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Item 17β-Estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin(American Society for Clinical Investigation, 2021-03-15) Frump, Andrea L.; Albrecht, Marjorie; Yakubov, Bakhtiyor; Breuils-Bonnet, Sandra; Nadeau, Valérie; Tremblay, Eve; Potus, Francois; Omura, Junichi; Cook, Todd; Fisher, Amanda; Rodriguez, Brooke; Brown, R. Dale; Stenmark, Kurt R.; Rubinstein, C. Dustin; Krentz, Kathy; Tabima, Diana M.; Li, Rongbo; Sun, Xin; Chesler, Naomi C.; Provencher, Steeve; Bonnet, Sebastien; Lahm, Tim; Medicine, School of MedicineWomen with pulmonary arterial hypertension (PAH) exhibit better right ventricular (RV) function and survival than men; however, the underlying mechanisms are unknown. We hypothesized that 17β-estradiol (E2), through estrogen receptor α (ER-α), attenuates PAH-induced RV failure (RVF) by upregulating the procontractile and prosurvival peptide apelin via a BMPR2-dependent mechanism. We found that ER-α and apelin expression were decreased in RV homogenates from patients with RVF and from rats with maladaptive (but not adaptive) RV remodeling. RV cardiomyocyte apelin abundance increased in vivo or in vitro after treatment with E2 or ER-α agonist. Studies employing ER-α–null or ER-β–null mice, ER-α loss-of-function mutant rats, or siRNA demonstrated that ER-α is necessary for E2 to upregulate RV apelin. E2 and ER-α increased BMPR2 in pulmonary hypertension RVs and in isolated RV cardiomyocytes, associated with ER-α binding to the Bmpr2 promoter. BMPR2 is required for E2-mediated increases in apelin abundance, and both BMPR2 and apelin are necessary for E2 to exert RV-protective effects. E2 or ER-α agonist rescued monocrotaline pulmonary hypertension and restored RV apelin and BMPR2. We identified what we believe to be a novel cardioprotective E2/ER-α/BMPR2/apelin axis in the RV. Harnessing this axis may lead to novel RV-targeted therapies for PAH patients of either sex.Item A systemic congestive index (systemic pulse pressure to central venous pressure ratio) predicts adverse outcomes in patients undergoing valvular heart surgery(Wiley, 2022) Knio, Ziyad O.; Morales, Frances L.; Shah, Kajal P.; Ondigi, Olivia K.; Selinski, Christian E.; Baldeo, Cherisse M.; Zhuo, David X.; Bilchick, Kenneth C.; Mehta, Nishaki K.; Kwon, Younghoon; Breathett, Khadijah; Thiele, Robert H.; Hulse, Matthew C.; Mazimba, Sula; Medicine, School of MedicineBackground and aims: Invasive hemodynamics may provide a more nuanced assessment of cardiac function and risk phenotyping in patients undergoing cardiac surgery. The systemic pulse pressure (SPP) to central venous pressure (CVP) ratio represents an integrated index of right and left ventricular function and thus may demonstrate an association with valvular heart surgery outcomes. This study hypothesized that a low SPP/CVP ratio would be associated with mortality in valvular surgery patients. Methods: This retrospective cohort study examined adult valvular surgery patients with preoperative right heart catheterization from 2007 through 2016 at a single tertiary medical center (n = 215). Associations between the SPP/CVP ratio and mortality were investigated with univariate and multivariate analyses. Results: Among 215 patients (age 69.7 ± 12.4 years; 55.8% male), 61 died (28.4%) over a median follow-up of 5.9 years. A SPP/CVP ratio <7.6 was associated with increased mortality (relative risk 1.70, 95% confidence interval [CI] 1.08-2.67, p = .019) and increased length of stay (11.56 ± 13.73 days vs. 7.93 ± 4.92 days, p = .016). It remained an independent predictor of mortality (adjusted odds ratio 3.99, 95% CI 1.47-11.45, p = .008) after adjusting for CVP, mean pulmonary artery pressure, aortic stenosis, tricuspid regurgitation, smoking status, diabetes mellitus, dialysis, and cross-clamp time. Conclusions: A low SPP/CVP ratio was associated with worse outcomes in patients undergoing valvular