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Introduction: Extracellular vesicles (EVs) can potently inhibit inflammation yet there is a lack of understanding about the impact of donor characteristics on the efficacy of EVs. The goal of this study was to determine whether the sex and age of donor platelet-derived EVs (PEV) affected their ability to inhibit viral myocarditis., Methods: PEV, isolated from men and women of all ages, was compared to PEV obtained from women under 50 years of age, which we termed premenopausal PEV (pmPEV). Because of the protective effect of estrogen against myocardial inflammation, we hypothesized that pmPEV would be more effective than PEV at inhibiting myocarditis. We injected PEV, pmPEV, or vehicle control in a mouse model of viral myocarditis and examined histology, gene expression, protein profiles, and performed proteome and microRNA (miR) sequencing of EVs., Results: We found that both PEV and pmPEV significantly inhibited myocarditis; however, PEV was more effective, which was confirmed by a greater reduction of inflammatory cells and proinflammatory and profibrotic markers determined using gene expression and immunohistochemistry. Proteome and miR sequencing of EVs revealed that PEV miRs specifically targeted antiviral, Toll-like receptor (TLR)4, and inflammasome pathways known to contribute to myocarditis while pmPEV contained general immunoregulatory miRs., Discussion: These differences in EV content corresponded to the differing anti-inflammatory effects of the two types of EVs on viral myocarditis., Competing Interests: AB, PS, and AT, along with Mayo Clinic have ownership interest in Rion, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2025 Beetler, Giresi, Di Florio, Fliess, McCabe, Watkins, Xu, Auda, Bruno, Whelan, Kocsis, Edenfield, Walker, Macomb, Keegan, Jain, Morales-Lara, Chekuri, Hill, Farres, Wolfram, Behfar, Stalboerger, Terzic, Cooper and Fairweather.)

Nigeria has the highest reported incidence of peripartum cardiomyopathy worldwide. This open-label, pragmatic clinical trial randomized pregnant and postpartum women to usual care or artificial intelligence (AI)-guided screening to assess its impact on the diagnosis left ventricular systolic dysfunction (LVSD) in the perinatal period. The study intervention included digital stethoscope recordings with point of-care AI predictions and a 12-lead electrocardiogram with asynchronous AI predictions for LVSD. The primary end point was identification of LVSD during the study period. In the intervention arm, the primary end point was defined as the number of identified participants with LVSD as determined by a positive AI screen, confirmed by echocardiography. In the control arm, this was the number of participants with clinical recognition and documentation of LVSD on echocardiography in keeping with current standard of care. Participants in the intervention arm had a confirmatory echocardiogram at baseline for AI model validation. A total of 1,232 (616 in each arm) participants were randomized and 1,195 participants (587 intervention arm and 608 control arm) completed the baseline visit at 6 hospitals in Nigeria between August 2022 and September 2023 with follow-up through May 2024. Using the AI-enabled digital stethoscope, the primary study end point was met with detection of 24 out of 587 (4.1%) versus 12 out of 608 (2.0%) patients with LVSD (intervention versus control odds ratio 2.12, 95% CI 1.05-4.27; P = 0.032). With the 12-lead AI-electrocardiogram model, the primary end point was detected in 20 out of 587 (3.4%) versus 12 out of 608 (2.0%) patients (odds ratio 1.75, 95% CI 0.85-3.62; P = 0.125). A similar direction of effect was observed in prespecified subgroup analysis. There were no serious adverse events related to study participation. In pregnant and postpartum women, AI-guided screening using a digital stethoscope improved the diagnosis of pregnancy-related cardiomyopathy. ClinicalTrials.gov registration: NCT05438576., (© 2024. The Author(s).)

Background: Cardiomyopathy is a leading cause of pregnancy-related mortality and the number one cause of death in the late postpartum period. Delay in diagnosis is associated with severe adverse outcomes., Objective: To evaluate the performance of an artificial intelligence-enhanced electrocardiogram (AI-ECG) and AI-enabled digital stethoscope to detect left ventricular systolic dysfunction in an obstetric population., Methods: We conducted a single-arm prospective study of pregnant and postpartum women enrolled at 3 sites between October 28, 2021, and October 27, 2022. Study participants completed a standard 12-lead ECG, digital stethoscope ECG and phonocardiogram recordings, and a transthoracic echocardiogram within 24 hours. Diagnostic performance was evaluated using the area under the curve (AUC)., Results: One hundred women were included in the final analysis. The median age was 31 years (Q1: 27, Q3: 34). Thirty-eight percent identified as non-Hispanic White, 32% as non-Hispanic Black, and 21% as Hispanic. Five percent and 6% had left ventricular ejection fraction (LVEF) <45% and <50%, respectively. The AI-ECG model had near-perfect classification performance (AUC: 1.0, 100% sensitivity; 99%-100% specificity) for detection of cardiomyopathy at both LVEF categories. The AI-enabled digital stethoscope had an AUC of 0.98 (95% CI: 0.95, 1.00) and 0.97 (95% CI: 0.93, 1.00), for detection of LVEF <45% and <50%, respectively, with 100% sensitivity and 90% specificity., Conclusion: We demonstrate an AI-ECG and AI-enabled digital stethoscope were effective for detecting cardiac dysfunction in an obstetric population. Larger studies, including an evaluation of the impact of screening on clinical outcomes, are essential next steps., (© 2024 Heart Rhythm Society.)

