tbuckley/cabot-search huggingface dataset:
Abstract 14663: Machine Learning to Detect Pulmonary Hypertension at Point-of-Care
Authors: Charles R Bridges, Timothy Burton, Farhad Fathieh, Navid Nemati, Horace R Gillins, Ian Shadforth, Shyam Ramchandani, Vallerie McLaughlin
Journal: Circulation (2023)

Introduction: Pulmonary hypertension (PH) is defined by mean pulmonary arterial pressure (mPAP) of ≥ 21 mmHg or ≥ 25 mmHg by right heart catheterization (RHC), (2022 and 2015 ERS/ESC guidelines). Based on a recent meta-analysis, the sensitivity and specificity of transthoracic echocardiography (TTE) is 83% and 72% in the 59% of patients where tricuspid regurgitant velocity (TRV) is available. Research Question: Can we develop a point of care method to detect PH, based on cardiac orthogonal voltage gradient (OVG) signals and photoplethysmographic (PPG) signals? Aim: Using OVG and PPG signals from subjects evaluated with RHC or TTE (independent of TRV), we built a machine learned (ML) model that can identify subjects with PH with high accuracy. Methods: 3298 features from PPG and OVG signals were reduced to 216 via univariate testing. ElasticNet and Random Forest models were developed using a coarse grid-search based on 5-fold cross-validation followed by a narrow search when the two algorithms were ensembled, performed on a naive set of subjects with confirmed PH (N=327, mPAP ≥ 21 mmHg; N=252, mPAP ≥ 25 mmHg) vs. subjects with high negative predictive value for absence of PH, i.e., meeting the 2022 ERS/ESC TTE guideline criteria for “Low Probability” of PH adjudicated by a core lab (N=204). The model prediction for the selected hyperparameters was generated for every subject using out-of-fold prediction. Results: Table 1 demonstrates strong performance across gender and PH subgroups. AUC for all PH/Pre-capillary PH based on the 2015 ERS/ESC guidelines is 0.92/0.95, sensitivity 90%/95% and specificity 75%/75%. Using the updated 2022 guidelines, AUC for all PH/Pre-capillary PH is 0.90/0.92, sensitivity 90%/93% and specificity 69%/69%. Conclusion: Clinically relevant performance using a ML algorithm based on non-invasive signals collected at point-of-care is achievable in the identification of PH (and specifically, Pre-capillary PH), not limited by availability of TRV.
Abstract 17611: Acute Ischemic Stroke in Patients With LDL Less Than 70, What Next? Potential Role of TG/HDL Ratio for Treatment Optimization and Risk Stratification
Authors: Alberto Romero Garcia, Pinal Patel, Rinku Bhatija, Fadima Elmi, Esra'A Alshdifat, Kai Wang, Aditya Bhaskaran, JEANIE GONZALES, vidya menon, Nehad Shabarek, Chee Yao Lim
Journal: Circulation (2023)

Introduction: There are no established guidelines stratifying risk factors for patients who develop ischemic stroke after goal LDL is achieved. The effect of TG-HDL ratio on cerebrovascular accidents is still being studied. We aim to study the impact of TG-HDL ratio on the outcome of the patients with stroke and LDL less than 70 mg/dl and to determine if it can be used to prognosticate the cardiovascular/cerebrovascular outcome among these patients. Methods: This is a single center prospective observational study including patients admitted between January 2021 and March 2023 with stroke and LDL less than 70 mg/dl. Baseline data was collected by chart review. Patients were followed up at 6-month intervals. Logistic regression was used to determine which factors influenced mortality outcomes. Results: Among 801 patients admitted for acute stroke during the study period, 153 (22%) had an ischemic event and baseline LDL less than 70. Mean age was 68 SD13 .Total number of patients with TG:HDL ratio &gt;2 was 91 vs 60 patients with ratio &lt;2. The use of statins was comparable in both groups 58% vs 57% respectively. In patients with TG:HDL ratio &gt;2, prevalence of DM was significantly higher than patients with ratio &lt;2 (72% vs 41%). Mean NIHSS among patients with TG:HDL ratio &gt;2 was 6.82 vs 5.95 in patients with ratio &lt;2 (p=0.1). Mortality among patients with ratio &gt;2 was 4.4% vs 17% in patients with ratio &lt;2 (p=0.01) but when logistic regression was performed to control for confounders such as BMI, Age, sex, SBP on admission, statin use and comorbidities including CAD, CHF, A.fib and substance use. Patients with TG/HDL&gt;2 had a higher risk of mortality (OR 7.3 IC95% 1.4-36.5, p=0.015). Total number of patients on follow up at 6 months were 32. Mortality at 6 months follow up was comparable between patient with TG:HDL ratio &lt;2 and &gt;2 (11.1% vs 14.3%, p=0.78). Conclusions: There is a potential role for TG-HDL ratio in determining cardio/cerebrovascular outcomes among patients who develop stroke with target LDL of ≤ 70 mgs/dl. Larger studies are needed to evaluate the role of the TG-HDL ratio as a biomarker to optimize risk stratification and improving outcomes in this population.
