Journal of the American Heart Association最新文献

{"title":"Nighttime Blood Pressure Matters Even in Heart Failure.","authors":"Christine Chow, William J Healy, Younghoon Kwon","doi":"10.1161/JAHA.125.043451","DOIUrl":"https://doi.org/10.1161/JAHA.125.043451","url":null,"abstract":"","PeriodicalId":54370,"journal":{"name":"Journal of the American Heart Association","volume":" ","pages":"e043451"},"PeriodicalIF":5.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144676530","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":"Unlocking Potential: The Untapped Resources to Expand the Field of Adult Congenital Heart Disease Providers.","authors":"Abigail Khan, Anitra Romfh","doi":"10.1161/JAHA.125.043295","DOIUrl":"https://doi.org/10.1161/JAHA.125.043295","url":null,"abstract":"","PeriodicalId":54370,"journal":{"name":"Journal of the American Heart Association","volume":" ","pages":"e043295"},"PeriodicalIF":5.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144676534","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":"Adult Congenital Heart Disease as a Career? Examining Encouraging and Deterring Factors in the Global ACHD Survey.","authors":"Katia Bravo-Jaimes, M H D Osama Srour, Petra Jenkins, Raquel Luna-Lopez, Oktay Tutarel, Geetha Kandavello, Carlos-Eduardo Guerrero-Chalela, Edgar García-Cruz, Judith Ackerman, Amalia Elizari, Miriam Valdez-Ramos, Blanche Cupido, Dominica Zentner, Murad Almasri, Sabrina Phillips, Christopher J McLeod, Luke J Burchill, Celia Kamath, Renee P Bullock-Palmer, Jonathan Windram","doi":"10.1161/JAHA.125.041276","DOIUrl":"https://doi.org/10.1161/JAHA.125.041276","url":null,"abstract":"<p><strong>Background: </strong>There is a global mismatch between the number of adults with congenital heart disease and adult congenital heart disease (ACHD) cardiologists, potentially impacting patient outcomes. This survey explores factors influencing trainees and cardiologists' career choices in ACHD.</p><p><strong>Methods: </strong>An online, anonymous global survey on demographics, ACHD as a career choice, encouraging and deterring factors assessed via a 5-point Likert scale and open-ended questions on recommending ACHD was distributed through targeted emails and social media. Responses meeting a 75% completion criterion were analyzed using descriptive statistics and thematic analysis.</p><p><strong>Results: </strong>Among 811 included responses, most were from women (53.5%), aged 31 to 40 years (48.3%), White individuals (43.3%), non-Hispanic individuals (85%), from outside the ACHD field (79.0%), and from North America (42.7%). Only 30.9% of non-ACHD physicians considered specializing in ACHD despite 78.9% recommending it. Encouraging factors included awareness of ACHD significance, mentor influence, and clinical exposure. Key deterrents were inadequate financial incentives, limited job opportunities, and lengthy training. Regional variations showed that longer training duration and lack of compensation incentives were the main deterrents in North America. Suggested solutions included structured training programs, salary improvements, and early ACHD exposure during medical education.</p><p><strong>Conclusions: </strong>Less than a third of respondents considered ACHD as a career largely due to inadequate financial incentives, limited job opportunities, and long training duration. Addressing these barriers could enhance recruitment and help meet the growing demands of the ACHD population.</p>","PeriodicalId":54370,"journal":{"name":"Journal of the American Heart Association","volume":" ","pages":"e041276"},"PeriodicalIF":5.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144676526","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":"Renal Denervation Improves Uremic Cardiomyopathy in Rats With Chronic Kidney Disease.","authors":"Philipp Markwirth, Simina-Ramona Selejan, Mathias Hohl, Stefan J Schunk, Andreas Müller, Stefan Wagenpfeil, Lea Wagmann, Florian Kahles, Mert Tokcan, Markus Therre, Emiel P C van der Vorst, Matthias Rau, Heidi Noels, Julia Wollenhaupt, Felix Mahfoud, Michael Böhm","doi":"10.1161/JAHA.124.038785","DOIUrl":"https://doi.org/10.1161/JAHA.124.038785","url":null,"abstract":"<p><strong>Background: </strong>Chronic kidney disease (CKD) is an independent cardiovascular risk factor. Patients with CKD develop uremic cardiomyopathy characterized by activation of the sympathetic nervous system, left ventricular hypertrophy, and accumulation of uremic toxins such as indoxyl sulfate (IS). The aim of this study was to assess the effects of renal denervation (RDN) on uremic cardiomyopathy in a rat model of CKD.