Tehran University of Medical Sciences The Research in Heart Yield and Translational Medicine (RHYTHM) 3115-7270 21 1 2026 04 26 71 84 EN Hoda Borooghani School of Medicine, Iran University of Medical Sciences, Tehran, Iran. Kiana Orangi School of Medicine, Iran University of Medical Sciences, Tehran, Iran. Parmida bagher zadi School of Medicine, Iran University of Medical Sciences, Tehran, Iran. Hoda Asefi Assistant Professor of Radiology,Department of Radiology, Sina Hospital,Tehran University of Medical Sciences, Tehran, Iran Mohsen Arabi Preventive Medicine and Public Health Research Center, Psychosocial Health Research Institute, Department of Community and Family Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran 2025 10 30 2025 11 28 Objectives: Hypertension is a major cause of cardiovascular and cerebrovascular morbidity and mortality worldwide. The ankle-brachial index (ABI) is a simple, noninvasive test usually used for peripheral artery disease detection, but its prognostic value in hypertensive patients is still poorly defined. In this study, we sought to systematically review the relationship between abnormal ABI values and cardiovascular and cerebrovascular events in adults with hypertension. Methods: A systematic literature search was conducted in PubMed, Scopus, and Web of Science up to March 2025 for observational studies evaluating ABI in hypertensive populations. Studies were included if they stratified outcomes by ABI categories and reported at least one cardiovascular or cerebrovascular outcome. Data on study design, population characteristics, measurement and cutoff values of ABI, outcomes, duration of follow-up, and adjustment for confounding variables were extracted. Study quality was assessed according to the Newcastle-Ottawa Scale. Results: Twenty-two studies from varied geographic and clinical populations were eligible. Both low ABI (≤0.9) and high ABI (>1.4) were consistently associated with elevated risks of myocardial infarction, heart failure, stroke, and all-cause or cardiovascular mortality, independent of conventional risk factors. Low ABI was also associated with subclinical target organ damage, such as left ventricular hypertrophy and silent brain infarct. Some studies have indicated that modified cutoffs (<1.05 or ≤1.10) help to detect risk in some populations, such as older and Asian cohorts. Measurement techniques and ABI cutoffs differed, reducing comparability. Conclusion: Abnormal ABI is independently associated with increased risks of adverse cardiovascular and cerebrovascular outcomes in patients with hypertension. Standardized protocols for ABI measurement and cutoff points are required to maximize its utility in risk stratification. Prospective studies are needed to determine whether ABI-guided interventions can improve outcomes.   https://jthc.tums.ac.ir/index.php/jthc/article/view/2384 https://jthc.tums.ac.ir/index.php/jthc/article/download/2384/1249

Tehran University of Medical Sciences The Research in Heart Yield and Translational Medicine (RHYTHM) 3115-7270 21 1 2026 04 26 1 11 EN Ellen Sepanian Institute of Biochemistry and Biotechnology, Martin Luther University, Halle-Wittenberg, Germany Orkideh Olang Iranian Tissue Bank & Research Center, Tehran University of Medical Sciences Mohsen Heydari Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Zanjan, Iran Seyed Amirhosein Tavakoli Iranian Tissue Bank & Research Center, Tehran University of Medical Sciences Seyed Kazem Hosseini Iranian Tissue Bank & Research Center, Tehran University of Medical Sciences Hamid Goodarzi Iranian Tissue Bank & Research Center, Tehran University of Medical Sciences Alireza Heidary Rouchi Iranian Tissue Bank & Research Center, Tehran University of Medical Sciences 2025 06 21 2025 09 21 Objective: The removal of residual antibiotics from whole homograft tissues after disinfection is a matter of concern. To avoid bacteriostasis, which causes falsely negative culture results, we investigated the effectiveness of a novel method applicable to whole homografts. Methods: Thirty homografts, assessed as unsuitable for transplantation, were obtained from 24 deceased donors. Fourteen days after freezing, each homograft was thawed and divided