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Gene expression profiling (GEP) is a reliable monitoring tool for rejection surveillance following heart transplantation (HT), but may also be helpful in assessing degree of immunosuppression. We aimed to evaluate changes in GEP with modern, rapid steroid weaning. GEP results collected on HT patients from January 2020-August 2022 were reviewed. At our center, a score ≥ 30 is considered high 2-6 months post-HT and ≥ 34 is considered high after 6-months post-HT. In patients without concern for clinical rejection or new donor specific antibody, steroids are weaned off by month 5-6 post-HT. A total of 561 GEP samples were obtained during the study period from patients 2 months to > 24 months post-transplant. The highest percentage of samples (42%) were collected between months 4-6 post-HT. There was a steady increase in mean GEP score from month 3 (22.5) to month 5 (32.5) as steroids were being quickly weaned (Figure 1a). Utilizing a threshold score of 30 in patients < 6 months post-transplant yielded approximately 60% of samples that would have been abnormal (above threshold). In contrast, only 31.3% would be considered abnormal (above threshold) if a threshold value of 34 were used during this time frame to reflect reduced steroid dosing from our modern taper (Figure 1b). GEP scores rise steadily during the first few months post-transplant as steroids are aggressively weaned. Lowering the threshold score within the first 6 months can help decrease the number of positive (above threshold) results and potentially decrease the need for unnecessary endomyocardial biopsies. [ABSTRACT FROM AUTHOR]

Cardiac allograft rejection (AR) diagnosis has historically relied on endomyocardial biopsy (EMBx) and histopathology (HP). Quantifying donor-derived cell free DNA (ddcfDNA) has recently offered a non-invasive alternative for detecting graft injury. EMBx mRNA analysis via the molecular microscope profiles (MMP) quantifies AR probability not subject to HP interpretation. Our aim was to evaluate the clinical role of MMP in cardiac transplant recipients (HTx) with positive ddcfDNA. We identified 39 patients with ddcfDNA testing and subsequent EMBx for HP (n=36) and MMP (n=39) analysis. MMP was conducted by the molecular microscope diagnostic system (MMDX™). Patients with multi-organ transplantation or coronary allograft vasculopathy were excluded. MMP, HP, echo and ddcfDNA association were assessed using logistical regression (SPSS™). Average time post-transplant was 1585 ±1435 days, average LVEF 55%, and average ddcfDNA 0.81 ± 1.1. Donor specific antibodies were present in 14/39 of patients. MMP was abnormal in 18/39 patients and correlated with ddcfDNA levels (p=0.007) and HP (p=0.05), but not with LVEF (p=0.71). MMP abnormalities included 9 antibody mediated rejection (AMR), 5 acute cellular rejection (ACR), and 4 injury patterns. By HP, biopsies were abnormal in 18/36 patients: 18 ACR (grade 1) and 1 AMR (grade 2). Abnormal HP did not correlate with ddcfDNA levels (p= 0.07). HP and MMP are often discordant, Table 1. Abnormal MMP correlated with both ddcfDNA and HP, but not with LVEF. Large prospective clinical trials are needed to define clinical outcomes from treatment strategies based on biopsy results. Multi-modality testing may be necessary to monitor cardiac transplant patients for rejection and avoid misclassification. [ABSTRACT FROM AUTHOR]

Although patients with familial dilated cardiomyopathy (DCM) usually present at earlier age, the impact of genetic susceptibility on the DCM severity has remained unclear. Advanced DCM may lead to heart failure requiring ventricular assisted device (VAD) or heart transplantation. This study aims to assess the role of a genetic signature of DCM on severity of DCM presentation. We analyzed clinical and genetic sequencing data from patients enrolled in the multisite DCM Precision Medicine Study, who were a geographically representative, multi-racial/ethnic cohort, between 2016 and 2021. A clinical evaluation included medical history, physical examination, electrocardiography, and echocardiography. Research exome sequencing and array-based genotyping were conducted for all patients. DCM severity was classified into 3 groups: VAD or heart transplant, ICD, or none. Genetic susceptibility was measured by the presence of DCM-related rare variants (LP, P, VUS) and more granular genetic risk groups based on the number of variant alleles or separate analyses for VUS/LP/P and LP/P variants. Confounding factors considered included gender, race/ethnicity, age at diagnosis, comorbidities, medication use, and DCM duration. Crude and adjusted associations between DCM severity and genetic susceptibility were assessed using generalized mixed models. Results :: Of 1,188 patients with DCM, mean (SD) age was 52.0 (13.6) years with 43% African American, 9% Hispanic, and 44% female participants. The analysis will: 1) compare clinical characteristics of DCM patients with VAD or heart transplant (n=342), with ICD alone (n=508), or none (n=338); 2) compare genetic profiles of patients in the 3 DCM severity groups; and 3) examine differences in DCM-related genetic variants (P, LP, VUS) among patients in the 3 severity groups after controlling for confounding factors. Contributions of specific DCM-related genetic variants will also be explored. Data from this study will help assess the risk of DCM outcomes for early patient management and guide genetic counseling regarding genetic and environmental exposure that may worsen DCM. [ABSTRACT FROM AUTHOR]