Patients with viral myocarditis are at risk of sudden death and may progress to dilated cardiomyopathy (DCM). Currently, no disease-specific therapies exist to treat viral myocarditis. Here it is examined whether reconstituted, lyophilized extracellular vesicles (EVs) from platelets from healthy men and women reduce acute or chronic myocarditis in male mice. Human-platelet-derived EVs (PEV) do not cause toxicity, damage, or inflammation in naïve mice. PEV administered during the innate immune response significantly reduces myocarditis with fewer epidermal growth factor (EGF)-like module-containing mucin-like hormone receptor-like 1 (F4/80) macrophages, T cells (cluster of differentiation molecules 4 and 8, CD4 and CD8), and mast cells, and improved cardiac function. Innate immune mediators known to increase myocarditis are decreased by innate PEV treatment including Toll-like receptor (TLR)4 and complement. PEV also significantly reduces perivascular fibrosis and remodeling including interleukin 1 beta (IL-1β), transforming growth factor-beta 1, matrix metalloproteinase, collagen genes, and mast cell degranulation. PEV given at days 7-9 after infection reduces myocarditis and improves cardiac function. MicroRNA (miR) sequencing reveals that PEV contains miRs that decrease viral replication, TLR4 signaling, and T-cell activation. These data show that EVs from the platelets of healthy individuals can significantly reduce myocarditis and improve cardiac function., (© 2023 The Authors. Small published by Wiley-VCH GmbH.)

