Circulation: Heart Failure最新文献

{"title":"Clonal Hematopoiesis of Indeterminate Potential Proteomic Risk Score for Predicting Clinical Outcome in Patients With Heart Failure With Preserved Ejection Fraction.","authors":"Minkwan Kim, Vinayak Subramanian, Hamed Tavolinejad, Mateo Sarmiento Bustamante, Bianca Pourmussa, Douglas L Mann, Ali Javaheri, A Mark Richards, Robert N Doughty, Ernst Rietzschel, Vanessa van Empel, Payman Zamani, Thomas P Cappola, Dan Tong, Stephen Chung, Ambarish Pandey, Julio A Chirinos","doi":"10.1161/CIRCHEARTFAILURE.126.014345","DOIUrl":"10.1161/CIRCHEARTFAILURE.126.014345","url":null,"abstract":"<p><strong>Background: </strong>Clonal hematopoiesis of indeterminate potential (CHIP) is common in heart failure with preserved ejection fraction (HFpEF). However, the proteomic signatures linked to CHIP driver mutations and their prognostic implications in HFpEF remain poorly defined. We aimed to identify plasma protein signatures associated with CHIP driver mutations and to develop and externally validate a CHIP-proteomic risk score (CHIP-ProtRS) for predicting clinical outcomes in HFpEF.</p><p><strong>Methods: </strong>The derivation cohort consisted of 118 TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) participants with available CHIP sequencing and proteomic profiling using the SomaScan platform. Associations between CHIP mutations and circulating proteins were assessed using gene-specific linear regression adjusted for age, with correction for multiple comparisons. Significant proteins were used to derive gene-specific proteomic classifiers using nested cross-validated least absolute shrinkage and selection operator logistic regression. A composite CHIP-ProtRS was generated using least absolute shrinkage and selection operator Cox regression and validated in a composite of 3 independent HFpEF cohorts (n=654). The primary end point was a composite of death and HF hospitalization.</p><p><strong>Results: </strong>In TOPCAT, 30.5% of tested participants carried ≥1 CHIP mutation. Significant protein associations were identified for <i>TET2</i> (7 proteins), <i>DNMT3A</i> (10), and <i>PPM1D</i> (5), all of which were enriched in immune and inflammatory pathways. Gene-specific least absolute shrinkage and selection operator models showed good discrimination for CHIP mutation (area under the curves, 0.752-0.898). The primary end point occurred in 28.0% of the derivation cohort and 34.7% of the validation cohorts. In the Cox-least absolute shrinkage and selection operator combination, only the <i>TET2</i>-derived proteomic signature retained a nonzero coefficient in the CHIP-ProtRS. The CHIP-ProtRS was independently associated with the primary end point after adjustment for age, sex, Meta-Analysis Global Group in Chronic Heart Failure score, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and atrial fibrillation in the derivation (adjusted hazard ratio, 1.42 [95% CI, 1.01-2.00]) and validation cohorts (adjusted hazard ratio, 1.16 [95% CI, 1.01-1.32]).</p><p><strong>Conclusions: </strong>CHIP is associated with alterations in plasma concentrations of immune/inflammatory proteins. A CHIP-ProtRS is independently associated with adverse outcomes in HFpEF, supporting its potential role as a biomarker of risk and underlying pathobiology.</p>","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e014345"},"PeriodicalIF":8.3,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13623081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149011973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Health-Related Quality of Life in Older Patients With Advanced Heart Failure From Before to 2 Years After Heart Transplantation or Long-Term Mechanical Circulatory Support: Findings From the SUSTAIN-IT Study.","authors":"Kathleen L Grady, John A Spertus, Mary Amanda Dew, Tingqing Wu, Scott Silvestry, Maryl Johnson, Eileen Hsich, Brent Lampert, Michael Petty, Salpy V Pamboukian, Andrew