tbuckley/cabot-search huggingface dataset:
Abstract 13260: Large Scale Plasma Proteomics Identifies MMP-12 as a Novel Biomarker of Aortic Stenosis Progression
Authors: Khaled Shelbaya, Victoria Lamberson, Yimin Yang, Pranav Dorbala, Leo Buckley, Brian Claggett, Hicham Skali, Line Dufresne, George Thanassoulis, Ta-Yu Yang, Jamie C Engert, James S Floyd, Thomas Austin, Anna E Bortnick, Jorge R Kizer, Renata Caroline C Costade Freitas, Sasha A Singh, Elena Aikawa, Christie M Ballantyne, Ron C Hoogeveen, Bing Yu, Josef Coresh, Kuni Matsushita, Amil M Shah
Journal: Circulation (2023)

Background: Aortic stenosis (AS) is associated with significant morbidity and mortality and is increasing in prevalence. Limited data exist regarding circulating biomarkers of AS risk. Methods: Among Atherosclerosis Risk in Communities study participants with available proteomics (Somascan v4) at study Visit 5 (2011-13; n=4,899; age 76 ± 5 years, 57% women), we used multivariable linear regression to evaluate the association of 4,877 plasma proteins with peak aortic valve (AV) velocity and AV dimensionless index. We then tested their association, when assessed at study Visit 3 (1993-95; n=11,430; age 60 ± 6, 54% women), with incident AV-related hospitalization post-Visit 3 (median follow-up 22, IQR 14 - 25 years) using multivariable Cox PH regression models. For the resulting candidate proteins, we assessed the association of Visit 5 protein levels with change in AV peak velocity over 6 years from Visit 5 to 7 (2018-19; n=2,314) and with quantitative AV calcification by cardiac CT at Visit 7 (n=1,804); associations with incident adjudicated AS in the Cardiovascular Health Study (CHS; n=3,413); and differences in AV tissue expression in normal, fibrotic, and calcific segments of explanted stenotic human AVs (n=3). Results: We identified 52 plasma proteins with consistent associations with AV peak velocity, AV dimensionless index, and incident AV hospitalization. Of these 52 proteins, MMP12 was also associated with magnitude of increase in AV peak velocity between Visits 5 and 7 (Figure), and with magnitude of AV calcification by CT at Visit 7 (adjusted OR 1.25 [95% CI 1.19-1.32], p=1.7x10 -17 ). Higher MMP12 was also associated with incident moderate or severe AS in CHS, an independent cohort. MMP12 expression was greater in calcific compared to fibrotic or normal AV tissue segments. Conclusions: Plasma MM12 is a potential novel circulating biomarker of AS risk.
Abstract 15129: Applying Magnetocardiography to Identify Asymptomatic Ischemic Heart Failure at an Early Stage
Authors: Yiming Dong, Xiaole Han, Xiaofei Yin, Ruochuan Li, Yansong Xu, Jiaxin Fan, Fei Xie, Feng Xu, Min Xiang, Dexin Yu, Xiaolin Ning, Jiaojiao Pang, Yuguo Chen
Journal: Circulation (2023)

Introduction: Asymptomatic cardiac dysfunction (ACD) has management implications, and been shown to have special cardiac electrical signal features, magnetocardiography (MCG) can be used in a range of cardiovascular diseases by tracing subtle changes of the cardiac electromagnetic activity. Hypothesis: MCG could be used to identify ACD in patients with heart failure (HF) risk factors. Methods: This study was a subcohort of a prospective MCG study (NCT05392712), in which patients hospitalized with ischemic heart disease (IHD) were all underwent MCG examination. Patients with asymptomatic HF, according to the American Heart Association Heart Failure Guideline, were divided into “at risk for HF” (stage A) or “pre-HF” (stage B, namely ACD). Supervised machine-learning were undertaken to select specific MCG features and establish MCG recognition model for pre-HF (MCG-HF model), which was further tested in an independent test set. In the end, we compared the performance of MCG-HF model with N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the optimized Atherosclerosis Risk in Communities (ARIC) HF risk score for identifying pre-HF. Results: A total of 420 inpatients with IHD, of which 111 were in stage A and 309 in stage B, were included in this study. In an independent test set (n= 126), the MCG-HF model for identifying patients at stage B demonstrated 95.7% sensitivity and 66.7% specificity (area under the receiver-operating characteristic curve [AUC]: 0.904; 95% confidence interval [CI]: 0.800 to 0.957). The AUC for optimized ARIC model and NT-proBNP model were 0.631 (95% CI:0.572 to 0.690) and 0.761 (95% CI:0.716 to 0.807), respectively. Conventional methods for pre-HF recognition showed inferior discriminative ability. Conclusions: The MCG based on machine learning shows valuable performance in identifying ACD, the cardiac magnetic signal detection technology provides a rapid and optimized screening tool in patients at risk for HF.
