tbuckley/cabot-search huggingface dataset:
Abstract 13124: Better Prognostic Value of Single Time Coronary Artery Calcium Score Over the 30-y Averaged Pooled Cohort Equation in Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Yejin Mok, Yasuyuki Honda, Frances Wang, Candace M Howard, Aaron R Folsom, Josef Coresh, Matthew J Budoff, Michael J Blaha, Kuni Matsushita
Journal: Circulation (2023)

Background: Cardiovascular disease (CVD) risk prediction in the 75-and-older population is challenging in part because traditional risk factors at older age may not reflect the risk factor profile over the life course. In this regard, coronary artery calcium (CAC) can be considered an integrated biomarker of exposure to CVD risk factors. However, the predictive value of a single time point CAC at older age vs. the cumulative exposure of traditional risk factors over three decades is unknown. Methods: In 1,875 ARIC participants (age 75-94 years) without a history of coronary heart disease (CHD), stroke, and heart failure (HF) at Visit 7 (2018-2019), we assessed the association of Visit 7 CAC vs. a weighted average of Pooled Cohort Equation (PCE) calculated 10-year atherosclerotic CVD (ASCVD) risk from Visit 1 (1987-89) to Visit 7 with the risk of ASCVD (CHD or stroke), HF, and all-cause mortality using adjusted Cox models. Risk prediction improvement was assessed using Harrel’s C-statistics. Results: The median CAC was 221 (IQI 35-743), and the median averaged PCE score was 15.0% (IQI 10.4%-21.2%). Over a median follow-up of 2.1 (IQI 1.7-2.5) years, there were 48 ASCVD events, 36 HF events, and 85 deaths. A higher CAC score was associated with a higher risk of ASCVD and HF, even after adjusting for averaged PCE (adjusted hazard ratio 3.33 [95% CI 1.53, 7.26] and 5.57 [1.95, 15.89] for CAC 1000+ vs. 0-99, respectively), but not all-cause mortality ( Table ). In contrast, averaged PCE was not associated with ASCVD or HF independent of CAC. However, averaged PCE showed robust associations with all-cause mortality. Notably, the addition of CAC to averaged PCE significantly improved risk prediction of HF, whereas adding averaged PCE to CAC did not significantly improve the risk prediction for any adverse outcome. Conclusions: The present study shows that a single time point CAC outperforms 30-y cumulative exposure of PCE for ASCVD and HF prediction in the 75-and-older population.
Abstract 15735: Antibody-Based Plasma Proteomics Profiling Reveals New Markers of Cardiorespiratory Fitness
Authors: Katie Fredrickson, Mahesh Manish, Jacob Barber, Shuliang Deng, Prashant Rao, Michael Mi, Prasun K Dev, Laurie Farrell, Clary Clish, Claude Bouchard, Robert E Gerszten, Mark A Sarzynski, Jeremy M Robbins
Journal: Circulation (2023)

Background: Plasma proteins can be biomarkers of cardiovascular health status but also physiologic effectors that mediate health benefits. Cardiorespiratory fitness (CRF) is an integrative measure of cardiovascular and metabolic health and independent predictor of future cardiovascular disease (CVD) and mortality risk, however limited knowledge exists regarding its molecular transducers. We sought to expand upon prior proteomic studies of CRF using an antibody-based technology (Olink TM ). Hypothesis: Olink proteomic profiling will identify new markers and potential mediators of CRF. Methods: We measured plasma proteins (N=1,472) using Olink’s platform in a pilot study within the HERITAGE Family Study (N=209 participants, mean age=34 years, 56% female, 36% Black) before and after 20 weeks of endurance exercise training (ET). We performed multivariable linear regression to measure the association between protein levels and CRF measured by CPET (VO 2 max in ml*kg -1 *min -1 ) adjusting for age and sex. Lean body mass was measured by hydrostatic weighing. Protein changes after ET were assessed using paired Student’s t-tests. Results: We identified 70 proteins significantly associated (FDR q &lt;0.05) with VO 2 max. Among these, 14 have not previously been measured in the context of CRF, including perilipin-1, a modulator of lipid homeostasis in adipocytes (beta=-3.8, q=2.4x10 -4 ); latent-transforming growth factor beta-binding protein 3 (beta=-2.6, q=1.3x10 -3 ), a key regulator of TGF-beta activation; and hydroxysteroid 11-beta dehydrogenase 1 (beta=3.2, q=1.2x10 -3 ), which regulates cortisol metabolism. Carbonic anhydrase (CA) XIV (CA14; beta=5.4, q=1.3x10 -8 ), a member of the CA family with extracellular activity, had the strongest positive association with VO 2 max in our primary model as well as after further adjusting VO 2 max for lean body mass. Further, CA14 levels increased significantly after ET (log2 fold change: 0.14, q=0.007). Conclusions: Antibody-based plasma proteomics profiling identified new markers of CRF, including a CA isoform that increases after ET. These findings motivate further study of CA14’s mechanistic role in CA14 and expanded proteomics profiling to investigate molecular transducers of CRF.
Abstract 13474: The Efficacy of Istaroxime for Patients With Acute Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Mohamed T Abuelazm, Abdelrahman Mahmoud, Mohammad Tanashat, Majd M. AlBarakat, Husam Abusuilik, Shafaqat Ali, Basel Abdelazeem
Journal: Circulation (2023)

