Pub Date : 2025-11-19DOI: 10.1001/jamacardio.2025.4283
Sadiya S Khan,Clyde W Yancy
{"title":"Detecting Atherosclerosis-From Autopsy to Angiography With Computed Tomography.","authors":"Sadiya S Khan,Clyde W Yancy","doi":"10.1001/jamacardio.2025.4283","DOIUrl":"https://doi.org/10.1001/jamacardio.2025.4283","url":null,"abstract":"","PeriodicalId":14657,"journal":{"name":"JAMA cardiology","volume":"1 1","pages":""},"PeriodicalIF":24.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-19DOI: 10.1001/jamacardio.2025.4271
Ángel Herraiz-Adillo,Hampus Eriksson,Viktor H Ahlqvist,Marcel Ballin,Patrik Wennberg,Bledar Daka,Cecilia Lenander,Daniel Berglind,Carl Johan Östgren,Oskar Lundgren,Karin Rådholm,Pontus Henriksson
ImportanceElevated blood pressure (BP) in adolescence has been linked to higher risk of cardiovascular disease mortality, as well as surrogate markers of atherosclerosis, such as carotid intima-media thickness and coronary artery calcification. However, these markers do not fully capture the complex spectrum of subclinical atherosclerotic cardiovascular disease.ObjectiveTo examine the association between systolic and diastolic BP in adolescence and atherosclerosis in middle age, measured by coronary computed tomography angiography (CCTA).Design, Setting, and ParticipantsThis population-based cohort study conducted in Sweden linked BP data from the Swedish Military Conscription Register (1972-1987) during adolescence to atherosclerosis data from the Swedish Cardiopulmonary Bioimage Study (2013-2018) during middle age. Data analyses were performed in May 2025.ExposureAdolescent BP was categorized according to the 2025 American College of Cardiology/American Heart Association (ACC/AHA) and the 2024 European Society of Cardiology (ESC) guidelines.Main Outcomes and MeasuresThe primary outcome was coronary atherosclerosis, evaluated via CCTA stenosis. The associations were analyzed using multinomial logistic regression, adjusted (marginal) prevalences, and restricted cubic splines.ResultsA total of 10 222 men with mean (SD) age of 18.3 (0.5) years at baseline and median (IQR) age of 57.8 (53.4-61.2) years at follow-up were included. At baseline, mean (SD) systolic BP (SBP) and diastolic BP (DBP) were 127.6 (10.7) mm Hg and 68.3 (9.5) mm Hg, respectively. After a median (IQR) follow-up of 39.5 (35.2-42.8) years, 4159 participants (45.7%) had 1% to 49% coronary stenosis and 784 (8.6%) had 50% or greater coronary stenosis. Elevated BP in adolescence was associated with coronary stenosis in a dose-response fashion. Adolescents with stage 2 hypertension had a higher risk of severe coronary stenosis (≥50%), with an odds ratio of 1.84 (95% CI, 1.40-2.42) and an adjusted prevalence of 10.1% (95% CI, 8.6%-11.5%) compared to those with normal BP (adjusted prevalence, 6.9%; 95% CI, 5.7%-8.1%). Elevated BP categories according to the 2025 ACC/AHA (120-129/<80 mm Hg) and the 2024 ESC (120-139/70-89 mm Hg) were associated with severe coronary atherosclerosis in middle age. The association was stronger for SBP than for DBP.Conclusions and RelevanceIn this population-based cohort study, higher BP levels in adolescence were associated with a dose-dependent higher risk for atherosclerosis in middle age, particularly for severe coronary atherosclerosis. Excess risks of atherosclerosis were even evident in the elevated BP range in adolescence as defined by the 2025 ACC/AHA and 2024 ESC BP guidelines.
{"title":"Blood Pressure in Adolescence and Atherosclerosis in Middle Age.","authors":"Ángel Herraiz-Adillo,Hampus Eriksson,Viktor H Ahlqvist,Marcel Ballin,Patrik Wennberg,Bledar Daka,Cecilia Lenander,Daniel Berglind,Carl Johan Östgren,Oskar Lundgren,Karin Rådholm,Pontus Henriksson","doi":"10.1001/jamacardio.2025.4271","DOIUrl":"https://doi.org/10.1001/jamacardio.2025.4271","url":null,"abstract":"ImportanceElevated blood pressure (BP) in adolescence has been linked to higher risk of cardiovascular disease mortality, as well as surrogate markers of atherosclerosis, such as carotid intima-media thickness and coronary artery calcification. However, these markers do not fully capture the complex spectrum of subclinical atherosclerotic cardiovascular disease.ObjectiveTo examine the association between systolic and diastolic BP in adolescence and atherosclerosis in middle age, measured by coronary computed tomography angiography (CCTA).Design, Setting, and ParticipantsThis population-based cohort study conducted in Sweden linked BP data from the Swedish Military Conscription Register (1972-1987) during adolescence to atherosclerosis data from the Swedish Cardiopulmonary Bioimage Study (2013-2018) during middle age. Data analyses were performed in May 2025.ExposureAdolescent BP was categorized according to the 2025 American College of Cardiology/American Heart Association (ACC/AHA) and the 2024 European Society of Cardiology (ESC) guidelines.Main Outcomes and MeasuresThe primary outcome was coronary atherosclerosis, evaluated via CCTA stenosis. The associations were analyzed using multinomial logistic regression, adjusted (marginal) prevalences, and restricted cubic splines.ResultsA total of 10 222 men with mean (SD) age of 18.3 (0.5) years at baseline and median (IQR) age of 57.8 (53.4-61.2) years at follow-up were included. At baseline, mean (SD) systolic BP (SBP) and diastolic BP (DBP) were 127.6 (10.7) mm Hg and 68.3 (9.5) mm Hg, respectively. After a median (IQR) follow-up of 39.5 (35.2-42.8) years, 4159 participants (45.7%) had 1% to 49% coronary stenosis and 784 (8.6%) had 50% or greater coronary stenosis. Elevated BP in adolescence was associated with coronary stenosis in a dose-response fashion. Adolescents with stage 2 hypertension had a higher risk of severe coronary stenosis (≥50%), with an odds ratio of 1.84 (95% CI, 1.40-2.42) and an adjusted prevalence of 10.1% (95% CI, 8.6%-11.5%) compared to those with normal BP (adjusted prevalence, 6.9%; 95% CI, 5.7%-8.1%). Elevated BP categories according to the 2025 ACC/AHA (120-129/<80 mm Hg) and the 2024 ESC (120-139/70-89 mm Hg) were associated with severe coronary atherosclerosis in middle age. The association was stronger for SBP than for DBP.Conclusions and RelevanceIn this population-based cohort study, higher BP levels in adolescence were associated with a dose-dependent higher risk for atherosclerosis in middle age, particularly for severe coronary atherosclerosis. Excess risks of atherosclerosis were even evident in the elevated BP range in adolescence as defined by the 2025 ACC/AHA and 2024 ESC BP guidelines.","PeriodicalId":14657,"journal":{"name":"JAMA cardiology","volume":"7 1","pages":""},"PeriodicalIF":24.