Abstract 18999: Long-Term Risk of Stroke After Coronary Artery Bypass Surgery With Carotid Revascularization: A Randomized Controlled Trial
Authors: Stephan C Knipp, Hans Torulv T Holst, Konstantinos Bilbilis, Markus Kamler, Christian Weimar
Journal: Circulation (2023)

Introduction: In patients with carotid artery stenosis, combined coronary and carotid surgery has been widely used despite lack of evidence from randomized trials. Moreover, there are no data on long-term outcome following carotid revascularization versus best medical treatment. Hypothesis: May simultaneous coronary artery bypass grafting (CABG) and carotid endarterectomy (CEA) prevent the long-term risk of stroke? Methods: In the Coronary Artery Bypass graft surgery in patients with Asymptomatic Carotid Stenosis (CABACS) trial, patients with coronary disease and high-grade carotid stenosis (NASCET &gt;=70%) were randomized to receive combined simultaneous CABG+CEA or CABG alone. Primary endpoint was the composite rate of non-fatal stroke or death within 30 days after surgery, with both treatments assumed to be equally safe and efficacious. Secondary endpoints included any stroke, stroke or vascular death and death of any cause, and follow-up was five years. While our previous report focused on primary outcome, here we evaluate the long-term results of the trial. Results: The trial was terminated prematurely after recruitment of 129 patients in 17 centers in Germany and the Czech Republic. The rate of stroke or death at 30 days was not significantly different following combined CABG+CEA and CABG alone (18.5% (95% confidence interval [95% CI]: 0.099-0.300) versus 9.7% (95% CI: 0.036-0.199), p=0.203). By 5 years, stroke or death rate was 40.6% (95% CI: 0.285-0.536) following CABG+CEA and 35.0% (95% CI: 0.231-0.484) following CABG alone (p=0.581). Strokes of any kind tended to occur more frequently after CABG+CEA (5 years: 29.4% vs. 18.8%, p=0.245), while death rate was similar in both treatment arms (25.4% vs 23.3% (p=0.837). Subgroup analysis revealed no significant effect of center on outcomes. Conclusions: Long-term risk of stroke or death was higher after combined CABG+CEA, mainly due to increased perioperative event rates. Because of minor power, further trials are warranted to confirm our results.
