathy not otherwise specified (2627 patients, 11 studies), and dilated cardiomyopathy (2345 patients, 14 studies). Among 42 studies that quantified LGE by percent myocardium, a 1 % increase in LGE burden was associated with life-threatening ventricular arrhythmias (LTVA) with a pooled hazard ratio of 1.04 (CI 1.02–1.05), and MACE with a pooled hazard ratio of 1.06 (CI 1.04–1.07). The risk of these events was similar across disease types, with minimal heterogeneity. ConclusionsDespite mechanistic differences myocardial injury, LGE appears to have a fairly consistent, dose-dependent effect on risk of LTVA, MACE, and mortality. This data can be applied to derive a patient's absolute risk of LTVA, and therefore can be clinically useful in informing decisions on primary prevention ICD implantation irrespective of the disease etiology.

A Systematic Review of Reporting and Handling of Missing Data in Observational Studies Using the UNOS Database

BackgroundMissing data can undermine a registry’s ability to draw valid inferences by decreasing study power and introducing bias. We evaluated how missing data are reported and addressed in observational studies of adult heart transplantation (HT) recipients using the United Network for Organ Sharing (UNOS) database. MethodsWe conducted a systematic literature search of Medline from January 1st, 2018 through August 22nd, 2023 and included studies that used the UNOS database to evaluate adult (≥18 years) de novo HT recipients. We collected details on the study population, timeframe, primary endpoint, use of missing data, and whether and what methods were used to handle missing data. Approaches were classified as variable selection, complete case analysis (CCA), missing indicator method, single imputation, or multiple imputation. Results229 studies were included from 2018-2023. 67 (29.3%) studies limited their cohorts to those without missing data for the outcome or key variables and 93 (40.6%) reported missing data in their final cohort. 78 (34.1%) studies reported how they handled missing data in their statistical modeling. Of these, CCA was most used (n=41, 52.6%) followed by multiple imputation (n=22, 28.2%), and other methods (n=15, 19.2%) including a combination of missing indicator method (for binary variables) and single imputation. Thirty-one (13.5%) studies reported removing covariates from their analysis because of missing data. Only four (5.1%) studies reported sensitivity analysis to evaluate different missing data approaches. ConclusionsMerely a third of the identified UNOS database studies reported how they handled missing data in their analysis, with strategies varying. Although no singular approach to handling missing data exists, methods are available that can improve upon the most used approaches by, for example, reducing bias and increasing statistical power. Though these improvements are contingent on the missing data mechanism and the goals of the analysis. Future best practices should include explicit reporting of missingness, detailed methods, and sensitivity checks to maximize the credibility of UNOS database analyses.

Impact of donor age ≥65 years on graft survival in large lung transplant cohorts

BackgroundAlthough the demand for allografts continuously surpasses the supply, the majority of lungs offered for transplant are declined based on various factors, including donor age. This in turn sustains the wait-list mortality of patients with end-stage pulmonary disease. MethodsIn this single center, observational cohort study we investigated the impact of donor age on graft survival. We additionally, compared our center’s data to data reported to the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Organ Transplant Registry. Kaplan-Meier method was used to describe overall graft survival. Multivariate Cox proportional hazards regression was used to assess clinical features associated with graft loss. ResultsBetween January 2010 and December 2023, the Alfred performed 1101 single and double lung transplant and the combined ISHLT cohort totaled 32,200 transplants. At the Alfred, grafts originating from donors ≥65 years were used in 13.3% of lung transplant cases and univariate analysis showed no impact of donor age ≥65 on graft survival (HR 0.86, p=0.34). In the combined cohort, North America had a lower proportion of donors aged ≥65 years compared to Europe and the Alfred (2.4% vs 9.8% vs 13.3%, p<0.001). The univariate analysis showed a negative impact of donor age ≥65 on graft survival (HR 1.16, p<0.001). However, this did not hold in a multivariate model (HR 1.06, p=0.298) when adjusted for center experience and recipient characteristics. ConclusionDonor age might impact outcomes to a lesser degree than previously suggested. Therefore, appropriately assessed age-extended lungs should be routinely considered for lung transplantation.

