Circulation: Heart Failure最新文献

{"title":"Sex Differences in Prognosis of Patients With Genetic Dilated Cardiomyopathy.","authors":"Sophie L V M Stroeks, Marco Merlo, Nerea Mora-Ayestaran, Max Jason, Upasana Tayal, Ping Wang, Antonio Cannatà, Maurits A Sikking, Matteo Dal Ferro, Belen Peiro, Myrthe Willemars, Debby M E I Hellebrekers, Rick E W van Leeuwen, Martina Setti, Esther Gonzalez-Lopez, Ingrid P C Krapels, Carola Pio Loco Detto Gava, Arthur van den Wijngaard, Michiel T H M Henkens, Manuela Iseppi, Anne G Raafs, Martijn F Hoes, Vanessa P M van Empel, Elizabeth A V Jones, Miranda Nabben, Matthew Taylor, Han G Brunner, Juan Pablo Ochoa, Fernando Dominguez, Neal K Lakdawala, Gianfranco Sinagra, Pablo Garcia-Pavia, Luisa Mestroni, Stephane R B Heymans, Job A J Verdonschot","doi":"10.1161/CIRCHEARTFAILURE.124.012592","DOIUrl":"https://doi.org/10.1161/CIRCHEARTFAILURE.124.012592","url":null,"abstract":"<p><strong>Background: </strong>Dilated cardiomyopathy (DCM) is a genetically heterogeneous disease, presenting diverse clinical phenotypes and outcomes based on the underlying gene affected. The influence of sex on the gene-specific long-term prognosis of patients with genetic DCM remains unclear. This study aims to determine the effect of sex on the long-term prognosis per underlying genogroup.</p><p><strong>Methods: </strong>A retrospective cohort study was conducted using data from 4 international referral centers. Baseline and longitudinal clinical data of patients with DCM, with a median follow-up of 6.7 years (interquartile range, 3.5-11.9 years), were collected. The study included men and women with DCM who had undergone genetic testing. Patients were categorized into 7 genotype groups: cytoskeletal/Z-disk, desmosomal, nuclear envelope, motor sarcomeric, <i>TTN</i>, other genetic, and genotype negative. The main outcomes measured were left ventricular reverse remodeling, mortality, heart failure hospitalization, heart transplantation, and malignant ventricular arrhythmias.</p><p><strong>Results: </strong>Among 1716 patients, 1130 (66%) were men and 510 (30%) had a (likely) pathogenic variant. Ventricular remodeling was gene-dependent in women, with TTN patients exhibiting the highest rate (<i>P</i>=0.003) and desmosomal patients the lowest (<i>P</i>=0.04) compared with the genotype-negative group. After a median follow-up of 6.7 years, 334 men (29%) and 140 women (24%) reached the primary end point. Men with a (likely) pathogenic variant had the poorest prognosis, showing a higher rate of major adverse events (adjusted hazard ratio, 1.48 [95% CI, 1.12-1.95]; <i>P</i>=0.02) and malignant ventricular arrhythmias (adjusted hazard ratio, 1.83 [95% CI, 1.16-2.88]; <i>P</i>=0.009) compared with genotype-negative women. Prognosis varied by gene in men (log-rank <i>P</i><0.0001) but not in women (log-rank <i>P</i>=0.1). The cytoskeletal/Z-disk, desmosomal, and nuclear envelope groups had the worst prognosis in men.</p><p><strong>Conclusions: </strong>The genetic architecture and sex are critical predictors of left ventricular reverse remodeling and long-term prognosis in DCM. These factors should be integrated into individualized risk prediction models to enhance clinical outcomes in patients with DCM.</p>","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e012592"},"PeriodicalIF":8.4,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130227","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":"National Differences in Trends for Heart Failure Hospitalizations by Sex and Race/Ethnicity.","authors":"Manyoo A Agarwal, Pratyakash K Srivastava, Carolyn S P Lam, Gregg C Fonarow, Boback Ziaeian","doi":"10.1161/CIRCHEARTFAILURE.125.013089","DOIUrl":"https://doi.org/10.1161/CIRCHEARTFAILURE.125.013089","url":null,"abstract":"","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e013089"},"PeriodicalIF":8.4,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130171","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":"Intraoperative