We sought to determine whether acute rejection in recipients of allografts recovered from donors after circulatory death (DCD) differs from grafts recovered after brain death (DBD). We used percentage of donor derived cell free DNA (%dd-cfDNA) in recipients as a surrogate marker for rejection. Venous blood was longitudinally sampled from heart transplant recipients from January 2021 - June 2022 and assayed for %dd-cfDNA by next generation sequencing with AlloSure® (CareDx Inc). A threshold of <0.2% was considered normal. Recipients with %dd-cfDNA available at months 2,4,6,9, and 12 post-transplantation were included and analyzed with repeated measures ANOVA for differences between DBD and DCD. In a sub-group analysis, we compared DCD grafts recovered with in-situ thoracoabdominal normothermic regional perfusion (TA-NRP) to direct procurement followed by ex-situ normothermic machine perfusion (DP-NMP). For DCD heart recipients who underwent for-cause endomyocardial biopsy (EMB), corresponding clinical workup including donor specific antibodies (DSA), molecular microscopy (MMDX), and ejection fraction was also assessed. Of 68 patients (52 DBD, 16 DCD) transplanted, 21 DBD and 8 DCD (4 TA-NRP + 4 DP-NMP) recipients completed 12 months follow-up and had complete set of AlloSure® results at all time points. No statistically significant difference in %dd-cfDNA was present between DBD and DCD recipients (P = 0.27). A trend toward higher levels of %dd-cfDNA was present in recipients of DCD grafts recovered with DP-NMP in comparison to both DCD TA-NRP and DBD (Figure 1). Table 1 depicts the results of EMB, MMDX, DSA, and TTE. In this single center cohort of DCD heart recipients, no difference in %dd-cfDNA was detected compared to DBD recipients. The observed trend toward higher levels of %dd-cfDNA in DCD DP-NMP may, if confirmed in a larger cohort, provide a rationale for individualized post-transplant immunosuppressive management in these patients. [ABSTRACT FROM AUTHOR]

Background: Clinical genetic evaluation of dilated cardiomyopathy (DCM) is implemented variably or not at all. Identifying needs and barriers to genetic evaluations will enable strategies to enhance precision medicine care., Methods: An online survey was conducted in June 2024 among cardiologist investigators of the DCM Consortium from US advanced heart failure/transplant (HF/TX) programs to collect demographics, training, program characteristics, genetic evaluation practices for DCM, and implementation needs. An in-person discussion followed., Results: Twenty-five cardiologists (28% female, 12% Hispanic, 68% White) participated in the survey and 15 in the discussion; genetics training backgrounds varied greatly. Clinical genetic testing for DCM was conducted by all programs with annual uptake ranging from 5%-70% (median 25%). Thirteen respondents (52%) did not use selection criteria for testing whereas others selected patients based on specific clinical and family history data. Eight (32%) ordered testing by themselves, and the remainder had testing managed mostly by a genetic counselor or others with genetic expertise (16/17; 94%). Six themes were distilled from open-ended responses regarding thoughts for the future and included access to genetics services, navigating uncertainty, knowledge needs, cost concerns, family-based care barriers, and institutional infrastructure limitations. Following an in-person discussion, four areas were identified for focused effort: improved reimbursement for genetic services, genetic counselor integration with HF/TX teams, improved provider education resources, and more research to find missing heritability and to resolve uncertain results., Conclusions: HF/TX programs have implementation challenges in the provision of DCM genetic evaluations; targeted plans to facilitate precision medicine for DCM are needed.

Background: Preoperative amiodarone effects on postorthotopic heart transplant (OHT) outcomes remain controversial., Objective: The purpose of this study was to determine the effect of cumulative pre-OHT amiodarone exposure on severe primary graft dysfunction (PGD)., Methods: We retrospectively reviewed adult OHT recipients between August 2012 and June 2018. Primary outcome was severe PGD in patients receiving amiodarone at 3, 6, and 12 months prior to OHT compared with those not receiving amiodarone. Secondary outcomes included intensive care unit (ICU) and hospital length of stay, duration of mechanical ventilation, early graft failure (EGF), mortality at 3, 6, and 12 months post-OHT, and 30-day incidence of postoperative tachyarrhythmias, bradycardia, permanent pacemaker implantation, and rejection., Results: Incidence of severe PGD was 12.5% in those who received amiodarone compared to 6.8% in those who did not (14 vs 6, P = 0.18). Cumulative preoperative amiodarone significantly increased the odds of severe PGD at 3 months (odds ratio [OR]: 1.03; 95% confidence interval [CI]: 1.001-1.06; P = 0.044) and 6 months (OR: 1.02, 95% CI: 1.003-1.044; P = 0.024) in a multivariate logistic regression. Patients on amiodarone had significantly higher rates of postoperative bradycardia (13.4% vs 4.5%, P = 0.03)., Conclusion and Relevance: A trend toward increased PGD was present in patients receiving preoperative amiodarone. This finding combined with the regression showing significantly increased odds of PGD with increasing 3 and 6 month cumulative amiodarone dose is clinically concerning. Escalation of care with pacemaker implantation was required more frequently in patients on pre-OHT amiodarone., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., Competing Interests: Disclosures None.

