Background: Genetic testing is a Class I recommendation for patients with hypertrophic cardiomyopathy (HCM). Variant classification relies on evidence from publicly available case data, evolving classification rules, and gene-disease associations. Thus, as knowledge increases, genetic variant classifications change over time. We evaluated the occurrence and reasons for variant reclassification from a large multi-center international HCM registry (Sarcomeric Human Cardiomyopathy Registry; SHaRe), with the goal to minimize uncertainty for patients and clinicians. Methods: Participants receive clinical care at specialized HCM centres. Baseline classifications were derived from the clinical genetic test report (original or updated) or prior further adjudication by SHaRe geneticists. All variants were then computationally reannotated and reevaluated during 2024-2025. Variants underwent expedited curation if no new evidence was present. The remainder underwent full manual curation using accepted criteria and classified as pathogenic/likely pathogenic (P/LP), variant of uncertain significance (VUS) and benign/likely benign (B/LB). VUS were sub-classified to high, mid or low. Results: Of 12,187 HCM patients, 8,054 (66%) had genetic testing between 1990-2024, and 4,923 (61%) had a variant identified in one of 29 ClinGen-validated HCM genes (1606 unique variants). Expedited curation was performed for 704 (44%) variants and 902 (56%) underwent manual curation. There were 1279 (79%) variants that retained their classification: 148 B/LB, 663 VUS, and 468 P/LP. While 276 (17%) variants (n=557 patients) were reclassified, including 73 upgrades: 61 from VUS to P/LP (199 patients), and 12 from B/LB to VUS. There were 203 downgrades: 108 from P/LP to VUS (196 patients), and 95 from P/LP or VUS to B/LB. VUS were additionally subclassified: 90 VUS-High, 129 VUS-Mid, 115 VUS-Low. Sub-classification of VUS resulted in less uncertainty, with 369 (40.6%) variants reclassified as VUS-Low or B/LB, indicating a very strong probability of not being HCM associated. Conclusions: Clinically meaningful reclassification occurred in 10% of variants identified in HCM probands. Most VUS were unlikely to be causal, and sub-classification has potential to reduce their burden on clinicians and families. Contemporary approaches to classification can minimize uncertainty of genetic results and highlight the need for periodic reevaluation. ### Competing Interest Statement SHaRe is supported by unrestricted funding from Bristol Myers Squibb, Cytokinetics, Alexion, and Lexicon. The sponsors had no role in the study design, data collection, data analysis, data interpretation, manuscript preparation, or the decision to submit the manuscript for publication. Dr. Ho is a consultant for or receives research funding from Bristol Myers Squibb, Pfizer, Cytokinetics, Tenaya, Biomarin, viz.AI, and Lexicon. Dr. Lakdawala recieves personal fees from Bridge Bio, Alexion, Tenaya, Cytokinetics, Bayer, and Gemma and grants from Bristol Myers Squibb and Pfizer. Dr. Owens consults for Avidity, Alexion, Bristol Myers Squibb, Bayer, Cytokinetics, Bridgebio, Braveheart, Edgewise, Imbria, Kardigan, Lexeo, Stealth, and Tenaya. Dr. Helms receives grants from Tenaya Therapeutics and Preload Therapeutics and personal fees from Lexeo Therapeutics, Preload Therapeutics, and Cytokinetics. Dr. Saberi receives grants from Bristol Myers Squibb during the conduct of the study as well as personal fees from Bristol Myers Squibb and Cytokinetics and grants from Cytokinetics, Lexicon, Edgewise, and Novartis. Dr. Parikh receives scientific advisory fees from Lexeo Therapeutics, Solid Biosciences, Constantiam Biosciences, Borrealis, and BioMarin. Dr. Ashley reported other from Personalis (founder and publicly traded stock), DeepCell (founder), Svexa (founder), Saturnus Bio (founder), Swift Bio (founder), Candela (founder, advisor), Parameter Health (founder, advisor), Pacific Biosciences (advisor, publicly traded stocks, collaborative support in kind), AstraZeneca (nonexecutive director, publicly traded stock), Dexcom (nonexecutive director), Illumina (collaborative support in kind), Oxford Nanopore (collaborative support in kind). Dr. Gray has received advisory board and education honoraria from Bristol Myers Squibb. Dr. Olivotto is a consultant for Bristol Myers Squibb, Cytokinetics, Tenaya, Lexeo, Edgewise, and Rocket Pharma. Dr. Michels is