Abstract 15316: Neonatal Mesenchymal Stem Cells Ameliorate Cardiac Fibrosis and Diastolic Dysfunction in HFpEF via Expanding CD4 <sup>+</sup> CD25 <sup>+</sup> Foxp3 <sup>+</sup> T <sub>regs</sub>
Authors: Zhi-Dong Ge, Rachana Mishra, Xuebin Fu, Sudhish Sharma, Mallory Filipp, Ling Chen, Progyaparamita Saha, Ching Man Wai, Ning-Yi Shao, Anshuman Sinha, Agata Bilewska, Sameer A Guru, Artur Stefanowicz, Emily Ciolak, Lydia Simms, Vivek M Mehta, Muthukumar Gunasekaran, Sanjiv J Shah, Edward B Thorp, Sunjay Kaushal
Journal: Circulation (2023)

Introduction: We have demonstrated that neonatal mesenchymal stem cells (nMSCs) extracted from human neonatal cardiac tissues and their exosomes, secretome, potently decrease cardiac fibrosis and improve cardiac function in the rat model of myocardial infarction. CD4 + CD25 + Foxp3 + (forkhead box 3) regulatory T cells (T regs ) are recently shown to regulate the formation of cardiac fibrosis in myocardial infarction. How nMSCs and secretome affect cardiac fibrosis and T regs of animals with heart failure with preserved ejection fraction (HFpEF) is unknown. Hypothesis: We hypothesized that nMSCs and secretome ameliorate cardiac fibrosis and diastolic dysfunction in HFpEF by regulating cardiac T regs . Methods: C57BL/6 mice were fed 60% high-fat diet and L-NAME to induce HFpEF or normal chow as a control. Left ventricular morphology and function were evaluated using an echocardiography. After the mice developed HFpEF, the animals were injected 10 6 nMSCs, 10 mg/kg of secretome, or equivalent amounts of vehicle as a control via tail vein. Myocardial fibrosis was quantified in trichrome-stained heart sections. Circulating and cardiac T regs were measured on a FACSCanto II cytometer. Fingolimod at a dose of 3 mg/kg was intraperitoneally injected daily for 18 days. Results: C57BL/6 mice fed high-fat diet and L-NAME for 5 weeks developed obesity, myocardial fibrosis, left ventricular hypertrophy and diastolic dysfunction (increases in mitral E/e’ ratio), and exercise intolerance with &gt; 50% of left ventricular ejection fraction. Compared to the HFpEF mice receiving vehicle, either nMSCs or secretome significantly decreased cardiac interstitial fibrosis and mitral E/e’ ratio and increased cardiac CD4 + CD25 + FoxP3 + T regs from 1 to 4 weeks post treatment. Importantly, either nMSCs or secretome enhanced the exercise speed and distance of the HFpEF mice. Fingolimod significantly decreased circulating and cardiac T regs in the HFpEF mice, which blocked the beneficial effects of nMSCs and secretome on cardiac fibrosis and diastolic function. Conclusions: nMSCs and secretome ameliorate cardiac fibrosis and diastolic dysfunction by expanding CD4 + CD25 + FoxP3 + T reg s in HFpEF. These results suggest that nMSCS and secretome have high therapeutic potential for HFpEF.
