Omar Wever-Pinzon

Background: Septal reduction therapy (SRT) is recommended in drug-refractory, symptomatic obstructive hypertrophic cardiomyopathy (oHCM). We evaluated whether aficamten, a novel cardiac myosin inhibitor, can reliably transition guideline-eligible SRT candidates to ineligibility, and the associated safety profile of aficamten in this group. Methods: We analyzed participants with oHCM enrolled in FOREST-HCM ( NCT04848506 ), the long-term open-label extension study of aficamten, from 28 May 2021 to 9 May 2025. Results: Three hundred and fifteen patients were included, of whom 104 met 2024 ACC/AHA guideline criteria for SRT eligibility at baseline. The SRT-eligible cohort was predominantly female (57%), with mean resting and Valsalva left ventricular outflow tract (LVOT) gradients of 63 ± 39 and 109 ± 42 mmHg, and all were in New York Heart Association (NYHA) class III. All baseline SRT-eligible patients became SRT-ineligible with aficamten therapy during study follow-up over a median of 42 days (IQR: 17, 49), except for one participant who withdrew from the study to pursue SRT (total of 3 participants withdrew). After dose titration, 3/104 (2.9%) remained guideline-eligible; by week 72 no patients met eligibility criteria. At maintenance, resting and Valsalva LVOT gradients improved by a least-squares mean of −41 mmHg ([95% CI −44 to −37]; P< 0.0001) and −56 mmHg ([95% CI −62 to −51]; P< 0.0001), respectively. Relative to baseline, NT-proBNP improved by 77% (95% CI 74 – 80%), high-sensitivity cardiac troponin I decreased by 38% (95% CI 30 – 46%), KCCQ-CSS improved by a mean of 20.2 (SD 19.3) points, and 95.2% of SRT-eligible patients had improved by ≥1 NYHA class. Overall, the safety profile was favorable, with 2 occurrences of left ventricular ejection fraction (LVEF) < 50% over 193.7 patient-years of follow-up (1 event per 100 patient-years), managed by down-titration. There were no baseline SRT-eligible patients who died or developed LVEF ClinicalTrials.gov , NCT04848506 ( https://clinicaltrials.gov/study/NCT04848506 ); Date of registration: April 19, 2021 Clinical Perspective: What is new?: - Aficamten is a cardiac myosin inhibitor that improved symptoms and left ventricular outflow tract gradients in almost all patients who were eligible for septal reduction therapy (SRT) in the FOREST-HCM trial. - Aficamten was safe with rare reduction in systolic function and no heart failure events. What are the clinical implications?: - Aficamten can be used as an alternative to patients who are eligible for SRT.

Transcriptomic changes in heart failure (HF) patients prior to and following left ventricular assist device (LVAD) support have been extensively studied. Recent studies focused on understanding DNA methylation changes in patients with cardiovascular diseases (CVD) and the role of circulating markers of DNA methylation as clinical predictors of the risk of CVD related morbidity and mortality. In this study, we used paired (pre- and post-LVAD) myocardial samples to examine changes in DNA methylation alongside RNA and protein expression. Our data suggests that patients with no improvement in cardiac function after LVAD therapy, despite showing an improvement in energy production (increased β-oxidation of fatty acid) exhibited persistent activation of profibrotic signaling, increased collagen deposition and cytoskeletal disarray evident from abnormal increase in sarcomeric distance following LVAD support. Contrarily, patients with improvement in cardiac function after LVAD therapy showed activation of pro-inflammatory signaling, collagen degradation and myogenesis. Both RNA sequencing and western blot data showed increased COL1A1 and decreased TPPP3 in post-NR thereby suggesting increased fibrosis and disrupted cytoskeletal signaling as potential barriers to myocardial recovery. Additionally, responders to LVAD therapy showed a significant reversal in myocardial interstitial fibrosis with a preserved sarcomeric architecture. Mice model of HF and recovery also confirmed our human findings, with reduced fibrotic signaling and improved cytoskeletal remodeling signaling observed in mice that showed improvement in cardiac function compared to mice with HF. Overall, our data suggests that altering extracellular matrix regulation and cytoskeletal signaling pathways may contribute to myocardial recovery. Further studies targeting these pathways are required to identify new HF therapeutic targets.