Optimized surveillance frequency for low bone mineral density (BMD) screening using dual energy X-ray absorptiometry (DXA) in patients after lung transplant

BackgroundApproximately 2700 lung transplants are performed annually in the United States. These patients are at increased risk of developing low bone mineral density (osteopenia/osteoporosis) and subsequent osteoporosis-related fractures. Dual energy x-ray absorptiometry (DXA) is the most common method used for screening for low BMD, however, the optimal surveillance frequency for low BMD using DXA is unknown. MethodsWe evaluated the change in femoral neck, total femur, L1, L2, L3 and L4 BMD after lung transplant in a retrospective cohort of 259 patients (69.9% male) who were followed with serial DXA scans for a median of 725 (interquartile range (IQR) (361-1116)) days after transplant. Generalized linear mixed effects models allowing for random intercepts and random slopes adjusting for sex, time, time-squared, baseline osteopenia/osteoporosis, active rejection, and their interaction terms were used to model the rate of change of BMD at each site. The final multivariable models for the femoral neck, L1, and L4 BMD measurements had random slopes and intercepts, and the models for the total hip, L2, and L3 measurements had random slopes. Results65% of the patients undergoing lung transplants had osteopenia or osteoporosis before transplant. Men exhibited higher baseline BMD levels compared to women at all sites (P<0.001 for all). After transplant, the greatest rate of BMD decrease was at the femoral neck. Although patients with low BMD (osteopenia/osteoporosis) had significantly lower baseline BMDs (P<0.001 for all), they experienced a slower rate of BMD decrease at all sites compared to patients with normal BMD at baseline (P<0.001 for all). All patients received corticosteroids. 25% of patients had a history of active rejection. Patients with low BMD at baseline had significantly higher odds of receiving bisphosphonate therapy (odds ratio (OR) = 3.95, 95% CI (1.44, 13.51), P=0.003). We estimated that a significant change in the femoral neck BMD would be expected to occur within 409 days (95% CI (131, 708)) and again at 867 days (95% CI (551, 1216)) after lung transplant. ConclusionsOn average, patients undergoing lung transplant should be screened annually with DXA for the first two years after transplant, consistent with the current International Society for Heart and Lung Transplantation (ISHLT) guidelines.

Lessons Learned From Extracorporeal Life Support Practice and Outcomes During the COVID-19 Pandemic.

Extracorporeal membrane oxygenation is increasingly being used to support patients with hypoxemic respiratory failure and cardiogenic shock. During the COVID-19 pandemic, consensus guidance recommended extracorporeal life support for patients with COVID-19-related cardiopulmonary disease refractory to optimal conventional therapy, prompting a substantial expansion in the use of this support modality. Extracorporeal membrane oxygenation was particularly integral to the bridging of COVID-19 patients to heart or lung transplantation. Limited human and physical resources precluded widespread utilization of mechanical support during the COVID-19 pandemic, necessitating careful patient selection and optimal management by expert healthcare teams for judicious extracorporeal membrane oxygenation use. This review outlines the evidence supporting the use of extracorporeal life support in COVID-19, describes the practice and outcomes of extracorporeal membrane oxygenation for COVID-19-related respiratory failure and cardiogenic shock, and proposes lessons learned for the implementation of extracorporeal membrane oxygenation as a bridge to transplantation in future public health emergencies.

The State of Combined Thoracoabdominal Triple Organ Transplantation in the United States

BackgroundAs triple organ transplants (TOT) have become more common, we evaluate patient characteristics, risk factors, and clinical outcomes of patients undergoing thoracoabdominal TOT. MethodsThis retrospective study utilized data from heart-lung-liver (HLL), heart-lung-kidney (HLK), heart-kidney-liver (HKL), and heart-kidney-pancreas (HKP) recipients from the UNOS registry between 1989 and 2023. Recipient and donor characteristics and risk factors for mortality were analyzed using Cox regression hazard models. Recipient survival up to 10-years were analyzed using the Kaplan-Meier method. ResultsDuring the study period, 81 TOTs were performed (13 HLLs, 13 HLKs, 46 HKLs, 9 HKPs). There were no statistically significant differences in long-term survival between TOTs (p=0.13). However, HLL and HLK recipients had significantly worse (p<0.0001) and improved (p<0.0001) survival, respectively, when compared to heart-lung, isolated heart, and lung transplant recipients. HLK was associated with improved survival (HR:0.22, p=0.033). We found no differences in survival among HKL (p=0.24) and HKP (p=0.19) recipients compared to their dual- and single-organ counterparts. TOTs after 2007 (HR: 0.29, p=0.003) were associated with improved survival, whereas increased recipient age (HR:1.06, p=0.037), eGFR (HR:1.02, p=0.005), and donor age (HR:1.05, p=0.031) were associated with higher mortality. ConclusionsThe prevalence of TOTs has dramatically increased over the past decade. While overall survival between TOTs appears similar, adding a liver to a heart-lung transplant may be associated with a poorer prognosis compared to adding a kidney. A careful, multidisciplinary approach to patient selection and management remains paramount in optimizing outcomes for high-risk patients undergoing TOTs.