Introduction: Acute heart failure (AHF) exacerbation is the leading cause of morbidity and mortality associated with HF. The current AHF management strategies are inotropic and vasoactive agents. Despite the transient improvement in hemodynamic status with these agents, they have not shown survival benefits. Istaroxime is a novel IV inotropic agent with a dual mechanism, increasing both cardiomyocyte contractility as well as relaxation. Methods: We conducted a systematic review and meta-analysis synthesizing randomized controlled trials (RCTs), which were retrieved by systematically searching: PubMed, Web of Science, SCOPUS, and Cochrane through April 24th, 2023. We used the fixed-effect or random-effects model, according to heterogeneity, to pool dichotomous data using risk ratio (RR) and continuous data using mean difference (MD), with a 95% confidence interval (CI). Results: We included three RCTs with a total of 300 patients. Istaroxime was significantly associated with increased LV ejection fraction (MD: 1.06, CI [0.29, 1.82], P = 0.007), stroke volume index (MD: 3.04, CI [2.41, 3.67], P = 0.00001), and cardiac index (L/min/m2) (MD: 0.18, CI [0.11, 0.25], P = 0.00001). Also, istaroxime was significantly associated with decreased E/A ratio (MD: -0.39, CI [-0.58, -0.19], P = 0.0001) and pulmonary artery systolic pressure (MD: -2.30, CI [-3.20, -1.40], P = 0.00001). Istaroxime was significantly associated with increased systolic blood pressure (MD: 5.32, CI [2.28, 8.37], P = 0.0006) and decreased heart rate (MD: -3.05, CI [-5.27, -0.82], P = 0.007). Conclusions: Istaroxime improved blood pressure and some echocardiographic parameters, forming a promising strategy for AHF management. However, the current is limited to a small number of RCTs, warranting further large-scale phase III trials before clinical endorsement.
Abstract 14701: Agreement Between Handheld and Standard Echocardiography for Diagnosis of Latent Rheumatic Heart Disease in Brazilian Schoolchildren From High-Prevalence Settings
Authors: Bruno R Nascimento, Kaciane Oliveira, Jessica Elvira M Veloso, Cássia Aparecida Silva, Maria D Nunes, Jessica Abrams, Marina G Diniz, Lucas Diamante, Arthur M Amaral, Luiza P Santos, Juliane Franco, Bruno F Galdino, Marcia M Barbosa, LUZ MARINA TACURI CHAVEZ, Lucas Fraga, Zilda Maria A Meira, Antonio L Ribeiro, Craig A Sable
Journal: Circulation (2023)

