tbuckley/cabot-search huggingface dataset:
Abstract 16516: CMR-ECG Imaging in Hypertrophic Cardiomyopathy Detects Electrophysiological Abnormalities Before Hypertrophy or ECG Changes
Authors: George Joy, Matthew Webber, Alessandra M Ardissino, James Wilson, Fiona Chan, Rebecca Hughes, Konstantinos Moschonas, Hunain Shiwani, Iain Pierce, Robert Jamieson, Vladan Koncar, xuyuan tao, Christoph Guger, Paula Velazquez, Erica Dall'Armellina, Peter Macfarlane, Peter Kellman, Rhodri Davies, Maite Tome, Yoram Rudy, Alun Hughes, Charlotte Manisty, Pier Lambiase, James C Moon, Luis Lopes, Michele Orini, Gabriella Captur
Journal: Circulation (2023)

INTRODUCTION: In hypertrophic cardiomyopathy (HCM), ventricular arrhythmia associates with severity of LVH and scar, and presence vs absence of a sarcomeric gene mutation (G+LVH+ vs G-LVH+). Also, ECG changes in subclinical HCM (G+LVH-) signal increased risk of phenotype progression. HYPOTHESES: ECG Imaging (ECGI) can detect: i) subtle electrophysiological (EP) abnormalities in subclinical HCM (pre-LVH). ii) EP abnormalities related to genetic status (G+ vs G-LVH+) and structural changes (late gadolinium enhancement [LGE], max. wall thickness [MWT]) in overt disease. METHODS: 200 participant multicenter study: 70 G+LVH-, 51 G+LVH+, 53 G-LVH+ and 26 healthy volunteers (HV) underwent 12-lead ECG (to detect abnormal Q-waves, repolarization changes, LVH criteria) and CMR-ECGI computing epicardial unipolar electrograms (UEGs) to derive: activation time (AT), activation-recovery intervals (ARIc), spatial gradients (activation: G AT , repolarisation: G RT ) and fractionation. RESULTS: Compared to HV, G+LVH- had prolongation of AT (40.3±7.3 vs 35.4±6.1 ms p=0.003) and steeper G RT (mean: 1.12±0.27 vs 1.00±0.23 ms/mm p=0.042, max: 11.7±2.8 vs 10.0±1.9 ms/mm p=0.005). AT was prolonged even in G+LVH- with a normal 12-lead ECG (p&lt;0.004). Compared to G+LVH-, G+LVH+ had similar AT but a more prolonged ARIc (275±29 vs 245±26 ms p&lt;0.001). Compared to G-LVH+, G+LVH+ had similar MWT and LGE, but more signal fractionation (0.02±0.02 vs 0.01±0.03% UEGs with ≥2 deflections p=0.002). In overt HCM (all LVH+), MWT associated with AT ( r s 0.25 p=0.011) while LGE burden associated with G AT ( r s=0.27 p=0.006) and fractionation ( r s=0.22 p=0.025). CONCLUSION: Cardiac activation prolongation and repolarization abnormalities occur in subclinical HCM (before hypertrophy). Activation is prolonged even in subclinical HCM with normal 12-lead ECG. In overt HCM, ECGI abnormalities track adverse structural changes and reveal greater fractionation in those with a sarcomeric mutation.