Kao, James K Kirklin, Duc Thinh Pham, Justin Hartupee, Margaret Murray, Melana Yuzefpolskaya, Koji Takeda, Jerian Dixon-Evans, Adin-Cristian Andrei","doi":"10.1161/CIRCHEARTFAILURE.125.013871","DOIUrl":"https://doi.org/10.1161/CIRCHEARTFAILURE.125.013871","url":null,"abstract":"<p><strong>Background: </strong>Health-related quality of life (HRQOL) is a key consideration among older patients with heart failure considering advanced therapies. We evaluated change in HRQOL from before to 24 months after heart transplantation (HT) or long-term mechanical circulatory support (MCS) among older (60-80 years) patients and identified factors associated with HRQOL changes.</p><p><strong>Methods: </strong>Data for this observational study were collected from 13 US sites via patient self-reported measures (EuroQol-5-dimension-3L visual analog scale score: 0=worst-100=best imaginable health state and dimension scores; Kansas City Cardiomyopathy Questionnaire-12 overall summary score/domain scores: 0-100, higher=better health status; other measures) and a 6-minute walk test. Analyses included multivariable linear mixed-effects models.</p><p><strong>Results: </strong>Of 393 enrollees, 305 underwent surgery: HT with pretransplant MCS (HT MCS)=69, HT without pretransplant MCS (HT non-MCS)=92, and long-term MCS=144. Cohort average age=66.9±4.7 years, 78% male, 83% White, 78% married/partnered, and 71% with >high school education. HT non-MCS and long-term MCS groups experienced significant improvement in average visual analog scale scores within 6 months after surgery, sustained through 24 months of follow-up; the HT MCS group EuroQol-5-dimension-3L baseline visual analog scale score was higher than those of the other 2 groups and did not improve significantly through 24 months of follow-up. The average Kansas City Cardiomyopathy Questionnaire-12 overall summary score improved in all 3 groups (baseline-6 months, sustained through 24 months). Compared with HT non-MCS, the main effect of long-term MCS showed decrements of -11.2 (-17.3 to -5.1; <i>P</i><0.001) points in Kansas City Cardiomyopathy Questionnaire-12 overall summary score and of -9.9 (-16.1 to -3.8; <i>P</i>=0.002) points in EuroQol-5-dimension-3L visual analog scale.</p><p><strong>Conclusions: </strong>HT MCS improvement in HRQOL varied by measure; HT non-MCS and long-term MCS improvement occurred through 24 months, regardless of measure. Domains of HRQOL improved after these surgeries, varying by surgical strategy and postoperative time period. Long-term MCS was associated with a decrease in HRQOL across time. These findings provide important information for patients considering treatment options.</p>","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e013871"},"PeriodicalIF":8.3,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149011953","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}

{"title":"Optimizing Screening Intervals for At-Risk Relatives of Dilated Cardiomyopathy Carrying a TTNtv.","authors":"Steven A Muller, Nina J Beelen, Alessia Paldino, Clea Gonzalez-Maniega, Henning Bundgaard, Alex H Christensen, Christoffer R Vissing, Renee Johnson, Daria R Kramarenko, Max F G H M Venner, Eva Del Mestre, Guilielmus H J M Ellenbroek, Fernando Dominiquez, Matteo Dal Ferro, Marco Merlo, Sophie L V M Stroeks, Gianfranco Sinagra, Ahmad S Amin, Diane Fatkin, Pablo Garcia-Pavia, Anneline S J M Te Riele, Job A J Verdonschot","doi":"10.1161/CIRCHEARTFAILURE.125.013822","DOIUrl":"https://doi.org/10.1161/CIRCHEARTFAILURE.125.013822","url":null,"abstract":"<p><strong>Background: </strong>Cardiomyopathy guidelines recommend routine screening of at-risk relatives with dilated cardiomyopathy (DCM). Titin-truncating variants are the most prevalent cause. However, the diagnostic yield of screening is low. Risk-based stratification could optimize screening intervals and resource allocation. This study aims to develop a safe, evidence-based gene-specific longitudinal screening algorithm for DCM development.