Abstract 16481: Comparative Measures of Physical Performance in Healthy Subjects and Patients With Subclinical Heart Failure or Coronary Artery Calcium in the Project Baseline Health Study
Authors: Zaniar Ghazizadeh, Albee Y Ling, Nicholas Cauwenberghs, Everton Santana, Ramzi Dudum, Sarah Short, Shannon Sullivan, David J Maron, Pamela S Douglas, Francois Haddad, Kenneth W Mahaffey
Journal: Circulation (2023)

Introduction: While exercise stress test is the traditional method for assessing cardiorespiratory fitness, 6-minute walk test (6MWT) and 10-meter walk test (10MWT) can be inexpensive alternatives for physical activity and fitness evaluation. We aim to identify conditions where 6MWT and 10MWT show comparable diagnostic yield to metabolic equivalents of task (MET). Methods: All participants in the Project Baseline Health Study (PBHS) with no missing data were included. Participants were assigned a heart failure (HF) stage according to the 2022 AHA/ACC HF guidelines. Mean and standard deviation (SD) were described for each measurement by HF stages: 0 (healthy), A (presence of risk factors (RF)), and B (presence of RF and LVEF&lt;50%, diastolic dysfunction or LVH); and by coronary artery calcium (CAC) score subgroups: 0, 1-99, ≥100 Agatson units (AU). Multinomial regression was applied to estimate the association of each measurement with HF stage and CAC subgroups adjusted for relevant covariates. Results: 2,181 (87%) of 2,502 PBHS participants had complete data on METs, 6MWT, and 10MWT. The mean (SD) age was 50.1 (17.1) years, with 1224 (56.1%) females. The cohort consisted of participants with Stage 0, A, B (n=711, 742, 372) and CAC = 0, 1-99, ≥ 100 (n=1275, 471, 348). The overall mean (SD) for 6MWT, 10MWT, and METs were 479.8 (79.1) m, 2.0 (0.5) m/s, and 11.6 (4.3), respectively. Each SD decrease of METs was significantly associated with increased odds for more advanced HF stages and CAC subgroups ( Figure A1-B2 ). The 10MWT and 6MWT were also able to differentiate significantly between subclinical stages of HF and compare CAC subgroups 1-99 and ≥100 to CAC=0, although with smaller odds ratios (Figure A1, A2, B1). Conclusions: METs, as measured in a graded exercise test, demonstrated the strongest association with HF stage or CAC subgroup. Based on our findings, there is potential for utilizing the simpler assessments of 10MWT and 6MWT to differentiate between subclinical HF stages.
Abstract 14454: Catheter Ablation of Atrial Fibrillation Reverses Morphological Changes of the Mitral Valve and Ameliorates Atrial Functional Mitral Regurgitation
Authors: Kazuhiro Nagaoka, Yasushi Mukai, Ryoko Yada, Shunsuke kawai, Nobuhiro Honda, Kiyohiro Ogawa, Susumu Takase, Kazuo Sakamoto, Hideki Tashiro, Hiroyuki Tsutsui
Journal: Circulation (2023)

Background: We previously reported that atrial functional mitral regurgitation (A-FMR) occurs with morphological changes of the mitral valve and can be improved by catheter ablation (CA) of atrial fibrillation (AF). However, it is unclear whether the unique morphological changes in the time-course of AF persistence are reversible with sinus rhythm restoration with CA. Aims: The aims of this study were 1) to compare morphological differences among paroxysmal AF (PAF) w/o MR, non-paroxysmal AF (NPAF) w/o MR, and A-FMR, and 2) to examine changes in degree of MR and morphology of the mitral valve after CA in patients with A-FMR. Methods: This is a multicenter (4 hospitals in Fukuoka) retrospective observational study. Protocol 1 : Eighty-four patients undergoing initial CA for AF (from 2010.January to 2021.May) were selected and divided into 3 groups after matching on age (68±8 y.o), sex (19 males), and body surface area (1.7±0,2 m 2 ); PAF w/o MR, NPAF w/o MR, and A-FMR (n=28 in each group). A-FMR was defined as at least mild MR accompanying with NPAF, preserved LVEF (≧ 50%), and no evidence of valve degeneration and other structurally heart diseases. Protocol 2 : Fifty-five patients with A-FMR (19 males, 71±9 y.o.) undergoing initial CA were enrolled. Clinical variables and echocardiographic parameters were analyzed. Results: In protocol 1, tethering angles of anterior and posterior mitral leaflet (AML and PML) were smaller in patients with A-FMR compared with PAF w/o MR (Table1). PML length was shorter in A-FMR than other groups (Table1). In protocol 2, the degree of MR was significantly reduced (Figure, p=0.0013) associated with reduction in MR vena contracta width and MR area (p&lt;0.001) at 11±7 months after CA. Tethering angles of AML and PML were increased after CA (Table2). Conclusion: A-FMR occurs via unique morphological changes of the mitral apparatus along with AF persistence and can be improved by CA of AF with significant reversals of the morphological changes.