heart surgery. This metric has potential utility in preoperative risk stratification to guide patient selection, prognosis, and surgical outcomes.Item Absolute lymphocyte count as a predictor of mortality and readmission in heart failure hospitalization(Elsevier, 2022-03-05) Majmundar, Monil; Kansara, Tikal; Park, Hansang; Ibarra, Gabriel; Lenik, Joanna Marta; Shah, Palak; Kumar, Ashish; Doshi, Rajkumar; Zala, Harshvardhan; Chaudhari, Shobhana; Kalra, Ankur; Medicine, School of MedicineBackground: There is renewed interest in pursuing frugal and readily available laboratory markers to predict mortality and readmission in heart failure. We aim to determine the relationship between absolute lymphocyte count (ALC) and clinical outcomes in patients with heart failure hospitalization. Methods: This was a retrospective cohort study of patients with heart failure. Patients were divided into two groups based on ALC, less than or equal to 1500 cells/mm3 and > 1500 cells/ mm3. The primary outcome was all-cause mortality. We did subgroup analysis based on ejection fraction and studied the association between ALC categories and clinical outcomes. Both ALC groups are matched by propensity score, outcomes were analyzed by Cox regression, and estimates are presented in hazard ratios (HR) and 95% confidence intervals (CI). Results: We included 1029 patients in the pre-matched cohort and 766 patients in the propensity-score matched cohort. The median age was 64 years (IQR, 54-75), and 60.78% were male. In the matched cohort, ALC less than or equal to 1500 cells/mm3 had a higher risk of mortality compared with ALC > 1500 cells/mm3 (HR 1.51, 95% CI: 1.17-1.95; P = 0.002). These results were reproducible in subgroups of heart failure. When ALC was divided into four groups based on their levels, the lowest group of ALC had the highest risk of mortality. Conclusions: In patients with heart failure and both subgroups, ALC less than or equal to 1500 cells/mm3 had a higher risk of mortality. Patients in lower groups of the ALC categories had a higher risk of mortality.Item ACE2 Deficiency Worsens Epicardial Adipose Tissue Inflammation and Cardiac Dysfunction in Response to Diet-Induced Obesity(American Diabetes Association, 2016-01) Patel, Vaibhav B.; Mori, Jun; McLean, Brent A.; Basu, Ratnadeep; Das, Subhash K.; Ramprasath, Tharmarajan; Parajuli, Nirmal; Penninger, Josef M.; Grant, Maria B.; Lopaschuk, Gary D.; Oudit, Gavin Y.; Department of Ophthalmology, IU School of MedicineObesity is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; angiotensin (Ang)-converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. We studied the role of ACE2 in obesity-mediated cardiac dysfunction. ACE2 null (ACE2KO) and wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet and studied at 6 months of age. Loss of ACE2 resulted in decreased weight gain but increased glucose intolerance, epicardial adipose tissue (EAT) inflammation, and polarization of macrophages into a proinflammatory phenotype in response to HFD. Similarly, human EAT in patients with obesity and heart failure displayed a proinflammatory macrophage phenotype. Exacerbated EAT inflammation in ACE2KO-HFD mice was associated with decreased myocardial adiponectin, decreased phosphorylation of AMPK, increased cardiac steatosis and lipotoxicity, and myocardial insulin resistance, which worsened heart function. Ang 1-7 (24 µg/kg/h) administered to ACE2KO-HFD mice resulted in ameliorated EAT inflammation and reduced cardiac steatosis and lipotoxicity, resulting in normalization of heart failure. In conclusion, ACE2 plays a novel role in heart disease associated with obesity wherein ACE2 negatively regulates obesity-induced EAT inflammation and cardiac insulin resistance.Item Advancing Research on the Complex Interrelations between Atrial fibrillation and Heart Failure: A Report from a National Heart, Lung, and Blood Institute Virtual Workshop(American Heart