</p><p><strong>Methods: </strong>We included likely pathogenic/pathogenic titin-truncating variant relatives from 7 centers who underwent cardiac screening. Relatives were stratified based on their baseline clinical phenotype: genotype-positive/phenotype-negative (no left ventricular dysfunction and dilatation) or partial DCM (ie, fulfilling only 1 criterion). DCM development predictors were identified based on follow-up data. Risk profiles were established and used to develop a multistate model to create a longitudinal screening algorithm to safely and effectively monitor titin-truncating variant relatives.</p><p><strong>Results: </strong>Among 413 relatives, follow-up data were available in 301 relatives (median follow-up 5.7 years), of whom 24.6% developed left ventricular dysfunction or dilatation and 17.3% developed DCM. In total, 16 relatives (5.3%) experienced a major adverse cardiac event after DCM diagnosis. Based on the identified risk factors, age ≥30 years, male sex, and partial DCM, 3 distinct profiles were established: (1) relatives with partial DCM, (2) females ≥30 years and males, and (3) female relatives <30 years. A screening algorithm was developed, recommending intervals of 1, 3, and 5 years, optimizing the balance between safety and effectiveness.</p><p><strong>Conclusions: </strong>An evidence-based genotype-specific longitudinal screening algorithm that integrates age, sex, and echocardiographic measurements may improve patient care and improve efficiency of clinical resource allocation.</p>","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e013822"},"PeriodicalIF":8.3,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149011999","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}

{"title":"Heart Failure and Neurocognitive Disorders: A Narrative Review.","authors":"Shuantong Lin, Qian Wang, Jiangbei Cao","doi":"10.1161/CIRCHEARTFAILURE.126.014265","DOIUrl":"https://doi.org/10.1161/CIRCHEARTFAILURE.126.014265","url":null,"abstract":"<p><p>Neurocognitive disorders-including mild cognitive impairment, dementia, and delirium-are common yet often underrecognized in heart failure, impairing self-care and outcomes. These heart failure-related neurocognitive disorders pose a significant public health challenge due to high morbidity and mortality. Despite recent advances, timely detection, prevention, and intervention remain difficult. Most research focuses on pharmacological treatments, with limited attention to nonpharmacological approaches and mental health integration in heart failure care teams. Progress requires collaboration among internal medicine, surgery, nursing, and psychology. This review highlights interconnected pathways-cerebral hypoperfusion, microvascular and endothelial dysfunction, thromboembolic injury, and neuroendocrine-inflammatory activation-and discusses targeted interventions like simplified treatment plans, caregiver involvement, and multidisciplinary referrals.</p>","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e014265"},"PeriodicalIF":8.3,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929170","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}

{"title":"Disentangling Pulmonary Vascular Phenotypes in Group 2 Pulmonary Hypertension Using Bioactive Lipid Profiling.","authors":"Jonah D Garry, Evan L Brittain","doi":"10.1161/CIRCHEARTFAILURE.126.014894","DOIUrl":"10.1161/CIRCHEARTFAILURE.126.014894","url":null,"abstract":"","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e014894"},"PeriodicalIF":8.3,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13564326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiac Resynchronization Therapy and Circulating Metabolomic Profile in Patients With Advanced Heart Failure.","authors":"Zhiyong Qian, Hon-Chi Lee, Siva K Mulpuru, Ivan Vuckovic, Abhishek J Deshmukh, Christopher V DeSimone, Samuel J Asirvatham, Songnan