Abstract 12848: Edaravone Dexborneol Protects Against Cerebral Ischemia/Reperfusion -Induced Blood-Brain Barrier Dysfunction by Inhibiting Ferroptosis via Activation of Nrf-2/HO-1/GPX4 Signaling
Authors: Peng Xiao, Hanshu Zhao, Ruijia Liu, Zhiyu Sun, Yushuang Liu, Nan Chen, Zhongling Zhang
Journal: Circulation (2023)

Background and aims: The blood-brain barrier (BBB) is a pivotal factor in the pathogenesis of cerebral ischemia-reperfusion (I/R) injury. Edaravone dexborneol (Eda.B) is a novel cytoprotective drug widely employed in ischemic stroke (IS). Recent research implicated ferroptosis in BBB disruption during cerebral ischemia. This study aimed to investigate the protective effects of Eda.B on the BBB in I/R from the standpoint of ferroptosis, exploring potential mechanisms and targets. Methods: An I/R model in Sprague-Dawley rats was established, and we assessed the effects of Eda.B by evaluating infarct volume, cellular apoptosis, and neurofunctional recovery through TTCstaining, TUNEL staining, and modified Garcia scoring system, respectively. The protective effects of Eda.B on BBB integrity was evaluated via Evans blue leakage measurement and protein expression of both ZO-1 and occludin. Additionally, we explored the correlation between ferroptosis and BBB integrity. Western blot analysis and immunohistochemical detection were used to detect changes in the expression levels of related proteins.Meanwhile the information of microscopic structural changes observation, GSH and MDA level measurements, and Fe 2+ tissue content determination were recorded. Bioinformatics analysis was also performed to probe the mechanisms of ferroptosis in BBB injury induced by cerebral ischemia, and we detected the expression of related proteins in the Nrf-2/HO-1 signaling pathway through western blot analysis. Results: Our findings revealed that Eda.B treatment enhanced neuro scores, diminished infarct volumes and cellular apoptosis, while ameliorated BBB integrity. Furthermore, expression of ZO-1, occludin, GPX4, and xCT protein expression was up-regulated, while 4-HNE expression was reduced in the Eda.B group. Eda.B also led to decreased MDA and Fe 2+ levels in the ipsilateral brain tissues, while GSH content was increased. Ultimately, an elevated expression of proteins associated with the Nrf-2/HO-1 signaling pathway has been discovered. Conclusions: Our study indicated that Eda.B safeguarded the blood-brain barrier (BBB) from cerebral I/R injury by inhibiting ferroptosis through the activation of the Nrf-2/HO-1/Gpx4 signaling pathway.
Abstract 14836: Left Ventricular Extracellular Volume on Computed Tomography is Useful for Predicting Reverse Remodeling After Catheter Ablation for Atrial Fibrillation
Authors: Kinoshita Makiko, Hiroyuki Takaoka, Joji Ota, Shuhei Aoki, Katsuya Suzuki, Satomi Yashima, Haruka Sasaki, Noriko Eguchi, Tomonori Kanaeda, Yusuke Kondo, Yoshio Kobayashi
Journal: Circulation (2023)

Introduction: In the CAMERA-MRI study, restoring sinus rhythm with catheter ablation (CA) for atrial fibrillation (AF) significantly improved left ventricular (LV) ejection fraction (EF), particularly in the absence of LV myocardial fibrosis, determined by magnetic resonance imaging (MRI). LV extracellular volume fraction (ECV) on MRI correlates with myocardial fibrosis. Recently analysis of LVECV on computed tomography (CT) has been feasible and LVECV on CT and MRI correlate well. Little is known about what predicts achieving LV reverse remodeling (LVRR) after CA. Hypothesis: LVECV on pre-ablation planning CT could predict LVRR after CA in patients with AF and reduced LVEF. Methods: One thousand three hundred twenty patients underwent CA for AF in our institutions from Apr 2014 to Aug 2022. Of these, 50 patients (4%) with LVEF under 50% on transthoracic echocardiography (TTE) were included. All patients underwent cardiac CT using 320-detector or 256-detector row CT before the CA. LVECV was measured by CT using non-contrast and late-phase cardiac images (Figure A). We defined LVRR as an LV end-systolic volume decrease of 15% or more, an increase in LVEF to 50% or more, or an absolute LVEF increase of 15% or more. We evaluated the utility of LVECV for the prediction of LVRR after CA. Results: LVRR was achieved in 31 patients (62%) after CA, and LVECV was significantly lower in them than in the others (31.3 ± 3.3% vs. 35.9 ± 6.6%, P &lt; 0.01) (Figure B). On receiver operating characteristic curve analysis, the best cut-off of LVECV for the prediction of LVRR was 34.8%, and the sensitivity and specificity of LVECV for the prediction of RR were 90 and 68% (the area under the curve was 0.72, Figure C). On multivariate logistic regression analysis, LVECV less than or equal to 34.8% was the only significant predictor of LVRR. Conclusion: LVECV on CT is useful for predicting LVRR in patients with AF after CA.