Association, 2020-06-09) Al-Khatib, Sana M.; Benjamin, Emelia J.; Albert, Christine M.; Alonso, Alvaro; Chauhan, Cynthia; Chen, Peng-Sheng; Curtis, Anne B.; Desvigne-Nickens, Patrice; Ho, Jennifer E.; Lam, Carolyn S.P.; Link, Mark S.; Patton, Kristen K.; Redfield, Margaret M.; Rienstra, Michiel; Rosenberg, Yves; Schnabel, Renate; Spertus, John A.; Warner Stevenson, Lynne; Hills, Mellanie True; Voors, Adriaan A.; Cooper, Lawton S.; Go, Alan S.; Medicine, School of MedicineThe interrelationships between atrial fibrillation (AF) and heart failure (HF) are complex and poorly understood, yet the number of patients with AF and HF continues to increase worldwide. Thus, there is a need for initiatives that prioritize research on the intersection between AF and HF. This report summarizes the proceedings of a virtual workshop convened by the National Heart, Lung, and Blood Institute to identify important research opportunities in AF and HF. Key knowledge gaps were reviewed and research priorities were proposed for characterizing the pathophysiological overlap and deleterious interactions between AF and HF; preventing HF in persons with AF; preventing AF in individuals with HF; and addressing symptom burden and health status outcomes in AF and HF. These research priorities will hopefully help inform, encourage, and stimulate innovative, cost-efficient, and transformative studies to enhance the outcomes of patients with AF and HF.Item Allogeneic Mesenchymal Cell Therapy in Anthracycline-Induced Cardiomyopathy Heart Failure Patients(Elsevier, 2020-11) Bolli, Roberto; Perin, Emerson C.; Willerson, James T.; Yang, Phillip C.; Traverse, Jay H.; Henry, Timothy D.; Pepine, Carl J.; Mitrani, Raul D.; Hare, Joshua M.; Murphy, Michael P.; March, Keith L.; Ikram, Sohail; Lee, David P.; O’Brien, Connor; Durand, Jean-Bernard; Miller, Kathy; Lima, Joao A.; Ostovaneh, Mohammad R.; Ambale-Venkatesh, Bharath; Gee, Adrian P.; Richman, Sara; Taylor, Doris A.; Sayre, Shelly L.; Bettencourt, Judy; Vojvodic, Rachel W.; Cohen, Michelle L.; Simpson, Lara M.; Lai, Dejian; Aguilar, David; Loghin, Catalin; Moyé, Lem; Ebert, Ray F.; Davis, Barry R.; Simari, Robert D.; Surgery, School of MedicineBackground: Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure (HF) treatment. Objectives: SENECA (Stem Cell Injection in Cancer Survivors) was a phase 1 study of allo-MSCs in AIC. Methods: Cancer survivors with chronic AIC (mean age 56.6 years; 68% women; NT-proBNP 1,426 pg/ml; 6 enrolled in an open-label, lead-in phase and 31 subjects randomized 1:1) received 1 × 108 allo-MSCs or vehicle transendocardially. Primary objectives were safety and feasibility. Secondary efficacy measures included cardiac function and structure measured by cardiac magnetic resonance imaging (CMR), functional capacity, quality of life (Minnesota Living with Heart Failure Questionnaire), and biomarkers. Results: A total of 97% of subjects underwent successful study product injections; all allo-MSC-assigned subjects received the target dose of cells. Follow-up visits were well-attended (92%) with successful collection of endpoints in 94% at the 1-year visit. Although 58% of subjects had non-CMR compatible devices, CMR endpoints were successfully collected in 84% of subjects imaged at 1 year. No new tumors were reported. There were no significant differences between allo-MSC and vehicle groups with regard to clinical outcomes. Secondary measures included 6-min walk test (p = 0.056) and Minnesota Living with Heart Failure Questionnaire score (p = 0.048), which tended to favor the allo-MSC group. Conclusions: In this first-in-human study of cell therapy in patients with AIC, transendocardial administration of allo-MSCs appears safe and feasible, and CMR was successfully performed in the majority of the HF patients with devices. This study lays the groundwork for phase 2 trials aimed at assessing efficacy of cell therapy in patients with AIC.Item The