Abstract 14717: Gene Therapy Mediated Rescue of Chronic Non-Ischemic Cardiomyopathy in Minipigs
Authors: Jing Li, Pia Balmaceda, Thuy Ha, Michel Accad, Robin M Shaw, Tingting Hong
Journal: Circulation (2023)

Heart failure (HF) is a major cause of morbidity and mortality worldwide, yet with limited therapeutic options. Recent evidence indicates that the cardiac bridging integrator 1 (cBIN1)-organizes transverse tubule microdomains which organize the calcium handling machinery important for cardiac function. In rodent models, adeno-associated virus 9 (AAV9)-cBIN1 effectively reconstitutes microdomains and rescues HF. Here we explored the therapeutic efficacy of AAV9-cBIN1 in a minipig model of non-ischemic HF. 6-7 months old Yucatan minipigs were subjected to continuous right ventricular rapid pacing (RVP) at 170 bpm. After continuous RVP for 5.7 ± 1.0 weeks (N=10), minipigs developed dilated cardiomyopathy with increased left ventricular (LV) end diastolic volume (EDV, 70.7 ± 4.5 vs. baseline 45.5 ± 1.6 mL) and reduced ejection fraction (EF, 36.5 ± 1.2 vs. baseline 71.3 ± 1.5 %). Once EF ≤ 40% over a week, pigs were randomized to receive intravenous AAV9-cBIN1 or control (AAV9-GFP or PBS). Pacing was continued throughout the study period. In control animals (N=5 with 4 PBS and 1 AAV9-GFP treatment), LV further dilated (78.0 ± 8.7 mL) with EF declining to 27.6 ± 6.7 % by four weeks post injection. The first three control animals already died of severe HF symptoms by 7 weeks post injection (Figure 1A) and the other two animals are currently at 4 weeks post injection with EF reduced to 27 and 33 %, respectively. Despite of continuous RVP, AAV9-cBIN1 rescued HF with EF recovered to 52.6 ± 4.0 % and EDV at 67.3 ± 6.6 mL at 4 weeks post injection. Three cBIN1-treated animals survived the full protocol of 6-month monitoring with EF maintained at 57.5 ± 15.5 % (Figure 1B-C), with two ongoing pigs currently surviving at 4 weeks post-injection with normal EF. Figure contains data of the animals who died or have already completed the 6-month protocol (N=3 per group). No toxicity was observed. In conclusion, intravenous cBIN1 gene therapy rescues non-ischemic HF and improves mortality in pigs.