Background: Handheld echocardiography (echo) is the tool of choice for Rheumatic Heart Disease (RHD) screening, based on the 2012 World Heart Federation (WHF) Criteria. We aimed to assess the agreement between screening and standard echo for diagnosis of latent RHD in schoolchildren from an endemic setting. Methods: Over 14 months, 3 non-physicians used handheld machines (GE, VSCAN) and the 2012 WHF Criteria to determine RHD prevalence in low-income public schools in Minas Gerais, Southeast Brazil. Consented children were eligible for participation. Studies were interpreted remotely using a telemedicine cloud-server by 2 experts in Brazil and the US. RHD-positive children (borderline and definite) and those with congenital heart disease (CHD) were referred for standard echo with portable devices (GE, Vivid IQ), with acquisition and interpretation by an expert cardiologist. Agreement between screening and standard echo, by category and according to the WHD criteria, was assessed, and the kappa statistic was applied. Results: A total of 1,390 students were screened in 6 schools and, among these, 110 (7.9%, 95% CI 6.5 - 9.5) were screen-positive and referred for standard echo, with mean age of 14±2 years, 80 (72%) women. Among the 16 cases initially diagnosed as definite RHD, 11 (69%) were confirmed, 4 (25%) reclassified to borderline and 1 to normal. Among the 79 cases flagged as borderline RHD, 19 (24%) were confirmed, 50 (63%) reclassified to normal, 8 (10%) to definite RHD and 2 had mild CHD. Among 11 children with CHD in screening, 4 were confirmed, 5 were reclassified to normal and 2 to RHD. Considering the 4 diagnostic categories, kappa was 0.18. In patients with borderline RHD reclassified to non-RHD, the most frequent WHF criteria was B (isolated mitral regurgitation): 64%, followed by A (2 morphological features of the mitral valve): 31%. In the only patient with definite RHD reclassified to normal, WHF criteria was D (borderline RHD in aortic and mitral valves). After standard echo, RHD prevalence was 3.2% (95% CI 2.3 - 4.2). Conclusions: Although practical, RHD screening with handheld devices tend to overestimate prevalence. Even in endemic settings, continuous education for detection, and application of risk stratification for management are crucial.
Abstract 15586: Efficacy and Safety of Cerebral Embolic Protection Devices in Transcatheter Aortic-Valve Replacement: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Muhammed K Elfaituri, Taha Khaled, Ahmed BenGhatnsh, Hazem Abdelkarem A Faraj, Ahmed Msherghi
Journal: Circulation (2023)

Introduction: Transcatheter aortic-valve replacement (TAVR) has emerged as a viable alternative to surgical aortic-valve replacement for high-risk patients. However, the procedure carries a significant risk of cerebral embolism. Cerebral embolic protection (CEP) devices have been proposed to mitigate this risk, yet current evidence of their efficacy remains inconsistent. Hypothesis: This study aims to comprehensively evaluate the effectiveness and safety of CEP devices during TAVR. Methods: A systematic literature search was conducted in MEDLINE, EMBASE, and Scopus up to April 2023. Randomized controlled trials (RCTs) comparing TAVR with and without CEP were included. The study assessed total lesion volume using mean difference (MD), while stroke, mortality, bleeding and vascular complications, and new magnetic resonance imaging (MRI) detected lesions were evaluated with relative risk (RR); both were analyzed via random-effects models using R software (version 4.0.3) with the metafor and meta packages. Results: The meta-analysis incorporated five RCTs involving 3,845 patients (2,070 received CEP devices, and 1,775 served as a control). The pooled analysis showed a non-significant mean difference in total lesion volume of -14.43 (95% CI: -104.97 to 76.09, P=0.75, I2=90%), indicating that CEP devices did not significantly alter the total lesion volume. In terms of other outcomes, the use of CEP devices did not significantly reduce the risk of stroke (RR 0.86, 95% CI: 0.62 to 1.22, P=0.41, I2=0%), disabling stroke (RR 0.50, 95% CI: 0.24 to 1.04, P=0.06, I2=0%), overall mortality (RR 1.35, 95% CI: 0.59 to 3.12, P=0.48, I2=0%), life-threatening or major bleeding (RR 1.09, 95% CI: 0.37 to 3.22, P=0.88, I2=19%), vascular complications (RR 1.83, 95% CI: 0.80 to 4.19, P=0.15, I2=29%), or the occurrence of new lesions seen on MRI (RR 0.99, 95% CI: 0.93 to 1.06, P=0.78, I2=17%). Conclusions: The results indicate that CEP devices during TAVR did not significantly alter important clinical outcomes, challenging the presumed benefits of these devices. Owing to the limited number of studies and short follow-up periods, further large-scale RCTs with more sophisticated designs and longer follow-ups are needed to validate these results and inform future guidelines.
Abstract 16713: Pre-Clinical 30-day Survival Results of the BiVACOR TAH
Authors: Trenton Gluck, Daniel L Timms, Abdelmotagaly Elgalad, Alexis Shafii, Miriam Freundt, Robert Dowling, William E Cohn, O Howard Frazier
Journal: Circulation (2023)

