ATP-dependent citrate lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling of the Heart.

Background: Metabolic remodeling is a hallmark of the failing heart. Oncometabolic stress during cancer increases the activity and abundance of the ATP-dependent citrate lyase (ACL, Acly ), which promotes histone acetylation and cardiac adaptation. ACL is critical for the de novo synthesis of lipids, but how these metabolic alterations contribute to cardiac structural and functional changes remains unclear. Methods: We utilized human heart tissue samples from healthy donor hearts and patients with hypertrophic cardiomyopathy. Further, we used CRISPR/Cas9 gene editing to inactivate Acly in cardiomyocytes of MyH6-Cas9 mice. In vivo, positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to the loss of ACL. We conducted a multi-omics analysis using RNA-sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level. Results: Here, we show that in mice, ACL drives metabolic adaptation in the heart to sustain contractile function, histone acetylation, and lipid modulation. Notably, we show that loss of ACL increases glucose oxidation while maintaining fatty acid oxidation. Ex vivo isotope tracing experiments revealed a reduced efflux of glucose-derived citrate from the mitochondria into the cytosol, confirming that citrate is required for reductive metabolism in the heart. We demonstrate that YAP inactivation facilitates ACL deficiency. Computational flux analysis and integrative multi-omics analysis indicate that loss of ACL induces alternative isocitrate dehydrogenase 1 flux to compensate. Conclusions: This study mechanistically delineates how cardiac metabolism compensates for suppressed citrate metabolism in response to ACL loss and uncovers metabolic vulnerabilities in the heart.

Importance of Transplant Era on Post-Heart Transplant Predictive Models: A UNOS Cohort Analysis.

BACKGROUND: The application of posttransplant predictive models is limited by their poor statistical performance. Neglecting the dynamic evolution of demographics and medical practice over time may be a key issue. OBJECTIVES: Our objective was to develop and validate era-specific predictive models to assess whether these models could improve risk stratification compared to non-era-specific models. METHODS: We analyzed the United Network for Organ Sharing (UNOS) database including first noncombined heart transplantations (2001-2018, divided into four transplant eras: 2001-2005, 2006-2010, 2011-2015, 2016-2018). The endpoint was death or retransplantation during the 1st-year posttransplant. We analyzed the dynamic evolution of major predictive variables over time and developed era-specific models using logistic regression. We then performed a multiparametric evaluation of the statistical performance of era-specific models and compared them to non-era-specific models in 1000 bootstrap samples (derivation set, 2/3; test set, 1/3). RESULTS: A total of 34 738 patients were included, 3670 patients (10.5%) met the composite endpoint. We found a significant impact of transplant era on baseline characteristics of donors and recipients, medical practice, and posttransplant predictive models, including significant interaction between transplant year and major predictive variables (total serum bilirubin, recipient age, recipient diabetes, previous cardiac surgery). Although the discrimination of all models remained low, era-specific models significantly outperformed the statistical performance of non-era-specific models in most samples, particularly concerning discrimination and calibration. CONCLUSIONS: Era-specific models achieved better statistical performance than non-era-specific models. A regular update of predictive models may be considered if they were to be applied for clinical decision-making and allograft allocation.

IgM marks persistent IgG anti-human leukocyte antigen antibodies in highly sensitized heart transplant patients.

BACKGROUND: Sensitization to human leukocyte antigens (HLA) is a persistent problem in heart transplant (HT) candidates. We sought to characterize the anti-HLA antibody and circulating B cell repertoire in a cohort of highly sensitized HT candidates. METHODS: We assessed immunoglobulin G (IgG) and immunoglobulin M (IgM) anti-HLA antibodies using Luminex single antigen bead assays in a cohort of 11 highly sensitized (HS; calculated panel reactive antibody ≥ 90%) and 3 mildly sensitized (MS) candidates. We also performed B cell receptor repertoire sequencing (BCRseq) in HS candidates and 33 non-candidate controls. HLA antibody strength was measured by mean fluorescence intensity (MFI). RESULTS: We found that IgM anti-HLA antibodies were present in all HS candidates, but with a lower breadth and strength as compared to IgG. When anti-HLA IgG specificities intersected with IgM, binding strength was higher. In contrast, there were IgM but no intersecting IgG specificities for the MS group. In four candidates in the HS group, IgG anti-HLA antibodies decreased in both breadth and strength after HT, but the decrease in strength was smaller if the IgG possessed a specificity that intersected with pre-transplant IgM. BCRseq revealed larger B cell clonotypes in HS candidates but similar diversity as compared to controls. CONCLUSIONS: IgM marks IgG anti-HLA antibodies with higher strength before HT and persistence after HT. The presence of IgM intersecting IgG for an anti-HLA specificity may be a useful approach to determine which donor HLA should be avoided for a sensitized candidate.