Abstract 16452: Targeting Notch3 Pathway and Using Extracellular Vesicles From Induced Pluripotent Stem Cell-Derived Cardiomyocytes is Effective in Porcine Chronic Myocardial Injury Model
Authors: Eileen Tzng, Sawye Raygani, Hiroyuki Inoue, Chunli Zhao, Tsuyoshi Ueyama, Maithri Kashipathy, Paul Cheng, jennifer lyins, Gentaro Ikeda, Phillip C Yang
Journal: Circulation (2023)

Introduction: Heart failure is the leading cause of hospital admission in the modern U.S. We previously demonstrated that exosomes (Ex) from iPSC-derived cardiomyocytes (iCMs) significantly restored murine peri-infarct region. We found that miR20/92/363 (CORE miRNA) activated iCM proliferation and myocardial restoration by repressing the Notch3 pathway. However, the optimal pre-clinical method to target the Notch3 pathway through Ex, miRNA, and siRNA remains to be assessed. Hypothesis: Exosomes are the most effective biologic for chronic porcine heart failure model. Methods: iPSCs were generated from four heart failure patients (Pt 1-4) and differentiated into iCMs. Ex were isolated from the iCM culture media and used to treat iCMs subjected to hypoxia-injury. The in vitro findings were then confirmed in vivo in Yorkshire pigs subjected to myocardial ischemia-reperfusion injury for one hour via balloon occlusion of the left descending artery. One month later, chronic heart failure model was developed, and percutaneous catheter system (Biocardia, Inc) delivered 10 11 Ex, 4200 μg of CORE miRNA, or 4200 μg of siNotch3 into porcine peri-infarct region. MRI and mRNA seq analyzed the porcine myocardium. Results: Viability of hypoxia-injured iCMs treated by siNotch3 (132.50% viability ± 23.54% SD)*, CORE miRNA (127.79% ± 10.06%)*, Pt 1 Ex (74.88% ± 3.11%)*, Pt 2 Ex (72.90% ± 4.50%)*, Pt 3 Ex (79.11% ± 7.23%)*, and Pt 4 Ex (77.81% ± 3.31%)* all significantly improved iCM viability compared to non-treated hypoxia-injured iCMs (26.09% ± 10.75%, *p&lt;0.05). In porcine chronic heart failure model (n=4 - 6/treatment group), the mean absolute change in LVEF of PBS (control), siNotch3, CORE miRNA, and Pt 1 Ex treatments were -3.55 ± 3.27, 1.19 ± 3.17*, 2.34 ± 1.53*, and 3.53 ± 3.59*, respectively (*p&lt;0.05). mRNA seq, gene ontology, and KEGG analysis of porcine myocardium suggested that myocardial repair occurred through the TGFβ pathway and cell cycle re-entry of cardiomyocytes. Conclusion: siRNA, miRNA, and exosomes are all effective methods to repair the porcine myocardium after chronic myocardial injury. Exosome showed the highest functional restoration. Determination of mechanism and optimal biologic and dose are underway.
Abstract 13389: Outcomes of Transcatheter Aortic Valve Replacement in Patients With Prior Mediastinal Radiation in the United States
Authors: Siddharth Agarwal, Vagisha Sharma, Agam Bansal, Khawaja Akhtar, Umair Khalid, Usman Baber
Journal: Circulation (2023)

Introduction: Although prior mediastinal radiation is associated with significantly worse clinical outcomes after SAVR, it is unknown if the same holds true for patients undergoing transcatheter aortic valve replacement (TAVR). Hypothesis: We hypothesized that the presence of prior mediastinal radiation may affect the outcomes of patients undergoing TAVR and tested this hypothesis using data from a nationally representative sample of the US population. Methods: The National Readmissions Database was analyzed from 2016-2019 to identify patients ≥ 18 years old undergoing TAVR. Patients with prior mediastinal radiation were then identified by using ICD-10 CM codes. Propensity score matching was used to adjust for confounders. Results: Our cohort included 173,743 patients undergoing TAVR, of which 2,780 (1.6%) had prior mediastinal radiation. Patients with prior mediastinal radiation undergoing TAVR were younger, had a higher proportion of females, and had a lower burden of comorbidities including hypertension, diabetes, and renal failure. Crude percentages are reported in Figure 1. On propensity score-matched analysis, the presence of prior mediastinal radiation was associated with similar odds of in-hospital mortality and peri-procedural complications including cardiovascular complications, peripheral vascular complications, pulmonary complications, neurological complications, major bleeding, and new pacemaker implantation along with similar odds of 30-day and 180-day all-cause, stroke-related, bleeding-related, and heart failure-related readmissions compared to those without prior mediastinal radiation. Conclusion: In conclusion, our data suggest that patients with prior mediastinal radiation undergoing TAVR have similar outcomes compared to those who have no history of mediastinal radiation.