lengthwise into 2 halves, with one serving as an unexposed control and the other as an exposed sample. Exposure was conducted using 400 µg/mL vitamin C. Five-step microbiological assays were performed using direct tissue samples and cryopreservation solution after thawing. The presence of residual antibiotics in tissue homogenates and cryopreservation solution was assessed by an agar diffusion test on seeded plates with 8 virulent strains. The effect of the intervention was determined by comparing the inhibition zones of exposed and unexposed tissue homogenates. Results: Blood culture results from all donors were negative. The initial contamination rate was 13.3%, and the isolates were not detected after disinfection. Thawed tissues that were not exposed to vitamin C all yielded negative culture results, whereas one tissue sample exposed to vitamin C had a positive result (Pantoea eucrina). The diameter of the inhibition zone in seeded plates was 14.4% smaller with tissue exposed to vitamin C than that of controls (P=0.021). Conclusion: The retention of antibiotics and carryover effect are unavoidable. Vitamin C can break down antimicrobial molecules and produce soluble by-products, which leads to a diminished amount of residual antimicrobials and a higher probability of detecting microorganisms in post-disinfection cultures. https://jthc.tums.ac.ir/index.php/jthc/article/view/2282 https://jthc.tums.ac.ir/index.php/jthc/article/download/2282/1240

Tehran University of Medical Sciences The Research in Heart Yield and Translational Medicine (RHYTHM) 3115-7270 21 1 2026 04 26 98 102 Ehsan Shahverdi Baqiyatallah University of Medical Sciences, Tehran, IR Iran Gayathri Santhosh Kumar Department of Cardiology, Rhythmology and Intensive Care Medicine, Med. Klinik I, Klinikum Osnabrück, Osnabrück, Germany. Carsten Schneider Department of Cardiology, Rhythmology and Intensive Care Medicine, Med. Klinik I, Klinikum Osnabrück, Osnabrück, Germany. Mathias Lange Department of Cardiology, Rhythmology and Intensive Care Medicine, Med. Klinik I, Klinikum Osnabrück, Osnabrück, Germany. 2025 08 01 2025 08 09 Background: Primary malignant pericardial mesothelioma (PMPM) is an exceptionally rare and aggressive cancer originating from the mesothelial lining of the heart. This distinct and challenging oncologic entity is typically discovered at an advanced stage due to vague, nonspecific symptoms—most commonly chest pain and dyspnea. These clinical features often mimic more common conditions, making early detection difficult. Diagnostic confirmation usually requires detailed histopathologic analysis, often obtained through surgical procedures or postmortem examination. The disease’s elusive nature and rapid progression contribute to its generally poor prognosis, underscoring the need for heightened clinical awareness and advanced diagnostic strategies. Case Report: A 58-year-old patient was diagnosed with malignant pericardial mesothelioma, which progressed rapidly and resulted in death within 1 month of diagnosis. Conclusions: PMPM remains a rare and highly aggressive cancer characterized by swift, fatal progression. Diagnosis is difficult because of nonspecific clinical symptoms. Accurate diagnosis is essential for subsequent treatment planning. Nonetheless, limited treatment alternatives, coupled with the minimal effectiveness of immunotherapy in advanced disease, highlight the pressing need for further research and therapeutic advances. https://jthc.tums.ac.ir/index.php/jthc/article/view/2322 https://jthc.tums.ac.ir/index.php/jthc/article/download/2322/1251