Wen, Chuanwei Li, Song Zhang, Surendra Dasari, Petras P Dzeja, Ian R Lanza, Bing Yu, Kent R Bailey, Horng H Chen, Yong-Mei Cha","doi":"10.1161/CIRCHEARTFAILURE.125.014148","DOIUrl":"https://doi.org/10.1161/CIRCHEARTFAILURE.125.014148","url":null,"abstract":"<p><strong>Background: </strong>It is unknown whether cardiac resynchronization therapy (CRT) improves systemic metabolomic profile by enhancing left ventricular function. The observational cohort study aimed to investigate the effect of CRT on left ventricular ejection fraction (LVEF) and circulating plasma metabolites in patients who had heart failure with reduced LVEF.</p><p><strong>Methods: </strong>We prospectively screened patients with ischemic cardiomyopathy and nonischemic cardiomyopathy who received CRT with a defibrillator for LVEF ≤35% according to current guidelines. Clinical assessment included echocardiography and device interrogation. Blood samples for metabolomic analysis were collected before CRT and at 6-month follow-up. Plasma was subjected to gas chromatography-mass spectrometry and ¹H nuclear magnetic resonance-based metabolomic analysis.</p><p><strong>Results: </strong>Totally 92 patients were enrolled, with a mean age of 67.3±11.3 years (37.0% female). LVEF was significantly improved from 28.9±7.6% at baseline to 36.0±11.3% at 6 months (<i>P</i><0.001) and to 40.1±12.6% at 12 months (<i>P</i><0.001). After CRT, 42 metabolite features were significantly decreased compared with the baseline. The ketone bodies, including 3-hydroxybutyrate (<i>P</i><0.001) and acetone (<i>P</i>=0.01), were reduced. A branched-chain amino acid, isoleucine, was also decreased after CRT (<i>P</i>=0.01). These metabolomic changes were mainly observed in the nonischemic cardiomyopathy group, while the metabolomic profile in the ischemic cardiomyopathy group was characterized by enhanced amino acid oxidation and elevated levels of lactate and pyruvate. The improvement in LVEF positively correlated with the ratio of changes in ketone bodies and isoleucine.</p><p><strong>Conclusions: </strong>CRT may modulate the systemic plasma metabolomic profile, which correlated with improvement in left ventricular function in patients with severe heart failure with reduced ejection fraction.</p>","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e014148"},"PeriodicalIF":8.3,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918565","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}

{"title":"Atrial Fibrillation in Genotyped Dilated Cardiomyopathy: Epidemiology, Risk Factors, and Outcomes: Insights From the SHaRe Registry.","authors":"Iswaree D Balakrishnan, Astrid B M Heymans, Brian Claggett, Garrick C Stewart, Christine E Seidman, Sophie L V M Stroeks, Nina J Beelen, Max F G H M Venner, Anjali T Owens, Sharlene M Day, Adam S Helms, Supriya Shore, Matthew T Wheeler, Alessandra Fornaro, Iacopo Olivotto, Luisa Mestroni, Sadiya S Khan, Gianfranco Sinagra, Marco Merlo, Joseph Rossano, Kimberly Y Lin, Lynne W Stevenson, Upasana Tayal, Matthew R G Taylor, Lisa D Wilsbacher, Sanjay K Prasad, Stephane R B Heymans, Carolyn Y Ho, Victoria N Parikh, Job A J Verdonschot, Neal K Lakdawala","doi":"10.1161/CIRCHEARTFAILURE.125.014322","DOIUrl":"https://doi.org/10.1161/CIRCHEARTFAILURE.125.014322","url":null,"abstract":"<p><strong>Background: </strong>Atrial fibrillation (AF) is the most common arrhythmia in dilated cardiomyopathy (DCM) and is associated with adverse outcomes. However, the genetic determinants of AF risk and its prognostic significance across genotyped DCM subtypes remain unknown.</p><p><strong>Methods: </strong>In this observational cohort study, we analyzed 3117 genotyped patients with DCM from the SHaRe (Sarcomeric Human Cardiomyopathy Registry). AF prevalence, incidence, and clinical characteristics were assessed by genotype. Patients were classified as genotype-positive [G(+)] if they had a pathogenic or likely pathogenic variant in a DCM-associated gene, and genotype-negative [G(-)] if genetic testing was negative. Factors associated with incident AF were evaluated using Cox regression. AF was modeled as a time-dependent variable to evaluate associations with clinical outcomes.