Does bortezomib influence pre-transplant desensitization therapy or benefit post-heart transplant outcomes for highly sensitized patients?

BACKGROUND: The use of bortezomib which is a proteasome inhibitor has been demonstrated to be efficacious in small number of patients as a desensitization strategy in heart transplant. We reviewed our single center's experience using Bortezomib along with plasmapheresis as desensitization therapy for highly sensitized patients to assess pre- and post-transplant outcomes. METHOD: We assessed 43 highly sensitized patients awaiting HTx (defined as cPRA > 50%) between 2010 and 2021 who underwent desensitization therapy with bortezomib. Only those patients who subsequently underwent HTx were included in this study. Enrolled patients received up to four doses of bortezomib (1.3 mg/m2 ) over 2 weeks in conjunction with plasmapheresis. The efficacy of PP/BTZ was assessed by comparing the calculated panel reactive antibodies to HLA class I or class II antigens. Post-transplant outcomes including overall survival and incidence of rejection were compared to those of non-sensitized patients (PRA < 10%, n = 649) from the same center. RESULTS: The average cPRA prior to PP/BTZ was 94.5%. Post-PP/BTZ there was no statistically significant decline in mean cPRA, class I cPRA, or class II cPRA, though the average percentage decrease in class I cPRA (8.7 ± 17.0%) was higher than the change in class II cPRA (4.4 ± 13.3%). Resulted were also replicated with C1q-binding antibodies showing more effect on I class compared to class II (15.0 ± 37.4% vs. 6.8 ± 33.6%) as well as with 1:8 dilutional assay (14.0 ± 23.0% vs. 9.1 ± 34.9%). Additionally, PP/BTZ treated patients and the control group of non-sensitized patients had similar overall 1 year survival (95.4 vs. 92.5%) but patients with PP/BTZ had increased incidence of AMR (79.1% vs. 97.1%, p = < .001), any treated rejection (62.8% vs. 86.7%, p = < .001) and de novo DSA development (81.4% vs. 92.5%, p = .007). Major side effects of PP/BTZ included thrombocytopenia (42%), infection requiring antibiotics (28%), and neuropathy (12%). CONCLUSION: The use of bortezomib in highly sensitized patients does not significantly lower circulating antibodies prior to heart transplantation. However, its use may improve the chances of obtaining an immuno-compatible donor heart and contribute to acceptable post-transplant outcomes.

Report of the 2022 Banff Heart Concurrent: Focus on non-human leukocyte antigen antibodies in rejection and the pathology of "mixed" rejection.

The Banff Heart Concurrent Session, held as part of the 16th Banff Foundation for Allograft Pathology Conference at Banff, Alberta, Canada, on September 21, 2022, focused on 2 major topics: non-human leukocyte antigen (HLA) antibodies and mixed rejection. Each topic was addressed in a multidisciplinary fashion with clinical, immunological, and pathology perspectives and future developments and prospectives. Following the Banff organization model and principles, the collective aim of the speakers on each topic was to • Determine current knowledge gaps in heart transplant pathology • Identify limitations of current pathology classification systems • Discuss next steps in addressing gaps and refining classification system.

HLA sensitization is associated with an increased risk of primary graft dysfunction after heart transplantation.