Massive Acute Ventricular Wall Thickening During HeartMate 3 Implantation.","authors":"Merna Hussien, Matthew Johnson, Elaine Huang, Tania A Vora, Farooq H Sheikh, Keki R Balsara, Alexander I Papolos","doi":"10.1161/CIRCHEARTFAILURE.125.012797","DOIUrl":"https://doi.org/10.1161/CIRCHEARTFAILURE.125.012797","url":null,"abstract":"","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e012797"},"PeriodicalIF":8.4,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130203","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":"Unraveling the Pathophysiological Mechanisms of Phospholamban R14del Cardiomyopathy: A Comprehensive Overview.","authors":"Renee G C Maas, Luuk Kerckhaert, Judy Broersma, Evangelia G Kranias, Pieter A Doevendans, Joost P G Sluijter, Francesca Stillitano","doi":"10.1161/CIRCHEARTFAILURE.124.012661","DOIUrl":"https://doi.org/10.1161/CIRCHEARTFAILURE.124.012661","url":null,"abstract":"<p><p>The discovery of the PLN-R14del (deletion of arginine 14 [p.Arg14del] within the phospholamban protein) genetic mutation, characterized by a deletion of R14 in phospholamban, in a large Greek family marked a significant milestone in understanding the cause of its associated cardiomyopathy. Since its initial identification in 2006, this mutation has been found in numerous patients across 11 countries. PLN-R14del carriers commonly exhibit both dilated cardiomyopathy and arrhythmogenic cardiomyopathy, accounting for a significant portion of annual heart transplants in the Netherlands. Under physiological conditions, PLN plays a crucial role in regulating the calcium pump SERCA2a (sarco[endo]plasmic reticulum calcium ATPase 2a) within cardiomyocytes. While the normal function of PLN has been extensively studied, the precise mechanisms underlying the pathogenesis of PLN-R14del-induced heart disease remain uncertain and subject to ongoing debate. The current review systematically summarizes existing literature on the PLN-R14del mutation, elucidating its pathological phenotypes and discussing its implications in PLN-R14del cardiomyopathy. Current knowledge is consolidated, and unresolved questions are addressed with the aim to contribute to a deeper understanding of PLN-R14del-associated cardiac pathology. Finally, this review provides guidance for future research to advance diagnosis and therapeutic approaches for affected individuals.</p>","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e012661"},"PeriodicalIF":8.4,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130255","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":"Transpulmonary Proteome Gradients Identify Pathways Involved in Pulmonary Vascular Disease Due To Heart Failure.","authors":"Vojtech Melenovsky, Petr Jarolim, Eva Kutilkova, Dominik Jenca, Jana Binova, Hikmet Al-Hiti, Janka Franekova, Sona Kikerlova, Svetlana Yarnykh, Marketa Adamova, Matus Miklovic, Barry A Borlaug","doi":"10.1161/CIRCHEARTFAILURE.125.013208","DOIUrl":"https://doi.org/10.1161/CIRCHEARTFAILURE.125.013208","url":null,"abstract":"<p><strong>Background: </strong>Some, but not all, patients with heart failure (HF) develop pulmonary vascular disease (PVD), which contributes to poor prognosis. Mechanisms leading to PVD in HF are poorly understood. We aimed to analyze transpulmonary gradients of proteins consumed or elaborated across the lungs to identify mediators of PVD by unbiased proteomics.</p><p><strong>Methods: </strong>Overall, 21 controls and 160 patients with HF with reduced ejection fraction underwent pulmonary artery catheterization with blood sampling from postcapillary (wedged balloon) and precapillary (unwedged) position to obtain transpulmonary gradients. The samples from controls and HF from the highest (Q4, n=40) and lowest quartile (Q1, n=40) of pulmonary vascular resistance (PVR) were analyzed using the proteomic proximity extension assay (Olink) of 275 proteins. Venous blood concentrations or transpulmonary gradients were analyzed to identify biomarkers or potential mediators of PVD.