</p><p><strong>Results: </strong>Among 3117 genotyped patients with DCM (mean age, 48±15 years; 39% were female; and 35% were G[+]), 12.3% (n=384) had prevalent AF. Of 2491 patients without prevalent AF and with follow-up, 312 (12.5%) developed AF during a median of 4.5 years (interquartile range, 1.6-9.0). Among 2851 patients with follow-up, cumulative AF prevalence was 23.6%. <i>LMNA</i> had the highest AF incidence (7.6/100 patient-years) and cumulative AF prevalence (56.7%) and was the only genotype independently associated with incident AF compared with that in G(-) patients (hazard ratio, 5.52 [95% CI, 3.84-7.95]; <i>P</i><0.001). <i>TTN</i> had an AF incidence of 2.1 per 100 patient-years and cumulative AF prevalence of 24.4%, comparable to that in G(-) patients. Older age, male sex, and prior heart failure hospitalization were also independently associated with incident AF. AF was independently associated with a higher risk of the composite clinical outcome (hazard ratio, 1.58 [95% CI, 1.29-1.94]; <i>P</i><0.001), including heart failure, ventricular arrhythmias, and all-cause mortality.</p><p><strong>Conclusions: </strong>In this large genotyped DCM cohort, AF burden and incident AF risk varied across genotypes. Only <i>LMNA</i> was associated with an increased risk of incident AF. AF onset was independently associated with adverse outcomes, supporting genotype-guided AF surveillance and management in DCM.</p>","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e014322"},"PeriodicalIF":8.3,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918615","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}

{"title":"Changes in Hemodynamic and Inferior Vena Cava Parameters during Supine and Upright Exercise in a Patient With a Left Ventricular Assisted Device.","authors":"Rebecca Steinberg, Veraprapas Kittipibul, Stuart D Russell, Marat Fudim","doi":"10.1161/CIRCHEARTFAILURE.125.014037","DOIUrl":"https://doi.org/10.1161/CIRCHEARTFAILURE.125.014037","url":null,"abstract":"","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e014037"},"PeriodicalIF":8.3,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918563","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}

{"title":"Fatty Acid and Oxylipin Metabolism Differentiate Isolated Postcapillary From Combined Pre- and Postcapillary Pulmonary Hypertension.","authors":"Mona Alotaibi, Amber Tang, Nancy Sun, Ian Gurholt, Emma Yuguchi, Kari Roberts, Ioana Preston, Rod Warburton, Jason X-J Yuan, Nick H Kim, Stephen Y Chan, Mohit Jain, Susan Cheng, Nicholas S Hill","doi":"10.1161/CIRCHEARTFAILURE.125.014073","DOIUrl":"10.1161/CIRCHEARTFAILURE.125.014073","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary hypertension (PH) due to left-sided heart disease (Group 2 PH) is the most common type of PH and comprises 2 subtypes with distinct clinical profiles and outcomes: isolated postcapillary PH and combined pre- and postcapillary PH (Cpc-PH). Bioactive lipid derivatives may underlie these divergent subphenotypes. This study aimed to investigate the molecular heterogeneity underlying Group 2 PH subtypes and identify shared pathways between Cpc-PH and pulmonary arterial hypertension (PAH).</p><p><strong>Methods: </strong>In a cross-sectional study, we profiled plasma bioactive lipids using liquid chromatography-mass spectrometry in 128 patients with isolated postcapillary PH (n=21), Cpc-PH (n=69), or PAH (n=38), as well as in plasma samples from animal models of severe PH.