Tehran University of Medical Sciences The Research in Heart Yield and Translational Medicine (RHYTHM) 3115-7270 21 1 2024 06 22 103 110 Hojjat Mortezaeian Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran MohamamdHossein MozafaryBazargany Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran Alireza Salmanipour Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran Amir Banazade Dardashty Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran 2024 02 19 2024 09 22 Background: Sinus venosus atrial septal defect (SVASD) is a congenital heart defect involving an opening between the superior vena cava (SVC) and the right upper pulmonary vein (RUPV). Surgical closure is the standard treatment. Nonetheless, it is more complex than secundum ASD reconstruction and is associated with higher complication rates. Transcatheter closure is an emerging alternative. Methods: We report 5 cases of transcatheter SVASD closure and 1 case of failure requiring surgical intervention. All patients underwent preprocedural computed tomography angiography to assess defect size and location and optimal stent dimensions. SVC stenting was performed using balloon-expandable stents, followed by RUPV angioplasty if necessary. Results: Final angiograms and pressure measurements in the SVC, RUPV, and right atrium confirmed the absence of residual shunt and pulmonary venous obstruction. Stent migration to the pulmonary artery occurred in 1 patient, necessitating surgical retrieval and defect closure. Conclusions: Balloon expansion testing is not mandatory before stent implantation. If RUPV obstruction occurs, flow can be reestablished via ballooning or stent implantation within the RUPV, and associated mild residual shunts may resolve spontaneously. https://jthc.tums.ac.ir/index.php/jthc/article/view/2023 https://jthc.tums.ac.ir/index.php/jthc/article/download/2023/1254

Tehran University of Medical Sciences The Research in Heart Yield and Translational Medicine (RHYTHM) 3115-7270 21 1 2026 04 26 12 19 Arya Aminorroaya Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT Ali Vasheghani Farahanni Tehran heart center Hamed Tavolinejad Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran Zahra Aryan Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA Somayeh Yadangi Tehran heart center Ali Bozorgi Tehran heart center Saeed Sadeghian Tehran heart center Mohammadali Boroumand Tehran heart center Masud Yunesian School of Public Health, Tehran University of Medical Sciences, Tehran, Iran Masih Tajdini Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 2025 11 07 2025 12 09 Background: Clinical evidence suggests an association between vitamin B12 deficiency and vasovagal syncope (VVS) in pediatric patients. This study investigated the association of vitamin B12 and folate deficiency with VVS in adults. Methods: In this case-control study, adult patients with VVS who presented to the tertiary syncope unit for head-up tilt table testing comprised the case group. Age- and sex-matched individuals without syncope history from the population-based Tehran Cohort Study served as the control group. Exclusion criteria included but were not limited to the use of vitamin B supplements, carbamazepine, or phenobarbital, and sleeve gastrectomy. Serum vitamin B12, folate, and homocysteine levels were measured and compared. Results: From February 2020 through February 2021, 44 patients comprised the case group, matched with 44 controls (mean age, 37.9 years; 23 [52.3%] females in each group). No statistically significant difference existed between the groups in vitamin B12 or folate deficiency or serum levels. Serum vitamin B12 levels were significantly lower in patients with frequent VVS (≥3 lifetime episodes) than in patients with infrequent VVS (<3 lifetime episodes) (233.8 [80.7] vs 305.2 [118.1] pg/mL; P=0.042), and the association remained significant after adjustment for confounders (P=0.026). Conclusion: No association existed between vitamin B12 or folate deficiency or serum levels and VVS. Frequent VVS was associated with lower serum vitamin B12 levels than infrequent VVS. https://jthc.tums.ac.ir/index.php/jthc/article/view/2390 https://jthc.tums.ac.ir/index.php/jthc/article/download/2390/1241

