tbuckley/cabot-search huggingface dataset:
Abstract 13230: Prediction of Coronary Artery Lesions Caused by Treatment-Resistant Kawasaki Disease Before Initial Treatment
Authors: Yukako Yoshikane, Tatsuki Miyamoto, Shinichiro Nagamitsu
Journal: Circulation (2023)

Introduction: Kawasaki disease (KD), which is the most common multisystem vasculitis with unknown causes in childhood, causes coronary artery lesions (CALs). Especially in the case of treatment resistance, CALs occur at a high rate. To prevent CALs, it is important to identify risks as early as possible and establish aggressive treatment strategies. Hypothesis: CALs caused by treatment-resistant KD cases can be predicted before initial treatment. Methods: Fifty-five KD patients who scored high in all three Japanese Intravenous immunoglobulin (IVIG) non-response prediction scoring systems were included. We detected independent risk factors that contribute to the prediction of CALs due to treatment-resistant KD by multivariate analysis, determined the cut-off value for identifying subjects at risk of CALs by receiver operating characteristic analysis, and developed a new model for predicting CALs (including transient dilatation) due to treatment-resistant KD. Results: Neutrophils and Total bilirubin (T-bil) before initial treatment were detected as independent risk factors. When both neutrophils &gt;20,000 and T-bil &gt;2.5 were present (high-risk group), CALs occurred with a sensitivity of 100%, a specificity of 96%, a positive predictive value of 71%, and a negative predictive value of 100%. There were five patients out of seven who had coronary artery dilation greater than z-score &gt;2.5 by treatment resistance, compared to zero patients out of forty-eight in low-risk group (p&lt;0.01). Conclusions: It may be possible to predict CALs caused by treatment-resistant KD cases with high sensitivity and specificity before initial treatment with a new model using neutrophils and T-bil. If the occurrence of CALs due to treatment-resistant KD is expected, it is possible to consider an aggressive treatment strategy from the initial treatment.
Abstract 15822: Cardiac Effects of EDG-7500, a Novel Cardiac Sarcomere Regulator: In vitro and in vivo Evidence for Slowing Isovolumic Contraction and Improved Ventricular Compliance
Authors: Carlos L Del Rio, Weikang Ma, Thomas Irving, Steve Roof, Jessica Tolley, Mike Duvall, Natalie Hawryluk, ALAN RUSSELL, marc Semigran, Marc Evanchik
Journal: Circulation (2023)

Background: Hypertrophic Cardiomyopathy (HCM) is a disease where excess acto-myosin crossbridge formation results in hyperdynamic contraction, LV hypertrophy, and diastolic dysfunction due to increased myocardial stiffness. Conventional negative inotropes alleviate, to some degree, the systolic alteration in HCM, but do not improve LV filling. EDG-7500 is a small molecule that preferentially decreases diastolic tension and slows the velocity of myocardial force generation by regulating, but not inhibiting, cardiac myosin. This study assessed pharmacodynamic responses to EDG-7500. Methods: Myofilament biomechanics and sarcomere structure were evaluated on LV permeabilized pig fibers. In vivo, dogs were instrumented for arterial pressure and LV pressure-volume recordings. Data were obtained with vehicle, EDG-7500 (n = 5; 0.3 mg/kg IV), or metoprolol (2-4 mg/kg IV, n = 3); systemic and LV hemodynamics and load-independent function were examined. *:P&lt;0.05 for EDG-7500 vs. vehicle Results: X-ray diffraction studies showed EDG-7500 preserved the myosin head population competent to form crossbridges as well as the recruitment of reserve myosin-heads during calcium activation. EDG-7500 (1μM) slowed crossbridge formation, with a limited reduction in maximal force (-6±2%) and decreased diastolic tension. At 0.3 mg/kg, EDG-7500 slowed early contraction (PEP: +10±1%*) and reduced the peak rate of LV pressure development (+dP/dtmax: -8 ± 1%*) with minimal reductions in peak end systolic elastance (Emax: -4±1%*). Systemic mean arterial pressure and cardiac output were unchanged. EDG-7500 increased LV end-diastolic volume (+5 ± 1%*) and preserved LV end-diastolic pressure (EDP: -8 ± 3%, 9 ± 1 to 8 ± 1 mmHg). A downward and rightward shift of the pressure-volume relationship indicated improved LV compliance. β-AR blockade did not elicit this pro-compliant effect (EDP: +26 ± 12%). Conclusions: Cardiac sarcomere regulation with EDG-7500 has a unique cardiovascular profile characterized by the overall preservation of the myosin motor-head population and a slowing of early cardiac contraction and improved LV distensibility. This cardiovascular profile could have salutary effects in patients with HCM or patients with impaired diastolic function.