Abstract 19062: Prognostic Impact of Coronary Microvascular Dysfunction on Diastolic Dysfunction and Cardiovascular Events in Patients With Acute Coronary Syndrome
Authors: Chang Ok Seo, Moojun Kim, Hangyul Kim, Kyehwan Kim, Jin-sin Koh, Seokjae Hwang, Jinyong Hwang, Min Gyu Kang
Journal: Circulation (2023)

Introduction: Coronary microvascular dysfunction (CMD) has prognostic value in coronary artery disease. Hypothesis: CMD could have an influence on progression of diastolic dysfunction and occurrence of cardiovascular events in acute coronary syndrome (ACS). Methods: We prospectively enrolled ACS patients who underwent successful percutaneous coronary intervention (PCI). CMD was defined by index of microcirculatory resistance (IMR &gt;40) after PCI. Cardiac diastolic dysfunction was defined by echocardiographic parameters (early diastolic transmitral flow velocity/early diastolic mitral annular velocity, e’ velocity, tricuspid regurgitation velocity, and left atrial volume index). The primary end point was 1-year diastolic dysfunction and secondary end point was cardiovascular death or admission for heart failure during 5 years of follow-up. Results: Among 163 patients, 39 patients (23.9%) had CMD. Prevalence of 1-year diastolic dysfunction was increased during 1 year (baseline 29.4% vs. 1 year 46.0%). Progression rate of diastolic dysfunction during 1 year was significantly higher in CMD (40.3% vs. 64.1%, OR 2.64, p=0.008) (Figure). After adjustment with clinical variables, presence of CMD was strongly associated with progression of 1-year diastolic dysfunction (HR, 2.95, 95% CI 1.30 - 8.74, p=0.030). Risk of cardiovascular death or admission for heart failure was increased in CMD (37.9% vs. 7.1%; Log-rank test p=0.003) Conclusions: This study showed the association between presence of CMD and progression of diastolic dysfunction during 1 year, they might have synergistic influence on occurrence of cardiovascular events in ACS patients.
Abstract 15835: Inhibition of Soluble Epoxide Hydrolase Reduces Cognitive Impairment and Improves Cerebral Hemodynamics in AD/ADRD
Authors: Chengyun Tang, Huawei Zhang, Jane J Border, Bruce D Hammock, Richard J Roman, Fan Fan
Journal: Circulation (2023)

Alzheimer's Disease and Alzheimer's Disease-Related Dementias (AD/ADRD) is an emerging global healthcare crisis. However, underlying mechanisms have not been understood well enough to translate into precision medicine. Recent human genetic evidence indicated that soluble hydrolase (sEH) is linked to AD/ADRD. Inhibition of sEH has been reported to improve cognition in AD mice due to its anti-inflammatory and neuronal protective effects. Here, we examined whether inhibition of sEH with TPPU could reduce cognitive impairments by improving cerebral hemodynamics in 18-month-old diabetes (DM)-related ADRD rats and 6 months of TgF344-AD rats. The myogenic responses of the middle cerebral artery (MCA) were impaired in both AD and ADRD rats and were normalized with TPPU. The inner diameters of MCA increased by 49.16 ± 17.02 % in DM rats but decreased by 16.06 ± 2.46% and 11.24 ± 0.05% in age-matched control and TPPU-treated DM rats when pressure was elevated from 40 to 180 mmHg. Similarly, TPPU-treated AD rats significantly enhanced the MCA constriction by 25%. Forced dilatation occurred at pressures &gt; 140 mmHg in MCAs in both rats and was rescued with TPPU treatment. Endothelial denuded MCAs from TPPU-treated DM rats constricted to 75.15 ± 4.25 % at a perfusion pressure of 140 mmHg and further constricted to 74.66 ± 4.01 % at 180 mmHg, compared to dilation of 155.48 ± 17.35 % and 172.78 ± 13.36 % in DM rats at the same pressures. The percentage of time spent with the novel object was 43.32 ± 8.04% and 83.23 ± 8.70% in DM and TPPU-treated DM rats, versus 75.68 ± 3.33% in non-DM rats. Impaired learning and short and long-term memory function examined with an 8-arm water maze in both DM and AD rats were rescued with TPPU treatment. These results provide the first evidence demonstrating that inhibition of sEH reverses cerebrovascular dysfunction and cognitive impairments in AD/ADRD.
