tbuckley/cabot-search huggingface dataset:
Abstract 4123630: MRPL44 Plays an Important Role in Cardiac Hypertrophy and Function
Authors: Ryuji Okamoto, Zhe Ye, Rie Ito, Keishi Moriwaki, Hiromasa Ito, Lupiya Kimena, Mizuki Ida, Kaoru Dohi
Journal: Circulation (2024)

Background: Mitochondrial ribosomal large subunit 44 (MRPL44) knockout mice were embryonic lethal, for which mutations are known to cause mitochondrial infantile cardiomyopathy and hypertrophic cardiomyopathy. However, it remains unknown how MRPL44 contributes to cardiac function and hypertrophy. Aims: Our aim is to investigate the effect of MRPL44 haploinsufficiency in mice. Methods: MRPL44 haploinsufficient (MRPL44 +/- ) mice were generated. Mineralocorticoid receptor-associated hypertension mice were induced in MRPL44 +/- and wild-type (WT, MRPL44 +/+ ) mice with subcutaneous infusion of aldosterone(Aldo) and 8% NaCl food for 4 weeks after uninephrectomy. Systolic blood pressure was measured by tail cuffs every week. WB, qPCR, cardiac echo, and histological examinations were performed. RNA sequencing analysis, electron microscopy examinations and mitochondrial activity assay were performed to find differences between MRPL44 +/- and MRPL44 +/+ mice. Results: MRPL44 haploinsufficient mice spontaneously developed left ventricular hypertrophy. Heart rate, blood pressure, and cardiac systolic function were normal in MRPL44 haploinsufficient mice. MRPL44 was decreased about to 70% in MRPL44 haploinsufficient mice and mitochondrial arrangement were impaired in electron microscopic analysis. After Aldo treatment, blood pressure elevation were similar, however, MRPL44 haploinsufficient mice developed left ventricular systolic dysfunction and dilation compared with MRPL44 +/+ mice. WB showed mitochondrial electron transport chain protein complex IV expression was significantly decreased. Furthermore, mitochondrial activity assay showed MRPL44 haploinsufficient mice had a significant reduction in complex IV activity, whereas complex I and II activity were similar to MRPL44 +/+ mice. RNA sequencing analysis showed the significant changes in the expression of ribosomal subunits coded by nucleus in addition to mitochondrial ribosomal subunits. These results indicate MRPL44 plays an important role in the cardiac function of mitochondrial electron transport chain protein complexes via the expression of ribosomal protein subunits coded by both nucleus and mitochondria. Conclusion: MRPL44 haploinsufficient mice spontaneously develop left ventricular hypertrophy and shows systolic dysfunction after aldosterone treatment accompanied with oxidative phosphorylation enzyme dysfunction.
Abstract 4136978: Six-month Changes in Lipid Management in the Veterans Affairs Lipid Optimization Reimagined Quality Improvement (VALOR-QI) Program
Authors: Rachel Ward, Helen Wellman, Nedim Yel, Mason Coleman-Lopez, Abigail Santos, Jen DelGrande, Abigail Fink, Kristin Colson, Eddie Pan, Tharen Leesch, David Pena, Michelle Congdon, Kelly Burlison, Luc Djousse, John Michael Gaziano
Journal: Circulation (2024)