a consultant or receives research funding from Bristol Myers Squibb, Cytokinetics, Bayer, Alnylam, Biomarin, and Sanofi. Dr. Ware has consulted for MyoKardia (now Bristol Myers Squibb), Foresite Labs, and Pfizer. Dr. Crotti has consulted for Bristol Myers Squibb. Dr. Bundgaard receives lecture fees from Amgen, MSD, Sanofi, Bristol Myers Squibb, and Pfizer. Dr. Rossano is a consultant for AskBio, Astellas, CRI Biotech, Bristol Myers Squibb, Bayer, and Merck. Dr. Abrams is a consultant for Dinaqor. Dr. Maurizi has received grants from Bristol Meier Squibb, Amicus, Foundation CVCL, AICARM APS Onlus, Bangarter-Rhyner Foundation and fees (honoraria or consulting) from Bristol Meier Squibb and Academic CM. Dr. Thompson receives compensation as editor for Merck Manuals. Dr. Day receives personal fees from Lexicon Pharmaceuticals and Cytokinetics and grants from Bristol Myers Squibb. Disclosures are unrelated to current manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Each participating site has received ethics approval in accordance with local policies as per the following: ethical approval requiring informed consent was obtained from Cincinnati Childrens Hospital USA; Childrens Hospital of Philadelphia USA; Michigan Medical USA; Yale Medical USA; Royal Brompton Hospital United Kingdom; Erasmus University Medical Center The Netherlands; Florence Centre for Cardiomyopathies Italy; Sydney Local Health District Royal Prince Alfred Hospital Australia; and InCor Heart Institute University of Sao Paulo Brazil ethics committees. Waiver of consent was granted by Stanford School of Medicine USA; Brigham and Womens Hospital USA; Boston Childrens Hospital USA; Pennsylvania University Medical Center USA and Sydney Local Health District Royal Prince Alfred Hospital Australia ethics committees. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors Australian Government, https://ror.org/0314h5y94 Bristol-Myers Squibb (United States), https://ror.org/00gtmwv55 Cytokinetics (United States), https://ror.org/03tx9ss94 Alexion Pharmaceuticals (United States), https://ror.org/031ywxc85 Lexicon Pharmaceuticals (United States), https://ror.org/00v64s089

Background Patients with heart failure (HF) with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) have a high comorbidity burden, which may require management with numerous medications. Patients and clinicians may be hesitant about initiating another medication, especially among individuals with polypharmacy. Objective This study sought to examine the efficacy and safety of adding finerenone based on the number of concomitant medications in patients with HFmrEF/HFpEF. Methods In this post hoc analysis of the FINEARTS-HF trial, baseline medication use was collected in all 6,001 participants with HFmrEF/HFpEF who were randomized to finerenone or placebo. Clinical outcomes were assessed by medication use categories (“non-polypharmacy”: <5 medications; “polypharmacy”: 5 to 9 medications; and “hyper-polypharmacy”: ≥10 medications) and continuously, adjusted for covariates including age. The primary outcome was a composite of cardiovascular death and total (first and recurrent) HF events. Results Overall (age: 72±10 years; 46% women), the total number of medications at baseline ranged from 0 to 29 and the mean number of medications was 8.4±3.6, with 3,588 (60%) patients met polypharmacy and 1,878 (31%) met hyper-polypharmacy. Patients with higher medication use were older and had a greater burden of comorbidities. Incidence rates for the primary outcome increased across medication categories: non-polypharmacy (10.2 per 100py), polypharmacy (12.3 per 100py), and hyper-polypharmacy (26.1 per 100py) (Figure A). The treatment benefits of finerenone in reducing risks of cardiovascular death and total HF events were consistent across the spectrum of total medication use (P for interaction = 0.94; Figure B). Although adverse events leading to study drug discontinuation increased with the higher number of medications, they were not more frequent with finerenone vs. placebo, regardless of polypharmacy categories. Conclusions In the FINEARTS-HF trial, >90% of patients with HFmrEF/HFpEF met the criteria for polypharmacy and these patients faced excess risks of cardiovascular events. Finerenone safely reduced cardiovascular death and total HF events across a broad range of baseline medication use, including among individuals with polypharmacy.