Introduction: The BiVACOR Total Artificial Heart (TAH) replaces the failing heart with a durable and physiologically adaptive pump, which combines magnetic levitation and rotary blood pump technology. The pump has large clearances to minimize shear stress, generates pulse pressure via cyclic changes in pump speed, and modulates total outflow based on physiological conditions. A single rotor design enables a small pump size. Aim: Primary endpoint was survival at 30 days with normal end-organ function and absence of device related thromboembolism at necropsy. Methods: Five calves (82 - 108 kg) were implanted with the BiVACOR TAH and underwent continuous hemodynamic monitoring for 30 days. The pumps ability to generate a pulse pressure, balance outflow to the systemic and pulmonary circulations and to increase outflow in response to increased physical activity was assessed. Hemocompatibility and end-organ function were routinely monitored. Necropsy was performed on day 30 to evaluate for evidence of thromboembolism and end organ damage. Explanted pumps were examined. Results: All five calves survived to 30 days with normal end-organ function. Stable hemodynamics were achieved with normal pressures in the aorta and left and right atrium (MAP 111 ± 6 mmHg, CVP 12 ± 5 mmHg, LAP of 20 +/- 5 mmHg). Average estimated pump output was 12 ± 2 L/min with average pulse pressure of 30 mmHg. Pump output increased during changes in daily physiological condition (10 to 14 L/min). No device-related thromboembolism or other end organ pathologies were detected at necropsy. All explanted pumps were free of internal pump thrombus. Hemocompatibility was demonstrated (pfHb 4.34 ± 0.74 mg/dL). Bypass time decreased by 34 minutes over the entire study cohort. Conclusion: The BiVACOR TAH demonstrates normal hemodynamics including left/right balance. Pump design allows for a normal pulse pressure, increased pump output in response to exercise, and excellent hemocompatibility without device-related thromboembolism. Operative time markedly improves with surgeon experience. The small pump size may expand the use of TAH to smaller patients. This device may address the need for select patients with advanced heart failure who require biventricular support.
Abstract 18642: GWAS to Function Highlights the Role of REST in Endothelial Biology and Atherosclerosis
Authors: Maria Viskadourou, Paula Reventun, Nunzio Alcharani, Carlos Villapudua Gastelum, William Osburn, Pablo Toledano Sanz, Charles J Lowenstein, Marios Arvanitis
Journal: Circulation (2023)

Introduction: Despite the emergence of new lipid-lowering therapies, coronary artery disease (CAD) remains the leading cause of death worldwide. Genome-wide association studies (GWAS) for CAD have discovered multiple novel loci that contribute to CAD pathogenesis. However, limitations in the interpretability of those GWAS associations have hindered the clinical translation of those findings. Hypothesis: In this study, we sought to evaluate the mechanisms of the association between chromosomal locus 4q12 and CAD, replicated in multiple independent GWAS for CAD. Methods: We utilized a combination of computational methods and in vitro assays to achieve our objectives. Results: Meta-analysis of public expression quantitative trait locus (eQTL) data and multi-trait colocalization across atherosclerosis-relevant cell types revealed that the CAD 4q12 locus regulates the expression of REST, a transcriptional repressor, in human aortic endothelial cells (HAEC) and prioritized 2 enhancer variants as candidate causal variants for the GWAS association. CRISPR interference confirmed that the rs6853156 variant regulates REST expression in inducible human endothelial cells. Pathway enrichment analysis in HAEC after REST silencing showed that epithelial to mesenchymal transition was the most upregulated pathway suggesting a potential mechanism via which silencing REST contributes to atherosclerosis. Endothelial to mesenchymal transition (endMT) was confirmed in HAEC after REST silencing at the RNA and protein level by rt-qPCR, western blot, and immunofluorescence. Concordantly, REST silencing increased endothelial permeability and matrix metalloproteinase activity in endothelial cell supernatants in vitro. L1CAM, a known endMT activator was only expressed in HAEC upon REST silencing. Chromatin immunoprecipitation sequencing supports direct binding of REST to the L1CAM promoter. Simultaneous silencing of L1CAM and REST in HAEC inhibited the observed upregulation of mesenchymal genes induced by REST silencing. Conclusions: In summary, our data reveal a novel role of REST as a repressor that functions as a constitutive inhibitor of endMT in human arterial endothelial cells.
Abstract 18686: Distinct Proteomic Signatures in Subjects With Elevated Lipoprotein(a) Levels With and Without Coronary Artery Disease
Authors: Sascha N Goonewardena, Waqas Malick, DILNA DAMODARAN, Jay Krishna Katragadda, Olga Grushko, Gillian Cady, Venkatesh L Murthy, Robert S Rosenson
Journal: Circulation (2023)