</p><p><strong>Results: </strong>Of the 844 profiled metabolites, 158 differed between Cpc-PH and isolated postcapillary PH at a false discovery rate of <i>q</i><0.05. Of those, 28 were higher in Cpc-PH, particularly those in the polyunsaturated fatty acid and fatty acyl esters of hydroxy fatty acid pathways. Notably, 24 of these 28 did not differ from PAH, indicating a PAH-like bioactive lipid signature. Several metabolites, including adrenic acid, linoleic acid, docosatrienoic acid, palmitoleic acid, and fatty acyl esters of hydroxy fatty acids, were associated with increased mortality. These findings were corroborated in the Su/Hx rat model of PAH, where a subset of Cpc-PH-elevated metabolites was similarly increased.</p><p><strong>Conclusions: </strong>Cpc-PH exhibits a distinct, PAH-like metabolomic signature characterized by higher polyunsaturated fatty acids and fatty acyl esters of hydroxy fatty acids and lower pro-resolvin/vasodilatory oxylipins compared with isolated postcapillary PH. These findings have implications for PH classification, may inform diagnostic strategies, and nominate lipid pathways for therapeutic targeting.</p>","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e014073"},"PeriodicalIF":8.3,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13564202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomics Profiling Reveals Molecular Subtypes of Transthyretin Cardiac Amyloidosis.","authors":"Itsuki Osawa, Sergio L Teruya, Dimitrios Bampatsias, Alfonsina Mirabal, Mathew S Maurer, Yuichi J Shimada","doi":"10.1161/CIRCHEARTFAILURE.125.012449","DOIUrl":"10.1161/CIRCHEARTFAILURE.125.012449","url":null,"abstract":"<p><strong>Background: </strong>Transthyretin cardiac amyloidosis (ATTR-CA) may involve heterogeneity in biological mechanisms (ie, molecular subtypes). Molecular subtypes potentially lead to differences in prognosis and treatment response to tafamidis-the first disease-modifying therapy for ATTR-CA. We aimed to derive molecular subtypes of ATTR-CA through comprehensive plasma proteomics profiling and to examine their associations with prognosis and estimated treatment effect of tafamidis.</p><p><strong>Methods: </strong>We applied unsupervised machine learning to comprehensive plasma proteomics profiling of 7289 proteins to identify molecular subtypes in our prospective cohort of patients with ATTR-CA enrolled at Columbia University. We compared all-cause mortality risk and estimated the treatment effect of tafamidis among the identified molecular subtypes, adjusting for age, sex, TTR genotype, and concomitant medication use. We also performed pathway analysis comparing the worst prognosis subtype with the other subtypes combined.</p><p><strong>Results: </strong>Among 142 patients eligible for analysis, 96 patients received tafamidis treatment. We identified 3 molecular subtypes (subtype A: n=49, subtype B: n=38, and subtype C: n=55) with different survival risks during a median follow-up of 5.2 years (log-rank <i>P</i>=0.035), without significant differences in traditional clinical stages. Mortality risk was highest in subtype A, followed by B and then C (eg, adjusted hazard ratio of subtype A versus C [95% CI], 1.95 [1.03-3.66]; <i>P</i>=0.04). The largest treatment effect of tafamidis was observed in subtype A compared with no tafamidis use within the same subtype (adjusted hazard ratio for mortality, 0.24 [0.10-0.55]), indicating heterogeneous treatment effects of tafamidis (<i>P</i> for interaction=0.001). Subtype A had dysregulation of Ras/MAPK (mitogen-activated protein kinase) pathways, pathways implicated in ATTR-CA pathogenesis, and metabolic/inflammatory pathways.</p><p><strong>Conclusions: </strong>Our prospective cohort study using comprehensive plasma proteomics profiling not only uncovered molecular ATTR-CA subtypes but also identified pathogenetic mechanisms associated with differential prognosis and estimated the treatment effect of tafamidis.</p>","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e012449"},"PeriodicalIF":8.3,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13597163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}