</p><p><strong>Results: </strong>Comparison of Q1 and Q4 of PVR identified PSP-D (pulmonary surfactant-associated protein D) as a marker of PVD. Examination of gradients across the lungs in high PVR HF revealed significant uptake of 18 proteins, mostly associated with inflammation (chemokines, oncostatin-M, MMP9 [matrix metalloproteinase 9]) or with TGF (transforming growth factor)/activin pathway (GDF2 [growth differentiation factor 2]/BMP9 [bone morphogenic protein 9]), and release of 5 proteins, notably IL (interleukin) 6 and IL33. In contrast, these protein gradients were negligible in controls and low PVR patients with HF. Active pulmonary release of IL6 contributed to systemic elevation of IL6 and correlated with right ventricular function.</p><p><strong>Conclusions: </strong>The lungs of patients with HF with high PVR display abnormal uptake and release of proinflammatory cytokines from IL6/gp130 family (IL6, IL33, oncostatin-M), along with increased transpulmonary uptake of GDF2/BMP9. The study shows that proteins orchestrating inflammation or pulmonary vessel remodeling in group 1 pulmonary hypertension, are also operating in patients with PVD due to HF.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT06331208.</p>","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e013208"},"PeriodicalIF":8.4,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124285","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":"Contextualizing the 2018 Heart Transplant Allocation Change: Progress Made, Yet Equity Gaps Remain.","authors":"Rebecca Cogswell, Thomas M Cascino","doi":"10.1161/CIRCHEARTFAILURE.125.013509","DOIUrl":"https://doi.org/10.1161/CIRCHEARTFAILURE.125.013509","url":null,"abstract":"","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e013509"},"PeriodicalIF":8.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074550","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":"TAPSE/sPAP Ratio to Improve Risk Assessment in Pulmonary Arterial Hypertension.","authors":"Roberto Badagliacca, Khodr Tello, Michele D'Alto, Stefano Ghio, Paola Argiento, Natale Daniele Brunetti, Vito Casamassima, Gavino Casu, Nadia Cedrone, Marco Confalonieri, Marco Corda, Michele Correale, Carlo D'Agostino, Lucrezia De Michele, Domenico Filomena, Giuseppe Galgano, Alessandra Greco, Carlo Lombardi, Rosalinda Madonna, Giovanna Manzi, Valentina Mercurio, Alexandra Mihai, Massimiliano Mulè, Giuseppe Paciocco, Silvia Papa, Zvonimir Rako, Tommaso Recchioni, Manuel Richte, Antonella Romaniello, Emanuele Romeo, Laura Scelsi, Davide Stolfo, Patrizio Vitulo, Athiththan Yogeswaran, Robert Naeije, Raymond Benza, Carmine Dario Vizza","doi":"10.1161/CIRCHEARTFAILURE.124.012518","DOIUrl":"https://doi.org/10.1161/CIRCHEARTFAILURE.124.012518","url":null,"abstract":"<p><strong>Background: </strong>Right ventricular functional adaptation to afterload is a major determinant of outcome in pulmonary arterial hypertension (PAH). We aimed to investigate if right ventricular-PA coupling evaluated by the ratio of tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (sPAP) improves risk assessment scores for survival prediction.</p><p><strong>Methods: </strong>A total of 677 consecutive patients with PAH (55% idiopathic) were prospectively enrolled with follow-up clinical, right heart catheterization, and echocardiographic evaluations within 12 months (interquartile range, 180-344 days) after initiation of targeted therapies in 11 Italian centers. European Society of Cardiology/European Respiratory Society guidelines-derived risk scores and REVEAL 2.0 (US Registry to Evaluate Early and Long-Term PAH Disease Management 2.0) risk scores were collected at baseline and follow-up. 254 consecutive patients with PAH retrospectively enrolled in a German reference center served as a validation cohort.