Background: Artificial intelligence (AI), and more specifically deep learning, models have demonstrated the potential to augment physician diagnostic capabilities and improve cardiovascular health if incorporated into routine clinical practice. However, many of these tools are yet to be evaluated prospectively in the setting of a rigorous clinical trial-a critical step prior to implementing broadly in routine clinical practice., Objectives: To describe the rationale and design of a proposed clinical trial aimed at evaluating an AI-enabled electrocardiogram (AI-ECG) for cardiomyopathy detection in an obstetric population in Nigeria., Design: The protocol will enroll 1,000 pregnant and postpartum women who reside in Nigeria in a prospective randomized clinical trial. Nigeria has the highest reported incidence of peripartum cardiomyopathy worldwide. Women aged 18 and older, seen for routine obstetric care at 6 sites (2 Northern and 4 Southern) in Nigeria will be included. Participants will be randomized to the study intervention or control arm in a 1:1 fashion. This study aims to enroll participants representative of the general obstetric population at each site. The primary outcome is a new diagnosis of cardiomyopathy, defined as left ventricular ejection fraction (LVEF) < 50% during pregnancy or within 12 months postpartum. Secondary outcomes will include the detection of impaired left ventricular function (at different LVEF cut-offs), and exploratory outcomes will include the effectiveness of AI-ECG tools for cardiomyopathy detection, new diagnosis of cardiovascular disease, and the development of composite adverse maternal cardiovascular outcomes., Summary: This clinical trial focuses on the emerging field of cardio-obstetrics and will serve as foundational data for the use of AI-ECG tools in an obstetric population in Nigeria. This study will gather essential data regarding the utility of the AI-ECG for cardiomyopathy detection in a predominantly Black population of women and pave the way for clinical implementation of these models in routine practice., Trial Registration: Clinicaltrials.gov: NCT05438576., Competing Interests: Conflict of interest Mayo Clinic has licensed the underlying technology to EKO devices, a maker of digital stethoscopes with embedded electrocardiogram electrodes and to Anumana. Mayo Clinic may receive financial benefit from the use of this technology, but at no point will Mayo Clinic benefit financially from its use for the care of patients at Mayo Clinic. Drs Attia, Lopez-Jimenez, and Friedman may also receive financial benefit from this agreement., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Current non-invasive screening methods for cardiac allograft rejection have shown limited discrimination and are yet to be broadly integrated into heart transplant care. Given electrocardiogram (ECG) changes have been reported with severe cardiac allograft rejection, this study aimed to develop a deep-learning model, a form of artificial intelligence, to detect allograft rejection using the 12-lead ECG (AI-ECG)., Methods and Results: Heart transplant recipients were identified across three Mayo Clinic sites between 1998 and 2021. Twelve-lead digital ECG data and endomyocardial biopsy results were extracted from medical records. Allograft rejection was defined as moderate or severe acute cellular rejection (ACR) based on International Society for Heart and Lung Transplantation guidelines. The extracted data (7590 unique ECG-biopsy pairs, belonging to 1427 patients) was partitioned into training (80%), validation (10%), and test sets (10%) such that each patient was included in only one partition. Model performance metrics were based on the test set ( n = 140 patients; 758 ECG-biopsy pairs). The AI-ECG detected ACR with an area under the receiver operating curve (AUC) of 0.84 [95% confidence interval (CI): 0.78-0.90] and 95% (19/20; 95% CI: 75-100%) sensitivity. A prospective proof-of-concept screening study ( n = 56; 97 ECG-biopsy pairs) showed the AI-ECG detected ACR with AUC = 0.78 (95% CI: 0.61-0.96) and 100% (2/2; 95% CI: 16-100%) sensitivity., Conclusion: An AI-ECG model is effective for detection of moderate-to-severe ACR in heart transplant recipients. Our findings could improve transplant care by providing a rapid, non-invasive, and potentially remote screening option for cardiac allograft function., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Atrial fibrillation/flutter (AF) is common among patients with pulmonary hypertension (PH) and is associated with poor clinical outcomes. AF has been shown to occur more commonly among patients with postcapillary PH, although AF also occurs among patients with precapillary PH. The goal of this study was to evaluate the independent impact of PH hemodynamic phenotype on incident AF among patients with PH., Methods: We retrospectively identified 262 consecutive patients, without a prior diagnosis of atrial arrhythmias, seen at the PH clinic at Mayo Clinic, Florida, between 1997 and 2017, who had right heart catheterization and echocardiography performed, with follow-up for outcomes through 2021. Kaplan-Meier analysis and Cox-proportional hazards regression modeling were used to evaluate the independent effect of PH hemodynamic phenotype on incident AF., Results: Our study population was classified into two broad PH hemodynamic groups: precapillary (64.9%) and postcapillary (35.1%). The median age was 59.5 years (Q1: 48.4, Q3: 68.4), and 72% were female. In crude models, postcapillary PH was significantly associated with incident AF (HR 2.17, 95% CI: 1.26-3.74, p = 0.005). This association was lost following multivariable adjustment, whereas left atrial volume index remained independently associated with incident AF (aHR 1.30, 95% CI: 1.09-1.54, p = 0.003)., Conclusion: We found PH hemodynamic phenotype was not significantly associated with incident AF in our patient sample; however, echocardiographic evidence of left atrial remodeling appeared to have a greater impact on AF development. Larger studies are needed to validate these findings and identify potential modifiable risk factors for AF in this population., (© 2023 S. Karger AG, Basel.)