</p><p><strong>Methods: </strong>Sprague-Dawley rats were fed a standard chow (control group, n=6) or a 0.25% adenine-enriched chow (n=16) for 16 weeks to induce CKD. After 4 weeks, CKD rats with CKD were subjected to bilateral RDN (AD-RDN, n=8) or to sham operation (AD, n=8). Blood pressure measurements, echocardiography, and cardiac magnetic resonance imaging were deployed during the experiment. Left ventricular hypertrophy was evaluated histologically. IS was measured using ELISA. In H9C2 cardiomyoblasts, the hypertrophic effects of IS were characterized in vitro.</p><p><strong>Results: </strong>In AD rats, left ventricular septal wall thickness (2.37±0.036 versus 1.91±0.014 mm in CTRL, <i>P</i> <0.0001), E/A ratio, and cardiomyocyte size were significantly increased. Following RDN, left ventricular wall thickness (<i>P</i> <0.0001 versus AD), E/A ratio (<i>P</i> <0.0001 versus AD), and myocyte hypertrophy were significantly reduced. Plasma IS was increased in AD (0.79±0.07 versus 0.2±0.12 μg/mg in the control group, <i>P</i>=0.0044) and reduced in AD-RDN (<i>P</i>=0.0073 versus AD). Urinary IS remained unchanged after RDN, whereas hepatic concentration of IS decreased after RDN (<i>P</i>=0.023). Plasma IS correlated with left ventricular hypertrophy (r=0.779, <i>P</i> <0.0001). Stimulation of H9C2 cardiomyoblasts with IS or serum from AD rats showed an increase in cell size (<i>P</i>=0.0015), whereas AD-RDN serum showed no effect.</p><p><strong>Conclusions: </strong>In a rat model of CKD, improved cardiac function following RDN was associated with reduced plasma concentrations of IS. To the present, IS remains a persistent clinical concern in patients with CKD due to its inefficient removal by conventional hemodialysis and its significant role in promoting both kidney and myocardial disease. Thus, RDN may ameliorate uremic cardiomyopathy by reducing IS and potentially represents a treatment option for patients with CKD and cardiovascular disease. Clinical trials are warranted to investigate the effects of RDN on cardiovascular outcomes in patients with CKD.</p>","PeriodicalId":54370,"journal":{"name":"Journal of the American Heart Association","volume":" ","pages":"e038785"},"PeriodicalIF":5.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144676532","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":"Nighttime Systolic Blood Pressure Determined by Pulse Transit Time Predicts Cardiac Events in Patients With Heart Failure.","authors":"Naoto Ohashi, Yu Sato, Akiomi Yoshihisa, Ryohei Takeishi, Tomofumi Misaka, Tetsuro Yokokawa, Takamasa Sato, Masayoshi Oikawa, Atsushi Kobayashi, Kazuhiko Nakazato, Yasuchika Takeishi","doi":"10.1161/JAHA.124.039917","DOIUrl":"https://doi.org/10.1161/JAHA.124.039917","url":null,"abstract":"<p><strong>Background: </strong>The optimal systolic blood pressure (SBP) target for heart failure (HF) patients has not been established. Although the association between daytime SBP and prognosis has been reported in patients with HF, the prognostic impact of nighttime SBP remains unclear.</p><p><strong>Methods: </strong>We conducted continuous nighttime SBP measurements noninvasively using pulse transit time in 366 patients with HF (median age, 72 years; male sex, 195), and followed up for cardiac events (HF hospitalization or cardiac death). Average values of nighttime pulse transit time -based SBP were used in the present study. The patients were divided into tertile groups based on nighttime pulse transit time-based SBP: high-SBP group (median SBP, 136 mm Hg; n=122), middle-SBP group (median SBP, 117 mm Hg; n=122), and low-SBP group (median SBP, 100 mm Hg; n=122).</p><p><strong>Results: </strong>During a median follow-up period of 1083 days after nighttime pulse transit time-based SBP measurement, 71 patients experienced a cardiac event. Kaplan-Meier analysis showed the highest incidence of cardiac events in the low-SBP group. Multivariate Cox proportional hazard analysis also showed that the lowest SBP tertile was associated with a higher risk of cardiac events compared with the highest SBP tertile as reference (hazard ratio, 2.100 [95% CI, 1.121-3.933]; <i>P</i>=0.021).</p><p><strong>Conclusions: </strong>Low nighttime SBP was associated with an increased cardiac event rate in patients with HF.</p>","PeriodicalId":54370,"journal":{"name":"Journal of the American Heart Association","volume":" ","pages":"e039917"},"PeriodicalIF":5.