tbuckley/cabot-search huggingface dataset:
Abstract 4119868: Statin and PCSK9 Inhibitor Utilization and Spending in Medicaid between 2018 to 2022: A National Analysis
Authors: Alexander Beschloss, Rishi Wadhera, Andrew Oseran
Journal: Circulation (2024)

Introduction: Low-income working-aged adults in the Medicaid program have a high burden of cardiovascular risk factors and disease, but often face barriers accessing necessary therapies. Little is known about contemporary patterns of utilization and spending on lipid-lowering therapies in Medicaid programs. Goal: To evaluate national trends in utilization and spending on statins and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in Medicaid. Methods: We performed a serial cross-sectional study using the Medicaid Spending by Drug Database, which contains national-level Medicaid spending data for medications partially or fully reimbursed by Medicaid for the approximately 84 million beneficiaries. We evaluated annual trends in utilization (prescription fills) and total spending for statins and PCSK9i from 2018 to 2022, both overall and by individual drug formulation. Spending was adjusted for inflation and reported in 2022 US dollars. Results: Medicaid beneficiaries filled 20.4 million statin prescriptions in 2018 compared to 20.3 million in 2022, representing a 0.4% decrease. However, Medicaid spending on statins decreased by 7.1%, from $246.2 million to $226.8 million over the same period. Prescription fills for generic Rosuvastatin increased the most (0.79 million to 2.6 million, +224.2%), while fills for brand-name Crestor decreased the most (0.065 million to 0.003 million, -95.2%). Medicaid beneficiaries filled 121,737 prescriptions for PCSK9 inhibitors in 2022 compared to 7,617 in 2018 (+1498%), coinciding with a 640% increase in total spending ($8.9 million to $65.7 million). Repatha Sureclick was the most filled PCSK9i in Medicaid with 80,503 fills in 2022, representing $43.9 million in total Medicaid spending. Conclusions: Despite almost no change in statin utilization between 2018 and 2022, Medicaid spending on statins fell by approximately $20 million, driven by a shift from brand-name to generic formulations. In contrast, spending on PCSK9 inhibitors increased by $57 million as these medications became more widely used. Understanding these trends is critical as Medicaid programs work to ensure access to effective cardiovascular therapies while also identifying opportunities for cost efficiencies nationwide.
Abstract 4120290: Sex-specific Impact of Early to Mid-gestational Testosterone Excess on Sheep Fetal and Adult Offspring Lungs
Authors: Md Rahatullah Razan, Kel Vin Woo, David Bernal, Vasantha Padmanabhan, Arpita Vyas
Journal: Circulation (2024)

Using the translationally relevant sheep model of prenatal testosterone (T) excess, we previously reported intrauterine growth retardation (IUGR) in both sexes, adverse sex specific programming of fetal heart and cardiometabolic dysfunction in adult female offspring. Because of the intricate reciprocal relationship between the heart and lungs, we hypothesized that gestational T excess will have detrimental sex-specific effects on offspring lungs beginning as early as fetal life and extending into adulthood. Pregnant ewes were intramuscularly injected with 100 mg of testosterone propionate twice weekly from gestational days (GD) 30-90 (term 147 days) and offspring lungs were harvested at GD120, 30 days after cessation of T treatment; (n=4-7/group) and in adulthood (n=4-6/group) and processed for molecular and histological analyses. Data was analyzed by student T test within each sex and Cohen (d) effect size was calculated (Cohens d&gt;0.8 represents large effect size. Lung collagen was significantly increased in T-male fetuses (TM) vs control males (CM) (p=0.01, d=1.99) that persisted into adulthood (TM vs CM: p=0.01, d=1.83). The effects of gestational T excess was evidenced as an increase in collagen only in the lungs of adult T-female fetuses (TF) relative to control females (CF) (p=0.003, d=2.38), but not during fetal life. Gestational T excess induced significant parallel increases in TUNEL positive nuclei/frame in TM fetuses relative to CM (n=3/group, p=0.01, d=3.35) persisting as a large magnitude increase of TUNEL positive nuclei/frame in adult TM (p=0.12, d=0.96). In TF females, apoptotic changes were not noted in fetal lungs but an increase of TUNEL positive nuclei/frame was evidenced in adult TF (p=0.08, d=1.14). At the molecular level prenatal T excess induced an increase in histone deacetylase 1 (HDAC1) expression in fetal TM vs CM (p=0.04, d=1.50), and decrease in HDAC1 in TF vs CF (p=0.10, d=1.09) suggestive of T-induced epigenetic alteration. Transcriptomic analysis of fetal lungs revealed upregulation of pathways associated with estrogen signaling and neuroactive ligand receptor interaction, and downregulation of pathways associated with protein processing in endoplasmic reticulum and antigen processing&amp;presentation (unadjusted p&lt; 0.05, log FC&gt;1.5) in both sexes. Overall, early to mid-gestational exposure to testosterone adversely reprograms the lungs in sex specific fashion as early as fetal life extending into postnatal adult life.
Abstract 4121348: Impairments in Left Atrioventricular Coupling Underpins Reductions in Skeletal Muscle Mass and Function in Ageing Older Adults
Authors: Alex Yufei Xie, Glades Tan, Shuang Leng, XIAODAN ZHAO, Liang Zhong, Wee Shiong Lim, Gina Lee, Ru Tan, Fei Gao, Angela Koh
Journal: Circulation (2024)