</p><p><strong>Results: </strong>A low-risk status at a median of 3.7 years (interquartile range, 1.2-6.8) follow-up was significantly associated with each unit (0.1 mm/mm Hg) increase in TAPSE/sPAP under targeted therapies (European Society of Cardiology/European Respiratory Society score: odds ratio, 1.78; <i>P</i>≤0.001; REVEAL 2.0 score: odds ratio, 1.43; <i>P</i>≤0.001). At follow-up, the TAPSE/sPAP ratio increased the prognostic information of each risk stratum of the European Society of Cardiology/European Respiratory Society risk score, except the highest risk stratum, with 0.5 mm/mm Hg, 0.35 mm/mm Hg, and 0.30 mm/mm Hg, from the lowest to the intermediate-high risk score, identified as the best cutoff value. TAPSE/sPAP ratio increased the prognostic information of the REVEAL 2.0 score at follow-up, with 0.35 mm/mm Hg identified as the best cutoff value to discriminate within a score of 5 to 8, with no added value for scores <5 and >8. These results were confirmed in the validation cohort.</p><p><strong>Conclusions: </strong>Assessment of right ventricular-PA coupling by the TAPSE/sPAP ratio in PAH improves risk assessment scores except in the lowest or most advanced stage of the disease.</p>","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e012518"},"PeriodicalIF":8.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074603","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":"Drug-Refractory Peripartum Cardiomyopathy With Novel Loss-of-function Variants in <i>LAMP2</i> and <i>TTN</i>.","authors":"Ryo Abe, Shunsuke Inoue, Seitaro Nomura, Minoru Ono, Norihiko Takeda, Issei Komuro","doi":"10.1161/CIRCHEARTFAILURE.125.012802","DOIUrl":"https://doi.org/10.1161/CIRCHEARTFAILURE.125.012802","url":null,"abstract":"","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e012802"},"PeriodicalIF":8.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074581","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":"Network Meta-Analysis of Quality of Life in Heart Failure With Reduced Ejection Fraction.","authors":"Robert Margaryan, Nariman Sepehrvand, Wouter Ouwerkerk, Jasper Tromp, Ricky D Turgeon, Justin A Ezekowitz","doi":"10.1161/CIRCHEARTFAILURE.125.013074","DOIUrl":"https://doi.org/10.1161/CIRCHEARTFAILURE.125.013074","url":null,"abstract":"<p><strong>Background: </strong>Although the effects of various combinations of treatments on mortality and morbidity outcomes in heart failure with reduced ejection fraction (HFrEF) have been evaluated, the impact on quality of life is unknown. This study evaluated and compared the composite impact of pharmacological therapies on quality of life in HFrEF using a frequentist network meta-analysis and systematic review methodology.</p><p><strong>Methods: </strong>We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for randomized controlled trials published between January 1, 2021 and August 10, 2024. We included all contemporary and efficacious HFrEF therapies used in adults. The primary outcome was change in quality of life measured through the Kansas City Cardiomyopathy Questionnaire and the Minnesota Living with Heart Failure Questionnaire, expressed as mean difference (MD).</p><p><strong>Results: </strong>We identified 41 randomized controlled trials representing 41 145 patients (76.5% male). The trials had a median of 276 participants (105-464), a mean left ventricular ejection fraction of 28%, and a median follow-up time of 5 months (3-8). A combination of angiotensin receptor blocker/neprilysin inhibitors (ARNi)+β-blockers (BB)+sodium-glucose cotransporter 2 inhibitors (SGLT2i; MD, +5.3 [+0.4, +10.3]) was the most effective at improving quality of life followed by ARNi+BB+mineralocorticoid receptor antagonists (MRA)+SGLT2i (MD, +7.1 [-1.0 to +15.2]), ACE inhibitor+BB+MRA+SGLT2i (MD, +5.3 [-2.6, to +13.3]), and ACE inhibitor+BB+MRA+ivabradine (MD, +5.2 [-3.1 to +13.6]), which were not statistically significant. Individually, the most effective treatments for improving quality of life were SGLT2i (MD, +3.4 [+1.4 to +5.30]), ivabradine (MD, +3.3 [+0.1 to +6.4]), ARNi (MD, +2.6 [-3.2 to +8.5]), and MRA (MD, +1.8 [-4.8 to +8.4]).