Abstract 16997: Cardiomyocyte-Autonomous and Microtubule Dependent Mechanisms Are Sufficient to Mediate Load-Dependent T-Tubule Remodeling
Authors: Vasiliki Courelli, Jenn Petrosino, Keita Uchida, Lan Cheng, Leo Song, Alexia Vite, Benjamin Prosser, Kenneth B Margulies, Michael Ibrahim
Journal: Circulation (2023)

Background: Mechanical overload is an established contributor to T-tubule (TT) remodeling and associated dyssynchronous Ca 2+ release leading to abnormal excitation-contraction coupling in cardiomyopathies. We examined the induction of pathological TT remodeling in isolated cardiomyocytes and the involvement of microtubules (MT) in this process. Methods: Adult rat ventricular myocytes (aRVMs) were cultured with applied variable in vitro load for 48hrs at either physiological (10kPa) or pathological (50kPa) stiffness, using custom magnetorheological elastomers with tunable stiffness. Cells were stained with Di-8-ANEPPS and Fluo-4-AM and imaged using confocal microscopy. Field stimulation of cells allowed for Ca 2+ transient acquisition via line scans. Protein expression changes were determined via Western blotting. IF staining allowed for visualization of the MT network and relevant TT proteins (TCAP, JPH2, BIN1). MT and tyrosination state dependency of remodeling was investigated by 1μM nocodazole (MT depolymerizer), taxol (MT stabilizer), and tubulin tyrosine ligase (TTL) treatments to alter the MT network accordingly. Results: Compared to the physiological stiffness group, aRVMs subjected to pathologically increased stiffness exhibited a 14.7% decrease in density, 18.9% decrease in regularity, and a 26.6% increase in luminal dimension of the TT system, along with an increase in longitudinal elements (p&lt;0.05). The changes in both Ca 2+ handling parameters and protein expression resembled those typical of the in vivo myopathic phenotype. This included a 21.7% decrease in amplitude, along with a 33.7%, 29.8% and 21.1% increase in time to peak (TTP), variance in TTP, and the signal decay tau, respectively (p&lt;0.05). Treatment of pathologically loaded cells with taxol worsened TT remodeling, specifically with respect to TT density which decreased by 12.5% compared to nontreatment cells, and longitudinal elements which increased by 24%. Increased MT tyrosination through TTL treatment showed a 37% recovery in TT density in cells cultured at pathological stiffness compared to nontreatment cells (p&lt;0.05). Conclusion: The results suggest that load-induced TT remodeling occurs via a cardiomyocyte autonomous, MT-dependent mechanism.
Abstract 14643: Coronary Spotty Calcification is Associated With a Higher Level of Plaque Vulnerability and Vascular Inflammation in Patients With Stable Angina
Authors: Daichi Fujimoto, Kinoshita Daisuke, Keishi Suzuki, Haruhito Yuki, Takayuki Niida, Damini Dey, Hang Lee, Iris McNulty, Tsunekazu Kakuta, Ik-kyung Jang
Journal: Circulation (2023)

Background: There is controversy on clinical implication of spotty calcification in the coronary arteries. Optical coherence tomography (OCT) enables detailed plaque characterization including features of plaque vulnerability. Pericoronary adipose tissue (PCAT) attenuation is a recently developed marker for perivascular inflammation. Methods: Patients with stable angina pectoris (SAP) who had both computed tomography angiography (CTA) and OCT prior to coronary intervention were included. They were classified into two groups: spotty calcification group (calcification arc &lt;90°, length &lt;4mm) and macro calcification group. Non-calcified plaques or plaques with mixed spotty and macro calcification were excluded. The OCT findings of the culprit lesion and PCAT attenuation of the culprit vessel were compared between the two groups. Results: Among 316 patients, 62 had spotty calcifications and 66 had macro calcification in the culprit lesion. The spotty calcification group showed a significantly higher prevalence of lipid rich plaque (91.9% vs. 74.2%, p=0.008; Figure A), greater mean lipid arc (183.1 vs. 150.5°, p=0.01), and a higher level of PCAT attenuation (-71.7 ± 7.68 vs. -74.9 ± 9.17 HU, p=0.03; Figure B), compared with the macro calcification group. Conclusion: Plaques with spotty calcification are associated with a higher prevalence of lipid-rich plaques and a higher level of perivascular inflammation, compared to those with macro calcification.