Tehran University of Medical Sciences The Research in Heart Yield and Translational Medicine (RHYTHM) 3115-7270 21 1 2026 04 26 85 97 EN Kaushal Sikka Riga Stradins University 2025 10 21 2025 11 20 Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome associated with substantial morbidity, mortality, and impaired quality of life. Despite its rising prevalence, particularly among older adults and women, HFpEF has historically been characterized as a “therapeutic graveyard” because of decades of inconclusive or neutral clinical trials. Methods: A secondary qualitative analysis of the literature indexed in PubMed, Scopus, and Embase from January 2018 through June 2025 was conducted. Randomized controlled trials, systematic reviews, meta-analyses, guideline statements, and high-quality observational studies were included. Data were extracted and synthesized thematically across five domains: epidemiology, pathophysiology, diagnostic strategies, therapeutic approaches, and future directions. Results: Epidemiological data confirm increasing global prevalence, driven by aging demographics and clustering of comorbidities such as obesity, hypertension, diabetes, and atrial fibrillation. Pathophysiological insights highlight a complex, multiorgan syndrome with distinct phenotypes. Diagnostic accuracy remains hampered by overlapping comorbidities, limited biomarker sensitivity in obese or renally impaired patients, and heterogeneity in imaging findings. Artificial intelligence and machine learning approaches are emerging but not yet established in clinical care. Therapeutically, sodium–glucose cotransporter-2 (SGLT2) inhibitors represent the first pharmacologic agents to consistently reduce hospitalization and improve outcomes in HFpEF, while lifestyle modification, rehabilitation, and device-based interventions offer complementary benefits. Emerging strategies emphasize precision medicine, digital health, and biomarker-driven stratification. Conclusion: HFpEF remains a major unexplained challenge in cardiovascular management. The efficacy of sodium–glucose cotransporter-2 inhibitors can mark a paradigm shift; however, significant weaknesses persist in diagnostic and therapeutic areas. Further progress depends on phenotype-specific, multimodal, and patient-centered strategies that combine clinical care, digital innovation, and molecular research. https://jthc.tums.ac.ir/index.php/jthc/article/view/2377 https://jthc.tums.ac.ir/index.php/jthc/article/download/2377/1250

Tehran University of Medical Sciences The Research in Heart Yield and Translational Medicine (RHYTHM) 3115-7270 21 1 2024 06 22 111 115 Farnaz Ahmadi Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Raha Parnia Simon Fraser University, Vancouver, British Columbia, Canada Bahamin Astani Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Mohammad-Sadegh Keshmiri Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Shakiba Khodadad Department of Gynecology Oncology, Erfan Hospital, Tehran, Iran Hakimeh Sheikhzadeh Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Zahra Daneshmandi Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Faezeh Ansari Mofid Children’s Hospital, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Mahsa Riahi Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Sima Noorali Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Hannaneh Yousefi-Koma Masih Daneshvari Hospital, Tehran, Iran Babak Sharif-Kashani Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Shadi Shafaghi Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2024 07 04 2024 09 22 Background: Pregnancy in women with pulmonary hypertension (PH) is contraindicated because of high mortality rates associated with physiological changes, particularly in the peripartum and postpartum periods. Termination is recommended early if pregnancy occurs. Consequently, clinical experience with continued pregnancy in patients with PH is scarce. Case Presentation: A 31-year-old woman was diagnosed with multiple bilateral pulmonary and right ventricular hydatid cysts. After surgical and pharmacologic treatments, she developed PH due to pulmonary artery obstruction 8 years later. Because of her condition, she was ineligible for surgery and received medical therapy, including tadalafil, bosentan, and eplerenone. After 3 years, she conceived despite advice to avoid pregnancy. At 37 weeks’ gestation, she underwent successful emergency cesarean delivery because of maternal dyspnea and tachycardia. Conclusion: Prompt treatment and regular follow-up in a tertiary care center using a multidisciplinary approach are crucial for managing pregnant patients with PH. https://jthc.tums.ac.ir/index.php/jthc/article/view/2118 https://jthc.tums.ac.ir/index.php/jthc/article/download/2118/1252