Primary graft dysfunction (PGD) is a leading cause of early morbidity and mortality following heart transplantation (HT). We sought to determine the association between pretransplant human leukocyte antigen (HLA) sensitization, as measured using the calculated panel reactive antibody (cPRA) value, and the risk of PGD. METHODS: Consecutive adult HT recipients (n = 596) from 1/2015 to 12/2019 at 2 US centers were included. Severity of PGD was based on the 2014 International Society for Heart and Lung Transplantation consensus statement. For each recipient, unacceptable HLA antigens were obtained and locus-specific cPRA (cPRA-LS) and pre-HT donor-specific antibodies (DSA) were assessed. RESULTS: Univariable logistic modeling showed that peak cPRA-LS for all loci and HLA-A was associated with increased severity of PGD as an ordinal variable (all loci: OR 1.78, 95% CI: 1.01-1.14, p = 0.025, HLA-A: OR 1.14, 95% CI: 1.03-1.26, p = 0.011). Multivariable analysis showed peak cPRA-LS for HLA-A, recipient beta-blocker use, total ischemic time, donor age, prior cardiac surgery, and United Network for Organ Sharing status 1 or 2 were associated with increased severity of PGD. The presence of DSA to HLA-B was associated with trend toward increased risk of mild-to-moderate PGD (OR 2.56, 95% CI: 0.99-6.63, p = 0.053), but DSA to other HLA loci was not associated with PGD. CONCLUSIONS: Sensitization for all HLA loci, and specifically HLA-A, is associated with an increased severity of PGD. These factors should be included in pre-HT risk stratification to minimize the risk of PGD.

Rare Variant Genetics and Dilated Cardiomyopathy Severity: The DCM Precision Medicine Study.

BACKGROUND: Dilated cardiomyopathy (DCM) can lead to advanced disease, defined herein as necessitating a durable left ventricular assist device or a heart transplant (LVAD/HT). DCM is known to have a genetic basis, but the association of rare variant genetics with advanced DCM has not been studied. METHODS: We analyzed clinical and genetic sequence data from patients enrolled between 2016 and 2021 in the US multisite DCM Precision Medicine Study, which was a geographically diverse, multiracial, multiethnic cohort. Clinical evaluation included standardized patient interview and medical record query forms. DCM severity was classified into 3 groups: patients with advanced disease with LVAD/HT; patients with an implantable cardioverter defibrillator (ICD) only; or patients with no ICD or LVAD/HT. Rare variants in 36 DCM genes were classified as pathogenic or likely pathogenic or variants of uncertain significance. Confounding factors we considered included demographic characteristics, lifestyle factors, access to care, DCM duration, and comorbidities. Crude and adjusted associations between DCM severity and rare variant genetic findings were assessed using multinomial models with generalized logit link. RESULTS: Patients' mean (SD) age was 51.9 (13.6) years; 42% were of African ancestry, 56% were of European ancestry, and 44% were female. Of 1198 patients, 347 had LVAD/HT, 511 had an ICD, and 340 had no LVAD/HT or ICD. The percentage of patients with pathogenic or likely pathogenic variants was 26.2%, 15.9%, and 15.0% for those with LVAD/HT, ICD only, or neither, respectively. After controlling for sociodemographic characteristics and comorbidities, patients with DCM with LVAD/HT were more likely than those without LVAD/HT or ICD to have DCM-related pathogenic or likely pathogenic rare variants (odds ratio, 2.3 [95% CI, 1.5-3.6]). The association did not differ by ancestry. Rare variant genetic findings were similar between patients with DCM with an ICD and those without LVAD/HT or ICD. CONCLUSIONS: Advanced DCM was associated with higher odds of rare variants in DCM genes adjudicated as pathogenic or likely pathogenic, compared with individuals with less severe DCM. This finding may help assess the risk of outcomes in management of patients with DCM and their at-risk family members. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03037632.

Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry.

Importance: Black patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients. Objective: To compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM. Design: Cross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance. Exposure: Presence of DCM. Main Outcomes and Measures: Variants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic). Results: A total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, -0.09 [95% CI, -0.14 to -0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, -0.06 [95% CI, -0.11 to -0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, -0.07 [95% CI, -0.22 to 0.09]) due to a larger number of non-TTN non-predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P < .001). Conclusion and Relevance: Patients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets.

Intermediate-term outcomes of complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients.