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-12DOI: 10.1001/jamacardio.2025.4151
Deborah M Siegal,Christian Sticherling,Jeff S Healey,William F McIntyre,Lene S Christensen,Ratika Parkash,Thomas Vanassche,David Conen,Michael Gold,Christopher B Granger,Jens Cosedis Nielsen,Marc Carrier,Daniel M Wojdyla,Julia W Erath,Lena Rivard,Valentina Kutyifa,David J Wright,Renato D Lopes
ImportanceThe Apixaban for the Reduction of Thromboembolism in Patients With Device-Detected Subclinical Atrial Fibrillation (ARTESiA) randomized clinical trial showed that in patients with subclinical atrial fibrillation (SCAF) apixaban, compared with aspirin, reduced stroke/systemic embolism but increased major bleeding.ObjectivesTo characterize major bleeding events (site and severity) and identify factors associated with major bleeding.Design, Setting, and ParticipantsThis was a prespecified subanalysis of the ARTESiA population who received treatment. This was an international, double-blind, double-dummy randomized clinical trial. Included were patients with 1 or more episodes of SCAF lasting 6 minutes to 24 hours with stroke risk factors (CHA2DS2-VASc score ≥3) or prior stroke without other risk factors. Study data were analyzed from August to November 2024.InterventionsApixaban, 5 mg, twice daily (2.5 mg twice daily when indicated) or aspirin, 81 mg, once daily.Main Outcomes and MeasuresMajor bleeding adjudicated by a blinded committee according to International Society on Thrombosis and Hemostasis criteria.ResultsA total of 3961 patients (mean [SD] age, 76.8 [7.6] years; 2535 male [64%]) were included in this analysis. After a mean (SD) follow-up of 3.5 (1.8) years, 1 or more major bleeding episodes occurred in 133 patients, 86 of 1989 taking apixaban and 47 of 1972 taking aspirin (1.71 vs 0.94 per 100-patient-years; hazard ratio [HR], 1.80; 95% CI, 1.26-2.57). The rates of intracranial (0.33 vs 0.40 per 100 patient-years; HR, 0.82; 95% CI, 0.43-1.57) and fatal (0.10% vs 0.16% per 100 patient-years; HR, 0.63; 95% CI, 0.20-1.91) bleeding were similar in the apixaban and aspirin groups, whereas the rate of gastrointestinal bleeding was higher in the apixaban group (0.89% vs 0.40% per 100 patient-years; HR, 2.23; 95% CI, 1.32-3.78). Among 133 index major bleeding events, those that occurred with apixaban were less likely to occur at critical sites (27.9% [24 of 86] vs 46.8% [22 of 47]; P = .03) including intracranial (18.6% [16 of 86] vs 42.6% [20 of 47]; P = .003). Most major bleeding events were nonemergencies characterized by decreased hemoglobin greater than or equal to 2 g/dL. Factors associated with major bleeding included nonsteroidal anti-inflammatory drug (NSAID) use (HR, 10.25; 95% CI, 6.57-15.99), cancer (HR, 2.87; 95% CI, 1.49-5.53), randomization to apixaban (HR, 1.84; 95% CI, 1.29-2.63), and age (HR, 1.47; 95% CI, 1.28-1.67, per 5-year increase).Conclusions and RelevanceResults of this subanalysis of the ARTESiA randomized clinical trial found that although the rate of major gastrointestinal bleeding was higher in patients with SCAF who were treated with apixaban vs aspirin, rates of fatal and intracranial bleeding were not different. Most major bleeding events were nonemergencies characterized by a decrease in hemoglobin level greater than or equal to 2 g/dL. NSAID use, cancer, randomization to apixaban, and increasing age wer
{"title":"Major Bleeding With Apixaban vs Aspirin: A Subanalysis of the ARTESiA Randomized Clinical Trial.","authors":"Deborah M Siegal,Christian Sticherling,Jeff S Healey,William F McIntyre,Lene S Christensen,Ratika Parkash,Thomas Vanassche,David Conen,Michael Gold,Christopher B Granger,Jens Cosedis Nielsen,Marc Carrier,Daniel M Wojdyla,Julia W Erath,Lena Rivard,Valentina Kutyifa,David J Wright,Renato D Lopes","doi":"10.1001/jamacardio.2025.4151","DOIUrl":"https://doi.org/10.1001/jamacardio.2025.4151","url":null,"abstract":"ImportanceThe Apixaban for the Reduction of Thromboembolism in Patients With Device-Detected Subclinical Atrial Fibrillation (ARTESiA) randomized clinical trial showed that in patients with subclinical atrial fibrillation (SCAF) apixaban, compared with aspirin, reduced stroke/systemic embolism but increased major bleeding.ObjectivesTo characterize major bleeding events (site and severity) and identify factors associated with major bleeding.Design, Setting, and ParticipantsThis was a prespecified subanalysis of the ARTESiA population who received treatment. This was an international, double-blind, double-dummy randomized clinical trial. Included were patients with 1 or more episodes of SCAF lasting 6 minutes to 24 hours with stroke risk factors (CHA2DS2-VASc score ≥3) or prior stroke without other risk factors. Study data were analyzed from August to November 2024.InterventionsApixaban, 5 mg, twice daily (2.5 mg twice daily when indicated) or aspirin, 81 mg, once daily.Main Outcomes and MeasuresMajor bleeding adjudicated by a blinded committee