Tehran University of Medical Sciences The Research in Heart Yield and Translational Medicine (RHYTHM) 3115-7270 21 1 2026 04 26 20 31 Rizki Hilman Department of Cardiology, Faculty of Medicine, Dr. Zainoel Abidin Hospital, Universitas Syiah Kuala, Banda Aceh, Indonesia Adi Purnawarman Department of Cardiology, Faculty of Medicine, Dr. Zainoel Abidin Hospital, Universitas Syiah Kuala, Banda Aceh, Indonesia Haris Munirwan Department of Cardiology, Faculty of Medicine, Dr. Zainoel Abidin Hospital, Universitas Syiah Kuala, Banda Aceh, Indonesia Muhammad Ridwan Department of Cardiology, Faculty of Medicine, Dr. Zainoel Abidin Hospital, Universitas Syiah Kuala, Banda Aceh, Indonesia Herlina Dimiati Department of Pediatric, Faculty of Medicine, Dr. Zainoel Abidin Hospital, Universitas Syiah Kuala, Banda Aceh, Indonesia 2025 12 26 2026 02 03 Background: Arrhythmia is a common and clinically significant complication during hospitalization for ST-segment elevation myocardial infarction (STEMI). This study aimed to identify factors associated with the occurrence of arrhythmia in the acute phase of STEMI. Methods: This single-center cross-sectional study was conducted among adult patients hospitalized with STEMI. Demographic and clinical variables, including cardiovascular risk factors and disease severity (Killip class, Thrombolysis in Myocardial Infarction [TIMI] score, and Global Registry of Acute Coronary Events [GRACE] score), were obtained from medical records. The primary outcome was in-hospital arrhythmia, defined as documented atrial or ventricular tachyarrhythmia or clinically significant bradyarrhythmia. Factors associated with arrhythmia were assessed using bivariate analyses followed by multivariable logistic regression. Results: This study involved 113 patients, with a mean age of 56.4 (11.1) years. Arrhythmia occurred in 26.5% (30 patients) during hospitalization. In bivariate analyses, arrhythmia was associated with higher Killip class (P<0.001), higher TIMI score (P=0.005), higher GRACE score (P=0.001), lower tricuspid annular plane systolic excursion (P=0.002), elevated serum potassium level (P=0.010), and impaired renal function, reflected by higher urea (P=0.005) and creatinine levels (P = 0.004). After multivariable adjustment, only Killip class remained independently associated with arrhythmia: patients presenting with Killip class I had a significantly lower risk of arrhythmia than those with higher Killip classes (adjusted OR, 0.404; 95% CI, 0.20 to 0.80; P=0.009). Conclusion: In hospitalized patients with STEMI, arrhythmic risk is chiefly driven by early clinical severity. Killip class is a simple bedside predictor of in-hospital arrhythmia and can aid early risk stratification and monitoring. https://jthc.tums.ac.ir/index.php/jthc/article/view/2417 https://jthc.tums.ac.ir/index.php/jthc/article/download/2417/1242

Tehran University of Medical Sciences The Research in Heart Yield and Translational Medicine (RHYTHM) 3115-7270 21 1 2026 04 26 32 39 Ali Mirzaei Department of Pharmacology & Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran Maryam Mehrpooya Department of Clinical Pharmacy, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran Akram Ranjbar Department of Pharmacology & Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran Sajad Naghdi Farshchian Cardiovascular Subspecialty Medical Center, Hamadan University of Medical Sciences, Hamadan, Iran Afsaneh Familmotaghi Farshchian Cardiovascular Subspecialty Medical Center, Hamadan University of Medical Sciences, Hamadan, Iran Seyed Saman Talebi Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran Seyed Kianoosh Hosseini Department of Cardiology, School of Medicine, Farshchian Cardiovascular Subspecialty Medical Center, Hamadan University of Medical Sciences, Hamadan, Iran 2025 07 26 2025 12 16 Background: Ischemic heart disease is the leading cause of death worldwide. Oxidative stress plays a key role in myocardial infarction (MI). Ferroptosis, a type of iron-dependent regulated cell death caused by lipid peroxide accumulation, has been identified as a key mechanism in ischemic injury. This study aimed to investigate the association between oxidative stress and ferroptosis in patients with non–ST-segment-elevation myocardial infarction (NSTEMI). Methods: In this case-control