Allosensitization represents a major barrier to heart transplantation. We previously reported favorable 1-year outcomes of complement inhibition at transplant in highly sensitized recipients. We now report a longer follow-up. In this single-arm trial (NCT02013037), 20 patients with panel reactive antibodies ≥70% and preformed donor-specific antibodies received eculizumab during the first 2 months post-transplant. The primary end-point was antibody-mediated rejection ≥ pAMR2 and/or left ventricular dysfunction. The median follow-up was 4.8 years. Beyond the first year post-transplant, there were no episodes of pAMR2 or greater and no Left Ventricular (LV) dysfunction. There were 3 deaths, 1 episode of pAMR1, and 1 patient with minimal de novo cardiac allograft vasculopathy. Compared to a matched control group, we observed a nonstatistically significant benefit of eculizumab with a lower incidence of the primary end-point or death (primary end-point: hazard ratio = 0.50, 95% confidence interval = 0.15-1.67, and p = 0.26; mortality: hazard ratio = 0.51, 95% confidence interval = 0.13-2.07, and p = 0.35). Our results support the utility of complement inhibition for high-immunological-risk recipients. CLINICAL TRIAL REGISTRATION: ClinincalTrials.gov, NCT02013037. https://clinicaltrials.gov/ct2/show/NCT02013037?term=eculizumab&cond=heart+transplantation&draw=2&rank=1.

Three year post heart transplant outcomes of desensitized durable mechanical circulatory support patients.

BACKGROUND: The risks and benefits of desensitization therapy (DST) in highly sensitized mechanical circulatory support (MCS) patients are not well known. We investigated 3 year post-transplant outcomes of desensitized durable MCS patients. METHODS: Among 689 consecutively enrolled heart transplantation recipients between 2010 and 2016, we categorized them into Group A (desensitized MCS patients, n = 21), Group B (desensitized non-MCS patients, n = 28) and Group C (all nondesensitized patients, n = 640). Post-transplant outcomes included the incidence of primary graft dysfunction, 3-year survival, freedom from cardiac allograft vasculopathy, nonfatal major adverse cardiac events, any treated rejection, acute cellular rejection, antibody mediated rejection (AMR) and infectious complications. RESULTS: The types of DST in Groups A and B were similar and included combinations of rituximab/intravenous immunoglobulin and plasmapheresis/bortezomib. Group A, compared with Group B, showed significantly higher pre-DST panel reactive antibody (PRA) (92.2 ± 9.8 vs. 83.3 ± 15.6, P = 0.007) and higher PRA reduction after DST (-22.2 ± 26.9 vs. -6.3 ± 7.5, P = 0.015). Groups A and C showed comparable primary graft dysfunction, 3-year survival, freedom from cardiac allograft vasculopathy, nonfatal major adverse cardiac events, any treated rejection, acute cellular rejection, and AMR. Although statistically not significant, Group A showed numerically higher 3-year freedom from AMR than Group B. Infectious complications were similar in both Groups A and B. CONCLUSIONS: DST for MCS patients showed significant PRA reduction, resulting in an expansion of the donor pool. The post-transplant outcome of desensitized MCS patients showed comparable clinical outcomes to non-desensitized control patients in the same study period, revealing the safety and efficacy of DST.

Screening for Dilated Cardiomyopathy in At-Risk First-Degree Relatives.