Background: Age-related cardiovascular disease (CVD) may manifest with changes in left ventricular (LV) systolic or left atrial (LA) dysfunction. Alterations in functional performance between the LV and LA chambers characterized by LA-LV coupling may be a sensitive marker representative of impairments in global cardiac performance, compared to either chamber alone. The increasing relevance of skeletal muscle function towards cardiac health in ageing, motivated our current work that investigated associations between skeletal muscle function and LA-LV coupling. Aim : Using advanced cardiac magnetic resonance (CMR) that characterizes cardiac volumetric parameters and strain functions, we determined the association between handgrip strength (HGS) and appendicular lean mass (ALM) with left atrioventricular coupling index (LACI). Methods: Community older adults without CVD underwent simultaneous assessment of HGS by hand dynamometer, height-square adjusted ALM by bio-impedance, and LA phasic function (namely reservoir, conduit, booster strain) as well as LA and LV volumetric parameters by CMR feature tracking. LACI is defined as the ratio of the ratio of LA to LV end-diastolic volumes. We performed linear regression and multivariable logistic regression to examine the relationship between HGS/ALM and LACI. Results: Among 251 study participants (mean age: 71 ± 9.1 years, female 44.7%), 149 (59%) had impaired LACI. HGS was linearly associated with LACI (β=-0.004, p=0.003) and LVEDV (β=1.62, p&lt;0.0001), and ALM was linearly associated with LA volume (β=0.55, p=0.018) and LVEDV (β=3.45, p&lt;0.0001) (Figure.1). Participants with impaired LACI (&gt; 25%) had lower HGS (mean=22.8 ± 7.1 kg vs 26.1 ± 6.4 kg, p= 0.0002), lower ALM (16.4 ± 4.2 kg/m2 vs 17.7 ± 3.8 kg/m2, p=0.014), higher LA volume (36.8 ± 15.2 ml vs 22.0 ± 5.5 ml, p &lt; 0.0001) and lower LV end-diastolic volume (101.0 ± 24.2 ml vs 111.9 ± 27.3 ml, p = 0.0011). The association between impaired LA-LV coupling and lower HGS (β=-0.0647, 95%CI -0.0255, -0.1040, p=0.001) and lower ALM (β=-0.0776, 95%CI -0.0107, -0.1444, p=0.011) persisted after adjusting for age. Conclusion: Reduced HGS and ALM among community-dwelling older adults was associated with impaired LA-LV coupling suggestive of underlying early-stage LA remodelling and impairments in left atrioventricular compliance. Detection of reduced HGS and ALM in community cohorts may prompt early identification of older adults at risk of dysfunctional cardiac aging.
Abstract 4120830: A Curious Case of Clozapine Carditis with Cardiac Convalescence
Authors: Dimitri Maamari, Vivek Koshti, Katarina Yaros, Rafic Berbarie
Journal: Circulation (2024)