AIMS:Clinicians may be less inclined to consider new therapies in patients with long-standing heart failure (HF) due in part to clinical inertia. Whether the treatment effects of the non-steroidal mineralocorticoid receptor antagonist finerenone vary according to HF duration remains uncertain. METHODS:In this prespecified analysis of the FINEARTS-HF trial, HF duration (defined as the time from diagnosis) was categorized into four groups: <3 months, ≥3 months to 2 years, ≥2 to 5 years, or ≥5 years. The primary outcome was a composite of cardiovascular death and total HF events. The efficacy and safety of finerenone were analyzed across the duration of HF. RESULTS:Among 5,977 participants with available data (age: 72±10 years; 46% female), those with longer duration HF were older and had a higher comorbidity burden, while most patients, irrespective of HF duration, had NYHA class II functional status. Compared with HF duration <3 months, longer HF duration experienced a significantly higher adjusted risk of the primary outcome. The benefit of finerenone was consistent across HF duration categories: the rate ratio (95%CI) for the primary outcome in the <3-month group was 0.84 (0.61-1.16); ≥3 months to 2 years, 0.95 (0.74-1.23); ≥2 to 5 years, 0.77 (0.61-0.98); and ≥5 years, 0.81 (0.64-1.02) (Pinteraction=0.46). Drug discontinuation due to serious adverse events was similar between finerenone and placebo, regardless of HF duration. CONCLUSIONS:These findings suggest that even patients with long-standing HF with only mild functional status limitation may still benefit from further therapeutic optimization with therapies such as finerenone.

BACKGROUND:Titin truncating variants (TTNtv) represent the most common genotype underlying dilated cardiomyopathy but are also detected in the general population, exhibiting incomplete penetrance and marked phenotypic variability. This heterogeneity complicates clinical interpretation and risk stratification. Emerging molecular evidence suggests that truncating location within the gene may influence disease mechanisms. We aimed to investigate whether TTNtv location also affects clinical phenotype and prognosis. METHODS:We established an international multicenter registry of phenotypically affected carriers of pathogenic or likely pathogenic TTNtv. Patients were classified into 3 groups: A-band, Z/I-band, and M-band. A case-control study assessed the enrichment of TTNtv across regions. The primary outcome was a composite of all-cause mortality and heart transplantation. Secondary outcomes included: (1) sudden cardiac death or major ventricular arrhythmias and (2) heart failure-related death/heart transplantation/left ventricular assist device implantation. RESULTS:The study included 467 patients (81% probands, 73% male, median age 47 years, 81% dilated cardiomyopathy phenotype). Most carried TTNtv in the A-band (80% versus 15% Z/I-band and 5% M-band). All groups showed enrichment compared with GnomAD, with greater Bayesian-estimated penetrance for A-band variants. Over a median follow-up of 83 months, the primary end point was similar across groups. However, the risk of sudden cardiac death/major ventricular arrhythmias was significantly higher in M-band carriers (45% M-band versus 23% Z/I-band versus 12% A-band; P=0.001), especially as the first disease manifestation. Band location independently predicted sudden cardiac death/major ventricular arrhythmias risk, whereas left ventricular ejection fraction was predictive only in A- and Z/I-band groups. CONCLUSIONS:TTNtv are differently enriched across the gene in patients with dilated cardiomyopathy/nondilated left ventricular cardiomyopathy. Penetrance and risk of sudden cardiac death/major ventricular arrhythmias differ according to variant location, supporting the TTN truncation site as a parameter that should be considered for personalized risk stratification in TTN cardiomyopathy.

