Citations

Abstract Backgrounds Transthoracic echocardiography (TTE) identifies a peculiar hypercontractile phenotype (HP) in patients with heart failure and preserved ejection fraction (HFpEF) with high resting left ventricular (LV) elastance (also called force). Objectives To assess the functional response and its prognosis associated with HP in HFpEF by stress echocardiography (SE). Methods In a prospective, observational, multicenter study, 1213 patients with HFpEF were divided into two groups based on the highest quartile of rest force: non-hypercontractile phenotype group (non-HP, < 5.64 mmHg/mL, Group 1, n= 910), and HP group (≥5.64 mmHg/mL, Group 2, n= 303). All patients underwent SE with at least 4 of the following stress parameters assessed: wall motion score index (WMSI), B-lines (4-site score), force-based LV contractile reserve, coronary flow velocity reserve (CFVR), and heart rate reserve (HRR). The employed stress was exercise (n=687), dobutamine (n=195), or vasodilators (n=331). SE score ranged from 0 (all steps normal) to 1-5, according to the number of abnormal steps. Follow-up was completed in a subset of 260 patients. Results The 2 groups showed similar values of peak stress WMSI but the global functional burden was higher in Group 2 patients: see table. In a subset of 260 patients who finished follow-up, there were 212 non-HP patients and 48 HP patients. During a median follow-up of 15 months (interquartile range: 10-20), 26 deaths, 20 heart failure (HF) rehospitalizations, and 64 major adverse cardiovascular events (MACEs) occurred. The cumulative HF rehospitalization rate and MACEs rate were higher in HP group (log-rank p<0.01): see figure. Rest force (HR, 1.17; 95% CI: 1.06-1.29; P: 0.040), rest SPAP (HR, 1.08; 95% CI: 1.02-1.14; P: 0.007) and ABCDE score (HR, 1.15; 95% CI: 1.01-1.66; P: 0.032) were independently associated with MACEs. Conclusions HFpEF patients with HP are functionally weaker with multiple vulnerabilities during stress and at higher risk of subsequent events compared to non-HP patients.Relation between resting values of force

Abstract Background In patients with heart failure with preserved ejection fraction (HFpEF), studies have described different HFpEF phenogroups based on medical comorbidities and variable echocardiographic, invasive hemodynamic, and biomarker data. We hypothesized that myocardial histopathologic findings may define phenogroups with differing clinical features and outcomes in patients with HFpEF. Methods We analyzed consecutive patients with left HF and EF ≥50% who underwent right ventricular septal endomyocardial biopsy (EMB) at our institution between 2001 and 2022 to investigate HF etiology. Patients with infiltrative or hypertrophic cardiomyopathy, sarcoidosis, myocarditis, primary valvular heart disease, constrictive pericarditis, isolated right HF, or insufficient EMB samples were excluded. Clinical, echocardiographic, and invasive hemodynamic data were collected. The severity of hypertrophy and fibrosis on EMB specimens was characterized (semiquantitative grading) by experienced cardiac pathologists based on standard histologic stains. Patients were stratified into four phenogroups based on EMB findings: "mild" (none/mild hypertrophy and fibrosis), "hypertrophy" (moderate/marked hypertrophy, minimal/mild fibrosis), "fibrosis" (moderate/marked fibrosis, none/mild hypertrophy), and "severe" (moderate/marked hypertrophy and fibrosis). Results Among the 121 patients analyzed, the median age was 67 years, 50% were female and cardiovascular conditions were common (Table 1). Fibrosis was graded as minimal in 21% (n=25), mild in 64% (n=77), moderate in 12% (n=15), and marked in 3% (n=4). Hypertrophy was graded as none in 4% (n=5), mild in 41% (n=50), moderate in 40% (n=48), and marked in 15% (n=18). Only one patient had the isolated "fibrosis" phenogroup and was excluded from further analysis, while 54 had the "mild", 48 had the "hypertrophy", and 18 had the "severe" phenogroup (Table 1). The "hypertrophy" phenogroup exhibited significantly higher rates of hypertension, diabetes, RV dilation, and higher pulmonary artery pressures. Over a median follow-up of 7.9 years (3.1–13.8), mortality rate varied according to the histopathologic phenogroups (Figure 1, p=0.034) with "severe" having the worst and "mild" having the best outcomes. Survival analyses based on fibrosis grades alone, hypertrophy grades alone, or echocardiographic hypertrophy did not reveal significant differences (all p = NS). Differences in survival remained significant adjusting for age (HR 3.39, 95% CI 1.20-9.58). Conclusions The integrated severity of histopathologic hypertrophic and fibrotic remodeling defined HFpEF phenogroups with variable prognosis. Clinical features did not reliably identify histopathologic phenogroups. These data suggest that advanced myocardial phenotyping (e.g., gene, protein, metabolism) may reveal unique HFpEF myocardial subtypes in need of specific therapies.Figure 1