BACKGROUND: Cardiovascular screening is recommended for first-degree relatives (FDRs) of patients with dilated cardiomyopathy (DCM), but the yield of FDR screening is uncertain for DCM patients without known familial DCM, for non-White FDRs, or for DCM partial phenotypes of left ventricular enlargement (LVE) or left ventricular systolic dysfunction (LVSD). OBJECTIVES: This study examined the yield of clinical screening among reportedly unaffected FDRs of DCM patients. METHODS: Adult FDRs of DCM patients at 25 sites completed screening echocardiograms and ECGs. Mixed models accounting for site heterogeneity and intrafamilial correlation were used to compare screen-based percentages of DCM, LVSD, or LVE by FDR demographics, cardiovascular risk factors, and proband genetics results. RESULTS: A total of 1,365 FDRs were included, with a mean age of 44.8 ± 16.9 years, 27.5% non-Hispanic Black, 9.8% Hispanic, and 61.7% women. Among screened FDRs, 14.1% had new diagnoses of DCM (2.1%), LVSD (3.6%), or LVE (8.4%). The percentage of FDRs with new diagnoses was higher for those aged 45 to 64 years than 18 to 44 years. The age-adjusted percentage of any finding was higher among FDRs with hypertension and obesity but did not differ statistically by race and ethnicity (16.2% for Hispanic, 15.2% for non-Hispanic Black, and 13.1% for non-Hispanic White) or sex (14.6% for women and 12.8% for men). FDRs whose probands carried clinically reportable variants were more likely to be identified with DCM. CONCLUSIONS: Cardiovascular screening identified new DCM-related findings among 1 in 7 reportedly unaffected FDRs regardless of race and ethnicity, underscoring the value of clinical screening in all FDRs.

Hypertrophic Cardiomyopathy After Heart Transplantation: A Single-Center Case Series.

We present 3 heart transplant recipients who developed hypertrophic cardiomyopathy years after transplantation. In all 3 cases, the diagnosis was initially made based on echocardiography and confirmed using cardiac magnetic resonance imaging. (Level of Difficulty: Advanced.).

Atypical cardiac amyloidosis phenotypes identified at transplant: a case series.

Background: Transthyretin amyloidosis (TTR) is increasingly implicated as an aetiology of advanced cardiomyopathy. Typically, both genetic variant (TTRv) and wild-type (TTRwt) amyloidosis present with a restrictive phenotype. We present a series of three patients who were found to have cardiac amyloidosis on explant following heart transplant (HT) who had atypical, non-restrictive phenotypes. Case Summary: All three patients were men, three were Black, and only one had an alternative pre-HT explanation for their advanced, dilated cardiomyopathy. Pre-HT transthoracic echocardiograms were notable for left ventricular (LV) dilation (>95th percentile for height and gender), low EF, and normal LV wall thickness. Explants showed varying amounts of amyloid deposition, ranging from diffuse biventricular patterns to perivascular involvement. Mass spectrometry confirmed the presence of TTRv (two cases) and TTRwt (one case). Discussion: Patients with dilated cardiomyopathy may harbour cardiac amyloidosis. Uncertainty remains regarding the contribution of amyloidosis to the development of a dilated phenotype. The pathogenic Val142Ile variant seen in two of these patients, a variant common in Black patients, suggests a need for further investigation into the potential relationship between TTRv amyloidosis and dilated cardiomyopathy.

Effectiveness of the Family Heart Talk Communication Tool in Improving Family Member Screening for Dilated Cardiomyopathy: Results of a Randomized Trial.

BACKGROUND: Managing disease risk among first-degree relatives of probands diagnosed with a heritable disease is central to precision medicine. A critical component is often clinical screening, which is particularly important for conditions like dilated cardiomyopathy (DCM) that remain asymptomatic until severe disease develops. Nonetheless, probands are frequently ill-equipped to disseminate genetic risk information that motivates at-risk relatives to complete recommended clinical screening. An easily implemented remedy for this key issue has been elusive. METHODS: The DCM Precision Medicine Study developed Family Heart Talk, a booklet designed to help probands with DCM communicate genetic risk and the need for cardiovascular screening to their relatives. The effectiveness of the Family Heart Talk booklet in increasing cardiovascular clinical screening uptake among first-degree relatives was assessed in a multicenter, open-label, cluster-randomized, controlled trial. The primary outcome measured in eligible first-degree relatives was completion of screening initiated within 12 months after proband enrollment. Because probands randomized to the intervention received the booklet at the enrollment visit, eligible first-degree relatives were limited to those who were alive the day after proband enrollment and not enrolled on the same day as the proband. RESULTS: Between June 2016 and March 2020, 1241 probands were randomized (1:1) to receive Family Heart Talk (n=621) or not (n=620) within strata defined by site and self-identified race/ethnicity (non-Hispanic Black, non-Hispanic White, or Hispanic). Final analyses included 550 families (n=2230 eligible first-degree relatives) in the Family Heart Talk arm and 561 (n=2416) in the control arm. A higher percentage of eligible first-degree relatives completed screening in the Family Heart Talk arm (19.5% versus 16.0%), and the odds of screening completion among these first-degree relatives were higher in the Family Heart Talk arm after adjustment for proband randomization stratum, sex, and age quartile (odds ratio, 1.30 [1-sided 95% CI, 1.08-∞]). A prespecified subgroup analysis did not find evidence of heterogeneity in the adjusted intervention odds ratio across race/ethnicity strata (P=0.90). CONCLUSIONS: Family Heart Talk, a booklet that can be provided to patients with DCM by clinicians with minimal additional time investment, was effective in increasing cardiovascular clinical screening among first-degree relatives of these patients. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03037632.