Background: US Veterans have a high burden of cardiovascular disease (CVD). While cholesterol management is one of the most effective approaches for reducing CVD burden, over two-thirds of Veterans with atherosclerotic cardiovascular disease (ASCVD) are not optimally managed. Aims: To evaluate LDL-C monitoring, lipid lowering therapy (LLT) use, and LDL-C levels at baseline and six-months for Veterans in the Veterans Affairs Lipid Optimization Reimagined Quality Improvement (VALOR-QI) Program. Methods: VALOR-QI is a national quality improvement collaboration between the US Department of Veterans Affairs and the American Heart Association (AHA) with the goal of improving lipid management among Veterans with ASCVD. To assess and address barriers to achieving optimal lipid levels, Clinical Champions, Health Care Coaches, and participating providers from 50 VA sites work with AHA QI Consultants. Eligible Veterans (those with an ASCVD diagnosis at two outpatient or one inpatient visit or one ASCVD procedure) were considered engaged in VALOR-QI if they had a qualifying appointment with a participating provider during the program. We examined rates of LDL-C monitoring and LLT use at baseline (start of site monitoring) and 6 months after. Among Veterans who were in the program ≥6 months and had &gt;1 LDL-C measure, we investigated percent meeting an LDL-C goal of &lt;70 mg/dL at their first LDL-C (closest to their first visit with priority given to labs within 365 days before their first visit) and follow-up LDL-C (closest to 6 months after entering the program) and mean LDL-C change (paired t-test). Results: Six months after starting VALOR-QI, sites had a 41% increase in LDL-C monitoring and a 6% increase in LLT use. Among 29,610 Veterans engaged in the program ≥6 months with at least two lipid labs [mean (SD) age 71.0 (9.3) years, 95% men, 72% white race], the proportion who met the LDL-C goal &lt;70 mg/dL increased from 44% at their first measure to 51% at 6-month follow-up. Among these Veterans, we observed a mean LDL-C decrease of 5.1 mg/dL (95% CI: -5.50, -4.78). Conclusion: We observed an increase in lipid monitoring and LLT use and improved LDL-C at 6-month follow-up among US Veterans engaged in VALOR-QI.
Abstract 4140149: Differences in Interventional Treatment Outcomes of Peripheral Arterial Disease between African American Females, African American Males, and Caucasian Females
Authors: Fedor Lurie, Babatunde Oriowo, Todd Russell, Kelly Hallett, Gregory Kasper
Journal: Circulation (2024)

Introduction: Several recent publications demonstrated worse outcomes of interventional treatment of peripheral arterial disease (PAD) in patients of African American (AA) descent compared to Caucasians (C), and in female patients compared to male patients. However, studies addressing sex differences in outcomes, included predominantly white female patients. To our knowledge, there are no published studies specifically addressing outcomes of interventional treatment of PAD in female patients of African American descent. Aims: 1. To determine if the outcomes of interventional treatment of PAD in female patients of African American (FAA) descent differ from male African American patients (MAA), and Caucasian female patients (FC). If such differences exist, to identify factors associated with it. Methods: This study has a cross-sectional design with systematically retrospective data collection by the National Vascular Quality Initiative. Included in this study was data on patients treated with endovascular and open surgical options for symptomatic PAD. Statistical analysis was done using IBM Statistic SPSS V25. Results: 447,263 unique cases containing required data were available in the VQI database. Among them, 171,250 were female patients, of which 32,966 were FAA, 126,519 FC, and 39,461 MAA. This race and gender distribution is not significantly different from the US population structure (US Census Bureau 2023). 1 However, female to male ratio was higher in AA (0.83) compared to C (0.58, p&lt;0.0001). FAA were younger (65.143+/-9.59) compared to FC (69.16+/-10.32, P&lt;0.00001). Comparison of comorbidities, smoking rates, pre-interventional medications and post-interventional outcomes are listed in Table 1. Multivariate analysis confirmed higher amputation rate among FAA compared to FC and to MAA and showed no significant difference in mortality. Conclusions: FAA patients who require interventional treatment for PAD have significantly higher rate of hypertension and diabetes compared to FC and MAA patients and have higher amputation rates. It appears that differences in clinical outcomes of PAD treatment in FAA are related mostly if not entirely to poorly managed comorbidities existed prior to intervention.
Abstract 4144585: Association of renal function with mortality and heart failure hospitalization rates after Transcatheter Mitral Valve Edge to Edge Repair
Authors: Wael Abuzeid, Ethan Sacoransky, Andrew Czarnecki, Danny Yu Jia Ke, Carolyn Teng, Prasham Dave, mark osten, Brigita Zile, Xuesong Wang, Mony Shuvy, Warren Cantor, Shamir Mehta, Neil Fam, Husam Abdel-Qadir
Journal: Circulation (2024)