according to International Society on Thrombosis and Hemostasis criteria.ResultsA total of 3961 patients (mean [SD] age, 76.8 [7.6] years; 2535 male [64%]) were included in this analysis. After a mean (SD) follow-up of 3.5 (1.8) years, 1 or more major bleeding episodes occurred in 133 patients, 86 of 1989 taking apixaban and 47 of 1972 taking aspirin (1.71 vs 0.94 per 100-patient-years; hazard ratio [HR], 1.80; 95% CI, 1.26-2.57). The rates of intracranial (0.33 vs 0.40 per 100 patient-years; HR, 0.82; 95% CI, 0.43-1.57) and fatal (0.10% vs 0.16% per 100 patient-years; HR, 0.63; 95% CI, 0.20-1.91) bleeding were similar in the apixaban and aspirin groups, whereas the rate of gastrointestinal bleeding was higher in the apixaban group (0.89% vs 0.40% per 100 patient-years; HR, 2.23; 95% CI, 1.32-3.78). Among 133 index major bleeding events, those that occurred with apixaban were less likely to occur at critical sites (27.9% [24 of 86] vs 46.8% [22 of 47]; P = .03) including intracranial (18.6% [16 of 86] vs 42.6% [20 of 47]; P = .003). Most major bleeding events were nonemergencies characterized by decreased hemoglobin greater than or equal to 2 g/dL. Factors associated with major bleeding included nonsteroidal anti-inflammatory drug (NSAID) use (HR, 10.25; 95% CI, 6.57-15.99), cancer (HR, 2.87; 95% CI, 1.49-5.53), randomization to apixaban (HR, 1.84; 95% CI, 1.29-2.63), and age (HR, 1.47; 95% CI, 1.28-1.67, per 5-year increase).Conclusions and RelevanceResults of this subanalysis of the ARTESiA randomized clinical trial found that although the rate of major gastrointestinal bleeding was higher in patients with SCAF who were treated with apixaban vs aspirin, rates of fatal and intracranial bleeding were not different. Most major bleeding events were nonemergencies characterized by a decrease in hemoglobin level greater than or equal to 2 g/dL. NSAID use, cancer, randomization to apixaban, and increasing age wer","PeriodicalId":14657,"journal":{"name":"JAMA cardiology","volume":"19 1","pages":""},"PeriodicalIF":24.0,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145491718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-10DOI: 10.1001/jamacardio.2025.4591
Sneha S. Jain, Tony Sun, Emma Pierson, Francisco Roedan Oliver, Paloma Malta, Michelle Castillo, Ningxin Wan, Shudhanshu Alishetti, Heidi Hartman, Joshua Finer, Kathleen L. Brown, Vijendra Ramlall, Nicholas Tatonetti, Noémie Elhadad, Fatima Rodriguez, Ronald Witteles, Parag Goyal, Shunichi Homma, Andrew J. Einstein, Mathew S. Maurer, Pierre Elias, Timothy J. Poterucha
Importance Transthyretin amyloid cardiomyopathy (ATTR-CM) is underdiagnosed despite expanding treatment options. Objective To develop and evaluate an artificial intelligence (AI)–augmented clinical program for ATTR-CM detection. Design, Setting, and Participants This nonrandomized clinical trial involved constructing an AI model, ATTRACTnet, using electrocardiogram waveforms, echocardiographic measurements, demographics, and diagnosis codes for orthopedic manifestations of amyloidosis. A single-system, multisite, single-arm, open-label trial was conducted to evaluate its real-world performance. The model was trained and validated at a large academic referral site for ATTR-CM with external validation at an academic site. The trial was conducted as a single-system, multisite trial. Patients with left ventricular (LV) wall thickness 12 mm or more and an ATTRACTnet score 0.5 or higher were eligible. Exclusions included prior ATTR-CM testing, hypertrophic cardiomyopathy, expected life span less than 1 year, nursing home residence, advanced dementia, or LV wall thickness less than 14 mm explained by uncontrolled hypertension or moderate/severe aortic stenosis. Intervention Eligible patients were notified and offered nuclear scintigraphy testing, monoclonal protein testing, and follow-up care on agreement from the treating physician. Main Outcomes and Measure The primary outcome was a diagnosis of ATTR-CM by consensus criteria. ATTR-CM testing positivity was compared with historical and contemporary controls. Results ATTRACTnet was developed in an internal test set of 799 patients (mean [SD] age, 75.1 [11.1] years; 516 [64.7%] male and 283 [35.3%] female) using 5-fold cross-validation with an additional external test set of 422 patients. It had good discrimination for ATTR-CM detection with an area under the receiver operator characteristic curve of 0.85 (5-fold cross-validation, 0.77-0.85) in the internal set and 0.82 (95% CI, .81-0.83) in the external test set with similar performance in Hispanic, non-Hispanic Black, and non-Hispanic White patients. A total of 1471 patients were identified with positive AI model scores 0.5 or more during the study period, with 256 eligible patients who met study criteria. Of these patients, 50 underwent amyloidosis testing after physician and patient approval; 24 (48%) were diagnosed with ATTR-CM, and 21 (88%) initiated treatment within 3 months. The positivity rate was more than 2.8 times higher than historical controls (15.3%; 95% CI, 13.1%-17.9%; P &lt; .001), with an 18% relative increase in new diagnoses vs the prior year. Conclusions and Relevance AI-augmented screening may improve ATTR-CM detection and identify patients who are missed by usual care. Prospective randomized trials are needed to determine if outcomes are improved. Trial Registration ClinicalTrials.gov Identifier:
{"title":"Detecting Transthyretin Cardiac Amyloidosis With Artificial Intelligence","authors":"Sneha S. Jain, Tony Sun, Emma Pierson, Francisco Roedan Oliver, Paloma Malta, Michelle Castillo, Ningxin Wan, Shudhanshu Alishetti, Heidi Hartman, Joshua Finer, Kathleen L. Brown, Vijendra Ramlall, Nicholas Tatonetti, Noémie Elhadad, Fatima Rodriguez, Ronald Witteles, Parag Goyal, Shunichi Homma, Andrew J. Einstein, Mathew S. Maurer, Pierre Elias, Timothy J. Poterucha","doi":"10.1001/jamacardio.2025.4591","DOIUrl":"https://doi.org/10.1001/jamacardio.2025.4591","url":null,"abstract":"Importance Transthyretin amyloid cardiomyopathy (ATTR-CM) is underdiagnosed despite expanding treatment options. Objective To develop and evaluate an artificial intelligence (AI)–augmented clinical program for ATTR-CM detection. Design, Setting, and Participants This nonrandomized clinical trial involved constructing an AI model, ATTRACTnet, using electrocardiogram waveforms, echocardiographic measurements, demographics, and diagnosis codes for orthopedic manifestations of amyloidosis. A single-system, multisite, single-arm, open-label trial was conducted to evaluate its real-world performance. The model was trained and validated at a large academic referral site for ATTR-CM with external validation at an academic site. The trial was conducted as a single-system, multisite trial. Patients with left ventricular (LV) wall thickness 12 mm or more and an ATTRACTnet score 0.5 or higher were eligible. Exclusions included prior ATTR-CM testing, hypertrophic cardiomyopathy, expected life span less than 1 year, nursing home residence, advanced dementia, or LV wall thickness less than 14 mm explained by uncontrolled hypertension or moderate/severe aortic stenosis. Intervention Eligible patients were notified and offered nuclear scintigraphy testing, monoclonal protein testing, and follow-up care on agreement from the treating physician. Main Outcomes and Measure The primary outcome was a diagnosis of ATTR-CM by consensus criteria. ATTR-CM testing positivity was compared with historical and contemporary controls. Results ATTRACTnet was developed in an internal test set of 799 patients (mean [SD] age, 75.1 [11.1] years; 516 [64.7%] male and 283 [35.3%] female) using 5-fold cross-validation with an additional external test set of 422 patients. It had good discrimination for ATTR-CM detection with an area under the receiver operator characteristic curve of 0.85 (5-fold cross-validation, 0.77-0.85) in the internal set and 0.82 (95% CI, .81-0.83) in the external test set with similar performance in Hispanic, non-Hispanic Black, and non-Hispanic White patients. A total of 1471 patients were identified with positive AI model scores 0.5 or more during the study period, with 256 eligible patients who met study criteria. Of these patients, 50 underwent amyloidosis testing after physician and patient approval; 24 (48%) were diagnosed with ATTR-CM, and 21 (88%) initiated treatment within 3 months. The positivity rate was more than 2.8 times higher than historical controls (15.3%; 95% CI, 13.1%-17.9%; <jats:italic>P</jats:italic> &amp;lt; .001), with an 18% relative increase in new diagnoses vs the prior year. Conclusions and Relevance AI-augmented screening may improve ATTR-CM detection and identify patients who are missed by usual care. Prospective randomized trials are needed to determine if outcomes are improved. Trial Registration ClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"uri\" xlink:href=\"https://cli","PeriodicalId":14657,"journal":{"name":"JAMA cardiology","volume":"140 1","pages":""},"PeriodicalIF":24.0,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImportanceClonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic cells with acquired preleukemic variants, has been associated with cardiometabolic diseases, including heart failure (HF). However, prior studies have lacked power to examine less common CHIP driver variants and have not investigated potential mediators of the CHIP-HF association.ObjectiveTo test whether specific CHIP subtypes are associated with incident HF and determine the extent to which CHIP-associated comorbidities mediate this association.Design, Setting, and ParticipantsThis was a UK Biobank prospective population-based cohort study of community-dwelling adults in the UK, with enrollment from 2006 to 2010 and follow-up through 2020. Included were participants with whole-exome sequencing (WES) and without prevalent HF, hematologic malignancy, or other CHIP-associated comorbidities (coronary artery disease [CAD], atrial fibrillation [AF], type 2 diabetes [T2D], or chronic kidney disease [CKD]) at baseline. Study data were analyzed from April through October 2025.ExposuresPresence of CHIP and gene-specific CHIP subtypes (DNMT3A, non-DNMT3A, TET2, ASXL1, JAK2, DNA damage repair genes, and spliceosome genes). Mediation analyses examined CHIP-associated comorbidities (CAD, AF, T2D, and CKD).Main Outcomes and MeasuresThe primary outcome was incident HF. Cox regression tested associations of CHIP and CHIP subtypes with incident HF, adjusted for age, sex, race, and cardiovascular risk factors.ResultsAmong 417 616 participants (mean [SD] age, 56.1 [8.1] years; 234 868 female [56.2%]), 7183 (1.7%) developed incident HF over a median (IQR) of 11.1 (10.4-11.8) years of follow-up. CHIP was associated with HF risk (adjusted hazard ratio [aHR], 1.27; 95% CI, 1.15-1.40; P < .001), driven by non-DNMT3A subtypes (aHR, 1.52; 95% CI, 1.33-1.75; P < .001), including associations with TET2, ASXL1, JAK2, and spliceosome CHIP. DNMT3A CHIP was more modestly associated with HF (aHR, 1.15; 95% CI, 1.00-1.31; P = .04). In mediation analyses, development of CAD, AF, T2D, and/or CKD collectively accounted for 28.2% of the association (95% CI, 11.6%-45.4%; P = .001) between non-DNMT3A CHIP and HF.Conclusions and RelevanceResults of this cohort study suggest that CHIP, especially non-DNMT3A CHIP, was associated with incident HF. Other CHIP-associated comorbidities explained only a minority of the association between non-DNMT3A CHIP and HF. These findings suggest that CHIP is an HF risk factor and potential therapeutic target.