Case Presentation: Clozapine is an antipsychotic used in treatment-resistant schizophrenia. Its use has been limited by adverse events, rarely including myocarditis. Here, we describe a rare case of clozapine-induced myocarditis and the improvement of cardiac function with avoidance of clozapine for one week and initiation of guideline-directed medical therapy (GDMT). A 29-year-old man with schizophrenia on risperidone and paroxetine was admitted with schizophrenia decompensation and suicidal ideations. He was transitioned to clozapine with improvement in his psychiatric symptoms. Thirteen days after starting clozapine, he developed nausea, vomiting, tachycardia, and low-grade fever. He had leukocytosis but it was thought to be, in part, secondary to methylprednisolone before rituximab infusions for his multiple sclerosis. An electrocardiogram revealed sinus tachycardia, and troponin, which was taken in the setting of clozapine therapy, was 6. Four days later, his fever and tachycardia with chills and dyspnea persisted; troponin was in the forties and increased to 235 within a few hours. Over the next 36 hours, troponin peaked at 3,600. C-reactive protein and erythrocyte sedimentation rates were elevated at 20.5 and 51, compared to 1.8 and 3 respectively upon initiation of symptoms a few days earlier. A respiratory viral panel, blood and urine cultures, human immunodeficiency virus, and an autoimmune workup were unrevealing. Clozapine was held. A transthoracic echocardiogram revealed a reduced systolic function with a left ventricular ejection fraction (LVEF) of 40%. A cardiac magnetic resonance imaging revealed acute myocarditis with LVEF 24%. He was started on GDMT and a repeat echocardiogram six days later revealed normalization of systolic function with LVEF 56% with clinical improvement. His last dose of clozapine was seven days earlier. He was discharged on GDMT and clozapine was added to his allergy list. Discussion: Myocarditis is a serious and rare adverse event to clozapine therapy. Symptoms are non-specific and delays in diagnosis may lead to myocardial damage and fatal arrhythmias. In light of the patient’s presentation, unrevealing workup, and improvement with avoidance of clozapine, we believe that the individual had clozapine-induced myocarditis. It is important to highlight the occurrence of this rare outcome to consider this toxicity and initiate treatment in time.
Abstract 4121555: Integrated Polygenic Score Stratifies Risk of Peripheral Artery Disease and Major Adverse Limb Events
Authors: Alyssa Monica Flores, Yunfeng Ruan, Anika Misra, Margaret Selvaraj, Tiffany Bellomo, Matthew Eagleton, Kenneth Rosenfield, Whitney Hornsby, Aniruddh Patel, Pradeep Natarajan
Journal: Circulation (2024)

Background: Peripheral artery disease (PAD) is a heritable atherosclerotic condition. With growing knowledge of the genetic basis for PAD and related risk factors, there is opportunity to identify high-risk individuals for prevention and potentially intervention based on polygenic background. Aims: To develop and validate an integrated genome-wide polygenic score for PAD (GPS PAD ), evaluate association of polygenic risk with major adverse limb events (MALE), and compare predictive performance in diverse ancestral populations to previously published polygenic scores. Methods: We developed GPS PAD by integrating genetic association summary statistics for PAD and related traits stratified by ancestry. GPS PAD was trained in a sample of 96,239 European individuals from the UK Biobank, and validated in multi-ancestry cohorts, including a holdout validation UK Biobank dataset (N=304,294), and external All of Us (AoU; N=237,173) and Mass General Brigham Biobank datasets (N=37,017). GPS PAD performance was benchmarked against previously published polygenic scores and clinical risk factors. Results: GPS PAD was comprised of 603,595 variants with weights informed by association with PAD and ten PAD risk factors across five ancestry groups. GPS PAD had an OR-per SD of 1.63 in the holdout UK Biobank dataset (95% CI 1.60-1.68). GPS PAD outperformed previously published scores in non-European subgroups in the UK Biobank and achieved superior cross-population portability in external validation cohorts. GPS PAD was associated with incident PAD in the UK Biobank (HR 1.66; 95% CI 1.61-1.71) and achieved improvements in discrimination (ΔC-statistic 0.030) that were nearly equivalent to the additive performances of diabetes (ΔC-statistic 0.029) and smoking (ΔC-statistic 0.034) to the baseline model including age, sex, and 10 principal components of ancestry. Among individuals with prevalent PAD, GPS PAD was associated with incident MALE in the UK Biobank (HR 1.48; 95% CI 1.24-1.77). GPS PAD consistently identified individuals with PAD at high MALE-risk in the Mass General Brigham Biobank (HR 1.34; 95% CI 1.12-1.60), and AoU (HR 1.33; 95% CI 1.12-1.58). Conclusions: These findings contribute a polygenic score for PAD that predicts disease and MALE with cross-cohort performance and transferability to diverse ancestries. Integrated polygenic scores may be used to stratify PAD risk and target more aggressive management, lifestyle modification, and surveillance efforts.
Abstract 4122612: Validation of a Machine Learning Model for Fetal Echocardiographic Prediction of Critical Coarctation of the Aorta
Authors: Robert McRae, Matthew Magoon, Aaron Phillips, Kathryn Virk, Malika Waschman, Shiraz Maskatia, Nelangi Pinto, Patrick Boyle, Bhawna Arya
Journal: Circulation (2024)