Abstract 15239: Patient Self-Care Mediates the Relationship Between Caregiver Contributions and Symptom Burden in Heart Failure
Authors: Giulia Locatelli, Paolo Iovino, Corrine Y Jurgens, Rosaria Alvaro, Izabella Uchmanowicz, Laura Rasero, Barbara J Riegel, Ercole Vellone
Journal: Circulation (2023)

Introduction: Patients with heart failure (HF) experience high symptom burden that can be mitigated with adequate self-care. The situation-specific theory of caregiver contribution to HF self-care suggests that caregivers have a key role in improving patient symptom burden. Hypothesis: a) caregiver contribution to self-care influences patient self-care; b) patient self-care influences symptom burden; c) patient self-care mediates the relationship between caregiver contribution to self-care and symptom burden. Methods: Secondary analysis of baseline and three-months data from the MOTIVATE-HF trial, which enrolled 510 HF patient-caregiver dyads in Italy. Data were collected using the Self-Care of HF Index v.6.2, the Caregiver Contribution to Self-Care of HF Index, and the HF Somatic Perception Scale. Autoregressive longitudinal path analysis with contemporaneous mediation was used to test study hypotheses. Results: On average, caregivers were 54 ± 15.46 years and mainly female (74.5%), while patients were 72.4 ± 12.28 years and mainly male (68%). Better caregiver contribution to self-care maintenance was associated with better patient self-care maintenance (β=0.280, p&lt;0.001), which, in turn, was associated with lower symptom burden (β=-0.280, p&lt;0.001). Patient self-care maintenance mediated the effect of caregiver contribution to self-care maintenance on symptom burden (β=-0.079, 95% BC bootstrapped CI: -0.130, -0.043). Better caregiver contribution to self-care management was associated with better patient self-care management (β=0.238, p=0.006). The model accounted for 37% of the variance in symptom burden (p&lt;0.001). Conclusions: Targeting caregivers to increase their contribution to self-care can increase patient self-care and, consequently, lower patients’ HF symptom burden.
Abstract 13312: Statin Signature: Using Proteomics to Detect Pharmacological Fingerprints
Authors: Jessica Kuzma, Sama Shrestha, Clare Paterson, Hannah Biegel, Lori Bogren, Michael Hinterberg, Yolanda Hagar, Jessica Chadwick, Stephen A Williams
Journal: Circulation (2023)

Introduction: Lowering low-density lipoprotein cholesterol with statin therapy is a primary strategy for reducing cardiovascular morbidity and mortality. Yet, adherence to and persistence with statin medication is generally low, complicating the ability to evaluate whether treatment is effective. Hypothesis: Statin treatment may yield significant differences in abundances of proteins detectable in blood samples. Using machine learning and high-throughput proteomics, a blood-based biomarker test can be developed to assess statin medication compliance and demonstrate drug fingerprinting useful for clinical trials. Methods: Using modified-aptamer proteomics technology, SomaScan® assay v4.0, we assessed ∼5,000 proteins in 8,395 EDTA plasma samples from individuals aged 29-64 at visit 1 of the Fenland study, totaling ∼42 million protein measurements. A total of 305 individuals (3.6%) reported active statin medication use at this study visit. Predicted statin use was modeled with protein measurements using machine learning methods in 70% of Fenland as a training dataset. A hold-out dataset was used to assess model performance. A predictive model using elastic net logistic regression was optimized based on AUC and robustness to assay noise and sample handling conditions to detect a signature of statin usage. Results: A total of 839 proteins differed significantly between the ‘active statin’ and ‘no statin’ use groups in univariate analysis (FDR &lt;0.01). Eight of the top 50 significant proteins have known mechanistic associations with statin pharmacology, including HMGCS1, PCSK9, and APOB. A six-protein model was developed with an AUC of 0.91 (sensitivity=0.82, specificity=0.88) and 0.90 (sensitivity=0.80, specificity=0.87) on the training and hold-out datasets, respectively, to predict whether a statin signature is present or not. Conclusions: We successfully developed a blood-based protein-only model that detects mechanistically-relevant protein changes to predict active statin use in adults. The protein model could compliment self-reported medication status in clinical trials and in healthcare.