Background: Transcatheter edge to edge repair (TEER) is an established treatment for patients with symptomatic severe functional MR on optimal medical therapy or severe symptomatic primary MR and high surgical risk. Renal dysfunction is associated with adverse outcomes but the threshold at which risks rise are uncertain. Aim To determine the association of estimated glomerular filtration rate (eGFR) with adverse outcomes in patients undergoing TEER for severe symptomatic mitral regurgitation (MR) in Ontario, Canada. Methods: This was a population-based retrospective cohort study using linked administrative datasets of patients who underwent TEER in Ontario, Canada, between 2011 and 2023. The key exposure was eGFR, which was modeled using restricted cubic splines. Outcomes were 1-year mortality, cardiovascular mortality (CV) and heart failure hospitalization (HF). Cause-specific hazards regression was used to model the association between eGFR and outcomes, utilizing eGFR 30ml/min/1.73m2 as the reference value. Results: We studied 2076 patients, of whom 294 (14.2%) had eGFR &lt;30ml/min/1.73m2 and 841 (40.5%) had eGFR 30-60ml/min/1.73m2. The incidence at one year was 16.8% for all-cause mortality, 11% for CV mortality and 14.2% for HF hospitalizations. The Figure illustrates that the predicted incidence of adverse outcomes increases with lower eGFR, with subtle differences in patterns of change in risk at lower eGFR levels such that all-cause mortality and CV mortality begin to rise rapidly at eGFR values ≤30ml/min/1.73m2, while HF hospitalization increases linearly at eGFR ≤50ml/min/1.73m2. Conclusions: There was a progressive increase in all-cause, CV mortality and HF hospitalization after TEER for patients with lower eGFR, particularly those with values &lt;30 ml/min/1.73m2. This data can inform patient discussions and guide post-procedural follow-up.
Abstract 4134320: Integrated safety and tolerability of mavacamten treatment over 5 years in patients with obstructive hypertrophic cardiomyopathy
Authors: Anjali Owens, Roberto Barriales-Villa, Milind Desai, Pablo Garcia-Pavia, Albert Hagege, iacopo olivotto, Wojtek Wojakowski, Sonia Afsari, Ganesh Balaratnam, Yu Mao Chen, Andrew Wang
Journal: Circulation (2024)

Background: Mavacamten, a cardiac myosin inhibitor, is approved across 5 continents for the treatment of obstructive hypertrophic cardiomyopathy (HCM). Long-term data of mavacamten are available from multiple studies, providing the opportunity to further understand mavacamten long term safety, including adverse events (AEs) of clinical interest. Aim: To present integrated safety data of patients who received mavacamten treatment for obstructive HCM across 5 studies. Methods: The pooled population included all patients who received ≥1 dose of mavacamten in PIONEER-HCM, PIONEER-Open Label Extension (data cut-off: May 31, 2022), EXPLORER-HCM, MAVA-Long-Term Extension (EXPLORER cohort; data cut-off: August 31, 2023) and VALOR-HCM including long-term extension (data cut-off: November 11, 2022). Results: The population consisted of 368 patients (mean [SD] age: 59.4 [12.2] years; male: 57.1%; White: 90.8%), including 350 patients who continued onto an extension study after completing a parent study. The majority of patients (57.6%) had a cumulative time on study of ≥3 years. Forty (10.9%) patients permanently discontinued treatment (13 due to AEs). In total, 20.7% of patients had a treatment emergent AE (TEAE) of Grade ≥3 and 14.7% had a TEAE leading to drug interruption. Overall, 4.3% of patients had drug-related serious TEAEs and 1.6% had a TEAE leading to death. The cumulative exposure adjusted incidence rates (EAIR) of all TEAEs, including AEs of clinical interest (atrial fibrillation [AF], ejection fraction [EF] decreased and heart failure [HF]), decreased as exposure increased over time, from 347.1/100 patient-years (P-Y) at Week 60 (~year 1) to 271.8/100 P-Y at Week 252 (~year 5). The EAIR of AF decreased over time from 13.3/100 P-Y at Week 60 (~year 1) to 6.2/100 P-Y at Week 252 (~year 5) ( Figure ). The EAIR for EF decreased and HF also decreased over time ( Figure ). Conclusions: This integrated analysis of all patients with obstructive HCM treated with mavacamten across the 5 clinical studies over 5 years demonstrated that mavacamten treatment is generally well tolerated and that the EAIRs of selected TEAEs of clinical interest (AF, EF decreased and HF) decreased as exposure increased over time.
Abstract 4145861: Systemic Sclerosis is Associated with Sub-Clinical Abnormalities in Myocardial Energetics, Perfusion and Increased Fibrosis
Authors: Chin Yit Soo, Nicholas Jex, Stefano Di Donato, Lucy Elizabeth Thornton, Vishal Kakkar, Riccardo Bixio, Raluca Tomoaia, Thomas Anderton, May Lwin, Christel Kamani, Amrit Chowdhary, Sharmaine Thirunavukarasu, Henry Procter, Sindhoora Kotha, Marilena Giannoudi, Eylem Levelt, Lesley-Anne Bissell, Francesco Delgado, Sven Plein
Journal: Circulation (2024)