study, 25 patients with NSTEMI and 25 controls were included. In serum samples, cardiac markers (troponin I and CK-MB), oxidative stress biomarkers including lipid peroxidation (LPO), total antioxidant capacity (TAC), total thiol groups (TTG), superoxide dismutase (SOD) activity, glutathione peroxidase (GPx) activity, and iron and ferritin levels were measured. Results: In patients with NSTEMI, serum levels of cardiac markers (troponin I and CK-MB), LPO, iron, and ferritin were significantly higher than in controls. In contrast, TAC, TTG, and SOD and GPx activities were significantly lower in patients with NSTEMI. Conclusion: This study demonstrated a possible role of oxidative stress in the pathophysiology of NSTEMI. Elevated iron and LPO levels and reduced GPx activity may contribute to cardiac cell death through ferroptosis. https://jthc.tums.ac.ir/index.php/jthc/article/view/2319 https://jthc.tums.ac.ir/index.php/jthc/article/download/2319/1243

Tehran University of Medical Sciences The Research in Heart Yield and Translational Medicine (RHYTHM) 3115-7270 21 1 2026 04 26 40 49 Fadhlan Rahman Citra Husada Jember Hospital Suryono Suryono Department of Cardiology and Vascular Medicine, Faculty of Medicine, Jember University, Jember, Indonesia; Dr. Soebandi General Hospital, Jember, Indonesia Aditha Maulana Department of Cardiology and Vascular Medicine, Faculty of Medicine, Jember University, Jember, Indonesia; Dr. Soebandi General Hospital, Jember, Indonesia Pipiet Wulandari Department of Cardiology and Vascular Medicine, Faculty of Medicine, Jember University, Jember, Indonesia; Dr. Soebandi General Hospital, Jember, Indonesia 2025 12 15 2026 02 02 Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with substantial morbidity and mortality. AF occurring in individuals without structural heart disease or conventional risk factors, currently referred to as AF without overt comorbidity, remains poorly understood. Genetic susceptibility is thought to contribute, but the underlying molecular mechanisms are incompletely defined. This study aimed to identify key genes and biological processes associated with AF without overt comorbidity using an in-silico bioinformatics approach. Methods: Genes associated with AF without overt comorbidity were retrieved from the GeneCards database using a knowledge-based, database-driven strategy. Functional enrichment analysis of Gene Ontology biological processes was performed using WebGestalt. Protein-protein interaction (PPI) analysis was conducted using STRING and visualized in Cytoscape. Hub genes were identified exclusively using the Density of Maximum Neighborhood Component (DMNC) algorithm via the CytoHubba plugin. Three-dimensional protein structures of selected hub genes were modeled using SWISS-MODEL and evaluated using PROCHECK for exploratory structural characterization. Results: Eighty-one genes associated with AF without overt comorbidity were identified. PPI analysis demonstrated significant interaction enrichment (P<1.0×10⁻¹⁶), indicating a nonrandom and biologically coherent network. Functional enrichment analysis revealed cardiac muscle cell action potential and cardiac muscle contraction as the most significantly enriched biological processes. Ten hub genes were identified based on DMNC ranking. Among these, GPD1L, SCN1B, SCN4B, and KCNE2 showed central network positions and acceptable stereochemical quality in exploratory structural evaluation. Conclusion: This in silico study identifies candidate genes and biological processes potentially involved in AF without overt comorbidity. The findings are hypothesis generating and warrant further functional and clinical validation. https://jthc.tums.ac.ir/index.php/jthc/article/view/2407 https://jthc.tums.ac.ir/index.php/jthc/article/download/2407/1244