不确定电位的克隆造血（CHIP），即与年龄相关的具有获得性白血病前变异的造血细胞克隆扩增，与心脏代谢疾病（包括心力衰竭（HF））相关。然而，先前的研究缺乏检查不太常见的CHIP驱动变异的能力，也没有调查CHIP- hf关联的潜在介质。目的检验特定CHIP亚型是否与HF事件相关，并确定CHIP相关合并症在多大程度上介导了这种关联。设计、环境和参与者这是一项基于英国生物银行的前瞻性人群队列研究，研究对象为英国社区居住的成年人，入组时间为2006年至2010年，随访至2020年。纳入了全外显子组测序（WES）的参与者，基线时没有流行的HF、血液恶性肿瘤或其他chip相关合并症（冠状动脉疾病[CAD]、心房颤动[AF]、2型糖尿病[T2D]或慢性肾脏疾病[CKD]）。研究数据从2025年4月到10月进行了分析。CHIP和基因特异性CHIP亚型（DNMT3A、非DNMT3A、TET2、ASXL1、JAK2、DNA损伤修复基因和剪接体基因）的存在。中介分析检查了chip相关的合并症（CAD、AF、T2D和CKD）。主要结局和测量：主要结局为偶发性心衰。Cox回归测试了CHIP和CHIP亚型与HF事件的相关性，校正了年龄、性别、种族和心血管危险因素。结果在417 616名参与者中（平均[SD]年龄56.1[8.1]岁；234 868名女性[56.2%]），7183名（1.7%）在中位（IQR） 11.1（10.4-11.8）年的随访期间发生心衰。CHIP与HF风险相关(校正风险比[aHR]， 1.27; 95% CI, 1.15-1.40; P <。001)，由非dnmt3a亚型驱动(aHR, 1.52; 95% CI, 1.33-1.75; P <。001)，包括与TET2、ASXL1、JAK2和剪接体CHIP的关联。DNMT3A CHIP与HF的相关性较低（aHR, 1.15; 95% CI, 1.00-1.31; P = 0.04）。在中介分析中，CAD、AF、T2D和/或CKD的发展共占28.2%的关联(95% CI, 11.6%-45.4%; P =。001)非dnmt3a CHIP和HF之间的差异。本队列研究的结果表明CHIP，尤其是非dnmt3a CHIP，与HF事件相关。其他CHIP相关的合共病仅解释了非dnmt3a CHIP与HF之间的一小部分关联。这些发现表明CHIP是HF的危险因素和潜在的治疗靶点。
{"title":"Clonal Hematopoiesis and Incident Heart Failure.","authors":"Spencer Flynn,Art Schuermans,Md Mesbah Uddin,Tetsushi Nakao,Victoria Viscosi,Peter Libby,Pradeep Natarajan,Michael C Honigberg","doi":"10.1001/jamacardio.2025.4603","DOIUrl":"https://doi.org/10.1001/jamacardio.2025.4603","url":null,"abstract":"ImportanceClonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic cells with acquired preleukemic variants, has been associated with cardiometabolic diseases, including heart failure (HF). However, prior studies have lacked power to examine less common CHIP driver variants and have not investigated potential mediators of the CHIP-HF association.ObjectiveTo test whether specific CHIP subtypes are associated with incident HF and determine the extent to which CHIP-associated comorbidities mediate this association.Design, Setting, and ParticipantsThis was a UK Biobank prospective population-based cohort study of community-dwelling adults in the UK, with enrollment from 2006 to 2010 and follow-up through 2020. Included were participants with whole-exome sequencing (WES) and without prevalent HF, hematologic malignancy, or other CHIP-associated comorbidities (coronary artery disease [CAD], atrial fibrillation [AF], type 2 diabetes [T2D], or chronic kidney disease [CKD]) at baseline. Study data were analyzed from April through October 2025.ExposuresPresence of CHIP and gene-specific CHIP subtypes (DNMT3A, non-DNMT3A, TET2, ASXL1, JAK2, DNA damage repair genes, and spliceosome genes). Mediation analyses examined CHIP-associated comorbidities (CAD, AF, T2D, and CKD).Main Outcomes and MeasuresThe primary outcome was incident HF. Cox regression tested associations of CHIP and CHIP subtypes with incident HF, adjusted for age, sex, race, and cardiovascular risk factors.ResultsAmong 417 616 participants (mean [SD] age, 56.1 [8.1] years; 234 868 female [56.2%]), 7183 (1.7%) developed incident HF over a median (IQR) of 11.1 (10.4-11.8) years of follow-up. CHIP was associated with HF risk (adjusted hazard ratio [aHR], 1.27; 95% CI, 1.15-1.40; P < .001), driven by non-DNMT3A subtypes (aHR, 1.52; 95% CI, 1.33-1.75; P < .001), including associations with TET2, ASXL1, JAK2, and spliceosome CHIP. DNMT3A CHIP was more modestly associated with HF (aHR, 1.15; 95% CI, 1.00-1.31; P = .04). In mediation analyses, development of CAD, AF, T2D, and/or CKD collectively accounted for 28.2% of the association (95% CI, 11.6%-45.4%; P = .001) between non-DNMT3A CHIP and HF.Conclusions and RelevanceResults of this cohort study suggest that CHIP, especially non-DNMT3A CHIP, was associated with incident HF. Other CHIP-associated comorbidities explained only a minority of the association between non-DNMT3A CHIP and HF. These findings suggest that CHIP is an HF risk factor and potential therapeutic target.","PeriodicalId":14657,"journal":{"name":"JAMA cardiology","volume":"143 1","pages":""},"PeriodicalIF":24.0,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-08DOI: 10.1001/jamacardio.2025.4466
Ezimamaka Ajufo, Shinwan Kany, Sean J. Jurgens, Timothy W. Churchill, J. Sawalla Guseh, Krishna G. Aragam, Victor Nauffal, James P. Pirruccello, Seung Hoan Choi, Neal K. Lakdawala, Carolyn Y. Ho, Patrick T. Ellinor, Shaan Khurshid
Importance Exercise may lead to disease progression and higher risk of sudden death in individuals with genetic cardiomyopathies, but the effects of exercise among individuals carrying a cardiomyopathy-associated variant without clinical manifestations (G+P−) are unclear. Objective To examine whether the effects of moderate to vigorous physical activity (MVPA) on cardiovascular (CV) outcomes, cardiac structure and function, and risk of developing overt cardiomyopathy and malignant ventricular arrhythmias (VAs) vary by G+P− status. Design, Setting, and Participants UK Biobank participants with whole-genome sequencing providing 1 week of accelerometer-based physical activity data and without prevalent heart failure (HF), atrial fibrillation (AF), cardiomyopathy, VAs, or implantable cardioverter-defibrillators were included in this cohort study. The study was conducted at 22 assessment centers throughout the UK from February 2013 to