Abstract 15875: Immediate Complete Revascularization Reduces Recurrent Myocardial Infarction and Repeat Revascularization in Patients Presenting With Acute Myocardial Infarction
Authors: Alina Upreti, Sunil Upadhaya
Journal: Circulation (2023)

Introduction: Studies have suggested that complete revascularization has better outcome compared with culprit-only revascularization for the treatment of enzyme-positive acute coronary syndrome. However, the optimal timing of complete revascularization remains unclear. We conducted a meta-analysis of randomized controlled trials (RCT) comparing immediate complete revascularization with staged revascularization in patients with ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI) with multi-vessel disease. Methods: We systematically searched the Cochrane Central Register of Controlled Trials, Embase, PubMed and clinicaltrials.gov databases for RCT comparing immediate complete revascularization with staged revascularization in patients with enzyme-positive acute coronary syndrome. The pooled outcome were major cardiovascular adverse event (MACE), all-cause death, cardiovascular death, recurrent MI and repeat revascularization. The random effect and Mantel-Haenszel method was used to analyze the data. Heterogeneity was measured using I 2 . Results: Five studies met the inclusion criteria ( 1187 patients in immediate complete revascularization group and 1176 patients in staged revascularization group). We did not find any significant difference in the rate of MACE (OR: 0.75 [95 % CI: 0.44-1.29] I 2 : 35%, p value = 0.30). Similarly, there was no significant difference in the rates of all-cause death (OR: 0.93 [95 % CI: 0.47-1.86] I 2 : 40%, p value = 0.84)and cardiac death (OR: 1.02 [95 % CI: 0.52-1.98] I 2 : 14%, p value = 0.96). However, immediate complete revascularization group had significant reduction in the rates of repeat revascularization (OR: 0.59 [95 % CI: 0.43-0.82] I 2 : 0%, p value = 0.002) and recurrent MI (OR: 0.52 [95 % CI: 0.32-0.84] I 2 : 1%, p value = 0.008). Subgroup analysis including STEMI patients only showed similar rate of MACE ((OR: 0.92 [95 % CI: 0.60-1.41] I 2 : 0%, p value = 0.70). Conclusions: Our results suggest that immediate complete revascularization is safe. There was significant reduction in recurrent MI and need for repeat revascularization in patients undergoing immediate complete revascularization.
Abstract 17453: In vitro Aspirin Responsiveness Can Predict Platelet Hyperreactivity and Cardiovascular Risk
Authors: Sarah Liberow, Elliot Luttrell-Williams, Yuhe Xia, Siobhan McGirl, Lauren Kennedy, Maja Fadzan, Adedoyin Akinlonu, Tessa A Barrett, Jeffrey S Berger
Journal: Circulation (2023)

Background: While antiplatelet therapy decreases cardiovascular events, insufficient platelet aggregation suppression by antiplatelet therapy is associated with an increased risk of cardiovascular events. In this study, we developed a diagnostic tool to establish an individual’s “aspirin (ASA) responsiveness” in vitro and investigated its association with other metrics of platelet activity and cardiovascular risk. Methods: In 115 subjects off all antiplatelet therapy, platelet aggregation in response to high-dose of arachidonic acid (AA; 1.5 mM) with and without incubation of platelet-rich plasma with ASA (3 mM) was measured by light transmission aggregometry (LTA). ASA responsiveness was defined as ([% aggregation to AA - % aggregation to AA + ASA] / % aggregation to AA) x 100. Next, we correlated ASA responsiveness with other metrics of platelet activity. Finally, we evaluated its clinical significance in a cohort of patients undergoing lower extremity revascularization (LER) followed longitudinally for cardiovascular events. Results: Among 115 participants (mean age 50.3 years old, 65% female, and 43.5% underrepresented minorities, off all antiplatelet therapy), mean % aggregation to high-dose AA was 89.5% ± 3.5. In vitro ASA responsiveness was variable, mean 73.72% ± 15 (range: 13.7% to 97.6%). ASA responsiveness was lower in older (P&lt;0.05) and female participants (P&lt;0.05) and was not associated with race/ethnicity, diabetes, or platelet count. Lower ASA responsiveness was associated with a significant increase in platelet aggregation to epinephrine (0.4 μM, P=0.0004), ADP (1.0 μM, P=8.89x10 -9 ), and collagen (0.2 μg/mL, P=1.16x10 -9 ). In an independent cohort of 67 patients undergoing LER, lower in vitro ASA responsiveness (e.g. a reduced platelet-inhibiting effect), was associated with a significantly increased risk of major adverse cardiac and limb events (1 st tertile-63.6%, 2 nd tertile-50.0% and 3 rd tertile-27.3%; P=0.016 for trend). Conclusions: Reduced ASA responsiveness is associated with increased platelet activity and a higher risk of cardiovascular events. We propose that this rapid, relatively simple assay may be used preclinically for ASA testing and to identify individuals at high cardiovascular risk.