Abstract 14818: Endothelial Specific Deletion of <i>Uchl1</i> Attenuates the Development of Pulmonary Hypertension
Authors: Aiai Chu, yangfan jia, Ang Luo, Shuxin Liang, Changlei Bao, Haiyang Tang, Ankit A Desai
Journal: Circulation (2023)

Introduction/Background: While ubiquitination of proteins plays an important role in the development of pulmonary arterial hypertension (PAH), little is known about the role of deubiquitinases (DUBs) and, more specifically, ubiquitin carboxyl-terminal esterase-L1 (UCHL1), in this process. Our prior work reported that reductions in endothelial UCHL1 lead to increased degradation and reduced activated levels of Akt1. Given the pathologic role of Akt1 in PAH, we now hypothesize that endothelial UCHL1 deficiency leads to reductions in activated Akt1, resulting in the attenuation of PAH. Methods/Results: Tissues from animal PH models, as well as human PA endothelial cells (hPAEC) from patients with PAH, exhibited increased vascular staining and protein expression of UCHL1. Inhibition of UCHL1 in cell culture reduced vascular endothelial growth factor (VEGF)-induced angiogenesis, proliferation and migration of hPAECs. Endothelial-specific Uchl1 knockout mice ( Uchl1 EC-/- ) demonstrated reduced right ventricular hypertrophy (RVH), RV systolic pressures (RVSP), and improved right heart function compared to control mice exposed to chronic hypoxia. Consistent with these findings, histologic examination revealed significantly improved vascular medial thickness and remodeling as well as reduced total and activated Akt1 levels in the lungs of hypoxia-exposed Uchl1 EC-/- mice compared to hypoxia-exposed control mice. Conclusions: Our findings reveal that a specific deficiency of Uchl1 in the endothelium results in PAH attenuation via reduced Akt1, highlighting a novel therapeutic target.
Abstract 16950: The Genetic Basis of Atrial Fibrillation in a Large-Scale Multi-Ancestry Sample
Authors: Lu-Chen Weng, Carolina Roselli, Joel Rämö, Timothy M Treu, Sophia Gunn, Xin Wang, Yan Sun, James Pirruccello, Victor Nauffal, Aneesh Bapat, Seung H Choi, Sean J Jurgens, Daniel Gudbjartsson, Hilma Holm, Kári Stefánsson, Ida Surakka, Cristen Willer, Kathryn Lunetta, Michael Gaziano, Kelly Cho, Peter Wilson, Patrick T Ellinor, Steven A Lubitz
Journal: Circulation (2023)

Introduction: Atrial fibrillation (AF) is a heritable arrhythmia and associated with substantial morbidity. Hypothesis/Aims: We sought to expand our understanding of the genetic basis of AF by examining a large and ancestrally diverse sample. Methods: We performed a meta-analysis of ancestry-specific GWAS results from 600K unrelated individuals (85K with AF) in the Million Veteran Program (MVP) with GWAS results from nearly 2.25 million individuals (267K with AF) in the Atrial Fibrillation Consortium (AFGen). We estimated genetic correlations across ancestry groups and traits in MVP. To evaluate GWAS loci, we examined possible gene functions, prioritized relevant genes and pathways, and explored potential drug targets. We derived a multi-ancestry polygenic risk score (PRS) and independently evaluated associations with AF in the All of Us cohort (nearly 100K individuals; 3K with AF). Results: We identified 376 loci associated with AF, including 63 that have not been reported. We observed closer genetic correlation of AF between