Abstract Background Elevated left ventricular filling pressure (LVFP) is associated with an increased risk of heart failure and mortality. Pulmonary artery wedge pressure (PAWP) is considered the gold standard for assessing LVFP. Recently, we validated an artificial intelligence-enabled electrocardiogram (AI-ECG) to assess LV diastolic function (LVDF) and LVFP. Herein, we compare AI-ECG with PAWP in predicting long-term mortality. Methods We included adults who had comprehensive echocardiography with available ECG within 14-days and right-heart-catheterization (RHC) within 30-days of echocardiography. Elevated-LVFP was defined as PAWP>15 mmHg by RHC, grades 2-3 LVDF by echocardiography, or as adjudicated by the AI-ECG algorithm. Prognosis by AI-ECG was compared to that by echocardiography and PAWP. Results Among 4,168 patients (median age 64 years, 47.7% female), 1,841 had normal-LVFP, and 2,327 had elevated-LVFP by RHC. Echocardiography classified 1,502 patients as normal-LVFP, 1,643 as elevated-LVFP, and 1,023 as indeterminate-LVFP. AI-ECG demonstrated an area-under-the-curve of 0.879 (95%-confidence-interval 0.867-0.891) for predicting elevated-LVFP as determined by echocardiography and 0.742 (95%-confidence-interval 0.724-0.759) for predicting elevated-LVFP as determined by RHC. Over a median follow-up of 7.7 years, 2,735 (34.4%) patients died. In multivariable models, elevated-LVFP by any modality was associated with an increased risk of death (AI-ECG: adjusted-hazard-ratio 1.80, 95% confidence-interval 1.55-2.09; echocardiography: adjusted-hazard-ratio 1.74, 95% confidence-interval 1.51-2.02; PAWP: adjusted-hazard-ratio 1.26, 95% confidence-interval 1.11-1.43). AI-ECG-derived LVFP provided incremental prognostic discrimination compared to echocardiography- or RHC-derived LVFP. Conclusions AI-ECG-derived LVFP offers an accessible, affordable, and noninvasive alternative for detecting elevated LVFP, with potential independent prognostic value beyond traditional echocardiographic and invasive assessments.Survival across LVFP concordance