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144676531","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":"Sleep Duration Irregularity and Risk for Incident Cardiovascular Disease in the UK Biobank.","authors":"Tianyi Huang, Sina Kianersi, Heming Wang, Kaitlin S Potts, Raymond Noordam, Tamar Sofer, Martin K Rutter, Susan Redline","doi":"10.1161/JAHA.124.040027","DOIUrl":"10.1161/JAHA.124.040027","url":null,"abstract":"<p><strong>Background: </strong>Emerging evidence supports a link between circadian disruption as measured by higher night-to-night variation in sleep duration and increased risk of cardiovascular disease (CVD). It remains unclear whether this association varies by CVD types or may be modified by average sleep duration and genetic risk for CVD.</p><p><strong>Methods: </strong>Our prospective analysis included 86 219 UK Biobank participants who were free from CVD when completing 7 days of accelerometer measurement from 2013 to 2015. Sleep irregularity was evaluated by the SD of accelerometer-measured sleep duration over 7 days. Incident major CVD events, defined as fatal or nonfatal myocardial infarction and stroke, were identified through linkage to Hospital Episode Statistics data until May 31, 2022. Multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs for associations of sleep duration SD with risk for major CVD events overall and for myocardial infarction and stroke separately.</p><p><strong>Results: </strong>We documented 2310 incident cases of major CVD events (myocardial infarction: 1183, stroke: 1175) over 636 258 person-years of follow-up. After adjusting for sociodemographic factors and family history of CVD, the HR associated with a 1-hour increase in sleep duration SD was 1.19 (95% CI, 1.10-1.27) for CVD (<i>P</i>-trend<0.0001), 1.23 (95% CI, 1.11-1.35) for myocardial infarction (<i>P</i>-trend<0.0001), and 1.17 (95% CI, 1.05-1.29) for stroke (<i>P</i>-trend=0.003). Additional adjustment for lifestyle factors, comorbidities, and sleep-related factors modestly attenuated these associations. Higher sleep irregularity was associated with higher CVD risk irrespective of genetic risk (<i>P</i>-interaction=0.43), but this association was stronger among individuals with longer average sleep duration >8 hours (<i>P</i>-interaction=0.006).</p><p><strong>Conclusions: </strong>Higher night-to-night variation in accelerometer-measured sleep duration was associated with consistently higher risks for major CVD events. The association did not seem to be modified by genetic risk for CVD and was more pronounced in long sleepers.</p>","PeriodicalId":54370,"journal":{"name":"Journal of the American Heart Association","volume":" ","pages":"e040027"},"PeriodicalIF":5.3,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144676533","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":"Comparative Evaluation of Resting and Hyperemic Angiography-Derived Index of Microcirculatory Resistance in Chronic Coronary Syndrome.","authors":"Yang Zhang, Quan Li, Yicong Ye, Xiliang Zhao, Liang Zhang, Zhennan Li, Tianyi Wang, Yaodong Ding, Li Lin, Yi Ye, Jiayi Han, Guosheng Fu, Jiancheng Xiu, Yongde Wang, Guipeng An, Ning Guo, Chao Zhang, Chunliang Wang, Qinghua Zhao, Huay-Cheem Tan, Yong Zeng","doi":"10.1161/JAHA.124.040173","DOIUrl":"https://doi.org/10.1161/JAHA.124.040173","url":null,"abstract":"<p><strong>Background: </strong>Angiography-derived index of microcirculatory resistance (IMR) has emerged as a feasible alternative to wire-based IMR, due to the elimination of specialized wire and simplifying of the procedure. However, the differences in diagnostic accuracy between hyperemic and resting angiography with this technology remain underexplored.</p><p><strong>Methods: </strong>This prospective, multicenter study was conducted to evaluate the feasibility and diagnostic accuracy of x-ray angiography-derived IMR (xaIMR) in patients with chronic coronary syndrome using wire-based functional indices as the reference. Angiography-derived functional indices were calculated using a computational fluid dynamics model. The xaIMR indices were derived from hyperemic and resting angiography, respectively.</p><p><strong>Results: </strong>A total of 139 vessels were included in the analysis of the present study. Both hyperemic xaIMR (<i>r</i>=0.82; <i>P</i><0.001) and resting xaIMR (R-xaIMR) (<i>r</i>=0.25; <i>P</i>=0.003) exhibited positive linear correlations with wire-based IMR. Notably, hyperemic xaIMR was associated with a higher diagnostic yield (area under the receiver operating characteristic curve) than resting xaIMR (area under the receiver operating characteristics curve, 0.95 versus 0.72; <i>P</i><0.001). Significant differences in diagnostic yield between these modalities were observed in vessels with compromised coronary flow reserve (<2.0). In contrast, such differences were not observed in vessels with normal coronary flow reserve (≥2.0).