individuals of European and Hispanic (r2=1.0) than with African ancestry (r2=0.6). AF is highly correlated genetically with multiple cardiovascular traits, especially coronary artery disease, heart failure, and hypertension. GWAS loci implicate 15 genetic regulators of the cardiac action potential, including targets of commonly used AF drugs and 2 potential therapeutic targets whose predicted cardiac expression is positively associated with AF risk (KCNJ5 and KCND3). A PRS derived from the meta-analysis outperforms all previously reported PRSs in European, African and Hispanic ancestry participants and is strongly associated with multiple cardiovascular outcomes. Conclusions: In the largest genetic study of AF to date, we identify disease-relevant pathways and improve polygenic prediction for AF. We demonstrate the importance of ancestry-specific analyses in assessing AF risk and suggest that further inclusion of participants from more diverse ancestries is likely to accelerate genetic discoveries.
Abstract 16861: Early Sedation With Dexmedetomidine in Patients With Acute Myocardial Infarction Who Require Mechanical Ventilation
Authors: Christopher S Schenck, Avinainder Singh, Soumya Banna, Sanjana Garimella, Alexander W Thomas, Cory Heck, Jonathan Ludmir, Tariq Ali, David M Dudzinski, Elliott Miller
Journal: Circulation (2023)

Background: Patients with acute myocardial infarction (AMI) who require mechanical ventilation (MV) are a critically ill population which require sedatives and analgesia for comfort. However, clinical trials, including those for dexmedetomidine, exclude or poorly represent patients with AMI. Research Question: Is early sedation with dexmedetomidine associated with lower hospital mortality compared to usual-care sedation in patients with AMI who require MV? Methods: We utilized the Vizient® Clinical Data Base to identify patients aged ≥18 years who were admitted between 2015 and 2019 with a primary diagnosis of AMI and required MV within 7 days of admission. Patients were assigned to the early dexmedetomidine group if they received dexmedetomidine on the first day of MV; the remaining patients were assigned to the usual care group. Inverse probability of treatment weighting (IPTW) was used to estimate adjusted risk differences between groups. Results: Of the 21,303 patients included in the study, 1,620 (7.6%) received early dexmedetomidine ( Table ). Patients who received early dexmedetomidine were younger (66 vs 67 years) and less likely to be female (29.3% vs 33.8%) (both, P &lt;0.05). Median ventilator days for early dexmedetomidine vs usual care was 4 and 3 days, respectively ( P &lt;0.001). Patients who received early dexmedetomidine had lower hospital mortality compared to usual care (33.0% vs 46.0%, P &lt;0.001) despite higher prevalence of cardiogenic shock. After IPTW, the early dexmedetomidine group had a 16.2% (95% confidence interval [CI]: 13.6%-18.7%) lower mortality. The early dexmedetomidine group had more ventilator-free days (13.6 vs 9.7, P &lt;0.001), which persisted after IPTW (mean difference: +4.9 days, 95% CI: 4.2-5.5 days). Conclusion: Early sedation with dexmedetomidine may be associated with lower mortality compared to usual care in patients with AMI who require MV. A randomized controlled trial of sedative agents in this population is warranted.