Importance Transthyretin amyloid cardiomyopathy (ATTR-CM), a progressive disease caused by misfolded transthyretin (TTR), occurs as wild-type (ATTRwt-CM) or variant (ATTRv-CM) forms. p.Val142Ile is the most common variant in the US, linked to rapid progression and increased mortality. Acoramidis achieves near-complete (≥90%) TTR stabilization and showed clinical benefit in the 30-month ATTRibute-CM trial and through month 42 in the ongoing open-label extension (OLE). Objective To evaluate the efficacy of acoramidis in ATTRwt-CM, ATTRv-CM, and variant subgroups (p.Val142Ile and non-p.Val142Ile). Design, Setting, and Participants This international, multicenter, phase 3, randomized placebo-controlled study took place from April 2019 to May 2023 with ongoing OLE (month 42). ATTRibute-CM enrolled 632 participants with ATTR-CM; 611 of 632 were included in the modified intention-to-treat (mITT) population. There were 380 participants who continued into the OLE. These data were analyzed from January 2025 to July 2025. Interventions Oral acoramidis, 712 mg, or placebo twice daily for 30 months, followed by 12 months of open-label treatment. Main Outcomes and Measures All-cause mortality (ACM), cardiovascular-related hospitalizations (CVH), serum TTR, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire Overall Summary score, and N-terminal pro B-type natriuretic peptide in participants with ATTRwt-CM and ATTRv-CM. Post-hoc analyses were conducted in variant subgroups, including p.Val142Ile. Results Overall, 552 participants with wild-type ATTR-CM (mean [SD] age, 78 [6.3] years; 92.0% male and 8.0% female) and 59 participants with variant ATTR-CM (mean [SD] age, 73 [7.7] years; 77.3% male and 22.7% female) were randomized (mITT population), including 35 with p.Val142Ile. Consistent efficacy was observed in wild-type and variant subgroups for ACM/CVH through month 30 and ACM through month 42. At month 30, acoramidis reduced the risk of ACM/first CVH vs placebo by 31% in ATTRwt-CM (hazard ratio [HR], 0.69; 95% CI, 0.52-0.90; P = .007) and by 59% in ATTRv-CM (HR, 0.41; 95% CI, 0.21-0.81; P = .01). ACM was reduced through month 42 with HRs of 0.70 (95% CI, 0.50-0.98; P = .04) and 0.41 (95% CI, 0.19-0.93; P = .03) in the ATTRwt-CM and ATTRv-CM groups, respectively. Consistent treatment benefit was observed in participants with ATTRwt-CM and ATTRv-CM for secondary end points. Within variant subgroups (p.Val142Ile vs non-p.Val142Ile), consistent treatment benefits were observed for ACM/CVH through month 30 and ACM through month 42. Conclusions and Relevance The beneficial effect of acoramidis was observed consistently in ATTRwt-CM and ATTRv-CM groups. These hypothesis-generating results indicate that further studies are warranted to better characterize the therapeutic benefit of acoramidis in variant subgroups. Trial Registration ClinicalTrials.gov Identifiers: NCT03860935 ; NCT04988386

BACKGROUND: Elevated blood pressure (BP) is a major contributor to coronary artery disease. We explored the impact of life-course BP on later-life normalized stress myocardial blood flow (sMBF N ) and myocardial perfusion reserve by cardiovascular magnetic resonance (CMR). METHODS: MyoFit46 prospectively recruited ≈500 National Survey of Health and Development 1946 birth cohort participants, aged ≈77 years, to undergo stress perfusion and late gadolinium enhancement CMR. Systolic (SBPs) and diastolic BPs were recorded at 36, 43, 53, 63, 69, and 77 years. For each participant, the annual rates of BP change (steepness of BP increase) and area under the BP trajectory curve (cumulative life-course BP burden) were derived using mixed-effects models. The associations between BP measures and CMR metrics were tested using generalized linear and additive models, adjusted for antihypertensive use, demographics, lifestyle choices, and comorbidities. Cross-sectional associations between CMR metrics and major adverse cardiovascular events (myocardial infarction, stroke, and heart failure) were also tested. Mediation analyses explored the mechanistic pathways linking life-course BPs, myocardial perfusion, and myocardial fibrosis. RESULTS: Among 459 included MyoFit46 participants, each 10 mm Hg higher SBP at 36 to 69 years was associated with 3% to 6% lower sMBF N by CMR at 77 years. At 43 to 63 years, as SBPs rose from 120 to 140 mm Hg, sMBF N was 18% to 24% lower. Having a sustained higher SBP by 10 mm Hg from 36 to 77 years was associated with 11% (95% CI, 8–14) lower sMBF N at 77 years. Each 1 mm Hg/y steeper SBP rise during age intervals 36 to 43, 43 to 53, 53 to 63, and 63 to 69 years was associated with 2% to 6% lower sMBF N at 77 years, associations not conditional on baseline or final BPs in each age interval. Associations may be clinically relevant as each 1% lower sMBF N was associated with 3% higher odds of major adverse cardiovascular events. sMBF N mediated ≈20% to ≈40% of the associations between life-course SBPs and late gadolinium enhancement at 77 years. Results were similar for diastolic BP, myocardial perfusion reserve, or sMBF (not normalized). CONCLUSIONS: Higher life-course BPs, steeper increases, and greater cumulative BP burden associate with lower myocardial perfusion by CMR at 77 years, which can be linked with higher odds of major adverse cardiovascular events and greater myocardial fibrosis burden. This underscores the importance of early life BP screening and guiding hyperetension treatment based on longitudinal BP trajectories (rather than relying solely on cross-sectional BPs). REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05455125.