A qualitative account of mothers of pediatric heart transplant recipients' experience at a pilot mindfulness-based retreat: insights for implementation.

To explore participants' shared experience attending a pilot mindfulness-based retreat (MBR) intervention supporting the psychological well-being of mothers of pediatric heart transplant (HTx) recipients. A qualitative description approach was used within a larger hybrid mixed-methods pilot study evaluating the implementation-effectiveness of a 2-day MBR tailored specifically for a pediatric HTx population. A purposive sample of mothers was recruited from a leading Canadian pediatric HTx center, and each represented a primary, female-identifying caregiver, sharing residence with a pediatric HTx recipient of at least 4 months post-transplant. Two focus groups were conducted after and 16 individual interviews 3 months after the MBR to elicit participants' in-depth experience attending the MBR. Reflexive thematic data analysis led to theme development through an iterative process with consensus among team members. Sixteen mothers of pediatric HTx recipients (mean patient age 9.8 years; mean time post-transplant 8.2 years) participated in the MBR held in Ontario, Canada. Qualitative findings illuminated mothers' shared experience attending the MBR, reflecting three themes that describe key intervention elements beyond those affiliated with mindfulness practice alone: "respite," "readiness," and "relationships." Findings highlight acceptability and appropriateness as distinct yet interrelated implementation outcomes. Elements of "respite," "readiness," and "relationships" are key components of the MBR experience that offer valuable intervention and clinical considerations related to mothers' psychological well-being. Aligning intervention acceptability and appropriateness through tailored strategies may aid implementation. Future research considering maternal readiness relative to support intervention participation is warranted.

Clinical Course of Patients Relisted for Orthotopic Heart Transplantation: A National Study

Clinical Course of Patients Relisted for Orthotopic Heart Transplantation: A National Study

AngioVac-Assisted Laser Lead Extraction in a Patient with Heterotopic Heart Transplant

AngioVac-Assisted Laser Lead Extraction in a Patient with Heterotopic Heart Transplant

Heart Transplantation for Adult Congenital Heart Disease: Where We Are Now, and What Comes Next?

Heart Transplantation for Adult Congenital Heart Disease: Where We Are Now, and What Comes Next?

OA06 Echoes of Hope: Navigating Pregnancy post heart transplant in the context of systemic sclerosis

OA06 Echoes of Hope: Navigating Pregnancy post heart transplant in the context of systemic sclerosis

Advancing Patient-Centered Metrics for Heart Transplantation: The Role of Days Alive and Outside the Hospital

Advancing Patient-Centered Metrics for Heart Transplantation: The Role of Days Alive and Outside the Hospital

Therapeutic Plasma Exchange is Associated with Increased Survival in Heart Transplant Recipients Experiencing Severe Primary Graft Dysfunction

Therapeutic Plasma Exchange is Associated with Increased Survival in Heart Transplant Recipients Experiencing Severe Primary Graft Dysfunction

Commentator Discussion: The impact of blood type and body size on successful bridging to heart transplantation using intra-aortic balloon pump or surgically implanted microaxial left ventricular assist device.

Commentator Discussion: The impact of blood type and body size on successful bridging to heart transplantation using intra-aortic balloon pump or surgically implanted microaxial left ventricular assist device.

Donor pulmonary hemodynamics does not impact recipient outcomes in adult heart transplantation.

Donor pulmonary hemodynamics does not impact recipient outcomes in adult heart transplantation.

Heart Transplant Rejection in the Setting of Glyphosate Herbicide Exposure; A Case Report

Glyphosate is a common herbicide utilized worldwide with known exposure related toxicities. Numerous adverse effects related to glyphosate exposure have been documented, specifically in non-human models, however literature is lacking on cardiotoxic effects specific to heart transplant patients. Rejection is the most common post-transplant complication and the diagnosis of such is vital in order to guide immediate and appropriate treatment. In addition to the endomyocardial biopsy, noninvasive genetic testing can aid in rejection diagnosis and distinguish between cell-mediated and antibody-mediated rejection. We describe a case of glyphosate exposure in a post orthotopic heart transplant and the subsequent heart transplant rejection, patient’s clinical course, treatment, and follow up.