analysis of heterotaxy patients reveals new loss-of-function variants of GRK5(SpringerNature, 2016-09-13) Lessel, Davor; Muhammad, Tariq; Tena, Teresa Casar; Moepps, Barbara; Burkhalter, Martin D.; Hitz, Marc-Phillip; Toka, Okan; Rentzsch, Axel; Schubert, Stephan; Schalinski, Adelheid; Bauer, Ulrike M. M.; Kubisch, Christian; Ware, Stephanie M.; Philipp, Melanie; Department of Pediatrics, IU School of MedicineG protein-coupled receptor kinase 5 (GRK5) is a regulator of cardiac performance and a potential therapeutic target in heart failure in the adult. Additionally, we have previously classified GRK5 as a determinant of left-right asymmetry and proper heart development using zebrafish. We thus aimed to identify GRK5 variants of functional significance by analysing 187 individuals with laterality defects (heterotaxy) that were associated with a congenital heart defect (CHD). Using Sanger sequencing we identified two moderately frequent variants in GRK5 with minor allele frequencies <10%, and seven very rare polymorphisms with minor allele frequencies <1%, two of which are novel variants. Given their evolutionarily conserved position in zebrafish, in-depth functional characterisation of four variants (p.Q41L, p.G298S, p.R304C and p.T425M) was performed. We tested the effects of these variants on normal subcellular localisation and the ability to desensitise receptor signalling as well as their ability to correct the left-right asymmetry defect upon Grk5l knockdown in zebrafish. While p.Q41L, p.R304C and p.T425M responded normally in the first two aspects, neither p.Q41L nor p.R304C were capable of rescuing the lateralisation phenotype. The fourth variant, p.G298S was identified as a complete loss-of-function variant in all assays and provides insight into the functions of GRK5.Item Artificial Intelligence, Wearables and Remote Monitoring for Heart Failure: Current and Future Applications(MDPI, 2022-11-26) Gautam, Nitesh; Ghanta, Sai Nikhila; Mueller, Joshua; Mansour, Munthir; Chen, Zhongning; Puente, Clara; Ha, Yu Mi; Tarun, Tushar; Dhar, Gaurav; Sivakumar, Kalai; Zhang, Yiye; Halimeh, Ahmed Abu; Nakarmi, Ukash; Al-Kindi, Sadeer; DeMazumder, Deeptankar; Al’Aref, Subhi J.; Medicine, School of MedicineSubstantial milestones have been attained in the field of heart failure (HF) diagnostics and therapeutics in the past several years that have translated into decreased mortality but a paradoxical increase in HF-related hospitalizations. With increasing data digitalization and access, remote monitoring via wearables and implantables have the potential to transform ambulatory care workflow, with a particular focus on reducing HF hospitalizations. Additionally, artificial intelligence and machine learning (AI/ML) have been increasingly employed at multiple stages of healthcare due to their power in assimilating and integrating multidimensional multimodal data and the creation of accurate prediction models. With the ever-increasing troves of data, the implementation of AI/ML algorithms could help improve workflow and outcomes of HF patients, especially time series data collected via remote monitoring. In this review, we sought to describe the basics of AI/ML algorithms with a focus on time series forecasting and the current state of AI/ML within the context of wearable technology in HF, followed by a discussion of the present limitations, including data integration, privacy, and challenges specific to AI/ML application within healthcare.Item Association Between the Affordable Care Act Medicaid Expansion and Receipt of Cardiac Resynchronization Therapy by Race and Ethnicity(American Heart Association, 2022) Mwansa, Hunter; Barry, Ibrahim; Knapp, Shannon M.; Mazimba, Sula; Calhoun, Elizabeth; Sweitzer, Nancy K.; Breathett, Khadijah; Medicine, School of MedicineBackground: Black and Hispanic patients are less likely to receive cardiac resynchronization therapy (CRT) than White patients. Medicaid