Abstract Background We examined real-world utilization of treat-to-target (TTT) strategies and conducted a quality improvement (QI) project to improve uptake of TTT strategies in a learning health system, IBD Qorus. Methods We implemented a structured QI intervention to increase uptake of TTT in 41 gastroenterology practices in the United States, over a 13-month intervention period (November 2020 to November 2021; modified breakthrough series [BTS] collaborative), and a 10-month post-BTS observation period (December 2021 to October 2022). Through encounter-level surveys, we examined providers’ “intention to TTT” based on discussion of TTT with patients, documentation of inflammation, and intention to change therapy to TTT. We examined changes in rates of “intention to TTT,” and whether improvement in intention to TTT influenced site-level rates of remission. Results Over 13 months, there were 7932 patient visits (55% with Crohn’s disease; 47% in clinical remission); patients in 2160 visits (27%) were not in endoscopic remission. Overall, rates of intention to TTT increased from 31% to 54% (P = .06) with considerable site-to-site variability and was maintained at 49% in the post-BTS observation period. The increased rate was attributable to higher rates of testing for inflammation. Despite an increase in the rate of intention to TTT, there was no significant change in site-level achievement of remission over the same time. Conclusions Through a QI initiative in a learning health system, rates of intention to TTT increased significantly over 12-months, though overall rates remained low. Assessing patient-, provider- and practice-level barriers and facilitators for successful implementation of a TTT strategy is warranted to improve clinical outcomes.

Abstract Rural health disparities in the United States remain poorly understood, in part due to inconsistent definitions of “rurality” and the failure to integrate both geographic and socially constructed dimensions of place. This commentary draws from insights shared during the panel “Addressing Diversity in Cancer Prevention, Control, and Survivorship Within Rural Communities” at the 2024 Transforming Community and Rural Healthcare (TCRH) conference. Panelists emphasized the limitations of current rural-urban classification systems, which often overlook the intersectional identities, cultural heterogeneity, and lived experiences of rural populations. They advocated for integrating community-based participatory research (CBPR) and identity-based approaches to define rurality more holistically. Such methods prioritize self-identification, social determinants of health (SDOH), and localized knowledge, allowing for a more accurate assessment of cancer disparities and the development of equitable interventions. The commentary outlines how geophysical and census-based metrics, although convenient, can misrepresent rural communities and inadvertently perpetuate disparities in cancer care access, outcomes, and policy. The authors argue for an identity- and community-centered conceptualization of rurality that is dynamic, inclusive, and responsive to the complexity of rural life.

Abstract Background The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood. Methods We investigated associations of genetic susceptibility to type 2 diabetes (T2D), 8 T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242 283 cases, 1 569 734 controls), T1D (18 942 cases, 501 638 controls), and PDAC (10 244 cases and 360 535 controls) in individuals of European ancestry. Results Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI = 1.05 to 1.15), particularly the T2D obesity (OR = 1.28; 95% CI = 1.15 to 1.42) and lipodystrophy (OR = 1.25; 95% CI = 1.03 to 1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI = 0.99 to 1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10−8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10−4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions. Conclusions Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.

Yao syndrome (YAOS) is a NOD2-associated autoinflammatory disease marked by periodic fevers, dermatitis, polyarthritis, distal extremity swelling, and nearly universal gastrointestinal symptoms. A recent study was the first to comprehensively assess the gastrointestinal symptoms and manifestations of YAOS, finding that most testing is normal, without gastrointestinal mucosal inflammation, and many patients have constipation and rectal evacuation disorders. Building on this foundation, this paper highlights future directions and research priorities in furthering the understanding of YAOS. These draw heavily from the literature on Crohn disease, which is also associated with NOD2 variants. These future research priorities include detailed genotype-phenotype correlation focusing on specific NOD2 variants, prospective, comprehensive gastrointestinal phenotyping, and multi-omics approaches to investigate genetic, microbiome, epigenetic, and environmental interactions underlying YAOS pathogenesis. Insights gained from such investigation may guide improved diagnostic criteria and targeted, personalized therapeutic development for patients with YAOS.