Background: Current fetal echocardiographic (F-echo) metrics have inadequate specificity for confident prediction of neonatal critical coarctation of the aorta (CoA). Using single-center data, our machine learning model for the prediction of fetal CoA demonstrated improved accuracy compared to published F-echo metrics for critical CoA assessment. External validation of this model is needed. Aim: Validate a machine learning F-echo predictive model for CoA with an external patient cohort. Methods: Initial model training and testing were performed using retrospective single center data on 9 F-echo measurements for patients with prenatal concern for CoA. A random forest classifier with 80:20 split and 5-fold cross-validation predicted CoA intervention within 30 days of life. A SHapley Additive exPlanations (SHAP) analysis assessed the marginal contribution of each feature. The model was retrained using the 5 most influential F-echo features. External validation for this model was then performed using patients with prenatal concern for CoA retrospectively collected at a partner institution. Results: Inclusion criteria were met by 132 patients in the initial cohort and 64 patients in the external validation cohort, of whom 44% (n=58) and 25% (n=16) respectively had CoA requiring intervention. SHAP analysis for both cohorts demonstrated transverse to descending aorta angle as the most influential feature, followed by ascending to descending aorta angle (Figure 1A). Using internal cross-validation on the initial cohort, the area under the receiver operating characteristic curve (AUC) was 0.93 ± 0.05 (sensitivity 0.97, specificity 1.0) with an F1 score of 0.97 ± 0.03. Validation of the model with the external cohort produced an AUC of 0.87 (sensitivity 0.81, specificity 1.0) and an F1 of 0.90 (Figure 1B). Conclusions: A random forest classifier using F-echo features predicted neonatal critical CoA with higher accuracy than previously published metrics. The model maintained high accuracy when validated with an external patient cohort. Arch angles most significantly impacted the model’s accuracy. Future directions include prospective validation and converting the model to a distributable clinical calculator.
Abstract 4121104: Fish Oil-Derived N-3 Very-Long-Chain Polyunsaturated Fatty Acids Improve Retinal Function in Aged Mice
Authors: Julia Kun, Zhihong Yang, Milton Pryor, Sophia Ibarguen, Isao Yamazaki, Hideaki Yamaguchi, Hairui Xie, Anand Swaroop, Alan Remaley
Journal: Circulation (2024)

Introduction: Epidemiological studies and clinical trials have revealed cardiometabolic benefits associated with dietary fish oil-derived omega-3 polyunsaturated fatty acids, particularly EPA and DHA. Omega-3 very-long-chain polyunsaturated fatty acids (VLCPUFA), synthesized in vivo by very-long-chain fatty acid elongase (ELOVL), e.g. ELOVL2 and 4, have recently garnered interest for their role in eye and cardiometabolic diseases. In our previous study, aging mice fed a VLCPUFA-rich diet for 8 weeks exhibited lowered plasma lipid levels, and repeated gavage of VLCPUFA in young mice resulted in improved retinal function. However, it is largely not known if VLCPUFA intake for a short term in aged mice would also improve retinal function and have beneficial effects in cardiometabolic risk factors. Hypothesis: We hypothesized that VLCPUFA may delay or rescue age-related vision loss by supplementing the products of ELOVL2, which decrease in quantity with age. We also hypothesize that short-term VLCPUFA intake may also confer favorable cardiometabolic benefits. Aims: We aimed to evaluate the effects of exogenous VLCPUFA on visual function and lipoprotein profiles in aged mice. Methods: Sixteen-month-old mice received a daily oral gavage of C24-28-rich VLCPUFA-oil (80 mg/kg BW) or an Intralipid vehicle for 15 consecutive days (n=8). The electroretinogram (ERG) instrument used was a UTAS E-3000 with gold corneal and stainless-steel scalp electrodes. Fast Protein Liquid Chromatography was performed using pooled plasma. Results: Consumption of VLCPUFA for 15 days increased scotopic a- (p &lt; 0.05 at −5, 0, 5, 10, and 15 dB) and b-wave (p &lt; 0.05 at 0 and 5 dB, p = 0.08 at 10 dB) amplitudes on ERG in both male and female mice compared with control. Although photopic ERG results did not exhibit statistically significant differences, likely due to low sample size, the overall results were consistent with those in our previous studies in young mice. We report no statistically significant difference in the composition of pro-atherogenic VLDL and LDL fractions due to VLCPUFA gavage. Increasing the duration and samples size in future gavage studies may be critical to determine the effects of VLCPUFA on eye and cardiovascular risk factors. Conclusions: This study revealed that a short-term oral administration of VLCPUFA was effective in improving ERG response overall, but not lipoprotein profiles.
Abstract 4120763: Predicting Disease Risk Among Variants in Cardiomyopathy-Associated Genes Across Diverse Genetic Ancestries
Authors: Rachel Wolfe, Manasa Gurumoorthi, Anwar Chahal, Ghaith Sharaf Dabbagh, Andrew Landstrom
Journal: Circulation (2024)