</p><p><strong>Conclusions: </strong>xaIMR, especially derived from hyperemic angiography, is a reliable, noninvasive alternative to wire-based IMR for assessing coronary microcirculatory resistance in chronic coronary syndrome. However, resting angiography-derived xaIMR may have limited diagnostic accuracy in patients with reduced coronary flow reserve. Further studies are warranted to validate these findings in broader populations.</p>","PeriodicalId":54370,"journal":{"name":"Journal of the American Heart Association","volume":" ","pages":"e040173"},"PeriodicalIF":5.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144676528","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":"Management and Outcomes of Patients Undergoing Cardiovascular Evaluation Across Health Care Systems: Comparison of Community Care and Integrated Veterans Affairs Health Care.","authors":"Stephen W Waldo, Thomas J Glorioso, Neel Butala, Paul Varosy, Claire S Duvernoy, Mary E Plomondon, Joseph Francis","doi":"10.1161/JAHA.125.041930","DOIUrl":"https://doi.org/10.1161/JAHA.125.041930","url":null,"abstract":"<p><strong>Background: </strong>The Veterans Affairs (VA) Healthcare System maintains the largest integrated health system in the United States but also supports fee-for-service insurance for veterans receiving care in community facilities outside the VA. We sought to evaluate the management and outcomes of patients referred for consultation in either venue, using cardiovascular evaluation as a model.</p><p><strong>Methods: </strong>We conducted a retrospective cohort study identifying patients enrolled in the VA Healthcare System referred for cardiovascular evaluation from October 2020 through September 2024 and stratified the population based on the venue in which evaluation was completed. The primary outcome was major adverse cardiovascular events (acute coronary syndromes/stroke/mortality) in a matched population.</p><p><strong>Results: </strong>Among 235 197 consultations for cardiovascular evaluation, 201 453 were completed in the chosen venue within 6 months. The time between consultation and evaluation was similar across venues (community, 35 days [95% CI, 17-65] versus VA, 33 days [95% CI, 19-53]), with comparable delays to diagnostic testing or therapeutic interventions. Patients receiving care in the community were more likely to undergo stress testing (43.2% versus 36.4%, <i>P</i>=1.5×10^-46) and coronary angiography (23.1% versus 17.4%, <i>P</i>=2.1×10^-51) within 2 years compared with those treated in the VA Healthcare System. Despite this, patients treated in the community had a significantly higher rate of major adverse events at 2 years (17.6% versus 15.3%, <i>P</i>=5.9×10^-10) compared with those treated in the VA Healthcare System.</p><p><strong>Conclusions: </strong>Patients undergoing cardiovascular evaluation in community practices were not evaluated more rapidly than those seen in the VA, though they were more likely to receive initial and repeat diagnostic testing. Adverse events were more common among community-treated patients than those in the VA, suggesting an opportunity to optimize access to care while improving clinical outcomes.</p>","PeriodicalId":54370,"journal":{"name":"Journal of the American Heart Association","volume":" ","pages":"e041930"},"PeriodicalIF":5.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661005","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":"Sex Differences in Stroke Frequency and Severity Following Transcatheter Aortic Valve Replacement.","authors":"Vijay A Joshi, Emily M Bucholz, Marshall Roll, Natalia Rahman, Dhaval Kolte, Carlos Davila, Robert W Yeh, David J Cohen, Stephen W Waldo, Neel M Butala","doi":"10.1161/JAHA.125.041943","DOIUrl":"https://doi.org/10.1161/JAHA.125.041943","url":null,"abstract":"<p><strong>Background: </strong>Stroke is a recognized complication following transcatheter aortic valve replacement (TAVR). Although women have historically had a higher rate of bleeding and vascular complications after TAVR, contemporary data on sex differences in post-TAVR stroke and stroke severity are lacking. Disabling strokes significantly affect quality of life and outcomes, underscoring the need to explore sex-specific variations in post-TAVR stroke risk.