Abstract 17931: Auxotonic MyoPod® Engineered Heart Tissues Enable Longitudinal Tracking of in vitro Development of Hypertrophic Cardiomyopathy
Authors: Cassady Rupert, Benjamin Archer, Viet Dau, Shannon Cirilli, xia li, Stuart G Campbell
Journal: Circulation (2023)

Introduction: Engineered heart tissues (EHTs) formed from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes carrying relevant mutations are a valuable tool for in vitro disease modeling and therapeutic testing. Tracking the emergence of a phenotype in vitro is key to targeting the optimal window to test therapeutic intervention. We hypothesized that auxotonic MyoPod® EHTs would enable longitudinal characterization with video analysis. Methods: Four auxotonic MyoPod® scaffold designs of decellularized porcine ventricular myocardium were seeded with wild type (WT) hiPSC-cardiomyocytes and human cardiac fibroblasts and cultured for 3 weeks. Mechanical testing was then performed on a MyoLab® instrument to obtain the contractile phenotype. One auxotonic MyoPod® design was then selected to form EHTs with WT or MYH7 R403Q +/- hiPSC-cardiomyocytes and fibroblasts. Videos of spontaneous contractions were obtained every 2-3 days. Results: All auxotonic MyoPod® scaffold designs tested (A-D) formed spontaneously contracting EHTs. In optimization studies, design C auxotonic MyoPod® EHTs were not significantly different from isometric control in any of the contractile metrics measured including twitch force (256.2 ± 25.8 μN vs 214.7 ± 78.1 μN) and time from peak force to 50% relaxation (103.8 ± 6.6 ms vs 111.2 ± 7.6 ms; control vs C, n=3 EHTs/group). When design C MyoPod® EHTs were seeded with WT and MYH7 R403Q +/- cardiomyocytes, video analysis showed slower relaxation time in MYH7 R403Q +/- EHTs that was significantly longer compared to WT control by one week of culture. Time to 90% relaxation (RT90) was lengthened by 38.8% ± 2.2% in MYH7 R403Q +/- (WT: n=7, MYH7 R403Q +/- : n=6; p&lt;0.01). These video analysis results agree with MyoLab® testing data of isometric WT and MYH7 R403Q +/- EHTs where RT90 was slowed by 36.8% ± 0.1% in MYH7 R403Q +/- (WT: n=8, MYH7 R403Q +/- : n=5; p&lt;0.01). Conclusion: In these studies, an auxotonic MyoPod® scaffold design was identified that does not alter the baseline contractile phenotype of EHTs, and it was used to track the development of relaxation deficit in MYH7 R403Q +/- EHTs over one week in culture. This technology can be used to track both the development of a disease phenotype and its response to therapies delivered in vitro.