</p><p><strong>Conclusions: </strong>A composite of ARNi+BB+SGLT2i or ARNi+BB+MRA+SGLT2i was the most effective at improving quality of life in patients with HFrEF.</p>","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e013074"},"PeriodicalIF":8.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999855","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":"Mitochondrial sORF-Encoded Peptide MODICA Protects the Heart From Doxorubicin-Induced Cardiac Injury by Suppressing VDAC Oligomerization.","authors":"Jialing Wu, Kang Li, Youchen Yan, Xingfeng Xu, Ting Xu, He Xu, Huimin Zhou, Tailai Du, Yan Li, Chen Liu, Xinxue Liao, Yugang Dong, Jing-Song Ou, Yili Chen, Zhan-Peng Huang","doi":"10.1161/CIRCHEARTFAILURE.125.013381","DOIUrl":"https://doi.org/10.1161/CIRCHEARTFAILURE.125.013381","url":null,"abstract":"<p><strong>Background: </strong>Doxorubicin (DOX) cardiotoxicity increases cardiovascular risk in cancer patients, mainly through mitochondrial damage. However, the underlying mechanisms remain unclear, and whether mitochondrial short open reading frame-encoded peptides can mitigate DOX-induced cardiotoxicity is unknown.</p><p><strong>Methods: </strong>Five adeno-associated viruses expressing mitochondrial short open reading frame-encoded peptides under the cardiac troponin T promoter, including MODICA (mito-SEP protector against DOX-induced cardiac injury), were screened in a DOX-induced cardiotoxicity mouse model (n=3-5 per group). Male and female mice were randomized to adeno-associated virus-CTRL or adeno-associated virus-MODICA, respectively, combined with saline or DOX treatment. Sample sizes were: males-saline-CTRL (n=4), saline-MODICA (n=4), DOX-CTRL (n=11), DOX-MODICA (n=10); females-saline-CTRL (n=8), saline-MODICA (n=10), DOX-CTRL (n=10), DOX-MODICA (n=13). MODICA-heterozygous mice generated by CRISPR/Cas9 were also included: saline-WT (n=7), saline-heterozygous (n=4), DOX-WT (n=11), DOX-heterozygous (n=8). Echocardiography was performed at baseline and after 2 weeks of DOX treatment; myocardial tissue and serum samples were collected for molecular and histological analyses.</p><p><strong>Results: </strong>The mitochondrial short open reading frame-encoded peptide MODICA was identified through biochemical analysis and functional screening in a DOX-induced cardiac injury model. MODICA localizes to the outer mitochondrial membrane and is significantly downregulated by DOX (1.00±0.08 versus 0.42±0.09; <i>P</i><0.001). Cardiac-specific overexpression of MODICA via adeno-associated viruses significantly attenuated DOX-induced cardiac injury in both males and females (fractional shortening: males 38.86% versus 51.54%, <i>P</i><0.001; females 39.81% versus 51.39%, <i>P</i><0.001, DOX-CTRL versus DOX-MODICA) and was supported by bulk RNA-seq analysis. Conversely, MODICA deficiency exacerbated DOX-induced injury, resulting in reduced fractional shortening (40.37% versus 31.85%, <i>P</i><0.001; DOX-WT versus DOX-heterozygous) and increased cardiac fibrosis (<i>P</i>=0.009). Proteomic analyses revealed that MODICA interacts with apoptosis-related voltage-dependent anion channel proteins, inhibiting their DOX-induced oligomerization (<i>P</i><0.001) on the outer mitochondrial membrane, thereby reducing mitochondrial permeability, decreasing cardiomyocyte apoptosis and improving calcium handling.</p><p><strong>Conclusions: </strong>Our study shows that the mitochondrial short open reading frame-encoded peptide MODICA alleviates DOX-induced cardiac dysfunction and may represent a therapeutic target against DOX cardiotoxicity.</p>","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e013381"},"PeriodicalIF":8.4,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991677","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}