expansion has been associated with increased access to cardiovascular care among racial and ethnic groups with higher prevalence of underinsurance. It is unknown whether the Medicaid expansion was associated with increased receipt of CRT by race and ethnicity. Methods and Results: Using Healthcare Cost and Utilization Project Data State Inpatient Databases from 19 states and Washington, DC, we analyzed 1061 patients from early‐adopter states (Medicaid expansion by January 2014) and 745 patients from nonadopter states (no implementation 2013–2014). Estimates of change in census‐adjusted rates of CRT with or without defibrillator by race and ethnicity and Medicaid adopter status 1 year before and after January 2014 were conducted using a quasi‐Poisson regression model. Following the Medicaid expansion, the rate of CRT did not significantly change among Black individuals from early‐adopter states (1.07 [95% CI, 0.78–1.48]) or nonadopter states (0.79 [95% CI, 0.57–1.09]). There were no significant changes in rates of CRT among Hispanic individuals from early‐adopter states (0.99 [95% CI, 0.70–1.38]) or nonadopter states (1.01 [95% CI, 0.65–1.57]). There was a 34% increase in CRT rates among White individuals from early‐adopter states (1.34 [95% CI, 1.05–1.70]), and no significant change among White individuals from nonadopter states (0.77 [95% CI, 0.59–1.02]). The change in CRT rates among White individuals was associated with the timing of the Medicaid implementation (P=0.003). Conclusions: Among states participating in Healthcare Cost and Utilization Project Data State Inpatient Databases, implementation of Medicaid expansion was associated with increase in CRT rates among White individuals residing in states that adopted the Medicaid expansion policy. Further work is needed to address disparities in CRT among Black and Hispanic patients.Item BMP10 preserves cardiac function through its dual activation of SMAD-mediated and STAT3-mediated pathways(Elsevier, 2019-12-27) Qu, Xiuxia; Liu, Ying; Cao, Dayan; Chen, Jinghai; Liu, Zhuo; Ji, Hongrui; Chen, Yuwen; Zhang, Wenjun; Zhu, Ping; Xiao, Deyong; Li, Xiaohui; Shou, Weinian; Chen, Hanying; Pediatrics, School of MedicineBone morphogenetic protein 10 (BMP10) is a cardiac peptide growth factor belonging to the transforming growth factor β superfamily that critically controls cardiovascular development, growth, and maturation. It has been shown that BMP10 elicits its intracellular signaling through a receptor complex of activin receptor-like kinase 1 with morphogenetic protein receptor type II or activin receptor type 2A. Previously, we generated and characterized a transgenic mouse line expressing BMP10 from the α-myosin heavy chain gene promoter and found that these mice have normal cardiac hypertrophic responses to both physiological and pathological stimuli. In this study, we report that these transgenic mice exhibit significantly reduced levels of cardiomyocyte apoptosis and cardiac fibrosis in response to a prolonged administration of the β-adrenoreceptor agonist isoproterenol. We further confirmed this cardioprotective function with a newly generated conditional Bmp10 transgenic mouse line, in which Bmp10 was activated in adult hearts by tamoxifen. Moreover, the intraperitoneal administration of recombinant human BMP10 was found to effectively protect hearts from injury, suggesting potential therapeutic utility of using BMP10 to prevent heart failure. Gene profiling and biochemical analyses indicated that BMP10 activates the SMAD-mediated canonical pathway and, unexpectedly, also the signal transducer and activator of transcription 3 (STAT3)-mediated signaling pathway both in vivo and in vitro Additional findings further supported the notion that BMP10's cardioprotective function likely is due to its dual activation of SMAD- and STAT3-regulated signaling pathways, promoting cardiomyocyte survival and suppressing cardiac fibrosis.