Background: Primary cardiac involvement in systemic sclerosis (SSc) is heterogenous, poorly defined and associated with significant cardiac morbidity and mortality. The underlying mechanism is not well understood but may include the impact of coronary microvascular dysfunction and myocardial inflammation. Myocardial cellular metabolic alterations in SSc are yet to be established. Aims: Using 31 Phosphorous magnetic resonance spectroscopy ( 31 P MRS) and cardiovascular magnetic resonance (CMR), we aimed to establish if myocardial energetics, measured as phosphocreatine (PCr) /ATP ratio, and quantitative myocardial perfusion were reduced in individuals with SSc compared to healthy volunteers (HV). Methods: A total of 35 age and sex matched participants were recruited (25 SSc, 10 HV). All subjects underwent 31 P MRS and comprehensive CMR protocol including volumetric analysis, quantitative myocardial perfusion and T1 mapping. Results: Table-1 shows clinical and CMR / 31 P MRS data. Bi-ventricular volumes, systolic function and left atrial function were similar in both groups. NT-Pro BNP and myocardial extra cellular volume (ECV) were significantly increased in SSc. Both PCr/ATP and myocardial perfusion reserve (MPR) were significantly reduced in SSc compared with controls. The disease activity as measured by the European Scleroderma Trials and Research group (EUSTAR) activity index did not correlate with either NTproBNP (P=0.79), PCr/ATP (P=0.35) or MPR (P=0.6). Conclusions: In addition to validating our previous observations of reduced perfusion and increased myocardial fibrosis in SSc, we have demonstrated for the first time significant reductions in myocardial energetics in patients with SSc. These findings provide further valuable insight into the pathogenesis of primary myocardial disease in SSc.
Abstract 4139169: Treatment with methotrexate associated with LDL-like nanoparticles prevents the development of left ventricular fibrosis in a spontaneously hypertensive rat model
Authors: Aline de Oliveira Silva, Maria Carolina Guido, Mauricio Costa, Priscila da Silva, Fatima Freitas, Amanda Silva, Maria Irigoyen, Raul Maranhao
Journal: Circulation (2024)

Introduction: Systemic arterial hypertension (SAH) can lead to left ventricle (LV) fibrosis and ventricular dysfunction. Methotrexate (MTX) associated with lipid nanoparticles (LDE) increases the cellular uptake of MTX by ninety-fold, which leads to therapeutic efficacy and reduces drug toxicity. Previously, treatment of rats with myocardial infarction with LDE-MTX decreased LV fibrosis and prevented ventricular dysfunction. The aim was to test LDE-MTX to preclude the development of cardiac damages caused by hypertension in spontaneously hypertensive rats (SHR). Methods: Twenty-four male rats with six-week-old were allocated in 3 groups: Control (CT): Wistar-Kyoto rats injected with saline; SHR: treated with LDE only and SHR-LDE-MTX: treated with LDE-MTX (1mg/Kg/week, I.P.). After 20 weeks of treatment, echocardiography, morphometry and protein expression were performed in the LV. The data were analyzed by ANOVA with Turkey’s post-test or Kruskal-Wallis test with Dunn's post-test. Linear regression was used to evaluate potential relationships. Results: Compared to CT, the two SHR groups showed dilation (increase in systolic and diastolic diameter); hypertrophy (increased thickness of the posterior wall) and systolic dysfunction (decreased ejection and shortening fractions). Furthermore, the SHR group showed increased LV fibrosis in both the interstitial region and the papillary muscle, possibly resulting from increased of type I collagen content. Treatment of SHR with LDE-MTX had no effect on LV dilation, hypertrophy or systolic dysfunction. However, LDE-MTX decreased LV fibrosis of the interstitial region and the papillary muscle. In addition, LDE-MTX increased the expression of MMP-2, and increased the bioavailability of intracellular adenosine, via increased expression of the adenosine A3 receptor. There was a negative correlation between the expression of the adenosine A3 receptor with interstitial fibrosis (r2=-0.31, p=0.03) and papillary muscle (r2=-0.47, p=0.03), indicating that the increased bioavailability of intracellular adenosine also contributed to the decrease in LV fibrosis in SHR. Conclusion: In SHR, treatment with LDE-MTX reduced LV fibrosis, possibly by modulating MMP-2 expression and increasing the bioavailability of intracellular adenosine, via the adenosine A3 receptor. These results suggest a therapeutic role for LDE-MTX in patients with LV fibrosis and heart failure caused by SAH, to be explored in future clinical studies.
Abstract 4145884: Left ventricular 3D-sphericity is associated with 92 genetic loci
Authors: James Pirruccello
Journal: Circulation (2024)