Abstract 14391: Biomarkers, Proteomics, and Echocardiography Lend Insights into Cardiovascular Death in HFrEF: A VICTORIA Substudy
Authors: Palak Shah, Yinggan Zheng, Burkert Pieske, Vojtech Melenovsky, Carolyn S Lam, Karen S Sliwa, Javed Butler, Justin A Ezekowitz, Christopher deFilippi, Christopher OConnor, Lothar Roessig, Jasper Tromp, Cynthia M Westerhout, Adriaan A Voors, Paul W Armstrong
Journal: Circulation (2023)

Background: Using data from the VICTORIA ECHO substudy in high-risk patients with heart failure with reduced ejection fraction (HFrEF), we evaluated the potential complementary role of cardiac function, biomarkers, and proteomics in association with cardiovascular death (CVD), a key component of the primary composite (HF hospitalization or CVD). Hypothesis: Measurement of cardiac biomarkers, proteins, and ECHO parameters may provide insights into the mechanism of CVD in HFrEF. Methods: At baseline, left ventricular ejection fraction (LVEF) and LV end-systolic volume index (LVESVI) on ECHO, 6 quantitative biomarkers, and 92 proteins (Olink CVD III panel) were assessed by blinded core labs. Adjusted (MAGGIC) associations and HRs (95% CIs) are presented. Proteomics associations were adjusted for false discovery rate. Results: Of 583 patients, 96 (16.5%) had CVD (21.6/100 pt-years) a median 8 months (IQR 6-11) from randomization. See Table for MAGGIC-adjusted HRs for LVEF, LVESVI, and biomarkers. NT-proBNP was most strongly associated with CVD (HR per doubling 1.53 [1.32-1.77]). Proteins significantly associated with CVD were cathepsin D (2.32 [1.62-3.32]), matrix metalloproteinase-2 (2.31 [1.45-3.68]), IL-2 receptor (1.74 [1.40-2.14]), transferrin receptor (1.64 [1.31-2.04]) and tumor necrosis superfamily (1.88 [1.41-2.50]) (Fig). Conclusions: After MAGGIC adjustment, a rise in LVESVI, but not LVEF, was associated with CVD. Upregulation of selected biomarkers/proteins related to myocardial wall stress, extracellular matrix turnover, inflammation, and oxidative stress were also associated with CVD and may serve as novel future therapeutic targets in HFrEF.
Abstract 15848: Hardly a Windfall: Prescribing Practices in Pediatric Heart Failure Before and After Food and Drug Administration Approval
Authors: Avital B Ludomirsky, Jonathan B Edelson, Justin Berger, Kimberly Y Lin, Matthew O'Connor, Carol Wittlieb-Weber, Heather Griffis, Bingqing Zhang, Steve Ampah, Joseph Rossano
Journal: Circulation (2023)

Background: Prior to the 2019 Food and Drug Administration (FDA) approval of ivabradine and sacubitril/valsartan, there were no medications approved for the treatment of pediatric heart failure (PHF). There are minimal data regarding the use of on- or off-label medications in PHF. Aims: We aim to describe medication use in PHF, factors associated with PHF medication use, and test the hypothesis that FDA approval is associated with changes in prescriber practice. Methods: Utilizing the Truven Health Marketscan Claims Encounter Database (2013-2021), we determined the prevalence of medication [diuretics, angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs), beta-blockers, pulmonary vasodilators, ivabradine, and sacubitril/valsartan] use in children ≤19yo with PHF and cardiomyopathy (CM), with a focus on use before and after FDA approval. Results: Of 2,218 children with PHF and CM, 76% were prescribed ≥ 1 HF medication. Diuretics (57%) and ACEi/ARBs (57%) were used most frequently ( Fig 1A) . Only 0.4% of patients were prescribed ivabradine and 3% sacubitril/valsartan. Patients enrolled in Medicaid were more likely to be prescribed HF medications than those with commercial insurance (OR 1.83, 95% CI 1.50-2.22). After FDA approval in 2019, sacubitril/valsartan prescription rose significantly from 0.4% in 2013-2018, to 3.9% in 2020-2021 (p &lt;0.001), and ivabradine use increased from 0.1% in 2018 to 0.5% (p = 0.043) in 2020-2021, but both remained rare (Fig 1B) . Conclusion: Diuretics and ACEi/ARBs are the most commonly used PHF medications, despite not being approved for this indication. The two FDA approved medications are used in ≤5% of patients. While FDA approval is important, it did not substantially influence physician prescribing behavior for PHF. Further study is needed to understand the value of FDA approval and the potential socioeconomic implications of the association between insurance type and medication use.