Abstract 17666: Impact of Myocardial Fibrosis and Female Sex on Life-Threatening Arrhythmias and Sudden Cardiac Death in MVP Patients: A Prospective CMR Study With Over 2300 Patient-Years of Follow Up
Authors: Amr Darwish, Duc Nguyen, Danai Kitkungvan, Kinan Carlos El Tallawi, Akila Bersali, Mujtaba Saeed, Fatima Qamar, Miguel Valderrabano, Edward Graviss, Dipan J Shah
Journal: Circulation (2023)

Background: Mitral valve prolapse (MVP) is a common condition that exhibits a benign course. Conversely, a small subset of patients experiences life-threatening arrhythmias and sudden cardiac death (SCD). Multiple risk factors have been proposed for arrhythmia in MVP; however, few have been validated as independent predictors of hard arrhythmic events on longitudinal follow-up. Methods: A prospective cohort of 550 consecutive patients with MVP underwent comprehensive clinical assessment and late gadolinium enhancement (LGE) cardiac magnetic resonance. Patients were longitudinally followed for a composite outcome of SCD, aborted SCD, sustained or symptomatic ventricular tachycardia (VT) requiring implantable cardiac defibrillator (ICD) placement, or ventricular ablation. In a multivariable cox regression analysis, we adjusted for female sex, LGE, MVP leaflet involvement, mitral annular disjunction (MAD), and mitral regurgitation (MR) severity. Results: The cohort median age was 62 (IQR 51-71) years, comprising 50% women. Over a mean follow-up of 4.3 years, 44 patients (mean age 62.5 years ±10) met the composite outcome, of which n=33 (75%) were women. Myocardial fibrosis (LGE) was present in 61% of the outcome group (n=27). LGE (HR 3.52 [95%CI, 1.87-6.63], P &lt;0.001) and female sex (HR 3.90 [95%CI, 1.92-7.95], P &lt;0.001) were associated with worse outcomes in univariate analysis. Kaplan Meier statistics (Figure, A) indicated patients with LGE had a higher 5-year cumulative incidence of arrhythmic composite events than those without LGE (14.8% vs 4.4%, P &lt;0.001). On multivariable analysis, female sex and myocardial fibrosis remained independent risk predictors across all models. (Figure, B). Conclusion: Female sex and myocardial fibrosis are independent predictors of life-threatening arrhythmic events and SCD in patients with MVP, suggesting that LGE should be an important component of risk stratification, especially in the female MVP population.
Abstract 16132: Cardiometabolic Risk Factors and Non-Culprit Plaque Characteristics in Patients With STEMI in REAL-TIMI 63B
Authors: Khaled Abdelrahman, Brian A Bergmark, Jeong-Gun Park, Andrea Vavere, Richard George, Udo Hoffmann, Marc S Sabatine, David Morrow, Marc P Bonaca
Journal: Circulation (2023)

Introduction: Greater non-calcified plaque volume (NCPV) measured by coronary CT angiography (CCTA) is associated with higher risk of future myocardial infarction in stable patients. However, NCPV and associations with clinical characteristics in patients presenting with a first acute STEMI are not well described. Methods: The REAL-TIMI 63B trial randomized 593 patients with no prior MI presenting with acute STEMI to intravenous recombinant human lecithin-cholesterol acyltransferase (MEDI6012) or placebo; a subset were to undergo CCTA 48-72h after STEMI. Global NCPV, low-attenuation PV (LAPV), and calcified PV (CPV) were measured by a centralized core laboratory blinded to treatment arm. Revascularized segments were excluded from coronary plaque quantification. Results: 188 patients had a CCTA performed at baseline. Of these, 80.3% had NCPV and 77.4% had LAPV outside of the revascularized segments. Median NCPV was 28.4mm 3 [IQR 1.4-92.1], LAPV 3.8mm 3 [0.1-14.9], and CPV 92.4mm 3 [22.6-201.8]. Among the characteristics examined, male vs. female sex (51.3 mm 3 [3.47-100.3] vs 5.6 mm 3 [0.0-17.3]; p=0.0003), BMI &gt;25 kg/m 2 (overweight or obese) (41.20 mm 3 [2.01-104.50] vs 10.98 mm 3 (0.0-61.5); p=0.01) and diabetes (82.6 mm 3 [59.0-123.4] vs 24.2 mm 3 [1.21-85.2]; p=0.038) were associated with greater NCPV (Figure). Conclusions: Among patients with no prior MI undergoing primary PCI for STEMI, we found that most patients had NCPV and LAPV outside the culprit lesion. Male sex and markers of cardiometabolic disease including higher BMI and diabetes were associated with a greater burden of NCPV. These observations underscore the need for intensive medical therapies that may stabilize vulnerable plaque in patients presenting with acute myocardial infarction.