Introduction: Left ventricular (LV) sphericity is a measure of the degree to which the LV blood pool resembles a sphere. Analyses of cardiovascular magnetic resonance imaging (MRI) in the MESA cohort have shown that LV sphericity is an important mode of variation in cardiac structure that is associated with ischemia, heart failure, and atrial fibrillation. A recent genome-wide association study (GWAS) of a two-dimensional estimate of sphericity in 38,000 UK Biobank participants identified 4 genetic loci (near PDZRN3, HLA, PLN, and ANGPT1). Genetic contributions to three-dimensional (3D) sphericity remain unknown. Aims: To measure 3D sphericity from cardiovascular MRI at scale and characterize the genetic contributions to 3D sphericity. Methods: Deep learning models were constructed to perform semantic segmentation in the short- and long-axis view from cardiovascular MRI in UK Biobank. These models were applied to all participants with MRI. Poisson surface reconstruction was used to build 3D meshes of the left ventricle. Sphericity was estimated at end-systole and end-diastole as the area of a perfect sphere with the same volume as the left ventricle, divided by the estimated surface area from the mesh. Heritability was estimated with ldsc; GWAS was conducted with REGENIE. Results: Sphericity was estimated in 68,978 individuals, of whom 3,096 were excluded due to atrial fibrillation or atrial dysfunction, and 2,686 were excluded during genetic quality control; 63,196 participants were included in the GWAS. Ldsc heritability was 29.7% for sphericity in diastole and 26.0% for sphericity in systole. 49 genetic loci were associated with 3D sphericity in diastole as were 64 in systole (92 distinct loci). 46 of these loci were unique to sphericity and not found for other LV traits, including loci near the genes encoding calsequestrin 2, troponin T2, palladin, supervillin, and angiopoietins 1 and 2. Shared loci included those near RXFP4, encoding a relaxin-family peptide receptor, and MICU2 (previously implicated in cardiac relaxation). Conclusion: Left ventricular sphericity is heritable, with genetic underpinnings distinct from standard LV measurements.
Abstract 4147640: Genetic Insights in Dilated Cardiomyopathy: SSPN as a Key Player
Authors: Karam Albdour, Bayan Abu Alragheb, Ahmad Younis, Ahmad Turk
Journal: Circulation (2024)

Background: Dilated cardiomyopathy (DCM) is a complex condition characterized by the dilation and impaired contraction of the left ventricle, which ultimately leads to heart failure. DCM has a multifactorial background, involving genetic, environmental, and infectious components. The genetic aspect of DCM is particularly significant, with numerous genes implicated in its pathogenesis. This study aims to identify differentially expressed genes (DEGs) involved in DCM, thereby contributing to the existing body of literature and facilitating further investigations into potential biomarkers and therapeutic targets for the disease. Methods: Data from the GSE1869, GSE3585, GSE4172, and GSE3586 datasets were obtained from the Gene Expression Omnibus (GEO) database. DEGs were identified using the GEO2R tool with an adjusted p-value cutoff of ≤0.05. Results: From the GSE1869 dataset, 3,692 DEGs were identified, alongside 691 DEGs from GSE4172, 889s DEG from GSE3586, and 95 DEGs from GSE3585. Intersection analysis revealed one mutual DEG across all four datasets: SSPN. SSPN, or sarcospan, is a component of the dystrophin-glycoprotein complex involved in stabilizing muscle cell membranes. As only one mutual DEG was identified, the findings suggest significant heterogeneity in gene expression profiles associated with DCM or potential limitations in the datasets. Conclusions: The identification of SSPN as a DEG associated with DCM provides valuable insights. Its expression in the heart has the potential to affect cardiac structural integrity and function. This gene holds promise as a potential biomarker that could inform the development of targeted therapies, highlighting its significance in the molecular mechanisms of the disease and warranting further investigation.