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.

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., Competing Interests: Funding Support and Author Disclosures Research reported in this publication was supported by a parent award from the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number R01HL128857, which included a supplement from the National Human Genome Research Institute. The DCM Precision Medicine Study was supported by computational infrastructure provided by The Ohio State University Division of Human Genetics Data Management Platform and the Ohio Supercomputer Center. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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.

Background: Guideline-directed medical therapy (GDMT) reduces mortality and hospitalizations in adults with heart failure with reduced ejection fraction (HFrEF); however, few are receiving GDMT. National registries show as few as 1% of patients are receiving appropriate GDMT. Development of heart failure clinics achieving optimal GDMT are crucial to improve outcomes for HFrEF patients., Objective: We developed a multidisciplinary HF-Optimize clinic aimed at improving GDMT use along with providing education, resources, and comorbidity screening for adults with HFrEF., Methods: We targeted patients with newly diagnosed HFrEF and/or recent or multiple admissions for 6 visits over 12 weeks. We measured medication use, ejection fraction, 6-minute walk test distance, and health-related quality of life (EuroQol Visual Analog Scale) at visits 1 and 6., Results: One-hundred ten patients completed all visits. Patients were a mean age of 58 (±14) years, 37% were female, and 42% were of non-White race. From visit 1 to visit 6, utilization of GDMT increased from 35.5% to 85.5% (p < 0.001) and significant improvements in ejection fraction (25.9% to 35.5%, p < 0.001), 6-minute walk distance (1032 feet to 1121.7 feet, p = 0.001), and quality of life (63.8/100 vs 70.8/100, p = 0.002). Only 2 patients (1.8%) that completed HF-Optimize had a 30-day heart failure readmission., Conclusion: Our multidisciplinary HF-Optimize clinic improved medication usage and clinical outcomes. Further studies are needed to validate outcomes of multidisciplinary GDMT clinics., Competing Interests: Declaration of Competing Interest No authors have conflicts of interest to disclose for our article, The Role of a Multidisciplinary Heart Failure Clinic in Optimization of Guideline-Directed Medical Therapy: HF-Optimize, (Copyright © 2022 Elsevier Inc. All rights reserved.)

Importance: Idiopathic dilated cardiomyopathy (DCM) aggregates in families, and early detection in at-risk family members can provide opportunity to initiate treatment prior to late-phase disease. Most studies have included only White patients, yet Black patients with DCM have higher risk of heart failure-related hospitalization and death., Objective: To estimate the prevalence of familial DCM among DCM probands and the age-specific cumulative risk of DCM in first-degree relatives across race and ethnicity groups., Design, Setting, and Participants: A family-based, cross-sectional study conducted by a multisite consortium of 25 US heart failure programs. Participants included patients with DCM (probands), defined as left ventricular systolic dysfunction and left ventricular enlargement after excluding usual clinical causes, and their first-degree relatives. Enrollment commenced June 7, 2016; proband and family member enrollment concluded March 15, 2020, and April 1, 2021, respectively., Exposures: The presence of DCM in a proband., Main Outcomes and Measures: Familial DCM defined by DCM in at least 1 first-degree relative; expanded familial DCM defined by the presence of DCM or either left ventricular enlargement or left ventricular systolic dysfunction without known cause in at least 1 first-degree relative., Results: The study enrolled 1220 probands (median age, 52.8 years [IQR, 42.4-61.8]; 43.8% female; 43.1% Black and 8.3% Hispanic) and screened 1693 first-degree relatives for DCM. A median of 28% (IQR, 0%-60%) of living first-degree relatives were screened per family. The crude prevalence of familial DCM among probands was 11.6% overall. The model-based estimate of the prevalence of familial DCM among probands at a typical US advanced heart failure program if all living first-degree relatives were screened was 29.7% (95% CI, 23.5% to 36.0%) overall. The estimated prevalence of familial DCM was higher in Black probands than in White probands (difference, 11.3% [95% CI, 1.9% to 20.8%]) but did not differ significantly between Hispanic probands and non-Hispanic probands (difference, -1.4% [95% CI, -15.9% to 13.1%]). The estimated prevalence of expanded familial DCM was 56.9% (95% CI, 50.8% to 63.0%) overall. Based on age-specific disease status at enrollment, estimated cumulative risks in first-degree relatives at a typical US advanced heart failure program reached 19% (95% CI, 13% to 24%) by age 80 years for DCM and 33% (95% CI, 27% to 40%) for expanded DCM inclusive of partial phenotypes. The DCM hazard was higher in first-degree relatives of non-Hispanic Black probands than non-Hispanic White probands (hazard ratio, 1.89 [95% CI, 1.26 to 2.83])., Conclusions and Relevance: In a US cross-sectional study, there was substantial estimated prevalence of familial DCM among probands and modeled cumulative risk of DCM among their first-degree relatives., Trial Registration: ClinicalTrials.gov Identifier: NCT03037632.