December 2015 with a median follow-up of 8 years. Data were analyzed from March 2024 to June 2025. Exposure Accelerometer-measured MVPA (minutes/week). Main Outcomes and Measures Associations were analyzed between MVPA volume and future incidence of adverse CV outcomes (AF, HF, myocardial infarction [MI], and stroke), cardiac magnetic resonance (CMR)–based measures of cardiac remodeling, and surrogates for clinical cardiomyopathy onset (cardiomyopathy and VA). Associations were compared between G+P− carriers and noncarriers. Results Among 84 699 individuals (mean [SD] age, 62 [8] years; 48 353 [57%] women; 3979 G+P− carriers), greater MVPA was associated with a lower risk of adverse CV outcomes over a median (IQR) 8.0 (7.5-8.5) years, irrespective of genotype. In multivariable models, higher MVPA was broadly associated with lower risk of incident CV disease in G+P− carriers (hazard ratio [HR] at optimal MVPA level vs zero [95% CI], AF: 0.68 [0.58–0.79]; HF: 0.58 [0.47-0.71]; MI: 0.49, [0.24-1.00]; stroke: 0.35 [0.12-0.99]). For G+P− carriers, MVPA in the range of 100 to 400 minutes per week was generally associated with lowest risk. Among individuals with CMR imaging, MVPA was associated with a similar pattern and extent of cardiac remodeling (eg, left ventricular dilation and left ventricular hypertrophy) in G+P− carriers vs noncarriers. Among G+P− carriers, higher MVPA was associated with lower risk of incident cardiomyopathy (HR at optimal MVPA vs 0, 0.03; 95% CI, 0.00-0.98) with no increase in risk of VA (eg, HR at 400 minutes of MVPA vs 0, 0.98; 95% CI, 0.83-1.14). Findings were generally consistent across variants associated with dilated cardiomyopathy, hypertrophic cardiomyopathy, or arrhythmogenic right ventricular cardiomyopathy, although precision of estimates for arrhythmogenic right ventricular cardiomyopathy were limited. Conclusions and Relevance In this cohort study, MVPA within the general range of guideline-based recommendations was associated with lower risk of adverse CV outcomes and similar degrees of
{"title":"Physical Activity and Cardiovascular Outcomes in Phenotype-Negative Cardiomyopathy Variant Carriers","authors":"Ezimamaka Ajufo, Shinwan Kany, Sean J. Jurgens, Timothy W. Churchill, J. Sawalla Guseh, Krishna G. Aragam, Victor Nauffal, James P. Pirruccello, Seung Hoan Choi, Neal K. Lakdawala, Carolyn Y. Ho, Patrick T. Ellinor, Shaan Khurshid","doi":"10.1001/jamacardio.2025.4466","DOIUrl":"https://doi.org/10.1001/jamacardio.2025.4466","url":null,"abstract":"Importance Exercise may lead to disease progression and higher risk of sudden death in individuals with genetic cardiomyopathies, but the effects of exercise among individuals carrying a cardiomyopathy-associated variant without clinical manifestations (G+P−) are unclear. Objective To examine whether the effects of moderate to vigorous physical activity (MVPA) on cardiovascular (CV) outcomes, cardiac structure and function, and risk of developing overt cardiomyopathy and malignant ventricular arrhythmias (VAs) vary by G+P− status. Design, Setting, and Participants UK Biobank participants with whole-genome sequencing providing 1 week of accelerometer-based physical activity data and without prevalent heart failure (HF), atrial fibrillation (AF), cardiomyopathy, VAs, or implantable cardioverter-defibrillators were included in this cohort study. The study was conducted at 22 assessment centers throughout the UK from February 2013 to December 2015 with a median follow-up of 8 years. Data were analyzed from March 2024 to June 2025. Exposure Accelerometer-measured MVPA (minutes/week). Main Outcomes and Measures Associations were analyzed between MVPA volume and future incidence of adverse CV outcomes (AF, HF, myocardial infarction [MI], and stroke), cardiac magnetic resonance (CMR)–based measures of cardiac remodeling, and surrogates for clinical cardiomyopathy onset (cardiomyopathy and VA). Associations were compared between G+P− carriers and noncarriers. Results Among 84 699 individuals (mean [SD] age, 62 [8] years; 48 353 [57%] women; 3979 G+P− carriers), greater MVPA was associated with a lower risk of adverse CV outcomes over a median (IQR) 8.0 (7.5-8.5) years, irrespective of genotype. In multivariable models, higher MVPA was broadly associated with lower risk of incident CV disease in G+P− carriers (hazard ratio [HR] at optimal MVPA level vs zero [95% CI], AF: 0.68 [0.58–0.79]; HF: 0.58 [0.47-0.71]; MI: 0.49, [0.24-1.00]; stroke: 0.35 [0.12-0.99]). For G+P− carriers, MVPA in the range of 100 to 400 minutes per week was generally associated with lowest risk. Among individuals with CMR imaging, MVPA was associated with a similar pattern and extent of cardiac remodeling (eg, left ventricular dilation and left ventricular hypertrophy) in G+P− carriers vs noncarriers. Among G+P− carriers, higher MVPA was associated with lower risk of incident cardiomyopathy (HR at optimal MVPA vs 0, 0.03; 95% CI, 0.00-0.98) with no increase in risk of VA (eg, HR at 400 minutes of MVPA vs 0, 0.98; 95% CI, 0.83-1.14). Findings were generally consistent across variants associated with dilated cardiomyopathy, hypertrophic cardiomyopathy, or arrhythmogenic right ventricular cardiomyopathy, although precision of estimates for arrhythmogenic right ventricular cardiomyopathy were limited. Conclusions and Relevance In this cohort study, MVPA within the general range of guideline-based recommendations was associated with lower risk of adverse CV outcomes and similar degrees of","PeriodicalId":14657,"journal":{"name":"JAMA cardiology","volume":"108 1","pages":""},"PeriodicalIF":24.0,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-08DOI: 10.1001/jamacardio.2025.4548