BACKGROUND:A deeper understanding of the association between blood pressure (BP) control and neighborhood-level social determinants of health (SDOH) may help elucidate nonclinical factors that contribute to hypertension disparities. We sought to evaluate patterns of BP elevations by neighborhood-level SDOH domains. METHODS:In this single-center retrospective cohort study at Cedars-Sinai Medical Center, adults with ≥2 outpatient visits/year in at least 2 consecutive years (each consecutive 2-year period forms a dyad) from 2018 to 2023 were linked to the Healthy Places Index (HPI), a measure of neighborhood SDOH. Among patients with normotensive BP (BP <130/80 mm Hg) in the first year of at least 1 dyad, we assessed for the development of high BP (systolic BP ≥ 130 or diastolic BP ≥ 80 mm Hg) in the following year. RESULTS:A total of 94,276 adults (median age 56.4 ± 18.8 years; 37.2% male) with BP <130/80 mm Hg, of whom 38,719 (41.1%) developed high BP. In analyses adjusting for demographic, clinical, and SDOH factors, risk of developing high BP was associated with living in a neighborhood with a HPI score in the lowest vs highest quartile (prevalence ratio [PR] 1.07, 95% CI: 1.05-1.10). This finding was primarily associated with the economic (1.04, 1.00-1.07) and educational attainment (1.05, 1.02-1.08) domains, captured as part of the HPI score. CONCLUSIONS:In a cohort of >94,000 adults starting with BP <130/80 mm Hg, an increase in BP above this threshold in the following year was associated with neighborhood-level SDOH status, particularly variations in economic and educational attainment.

AIMS:Sex differences in transthyretin cardiac amyloidosis (ATTR-CM) are increasingly recognised; however, women are underrepresented in trials and sex-specific treatment effects remain incompletely understood. We evaluated sex differences in baseline phenotype, outcomes and vutrisiran response in ATTR-CM. METHODS:HELIOS-B was a phase 3, randomised, double-blind, placebo-controlled trial enrolling patients with wild-type or variant ATTR-CM, randomised 1:1 to receive subcutaneous vutrisiran (25 mg every 12 weeks) or placebo. This prespecified analysis assessed baseline characteristics, efficacy, and safety according to sex. RESULTS:Among 654 participants, 49 (7.5%) were women. Variant ATTR-CM was more prevalent in women (42.9% vs 9.1%, p < 0.001). At baseline, women had smaller absolute left ventricular dimensions and wall thicknesses (p < 0.05), but when indexed to body surface area, wall thicknesses were higher. Women demonstrated better systolic function, but worse 6-minute walk distances and quality-of-life scores. Vutrisiran reduced the primary composite endpoint of all-cause mortality and recurrent cardiovascular events in both sexes (women, HR 0.59, 95% CI 0.26-1.30; men, HR 0.71, 95% CI 0.54-0.94; p-interaction = 0.66). Confidence intervals were wide in women, reflecting limited precision from small subgroup size. Mortality reduction was observed in both sexes (HR 0.56, 95% CI 0.14-2.34 in women, HR 0.65, 95% CI 0.46-0.90 in men, p-interaction = 0.91 for all-cause mortality at 42 months). Decline in 6-minute walk distance and quality-of-life scores was attenuated in both sexes, with no statistically detectable sex-specific interaction, and safety outcomes were comparable. CONCLUSION:Women with ATTR-CM demonstrated a distinct baseline phenotype in HELIOS-B. Despite this, vutrisiran showed no statistically detectable heterogeneity of treatment effect by sex within the limits of statistical power, supporting therapeutic benefit across the phenotypic spectrum of ATTR-CM.