Donor hyperoxia is a novel risk factor for severe cardiac primary graft dysfunction.

BACKGROUND: Primary graft dysfunction (PGD) is a major cause of early mortality following heart transplant (HT). Donor risk factors for the development of PGD are incompletely characterized. Donor management goals (DMG) are predefined critical care endpoints used to optimize donors. We evaluated the relationship between DMGs as well as non-DMG parameters, and the development of PGD after HT. METHODS: A cohort of HT recipients from 2 transplant centers between 1/1/12 and 12/31/19 was linked to their respective donors in the United Network for Organ Sharing (UNOS) DMG Registry (n = 1,079). PGD was defined according to modified ISHLT criteria. Variables were subject to univariate and multivariable multinomial modeling with development of mild/moderate or severe PGD as the outcome variable. A second multicenter cohort of 4,010 donors from the DMG Registry was used for validation. RESULTS: Mild/moderate and severe PGD occurred in 15% and 6% of the cohort. Multivariable modeling revealed 6 variables independently associated with mild/moderate and 6 associated with severe PGD, respectively. Recipient use of amiodarone plus beta-blocker, recipient mechanical circulatory support, donor age, donor fraction of inspired oxygen (FiO2), and donor creatinine increased risk whereas predicted heart mass ratio decreased risk of severe PGD. We found that donor age and FiO2 ≥ 40% were associated with an increased risk of death within 90 days post-transplant in a multicenter cohort. CONCLUSIONS: Donor hyperoxia at heart recovery is a novel risk factor for severe primary graft dysfunction and early recipient death. These results suggest that excessive oxygen supplementation should be minimized during donor management.

Assessment and management of allosensitization following heart transplant in adults.

Immunological injury to the allograft, specifically by antibodies to de novo donor specific human leukocyte antigen (dnDSA) and antibody mediated injury and rejection are the major limitations to graft survival after heart transplantation (HT). As such, our approach to allosensitization remains limited by the inability of contemporaneous immunoassays to unravel pathogenic potential of dnDSA. Additionally, the role of dnDSA is continuously evaluated with emerging methods to detect rejection. Moreover, the timing and frequency of dnDSA monitoring for early detection and risk mitigation as well as management of dnDSA remain challenging. A strategic approach to dnDSA employs diagnostic assays to determine relevant antibodies in conjunction with clinical presentation and injury/rejection of allograft to tailor therapeutics. In this review, we aim to outline contemporary knowledge involving detection, monitoring and management of dnDSA after HT. Subsequently, we propose a diagnostic and therapeutic approach that may mitigate morbidity and mortality while balancing adverse reactions from pharmacotherapy.

Detection and management of HLA sensitization in candidates for adult heart transplantation.

Heart transplantation (HT) remains the preferred therapy for patients with advanced heart failure. However, for sensitized HT candidates who have antibodies to human leukocyte antigens , finding a suitable donor can be challenging and can lead to adverse waitlist outcomes. In recent years, the number of sensitized patients awaiting HT has increased likely due to the use of durable and mechanical circulatory support as well as increasing number of candidates with underlying congenital heart disease. This State-of-the-Art review discusses the assessment of human leukocyte antigens antibodies, potential desensitization strategies including mechanisms of action and specific protocols, the approach to a potential donor including the use of complement-dependent cytotoxicity, flow cytometry, and virtual crossmatches, and peritransplant induction management.