Vencel Juhasz, Zsofia D. Drobni, Thiago Quinaglia, Hannah K. Gilman, Jan M. Brendel, Giselle Alexandra Suero-Abreu, Azin Ghamari, Julius C. Heemelaar, Donna S. Neuberg, Yuchi Han, Bonnie Ky, Raymond Y. Kwong, James L. Januzzi, Aarti Asnani, Negareh Mousavi, Robert A. Redd, Michael Jerosch-Herold, Marielle Scherrer-Crosbie, Tomas G. Neilan
Importance Anthracyclines, which are key to many chemotherapeutic protocols, have been associated with increased vascular stiffness, a major factor associated with cardiovascular morbidity and mortality. There is no evidence-based intervention to prevent anthracycline-associated vascular dysfunction. Objective To investigate whether atorvastatin pretreatment is associated with attenuation of the anthracycline-induced increase in aortic stiffness. Design, Setting, and Participants This study is a secondary analysis of a double-blind, randomized clinical trial (Statins to Prevent the Cardiotoxicity From Anthracyclines [STOP-CA]). Enrollment occurred between January 25, 2017, and September 10, 2021, with the last follow-up on October 10, 2022. Primary analyses were reported on August 8, 2023. STOP-CA was a multicenter trial across 9 academic centers in the US and Canada. Participants were patients with newly diagnosed lymphoma scheduled to undergo anthracycline-based chemotherapy with no clinical indication for a statin. Intervention Atorvastatin (40 mg, once daily) or placebo for 12 months. Main Outcomes and Measures This subanalysis of the STOP-CA trial includes post hoc end points with cardiac magnetic resonance imaging–derived aortic arch pulse wave velocity (PWV) and aortic distensibility (AD). An intention-to-treat approach was applied. The proportions of participants with a 1 SD or more increase in PWV and a 1 SD or more decrease in ascending aortic distensibility (AAD) were calculated in each group over 12 months. An increase in PWV of 0.15 m per second or more, a previously defined annual rate in individuals of similar age, was also assessed as a secondary end point. Results Of the 300 participants (150 randomized to atorvastatin and 150 randomized to placebo), 152 (mean [SD] age, 51 [17] years; 72 female [47%]; 82 treated with atorvastatin) had paired PWV data, and 168 had paired AD data. The PWV values remained similar in the atorvastatin group (mean [SD], 6.5 [1.9] vs 6.5 [2.0] m per second) but increased in the placebo group (5.7 [1.8] vs 6.8 [2.0] m per second) over 12 months. A 1 SD or more increase (0.8 m per second) in PWV was observed among 4 of 82 patients (5%) with atorvastatin and 35 of 70 patients (50%) with placebo (odds ratio, 0.05; 95% CI, 0.02 to 0.16; <jats:italic>P</jats:italic> &lt; .001) at 12 months. A 1 SD or more decrease (1.8 × 10 <jats:sup>−3</jats:sup> mm Hg <jats:sup>−1</jats:sup> ) in AAD was observed among 6 of 88 patients (7%) with atorvastatin and in 14 of 80 patients (18%) with placebo. A 1 SD or more increase in PWV was associated with a mean left ventricular ejection fraction decline of 2.70% (95% CI, −4.65% to −0.81%; <jats:italic>P</jats:italic> = .006). Conclusions and Relevance Pretreatment with atorvastatin was associated with preservation of vascular function among patients with lymphoma undergoing anthracycline-based chemotherapy. Trial Registration ClinicalTrials.gov Identifier: <jats:ext-l
{"title":"Atorvastatin and Aortic Stiffness During Anthracycline-Based Chemotherapy","authors":"Vencel Juhasz, Zsofia D. Drobni, Thiago Quinaglia, Hannah K. Gilman, Jan M. Brendel, Giselle Alexandra Suero-Abreu, Azin Ghamari, Julius C. Heemelaar, Donna S. Neuberg, Yuchi Han, Bonnie Ky, Raymond Y. Kwong, James L. Januzzi, Aarti Asnani, Negareh Mousavi, Robert A. Redd, Michael Jerosch-Herold, Marielle Scherrer-Crosbie, Tomas G. Neilan","doi":"10.1001/jamacardio.2025.4548","DOIUrl":"https://doi.org/10.1001/jamacardio.2025.4548","url":null,"abstract":"Importance Anthracyclines, which are key to many chemotherapeutic protocols, have been associated with increased vascular stiffness, a major factor associated with cardiovascular morbidity and mortality. There is no evidence-based intervention to prevent anthracycline-associated vascular dysfunction. Objective To investigate whether atorvastatin pretreatment is associated with attenuation of the anthracycline-induced increase in aortic stiffness. Design, Setting, and Participants This study is a secondary analysis of a double-blind, randomized clinical trial (Statins to Prevent the Cardiotoxicity From Anthracyclines [STOP-CA]). Enrollment occurred between January 25, 2017, and September 10, 2021, with the last follow-up on October 10, 2022. Primary analyses were reported on August 8, 2023. STOP-CA was a multicenter trial