</p><p><strong>Methods: </strong>In this retrospective cohort study, we included all patients who underwent TAVR in the National Inpatient Sample from 2016 to 2021. Stroke and stroke severity were ascertained using validated claims-based algorithms. Disabling strokes were defined as those resulting in death or discharge to a nonhome location. We used multivariable logistic regression to evaluate the association between sex and stroke while adjusting for covariates, including cerebral embolic protection use, and accounting for survey weights.</p><p><strong>Results: </strong>Among our weighted sample of 379 410 patients (43.9% female), women demonstrated higher overall in-hospital stroke incidence compared with men (2.31% versus 1.69%; adjusted odds ratio [aOR], 1.208 [95% CI, 1.082-1.350]). This difference was driven primarily by disabling strokes, which were more common in women (1.61% versus 1.01%; aOR, 1.327 [95% CI, 1.158-1.520]). Conversely, the incidence of nondisabling stroke was not statistically different between sexes (0.70% versus 0.67%;( aOR, 1.013 [95% CI, 0.844-1.215]).</p><p><strong>Conclusions: </strong>Among patients undergoing TAVR in contemporary practice, women had a higher rate of any stroke and disabling strokes compared with men. These findings emphasize the need for tailored strategies to mitigate stroke risk and improve outcomes for female TAVR patients.</p>","PeriodicalId":54370,"journal":{"name":"Journal of the American Heart Association","volume":" ","pages":"e041943"},"PeriodicalIF":5.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651147","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":"Targeting <i>Mettl14</i> Using an RNA-Targeting Clustered Regularly Interspaced Short Palindromic Repeat-<i>High-Fidelity</i> Cas13x System Attenuates Doxorubicin-Induced Cardiotoxicity.","authors":"Wensi Wan, Caiyue Cui, Yi Zhou, Jiaqi Wang, Xuan Zhao, Xinxin Cui, Jiangpeng Sun, Pujiao Yu, Jingyi Feng, Tianhui Wang, Lijun Wang, Jiahong Xu","doi":"10.1161/JAHA.124.040700","DOIUrl":"https://doi.org/10.1161/JAHA.124.040700","url":null,"abstract":"<p><strong>Background: </strong>Doxorubicin is an effective chemotherapy drug used to treat various types of cancer. However, doxorubicin treatment is associated with cardiotoxicity, which limits its clinical use. Exercise can benefit both cancer and cardiovascular disease. Clustered regularly interspaced short palindromic repeat (CRISPR)-Cas13 (CRISPR-associated protein 13) platforms have emerged as effective technologies for targeting the expression of RNA in transcript levels. To develop exercise mimetics that can mimic the beneficial effects of exercise training to attenuate doxorubicin-induced cardiotoxicity, we are using the CRISPR-<i>hf</i> (<i>high-fidelity</i>)Cas13x system.</p><p><strong>Methods: </strong>Adult male mice were swim-trained twice a day for 4 weeks to induce exercise-induced physiological cardiac hypertrophy. Adeno-associated virus 9-mediated METTL14 (methyltransferase-like 14) overexpression under the cardiac-specific <i>ctnt</i> promoter was used to overexpression METTL14 in vivo. RNA N⁶-methyladenosine inhibitor STM2457 was used to modulate global total RNA m⁶A levels in vivo. CRISPR-cr3-4/<i>hf</i>Cas13x system was generated by <i>hf</i>Cas13x guided crRNA3 and crRNA4 targeting the <i>Mettl14</i> expressed under <i>ctnt</i> promoter and packaged in an adeno-associated virus 9.</p><p><strong>Results: </strong>Swimming exercise alleviated doxorubicin-induced cardiotoxicity. METTL14 was increased in doxorubicin-treated hearts but decreased in exercised hearts. METTL14 overexpression inhibited exercise-induced physiological cardiac hypertrophy. Conversely, STM2457 treatment reversed the suppressive effects of METTL14 overexpression on the physiological cardiac hypertrophy induced by exercise. Treatment with CRISPR-cr3-4/<i>hf</i>Cas13x effectively inhibiting the expression of METTL14 in the heart, alleviating doxorubicin treatment-induced cardiac dysfunction and cardiac fibrosis.</p><p><strong>Conclusions: </strong>Our results suggest that the CRISPR-<i>hf</i>Cas13x system has the potential for generating exercise mimetics. Mimicking exercise by RNA-targeting <i>Mettl14</i> suppression could be a therapeutic strategy for doxorubicin-induced cardiotoxicity.</p>","PeriodicalId":54370,"journal":{"name":"Journal of the American Heart Association","volume":" ","pages":"e040700"},"PeriodicalIF":5.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651150","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}