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. Cardiologist investigators of the DCM Consortium from US advanced heart failure/transplant (HF/TX) programs conducted an online survey in June 2024 to collect demographics, training, program characteristics, genetic evaluation practices, and implementation needs for DCM. An in-person discussion followed. 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 at all institutions with annual patient uptake ranging from 5%-70% (median 25%). Thirteen respondents (52%) did not use selection criteria for offering testing in their personal practice 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, including 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. This needs assessment of the DCM Consortium underscores the implementation challenges in the provision of DCM genetic evaluations in HF/TX programs. Targeted plans to facilitate precision medicine for DCM are needed.

BACKGROUND: The left atrium (LA) maintains a dynamic interaction with the left ventricle (LV). LA forward and reverse remodeling affect prognosis in patients with chronic heart failure. We examined LA reverse remodeling in patients supported with LV assist devices (LVADs) and investigated a potential impact on clinical outcomes. METHODS: Consecutive patients with advanced heart failure receiving durable, continuous-flow LVADs were prospectively evaluated (n=263). After excluding patients with unavailable echocardiographic data, 241 patients were studied. Echocardiographic assessment was performed pre- and serially post-LVAD implantation. We assessed LA and LV structure and function and their association, and the impact of LA reverse remodeling on all-cause mortality, LVAD-related adverse events, and atrial fibrillation (AF). RESULTS: Most patients were male, White, with a mean age of 56±15 years. Forty-four percent had underlying ischemic cardiomyopathy, and 65% were profile 1 to 3 as per the Interagency Registry for Mechanically Assisted Circulatory Support, with a mean LV ejection fraction of 19±7%, and end-diastolic diameter of 6.7±1.1 cm pre-LVAD. LA structure and function improved by 1 month on LVAD support and remained improved by 12 months, as evidenced by LA volumes, emptying volumes, emptying fractions, and strain parameters. LA changes were shown to be associated with LV structural and functional changes. The magnitude of LA reverse remodeling was associated with all-cause mortality, but not cerebrovascular accident/transient ischemic attack, LVAD thrombosis, or late right heart failure rates by 12 months on LVAD support. Of 46 patients with AF pre-LVAD, 28 (61%) converted to sinus rhythm, and 18 (39%) remained in AF during serial echocardiographic assessment. CONCLUSIONS: LA structure and function improved early post-LVAD support, showed stability of improvement during follow-up, and were associated with simultaneous LV changes. Implications on all-cause mortality and AF might inform the care of heart failure patients being considered for advanced therapies, as well as the broader population of patients with heart failure and concomitant AF undergoing pharmacological unloading.

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: Type 2 diabetes is prevalent in cardiovascular disease and contributes to excess morbidity and mortality. We sought to investigate the effect of glycemia on functional cardiac improvement, morbidity, and mortality in durable left ventricular assist device (LVAD) recipients. Methods and Results: Consecutive patients with an LVAD were prospectively evaluated (n=531). After excluding patients missing pre‐LVAD glycated hemoglobin (HbA1c) measurements or having inadequate post‐LVAD follow‐up, 375 patients were studied. To assess functional cardiac improvement, we used absolute left ventricular ejection fraction change (ΔLVEF: LVEF post‐LVAD−LVEF pre‐LVAD). We quantified the association of pre‐LVAD HbA1c with ΔLVEF as the primary outcome, and all‐cause mortality and LVAD‐related adverse event rates (ischemic stroke/transient ischemic attack, intracerebral hemorrhage, gastrointestinal bleeding, LVAD‐related infection, device thrombosis) as secondary outcomes. Last, we assessed HbA1c differences pre‐ and post‐LVAD. Patients with type 2 diabetes were older, more likely men suffering ischemic cardiomyopathy, and had longer heart failure duration. Pre‐LVAD HbA1c was inversely associated with ΔLVEF in patients with nonischemic cardiomyopathy but not in those with ischemic cardiomyopathy, after adjusting for age, sex, heart failure duration, and left ventricular end‐diastolic diameter. Pre‐LVAD HbA1c was not associated with all‐cause mortality, but higher pre‐LVAD HbA1c was shown to increase the risk of intracerebral hemorrhage, LVAD‐related infection, and device thrombosis by 3 years on LVAD support ( P P <0.001). Conclusions: Type 2 diabetes and pre‐LVAD glycemia modify the potential for functional cardiac improvement and the risk for adverse events on LVAD support. The degree and duration of pre‐LVAD glycemic control optimization to favorably affect these outcomes warrants further investigation.