Introduction: Genetic and observational studies suggest a causal link between an elevated lipoprotein(a) [Lp(a)] and coronary artery disease (CAD). Although Lp(a) is one of the strongest genetic risk factors for CAD, not all subjects with an elevated Lp(a) develop CAD. Hypothesis: We hypothesized that in subjects with an elevated Lp(a) (&gt;150nmol/L), proteomic signatures could differentiate between those with and without CAD. Methods: Outpatients with known Lp(a) levels and a coronary CT between April 2021 to April 2023 were enrolled and circulating biomarkers were measured using Olink proteomic platform. This study was approved by the IRB at the Icahn School of Medicine, New York, NY. Results: First we analyzed clinical markers and proteomic signatures in subjects with and without CAD. An elevated Lp(a) level was a critical feature between the two groups. We then focused our analysis on differences in clinical and proteomic signatures in subjects with an elevated Lp(a). High Lp(a) subjects with (n=28) and without CAD (n=7) were well matched with respect to clinical characteristics including age (66 vs 52y; NS) and median Lp(a) levels (228; [203-270] vs 222; [204-323]). Additionally, hsCRP and LDL-C levels were well matched between groups. 2907 unique proteomic markers were detected and there were 29 markers that were significantly different in high Lp(a) subjects with CAD compared with those without CAD. An unsupervised principal component analysis was performed, and we found that markers of thrombosis (PARP1, tissue factor), inflammation (CCL3, CD40) were key proteomic markers that separated high Lp(a) subjects with and without CAD, suggesting a bidirectional relationship between inflammatory and thrombotic pathways in Lp(a)-driven CAD. Conclusions: To our knowledge, this is the first prospective study to examine proteomic differences in high Lp(a) subjects with and without CAD. Profiling over 3000 unique proteomic markers, we found that in high Lp(a) subjects, there were differences in thrombotic and inflammatory markers in those with CAD compared to those without CAD. These findings have important implications to understanding the mechanisms through which Lp(a) drives CAD and in risk stratifying high Lp(a) subjects susceptible to CAD.
Abstract 16284: Atypical Cause of Embolic Stroke; Intracardiac Metastasis of Mixed Germ Cell Tumor
Authors: Sarala Kal, Vinisha Garg
Journal: Circulation (2023)

Testicular neoplasm constitutes the most common solid organ malignancy in males between the ages of 15 and 35. Metastatic disease to the heart is a rare entity. In most cardiac cases, metastasis is by direct hematogenous spread via the inferior vena cava to the right heart. Metastatic disease to the left heart is even more infrequent. We present the case of intracardiac metastasis of mixed germ cell tumor presenting with an embolic stroke. A 47-year-old Latinx male with a history of stage IV testicular cancer s/p left radical orchiectomy with multiple bilateral pulmonary masses (largest 6x9 cm), atrial fibrillation s/p ablation, left lower extremity iliac thrombus s/p thrombectomy, HTN, and diabetes who presented with sudden onset expressive aphasia and dysarthria. CT head showed a 3x5 cm left occipital intraparenchymal hemorrhage suspected to be an embolic stroke with hemorrhagic conversion. Further evaluation with TTE and TEE revealed a highly mobile and friable multi-lobar mass attached to the anterior mitral leaflet occupying most of the left atrial cavity (4.2x4.9 cm), a small mass attached to the right ventricular aspect of the tricuspid valve, an echo-dense mass in the left lower pulmonary vein at the left atrial junction, and a large mass abutting the rim of the superior vena cava. Definitive surgical management was considered; however, patient was deemed a high-risk candidate given high burden of cardiac metastases. After multidisciplinary discussion, it was decided to pursue systemic chemotherapy. This case illustrates an exceptionally rare presentation of advanced stage testicular cancer metastasizing to the heart with large intracardiac tumor burden resulting in embolic stroke. Early cardiac screening may be beneficial in individuals with history of cancer who present with stroke symptoms. Embolization of cardiac metastasis to other organs poses a great clinical challenge and multidisciplinary decision-making is crucial to clinical management.