Abstract 14824: Reduced Endothelial ADAR1-Dependent RNA Editing Induces NOCT-Driven Immunoactivation and Promotes Pulmonary Hypertension
Authors: Chen-Shan J Woodcock, Giovanni Maroli, Hyunbum Kim, Ying Tang, Yi Yin Tai, Satoshi Okawa, Shu-Ting Cho, Robert Lafyatis, Caroline Chauvet, Tatiana Kudryashova, Elena A Goncharova, Thomas Bertero, Ke Yuan, Soni Pullamsetti, Stephen Y Chan
Journal: Circulation (2023)

Introduction: Early apoptosis of pulmonary artery endothelial cells (PAECs) is a key driver of vascular remodeling and pulmonary hypertension (PH), but its regulation is poorly defined. Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA editing enzyme that converts adenosine to inosine (A-to-I) in RNA transcripts. We found that ADAR1 expression was reduced in PH endothelium. While reduced RNA editing stimulates aberrant cytosolic innate immunity and can drive apoptosis, the exact RNA editing targets and downstream mechanisms regulating pulmonary endothelial survival are unknown. Hypothesis: Deficiency in ADAR1-mediated RNA editing promotes pulmonary endothelial pathophenotypes and drives PH. Methods &amp; Results: ADAR1 expression was downregulated in the pulmonary vascular endothelium and in lung tissues of human and mouse PH. Global A-to-I editing was decreased in the whole lungs and PBMCs from PAH patients. In vitro , hypoxia, a known PH trigger, downregulated ADAR1 in PAECs via upregulation of the ADAR1-targeting microRNA, miR-17. By RNA sequencing of PAECs after ADAR1 knockdown, we identified the circadian gene Nocturnin ( NOCT ) as a direct ADAR1 target that carries two active A-to-I RNA editing sites in the 3’UTR. By single cell RNA sequencing of human PAH lungs, NOCT editing levels were reduced, while NOCT transcript levels increased. Correspondingly, in vitro , ADAR1 silencing increased NOCT mRNA levels, thus activating an innate immune response and PAEC apoptosis. Forced NOCT expression phenocopied the effect of ADAR1 deficiency, inducing RNA sensing innate immunity signaling pathway and increasing apoptosis. In vivo , in mice chronically exposed to hypoxia, administration of the ADAR1 inhibitor 8-Azaadenosine (Aza) resulted in worsened indices of PH. Notably, genetic deletion of NOCT mitigated PH induced by Aza in hypoxic IL6 transgenic mice, emphasizing the crucial role of NOCT in ADAR1-mediated pathogenesis. Conclusions: Hypoxia-induced ADAR1 deficiency promotes NOCT mRNA dysregulation to induce PAEC innate immunity, PAEC apoptosis, and PH. This study provides impetus to target the ADAR1-NOCT axis for more effective diagnostics and therapeutics for PH.