Abstract 15269: Effect of a Systemic Right Ventricle With A Biventricular Circulation on Cardiorespiratory Fitness
Authors: Charles Desrosiers-Gagnon, Naima-Ayane Mahdi, Michel White, Paul Khairy, Francois P Mongeon, Blandine Mondésert, Annie Dore, Daniel Gagnon, Marie-Alexandre CHAIX
Journal: Circulation (2023)

Background: The clinical care of adults with a systemic right ventricle with biventricular circulation (sRV-biV) is influenced by cardiorespiratory fitness (CRF) evaluation. However, prognostic markers for CRF are derived from analyses of adults with a systemic left ventricle (sLV). While some studies suggest that CRF is lower in adults with sRV-biV compared to those with a sLV, they have not controlled for key clinical characteristics and ventricular function of the systemic ventricle. Research Question: Is CRF lower in adults with a sRV-biV compared to adults with sLV matched for clinical characteristics and systemic ventricular function? Methods: A retrospective cross-sectional comparison of exercise stress test results was performed comparing 24 adults with sRV-biV to 24 adults with a sLV matched for sex (4 females), age (sRV-biV: 46 ± 9 years, sLV: 46 ± 11 years), body mass index (sRV-biV: 28 ± 4 kg/m 2 , sLV: 27 ± 4 kg/m 2 ), ejection fraction of the systemic ventricle (normal: 2, mild: 4, moderate: 11, severe: 7), NYHA class (I: 6, II: 17, III: 1), and doses of diuretics (spironolactone ≤ 25 mg: 24, furosemide ≤ 80 mg: 24 ). Peak VO 2 was compared between groups with Wilcoxon signed-rank tests. Effect sizes are reported as Cohen’s d . Results: Peak VO 2 did not differ significantly between groups (sRV-biV: 20.3 ± 4.2 vs. sLV: 20.9 ± 6.0 mL/kg/min, p=0.43, d =0.18). When patients were dichotomized according to the Weber criterion for optimal versus suboptimal CRF (sLV peak VO 2 &gt; or ≤ 20 mL/kg/min), peak VO 2 was lower in sRV-biV in those with optimal CRF (sRV-biV: 21.0 ± 4.8 vs sLV: 26.6 ± 5.1 mL/kg/min, p=0.006, d =0.72). In contrast, peak VO 2 was greater in sRV-biV in those with suboptimal CRF (sRV-biV: 19.3 ± 3.5 vs. sLV: 16.9 ± 2.0 mL/kg/min, p=0.12, d =NA). Conclusion: Although peak VO 2 values are similar among patients with a sRV-biV and matched controls with a sLV, differences are observed when stratified according to the Weber criteria for optimal CRF. These results may reflect different pathophysiological adaptive mechanisms of a sRV vs sLV. Further studies are required to establish specific prognostic thresholds for patients with sRV-biV.