Tehran University of Medical Sciences The Research in Heart Yield and Translational Medicine (RHYTHM) 3115-7270 21 1 2026 04 26 50 70 Mohammadsadegh Talebi Kahdouei Fetal and Pediatric Cardiovascular Research Center, Children’s Medical Center, Tehran, Iran, Islamic Republic Of Hosein Ghasempour Fetal and Pediatric Cardiovascular Research Center, Children’s Medical Center, Tehran, Iran, Islamic Republic Of Fatemeh Aghaei Fetal and Pediatric Cardiovascular Research Center, Children’s Medical Center, Tehran, Iran, Islamic Republic Of Elaheh Vafaei Fetal and Pediatric Cardiovascular Research Center, Children’s Medical Center, Tehran, Iran, Islamic Republic Of Behnaz Sohrabi School of Medicine, Isfahan University of Medical Science, Isfahan, Iran, Islamic Republic of Ehsan Aghaei Moghadam Fetal and Pediatric Cardiovascular Research Center, Children’s Medical Center, Tehran, Iran, Islamic Republic Of Negin Rahimidanesh School of Medicine, Islamic Azad University, Tehran Medical Branch, Tehran, Iran, Islamic Republic of, Ali Dahmarde Ei Department of General Surgery, Shariati Hospital, Tehran University of Medical Science, Tehran, Iran, Islamic Republic of Mojtaba Shurmij Department of General Surgery, Shariati Hospital, Tehran University of Medical Science, Tehran, Iran, Islamic Republic of 2025 11 17 2026 01 11 Background: Rheumatic heart disease (RHD) remains a major cause of preventable cardiovascular morbidity and mortality, particularly in low- and middle-income countries. Despite the World Health Organization’s 2018 resolution calling for global elimination of RHD, substantial disparities in disease burden persist across regions and levels of socio-economic development. While previous studies have reported global trends, a clear comparative assessment of long-term changes in both fatal and non-fatal RHD burden across socio-demographic and geographic regions remains limited. This study aimed to assess long-term changes in the global burden of RHD between 1990 and 2021, with a specific focus on regional and socio-demographic disparities, using the most recent estimates from the Global Burden of Disease (GBD) 2021 study. We additionally assessed temporal trends across Socio-demographic Index (SDI) groups and GBD regions, with a specific focus on fatal (YLL) and non-fatal (YLD) components of disease burden. Methods: We conducted a secondary analysis of model-based estimates from the Global Burden of Disease (GBD) 2021 study to assess the burden of RHD between 1990 and 2021. Metrics included age-standardized and all-age incidence, prevalence, mortality, years of life lost (YLL), years lived with disability (YLD), and disability-adjusted life years (DALY). Data were stratified by five Socio-demographic Index (SDI) levels and 13 global regions. Estimates were produced using DisMod-MR 2.1 and CODEm and are reported as means with 95% uncertainty intervals (UIs). Results: Globally, age-standardized mortality and DALY rates for RHD declined by 56% and 53%, respectively, from 1990 to 2021. YLL decreased by 59%, while YLD rose by 11%, indicating a shift toward chronic non-fatal burden. For instance, the global age-standardized mortality rate fell from 9.1 (95% UI: 8.4–9.8) to 4.0 (3.6–4.5) per 100,000. High and high-middle SDI regions achieved the greatest reductions across all indicators. In contrast, low and low-middle-SDI regions experienced persistently high absolute deaths and DALYs, with South Asia alone accounting for over 27% of global RHD deaths in 2021. Females consistently bore a higher non-fatal burden (YLD) than males. Although the dataset includes the COVID-19 era, the specific impacts of the pandemic on RHD care and outcomes warrant further investigation. Across all SDI groups and regions, declines in DALYs were largely driven by reductions in years of life lost (YLLs), whereas years lived with disability (YLDs) remained relatively stable. Conclusions: While global RHD mortality has declined, substantial regional and socioeconomic disparities persist. The epidemiologic transition towards disability highlights the need for long-term care infrastructure, particularly for women, children, and low-SDI regions. While based on modelled estimates, this analysis offers the best available insight into global RHD epidemiology and informs data-driven health policy and planning. Despite overall improvements, substantial disparities persist between low and high SDI settings, underscoring the need for context-specific prevention and long-term management strategies. https://jthc.tums.ac.ir/index.php/jthc/article/view/2392 https://jthc.tums.ac.ir/index.php/jthc/article/download/2392/1255