Background: Many cases of cardiomyopathy (CM) are genetically inherited, and the expansion of broad genomic sequencing has opened the door for predicting those at risk for developing disease. However, genetic tools that help determine variant pathogenicity employ genetic data from predominantly European genetic ancestries. Understanding the full diversity of genetic variants in cardiomyopathy genes is central to identifying which variants will cause disease. Hypothesis: Participants of non-European genetic ancestry will have a higher burden of cardiomyopathy gene variants with "VUS" designation in ClinVar but will have equivalent/less penetrance of clinical cardiomyopathy compared to a European ancestry group. Methods: Participants in the AllofUs database with exome sequencing (ES) were queried and a cohort of 230,013 participants were retained after sample quality control filters. Participant genetic ancestry was based on the designated ancestry group determined via AllofUs as previously described (1). Participants were queried for variants in genes with definitive or moderate evidence of hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic cardiomyopathy (ACM) in ClinGen. Variants were filtered by ClinVar status (1* and above P/LP, 1* and above B/LB, and VUS). Participant CM disease status was determined via ICD-9/10 code. Results: For each ancestry group, prevalence of cardiomyopathy ranged from 0.34% in the Latino/admixed American ancestry group to 1.09% in the African group, with an average prevalence of 0.91% across all groups. The European group had a statistically significant lower percentage of ClinVar VUS variants at 26%, while all other non-European ancestry groups had a combined VUS prevalence rate of 35% (****p&lt;0.0001). The penetrance of CM in participants with CM VUS variants was lower in combined non-European ancestry groups (0.84%) than European ancestry (1.02%) (*p=0.0156). Conclusion: Prevalence of ClinVar VUS variants varies across different genetic ancestry groups, with European ancestry having a lower burden of VUS variants compared to non-European groups. However, non-European ancestry groups with increased burden of VUS variants have lower disease penetrance. Citations: (1) The All of Us Research Program Genomics Investigators. Genomic data in the All of Us Research Program. Nature 627 , 340–346 (2024). https://doi.org/10.1038/s41586-023-06957-x
Abstract 4118949: Factors Influencing Left Ventricular Function Recovery Following Left Ventricular Assist Device Implantation in Pediatric Dilated Cardiomyopathy: Insights from Single-Cell RNA Sequencing Analysis
Authors: Yosuke Kugo, Takuji Kawamura, Akima Harada, Takuji Watanabe, Takashi Kido, Masaki Taira, Shigeru Miyagawa
Journal: Circulation (2024)

Background and Objective: Heart transplantation is a recognized treatment for pediatric severe heart failure, but long-term issues necessitate alternative treatments. Some dilated cardiomyopathy (DCM) cases show left ventricular function recovery after LVAD implantation. This occurrence could lead to new treatments, but mechanisms are unclear. This study explores preoperative molecular factors interacting with LVAD's effects using single-cell transcriptomics on clinical samples. Methods: Twenty-five pediatric DCM patients underwent Berlin Heart EXCOR (BHE) implantation at our institution since 2013. Those with left ventricular ejection fraction (LVEF) improving by &gt;20% were in the Recovery group (R), others in Non-Recovery (NR). Single-cell RNA-sequence was performed on myocardial tissue from six patients (three per group). Differential gene expression and pathway analysis were conducted for each cell type. Findings were validated by comparing them with histological evaluation or clinical examination in all 25 cases. Results: R: 10 patients; NR: 15. R's weight was 6.3 kg, NR's 9.9 kg (p=0.049); LVEF: R 23%, NR 16.5% (p=0.61). In pseudobulk analysis of cardiomyocytes, upregulated genes in R included NPPB, MYL7, PCDH9. KEGG analysis indicated activation of Tight Junction and ECM receptor pathways in R. In fibroblasts, major extracellular matrix proteins were higher in R, GSL gene expression in NR. Plasma Brain Natriuretic Peptide (BNP) at BHE implantation was significantly higher in R; 2913 [1836-3990 (95% CI)] vs 1278 [667-1888] pg/ml (Image1,2). No differences in tissue fibrosis rates were found between the groups. Conclusion: Alterations in gene expression patterns in some cell clusters, including cardiomyocytes, may contribute to left ventricular function recovery post-BHE implantation in pediatric DCM patients. Plasma BNP levels correlated with gene expression alterations, suggesting both a potentially protective effect on cardiomyocytes and a useful marker of LV functional recovery. Further validation of these candidate genes may elucidate intracellular molecular mechanisms.