**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was | POSTER

Mechanical unloading and circulatory support with left ventricular assist devices (LVADs) mediate significant myocardial improvement in a subset of advanced heart failure (HF) patients. The clinical and biological phenomena associated with cardiac recovery are under intensive investigation. Left ventricular (LV) apical tissue, alongside clinical data, were collected from HF patients at the time of LVAD implantation (n=208). RNA was isolated and mRNA transcripts were identified through RNA sequencing and confirmed with RT-qPCR. To our knowledge this is the first study to combine transcriptomic and clinical data to derive predictors of myocardial recovery. We used a bioinformatic approach to integrate 59 clinical variables and 22,373 mRNA transcripts at the time of LVAD implantation for the prediction of post-LVAD myocardial recovery defined as LV ejection fraction (LVEF) ≥40% and LV end-diastolic diameter (LVEDD) ≤5.9cm, as well as functional and structural LV improvement independently by using LVEF and LVEDD as continuous variables, respectively. To substantiate the predicted variables, we used a multi-model approach with logistic and linear regressions. Combining RNA and clinical data resulted in a gradient boosted model with 80 features achieving an AUC of 0.731±0.15 for predicting myocardial recovery. Variables associated with myocardial recovery from a clinical standpoint included HF duration, pre-LVAD LVEF, LVEDD, and HF pharmacologic therapy, and LRRN4CL (ligand binding and programmed cell death) from a biological standpoint. Our findings could have diagnostic, prognostic, and therapeutic implications for advanced HF patients, and inform the care of the broader HF population. GRAPHICAL

Background: Extensive evidence from single-center studies indicates that a subset of patients with chronic advanced heart failure (HF) undergoing left ventricular assist device (LVAD) support show significantly improved heart function and reverse structural remodeling (ie, termed “responders”). Furthermore, we recently published a multicenter prospective study, RESTAGE-HF (Remission from Stage D Heart Failure), demonstrating that LVAD support combined with standard HF medications induced remarkable cardiac structural and functional improvement, leading to high rates of LVAD weaning and excellent long-term outcomes. This intriguing phenomenon provides great translational and clinical promise, although the underlying molecular mechanisms driving this recovery are largely unknown. Methods: To identify changes in signaling pathways operative in the normal and failing human heart and to molecularly characterize patients who respond favorably to LVAD unloading, we performed global RNA sequencing and phosphopeptide profiling of left ventricular tissue from 93 patients with HF undergoing LVAD implantation (25 responders and 68 nonresponders) and 12 nonfailing donor hearts. Patients were prospectively monitored through echocardiography to characterize their myocardial structure and function and identify responders and nonresponders. Results: These analyses identified 1341 transcripts and 288 phosphopeptides that are differentially regulated in cardiac tissue from nonfailing control samples and patients with HF. In addition, these unbiased molecular profiles identified a unique signature of 29 transcripts and 93 phosphopeptides in patients with HF that distinguished responders after LVAD unloading. Further analyses of these macromolecules highlighted differential regulation in 2 key pathways: cell cycle regulation and extracellular matrix/focal adhesions. Conclusions: This is the first study to characterize changes in the nonfailing and failing human heart by integrating multiple -omics platforms to identify molecular indices defining patients capable of myocardial recovery. These findings may guide patient selection for advanced HF therapies and identify new HF therapeutic targets.