Abstract 17081: Targeted Proteomics Identifies Circulating Biomarkers Associated With Biological Sex in Dilated Cardiomyopathy
Authors: Upasana Tayal, James L Januzzi, Brian Halliday, Amrit S Lota, James S Ware, Dudley Pennell, Sanjay K Prasad
Journal: Circulation (2023)

Background: The pathophysiology underlying sex specific differences in dilated cardiomyopathy (DCM) is incompletely understood. Targeted proteomic discovery enables quantification of low abundance circulating proteins to elucidate mechanisms of disease. Hypothesis: Female sex is associated with a distinct biomarker profile that confers insights into DCM pathogenesis. Aim: Evaluate the biomarker profile associated with biological sex in dilated cardiomyopathy. Methods: Cross sectional analysis of 490 patients with dilated cardiomyopathy confirmed by cardiovascular magnetic resonance imaging. Targeted proteomic analysis was performed with proximity extension assays to determine sex differential expression of 276 proteins associated with inflammation or cardiovascular disease. Expression was compared between males and females. Results: A third of patients were female (n=160, 33%). After adjusting for false discovery, 10 proteins were significantly upregulated and 8 were significantly downregulated in female compared to male patients (A Inflammatory panel, B Cardiovascular panel). These were grouped into 3 clusters (C), enriched for cytokine pathways (red), regulators of cardiac function (green), and markers of fat metabolism (blue). Of the sex differentially expressed proteins, GDF2 (regulates angiogenesis), protein BOC (augments cardiac tissue repair) and CD5 (linked to inflammation) were top determinants of biological sex after adjusting for age, renal function, body mass, and cardiac function (D). Conclusion: Sex specific proteomic signatures provide new insights into the pathophysiology underlying sex differences in DCM. Figure: Volcano plots showing log2 fold change in protein expression in inflammatory (A) and cardiovascular (B) proteins. Blue = lower and red = higher levels in females. Protein interactions shown in C. Top predictive feature of sex is body surface area, followed by biomarkers GDF2 and Protein BOC, shown in D.
Abstract 17073: Evaluation of Impact of Septal Reduction Therapy on Deep Learning-Based Electrocardiographic Markers Hypertrophic Cardiomyopathy
Authors: Lovedeep S Dhingra, Arya Aminorroaya, Akshay Khunte, Veer Sangha, Evangelos K Oikonomou, Sounok Sen, Harlan M Krumholz, Christopher M Kramer, Milind Y Desai, Rohan Khera
Journal: Circulation (2023)

Background: Deep learning-based models could identify hypertrophic cardiomyopathy (HCM) signatures on ECG, with emerging evidence of being able to track disease modification with mavacamten. To explore the mechanism of HCM detection on ECG, we developed an AI-ECG model for echocardiographically confirmed HCM and evaluated HCM detection after septal reduction therapy (SRT, alcohol septal ablation [ASA] or ventricular myectomy [VM]). Methods: The AI-ECG model for HCM detection was developed in a cohort of 25,652 ECGs (1:10, age-sex matched HCM to control) obtained within 30 days of a transthoracic echocardiogram (TTE) at Yale (2015-21). We defined HCM by end-diastolic interventricular septal wall thickness &gt; 15 mm with moderate to severe diastolic dysfunction on TTE. The model was developed using a convolutional neural network and transfer learning. HCM phenotype was defined by high predicted probabilities for HCM and was assessed on ECGs spanning SRT. Results: Our AI-ECG model for HCM had an AUROC of 0.93 (0.88-0.97), sensitivity of 0.90, and specificity of 0.89 in the held-out test set. The mean HCM probability among HCM patients vs control was 0.51±0.33 vs 0.07±0.20 (P&lt;.001). The mechanism of detection was evaluated in 1400 ECGs from 78 patients (mean age 66 y; 47% women) spanning SRT (20 ASA, 58 VM). In this group, the mean HCM probability for all ECGs performed before &amp; after SRT was 0.49±0.34 &amp; 0.72±0.30, respectively. The mean HCM probability in the closest ECGs per patient before SRT (median 35 days before SRT) was 0.53±0.35, and in farthest ECGs after SRT (median 536 days) was 0.70±0.32 (P diff = 0.002). Conclusion: We developed and validated an AI-ECG model that detects HCM from 12-lead ECG. The model does not merely detect thickened septum, and the continued identification of HCM signature after SRT suggests HCM prediction based on disordered myocardial kinetics. This supports the role of AI-ECG in both detection and monitoring of phenotypic effects of therapies in HCM.