Background: Little is known about the association of comorbidities with sex and age at diagnosis in Sjögren's disease. We tested the hypothesis that sex differences occur in comorbidities in patients with Sjögren's disease., Methods: Patients with Sjögren's disease were identified from 11/1974 to 7/2018 in the Mayo Clinic electronic medical record and assessed for 22 comorbidities according to sex and age at diagnosis., Results: Of the 13,849 patients identified with Sjögren's disease, 11,969 (86%) were women and 1,880 (14%) men, primarily white (88%) with a sex ratio of 6.4:1 women to men. The mean age at diagnosis was 57 years for women and 59.7 years for men, and 5.6% had a diagnosis of fibromyalgia at Sjögren's diagnosis. Men with Sjögren's disease were more likely than women to be a current or past smoker. The average time to diagnosis of comorbidities after diagnosis of Sjögren's disease was 2.6 years. The top comorbidities in patients with Sjögren's disease were fibromyalgia (25%), depression (21.2%) and pain (16.4%). Comorbidities that occurred more often in women were hypermobile syndromes (31:1), CREST (29:1), migraine (23:1), Ehlers-Danlos syndrome (EDS) (22:1), Raynaud's syndrome (15:1), SLE (13:1), systemic sclerosis (SSc) (13:1), and fibromyalgia (12:1). Women with Sjögren's disease were at increased risk of developing hypermobile syndromes (RR 7.27, CI 1.00-52.71, p = 0.05), EDS (RR 4.43, CI 1.08-18.14, p = 0.039), CREST (RR 4.24, CI 1.56-11.50, p = 0.005), migraine (RR 3.67, CI 2.39-5.62, p < 0.001), fibromyalgia (RR 2.26, CI 1.92-2.66, p < 0.001), Raynaud's syndrome (RR 2.29, CI 1.77-2.96, p < 0.001), SLE (RR 2.13, CI 1.64-2.76, p < 0.001), and SSc (RR 2.05 CI 1.44-2.92; p < 0.001). In contrast, men with Sjögren's were at increased risk for developing myocardial infarction (RR 0.44, CI 0.35-0.55, p < 0.001), atherosclerosis/CAD (RR 0.44, CI 0.39-0.49, p < 0.001), cardiomyopathy (RR 0.63, CI 0.46-0.86, p = 0.003), stroke (RR 0.66 CI 0.51-0.85, p = 0.001), and congestive heart failure (RR 0.70, CI 0.57-0.85, p < 0.001)., Conclusions: The top comorbidities in Sjögren's disease were fibromyalgia, depression, and pain. Women with Sjögren's disease had a higher relative risk of developing fibromyalgia, depression, pain, migraine, hypermobile syndrome, EDS and other rheumatic autoimmune diseases. Men with Sjögren's disease had higher risk of developing cardiovascular diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bruno, Morales-Lara, Bittencourt, Siddiqui, Bommarito, Patel, Sousou, Salomon, Paloka, Watford, Hodge, Lieberman, Rozen, Atwal, Dorsher, Seim and Fairweather.)

Background: Transcatheter aortic valve replacement (TAVR) is now an approved alternative to surgical aortic valve replacement for the treatment of severe aortic stenosis. As the clinical adoption of TAVR expands, it remains important to identify predictors of mortality after TAVR. We aimed to evaluate the impact of sex differences in aortic valve calcium score (AVCS) on long-term mortality following TAVR in a large patient sample., Methods: We included consecutive patients who successfully underwent TAVR for treatment of severe native aortic valve stenosis from June 2010 to May 2021 across all US Mayo Clinic sites with follow-up through July 2021. AVCS values were obtained from preoperative computed tomography of the chest. Additional clinical data were abstracted from medical records. Kaplan-Meier curves and Cox-proportional hazard regression models were employed to evaluate the effect of AVCS on long-term mortality., Results: A total of 2543 patients were evaluated in the final analysis. Forty-one percent were women, median age was 82 years (Q1: 76, Q3: 86), 18.4% received a permanent pacemaker following TAVR, and 88.5% received a balloon expandable valve. We demonstrate an increase in mortality risk with higher AVCS after multivariable adjustment ( P <0.001). When stratified by sex, every 500-unit increase in AVCS was associated with a 7% increase in mortality risk among women (adjusted hazard ratio, 1.07 [95% CI, 1.02-1.12]) but not in men., Conclusions: We demonstrate a notable sex difference in the association between AVCS and long-term mortality in a large TAVR patient sample. This study highlights the potential value of AVCS in preprocedural risk stratification, specifically among women undergoing TAVR. Additional studies are needed to validate this finding.

Background: Doxorubicin is a widely used and effective chemotherapy, but the major limiting side effect is cardiomyopathy which in some patients leads to congestive heart failure. Genetic variants in TRPC6 have been associated with the development of doxorubicin-induced cardiotoxicity, suggesting that TRPC6 may be a therapeutic target for cardioprotection in cancer patients. Methods: Assessment of Trpc6 deficiency to prevent doxorubicin-induced cardiac damage and function was conducted in male and female B6.129 and Trpc6 knock-out mice. Mice were treated with doxorubicin intraperitoneally every other day for a total of 6 injections (4 mg/kg/dose, cumulative dose 24 mg/kg). Cardiac damage was measured in heart sections by quantification of vacuolation and fibrosis, and in heart tissue by gene expression of Tnni3 and Myh7 . Cardiac function was determined by echocardiography. Results: When treated with doxorubicin, male Trpc6 -deficient mice showed improvement in markers of cardiac damage with significantly reduced vacuolation, fibrosis and Myh7 expression and increased Tnni3 expression in the heart compared to wild-type controls. Similarly, male Trpc6 -deficient mice treated with doxorubicin had improved LVEF, fractional shortening, cardiac output and stroke volume. Female mice were less susceptible to doxorubicin-induced cardiac damage and functional changes than males, but Trpc6 -deficient females had improved vacuolation with doxorubicin treatment. Sex differences were observed in wild-type and Trpc6 -deficient mice in body-weight and expression of Trpc1, Trpc3 and Rcan1 in response to doxorubicin. Conclusions: Trpc6 promotes cardiac damage following treatment with doxorubicin resulting in cardiomyopathy in male mice. Female mice are less susceptible to cardiotoxicity with more robust ability to modulate other Trpc channels and Rcan1 expression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Norton, Bruno, Di Florio, Whelan, Hill, Morales-Lara, Mease, Sousou, Malavet, Dorn, Salomon, Macomb, Khatib, Anastasiadis, Necela, McGuire, Giresi, Kotha, Beetler, Weil, Landolfo and Fairweather.)