Background: Global clinical trials collect extensive unstructured medical records that richly describe participants’ clinical presentation, but their narrative format precludes quantitative analysis. Converting these records into structured data could reveal new insights into events like heart failure hospitalization (HFH) but is prohibitively labor intensive. Varied documentation styles, translated text, and scanned or handwritten documents challenge data extraction in clinical trials. Research Question: Can a carefully prompted large language model (LLM) accurately extract structured data on the clinical presentation of HFHs from unstructured adjudication dossiers in a global trial? Methods: We extracted structured data for 51 variables—symptoms, signs, laboratory values, imaging findings, and treatments—from unstructured medical record dossiers in the DELIVER trial utilizing a prompting workflow for the OpenAI o1-mini LLM. We validated LLM-extracted data with physician chart review in a random sample of 125 dossiers and calculated the accuracy, positive predictive value (PPV), and negative predictive value (NPV). A second physician reviewed 25 dossiers to assess inter-reviewer reproducibility. The validated model was applied to extract presenting features in all 1,111 HFHs in the trial. Results: LLM-extracted data achieved high overall accuracy of 0.96 (95% CI: 0.96–0.97), PPV of 0.94 (95% CI: 0.93–0.95), and NPV of 0.97 (95% CI: 0.97–0.98) on physician validation. Accuracy exceeded 0.90 for all variables except numeric BNP and Troponin I, where errors mainly reflected confusion between biomarker subtypes (BNP vs NT-proBNP or troponin I vs T). The reproducibility of human review was 98%. In the full trial, dyspnea (92%), peripheral edema (68%), pulmonary crackles (51%), congestion on chest imaging (59%) and natriuretic peptide elevation (65%) were reported frequently. Mean peri-admission ejection fraction was 46% ± 12% (n=481 with available data), vs a baseline mean of 53% ± 9%. Intravenous diuretics were used in 85% of hospitalizations, and oral diuretic doses were increased in 45%. Conclusion: A prompt-engineered LLM accurately extracted structured data, including signs and symptoms, laboratory and imaging data from adjudication dossiers at scale in a global clinical trial to generate a structured useable database. LLM-based data extraction could be extended to unlock quantitative insights from a wide range of narrative trial records.

AIMS:The association between heart rate (HR) and clinical outcomes is well understood in patients with heart failure with reduced ejection fraction (HFrEF) but less clear in those with HFmrEF/HFpEF, especially among individuals with atrial fibrillation (AF). In a prespecified analysis of the FINEARTS-HF trial, we examined the association between baseline HR and clinical outcomes by heart rhythm and evaluated finerenone's effect across the spectrum of HR. METHODS:The primary outcome was a composite of cardiovascular death and total (first and recurrent) HF events. Heart rhythm (sinus rhythm or AF) was determined from the baseline ECG. Patients with pacemaker rhythm or missing HR/rhythm data were excluded. RESULTS:Among patients with sinus rhythm (SR n = 3497; 62%), higher baseline HR was associated with a higher incidence rate for the primary outcome. In patients with AF (n = 2190; 38%), no association between HR and outcomes was observed. The effect of finerenone on the primary outcome was consistent across the HR spectrum, regardless of rhythm (P for interaction = 0.96 in SR; 0.49 in AF). In patients with SR, there was no significant HR change with finerenone versus placebo. In AF patients, finerenone led to a small but statistically significant HR reduction: a placebo-corrected decrease of 1.35 bpm (95% CI: 0.41-2.29) from baseline to 12 months. CONCLUSIONS:Among patients with HFpEF/HFmrEF in FINEARTS-HF, higher baseline HR was associated with a higher risk of the primary outcome in patients with SR but not in those with AF. Finerenone's effect on the primary outcome was consistent across the HR spectrum, irrespective of rhythm. TRIAL REGISTRATION:ClinicalTrials.gov NCT04435626.