across 9 academic centers in the US and Canada. Participants were patients with newly diagnosed lymphoma scheduled to undergo anthracycline-based chemotherapy with no clinical indication for a statin. Intervention Atorvastatin (40 mg, once daily) or placebo for 12 months. Main Outcomes and Measures This subanalysis of the STOP-CA trial includes post hoc end points with cardiac magnetic resonance imaging–derived aortic arch pulse wave velocity (PWV) and aortic distensibility (AD). An intention-to-treat approach was applied. The proportions of participants with a 1 SD or more increase in PWV and a 1 SD or more decrease in ascending aortic distensibility (AAD) were calculated in each group over 12 months. An increase in PWV of 0.15 m per second or more, a previously defined annual rate in individuals of similar age, was also assessed as a secondary end point. Results Of the 300 participants (150 randomized to atorvastatin and 150 randomized to placebo), 152 (mean [SD] age, 51 [17] years; 72 female [47%]; 82 treated with atorvastatin) had paired PWV data, and 168 had paired AD data. The PWV values remained similar in the atorvastatin group (mean [SD], 6.5 [1.9] vs 6.5 [2.0] m per second) but increased in the placebo group (5.7 [1.8] vs 6.8 [2.0] m per second) over 12 months. A 1 SD or more increase (0.8 m per second) in PWV was observed among 4 of 82 patients (5%) with atorvastatin and 35 of 70 patients (50%) with placebo (odds ratio, 0.05; 95% CI, 0.02 to 0.16; <jats:italic>P</jats:italic> &amp;lt; .001) at 12 months. A 1 SD or more decrease (1.8 × 10 <jats:sup>−3</jats:sup> mm Hg <jats:sup>−1</jats:sup> ) in AAD was observed among 6 of 88 patients (7%) with atorvastatin and in 14 of 80 patients (18%) with placebo. A 1 SD or more increase in PWV was associated with a mean left ventricular ejection fraction decline of 2.70% (95% CI, −4.65% to −0.81%; <jats:italic>P</jats:italic> = .006). Conclusions and Relevance Pretreatment with atorvastatin was associated with preservation of vascular function among patients with lymphoma undergoing anthracycline-based chemotherapy. Trial Registration ClinicalTrials.gov Identifier: <jats:ext-l","PeriodicalId":14657,"journal":{"name":"JAMA cardiology","volume":"82 1","pages":""},"PeriodicalIF":24.0,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-08DOI: 10.1001/jamacardio.2025.4477
Kevin M Alexander,Margot K Davis,Olakunle Akinboboye,John Berk,Kunal Bhatt,Francesco Cappelli,Sarah A M Cuddy,Marianna Fontana,Pablo Garcia-Pavia,Julian D Gillmore,Jan M Griffin,Justin L Grodin,Daniel P Judge,Michel G Khouri,Kaitlyn Lam,Ahmad Masri,Mathew S Maurer,Laura Obici,Frederick L Ruberg,Nitasha Sarswat,Keyur Shah,Prem Soman,Lily Stern,Richard Wright,Kuangnan Xiong,Xiaofan Cao,Ted Lystig,Jean-François Tamby,Adam Castaño,Leonid Katz,Uma Sinha,Jonathan C Fox,Scott D Solomon,Martha Grogan
ImportanceTransthyretin 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).ObjectiveTo evaluate the efficacy of acoramidis in ATTRwt-CM, ATTRv-CM, and variant subgroups (p.Val142Ile and non-p.Val142Ile).Design, Setting, and ParticipantsThis 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.InterventionsOral acoramidis, 712 mg, or placebo twice daily for 30 months, followed by 12 months of open-label treatment.Main Outcomes and MeasuresAll-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.ResultsOverall, 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 RelevanceThe 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 RegistrationClinicalTrials.gov Identifiers: NCT03860935; NCT04988386.
{"title":"Efficacy of Acoramidis in Wild-Type and Variant Transthyretin Amyloid Cardiomyopathy: Results From ATTRibute-CM and Its Open-Label Extension.","authors":"Kevin M Alexander,Margot K Davis,Olakunle Akinboboye,John Berk,Kunal Bhatt,Francesco Cappelli,Sarah A M Cuddy,Marianna Fontana,Pablo Garcia-Pavia,Julian D Gillmore,Jan M Griffin,Justin L Grodin,Daniel P Judge,Michel G Khouri,Kaitlyn Lam,Ahmad Masri,Mathew S Maurer,Laura Obici,Frederick L Ruberg,Nitasha Sarswat,Keyur Shah,Prem Soman,Lily Stern,Richard Wright,Kuangnan Xiong,Xiaofan Cao,Ted Lystig,Jean-François Tamby,Adam Castaño,Leonid Katz,Uma Sinha,Jonathan C Fox,Scott D Solomon,Martha Grogan","doi":"10.1001/jamacardio.2025.4477","DOIUrl":"https://doi.org/10.1001/jamacardio.2025.4477","url":null,"abstract":"ImportanceTransthyretin 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).ObjectiveTo evaluate the efficacy of acoramidis in ATTRwt-CM, ATTRv-CM, and variant subgroups (p.Val142Ile and non-p.Val142Ile).Design, Setting, and ParticipantsThis 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.InterventionsOral acoramidis, 712 mg, or placebo twice daily for 30 months, followed by 12 months of open-label treatment.Main Outcomes and MeasuresAll-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.ResultsOverall, 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 RelevanceThe 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 RegistrationClinicalTrials.gov Identifiers: NCT03860935; NCT04988386.","PeriodicalId":14657,"journal":{"name":"JAMA cardiology","volume":"39 1","pages":""},"PeriodicalIF":24.0,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：