Background: Myocarditis is an inflammatory heart disease caused by viral infections that can lead to heart failure, and occurs more often in men than women. Since animal studies have shown that myocarditis is influenced by sex hormones, we hypothesized that endocrine disruptors, which interfere with natural hormones, may play a role in the progression of the disease. The human population is exposed to the endocrine disruptor bisphenol A (BPA) from plastics, such as water bottles and plastic food containers., Methods: Male and female adult BALB/c mice were housed in plastic versus glass caging, or exposed to BPA in drinking water versus control water. Myocarditis was induced with coxsackievirus B3 on day 0, and the endpoints were assessed on day 10 post infection., Results: We found that male BALB/c mice that were exposed to plastic caging had increased myocarditis due to complement activation and elevated numbers of macrophages and neutrophils, whereas females had elevated mast cell activation and fibrosis., Conclusions: These findings show that housing mice in traditional plastic caging increases viral myocarditis in males and females, but using sex-specific immune mechanisms.

Background: The incidence of peripartum cardiomyopathy (PPCM) is known through referral center databases that may be affected by referral, misclassification, and other biases. We sought to determine the community-based incidence and natural history of PPCM using the Rochester Epidemiology Project., Methods and Results: Incident cases of PPCM occurring between January 1, 1970, and December 31, 2014, were identified in Olmsted County, Minnesota. A total of 15 PPCM cases were confirmed yielding an incidence of 20.3 cases per 100,000 live births in Olmsted County, Minnesota. Clinical information, disease characteristics, and outcomes were extracted from medical records in a 27-county region of the Rochester Epidemiology Project including Olmsted County and matched in a 1:2 ratio with pregnant women without PPCM. A total of 48 women were identified with PPCM in the expanded 27-county region. There was 1 death and no transplants over a median of 7.3 years of follow-up. Six of the 23 women with subsequent pregnancies developed recurrent PPCM, all of whom recovered. Migraine and anxiety were identified as novel possible risk factors for PPCM., Conclusions: The population-based incidence of PPCM was 20.3 cases per 100,000 live births in Olmsted County, Minnesota. Cardiovascular outcomes were generally excellent in this community cohort., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Myocarditis is an inflammatory heart disease that leads to dilated cardiomyopathy (DCM) and heart failure. Sex hormones play an important role in the development of myocarditis with testosterone driving disease in males and estrogen being cardioprotective in females. The human population is widely exposed to the endocrine disruptor bisphenol A (BPA) from plastics such as water bottles, plastic food containers, copy paper, and receipts. Several clinical and numerous animal studies have found an association between elevated BPA levels and cardiovascular disease. A recent report found elevated levels of BPA in the serum of patients with DCM compared to healthy controls. In this study we examined whether exposure to BPA for 2 weeks prior to viral infection and leading up to myocarditis at day 10 altered inflammation in female BALB/c mice housed in standard plastic cages/water bottles with soy-free food and bedding. We found that a human relevant dose of BPA (25 μg/L) in drinking water, with an estimated exposure of 5 μg BPA/kg BW, significantly increased myocarditis and pericarditis compared to control water without altering viral genome levels in the heart. BPA exposure activated ERα and ERβ in the spleen 24 h after infection and phosphorylated ERα and ERβ during myocarditis, but decreased ERα and increased ERβ mRNA in the heart as measured by qRT-PCR. Exposure to BPA significantly increased CD4 + T cells, IFNγ, IL-17A, TLR4, caspase-1, and IL-1β in the heart. BPA exposure also increased cardiac fibrosis compared to controls. Mast cells, which are associated with cardiac remodeling, were found to increase in number and degranulation, particularly along the pericardium. Interestingly, plastic caging/water bottle exposure alone led to increased mast cell numbers, pericardial degranulation and fibrosis in female BALB/c mice compared to animals housed in glass cages/water bottles with soy-free food and bedding. These data suggest that BPA exposure may increase the risk of developing myocarditis after a viral infection in women.