Abstract 14485: LDHA-Lactate Promotes Smooth Muscle Remodeling and Pulmonary Hypertension Through Lactylation of TOP1 and EMILIN1
Authors: Lifeng Jiang, Iryna Zhyvylo, Dmitry Goncharov, Leyla Teos, Derek Lin, Lisa Franzi, Aisha Saiyed, Sanjana Neeli, Nicholas Kenyon, Paul Wolters, Horace Delisser, Tatiana Kudryashova, Elena Goncharova
Journal: Circulation (2023)

Background: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by remodeling of small pulmonary arteries (PA) due to hyper-proliferation of resident PA cells, leading to elevated right ventricular (RV) afterload and heart failure. PA smooth muscle (SM) cells (PASMC) in PAH have metabolic shift to glycolysis and lactate over-production. Goals: To investigate the role of lactate over-production in PA remodeling and PAH. Methods: RT-PCR, immunohistochemical, immunoblot, proteomic analyses; proliferation (Ki67), lactate, apoptosis assays; SU5416/Hypoxia (SuHx) rat and mouse models of PH. Results: Lactate dehydrogenase A (LDHA) was over-expressed in SMα-actin-positive areas of small muscular PAs from PAH subjects and rodents with SuHx PH, and distal human PAH PASMC compared to controls, promoting lactate over-production, consequent up-regulation of Yap/Taz, Akt-mTOR, increased proliferation and survival. SM22α-Ldha-/- mice were protected from SuHx-induced PH and RV hypertrophy. Lysine lactylation (Kla) was increased in small PAs and PASMC from human PAH lungs. Proteomic analysis identified 12 non-histone proteins that were hyper-lactylated in PAH PASMC. Following validation revealed that hyper-lactylation induced over-accumulation of TOP1 and deficiency of EMILIN1 in small PAs and PASMC from PAH lungs, leading to up-regulation of Yap/Taz, Akt-mTOR, TGFβ1, and increased proliferation. Lactate self-supported its over-production by up-regulating glycolysis and LDHA overexpression through EMILIN1-TGFβ1-HIF1α loop. Human PAH PASMC had elevated lactate secretion; exogenous lactate induced proliferation of control PAEC and PAAF. Pharmacological inhibition of LDHA-lactate reduced proliferation and selectively promoted apoptosis in human PAH PASMC, reversed SuHx-induced PA remodeling, PH, and RV hypertrophy in mice. Conclusions: LDHA-driven lactate over-production promotes proliferative, apoptosis-resistant PASMC phenotype, pulmonary vascular remodeling, and PH via hyper-lactylation and over-accumulation of TOP1, deficiency of EMILIN1, and consequent activation of Yap/Taz, Akt/mTOR, and TGFβ1. Targeting LDHA-lactate network could represent potentially attractive strategy to treat PAH.
Abstract 13434: Prognostic Impact of Functional Limitations in Acute Decompensated Heart Failure Patients With Reduced &amp; Preserved Left Ventricular Ejection Fraction
Authors: Takeshi Fujita, Takahisa Yamada, Tetsuya Watanabe, Takashi Morita, Masato Kawasaki, Atsushi Kikuchi, Takumi Kondo, Tsutomu Kawai, Yuji Nishimoto, Yongchol Chang, Masanao Taniichi, Takuya Oshita, Yuki Kokubu, Yuto Fukuda, Makoto Kinugawa, KENTARO SHIMIZU, Katsuyoshi Sakai
Journal: Circulation (2023)

Background: Although functional limitations (FL) could predict clinical status in patients with heart failure (HF), these clinical significances have not been fully elucidated. Hypothesis: Severe FL would be associated with poor prognosis both in patients with HFrEF and HFpEF. Aims: The purpose of this study was to examine the prognostic significance of FL in patients with acute decompensated heart failure (ADHF), relating to left ventricular ejection fraction (LVEF). Methods: We studied 340 patients admitted for ADHF in our prospective cohort study (Osaka Prefectural Acute heart failure Registry: OPAR study)(HFrEF[LVEF≤50%]:n=175 and HFpEF[LVEF&gt;50%]:n=165). Clinical data, echocardiography and venous blood sampling were performed just before discharge. FL were evaluated using the Performance Measure for Activities of Daily Living-8 (PMADL-8 ranges 8-32, and higher scores indicate worse FL). The endpoint was the composite of worsening heart failure rehospitalization and cardiac death. Results: During a follow up period of 3.0±1.9 years, 123 patients (64 patients in HFrEF and 59 patients in HFpEF) reached the primary endpoint. PMADL-8 was significantly smaller in patients with HFrEF than HFpEF (18.9±7.1 vs 21.0±6.1, p=0.004). On multivariate Cox analysis, PMADL-8 score was an independent risk factor for the primary endpoint both in HFrEF and HFpEF after adjustment for major confounders (age, sex, systolic blood pressure, and plasma brain natriuretic peptide level). Patients with high PMADL-8 scores had a higher risk of the primary endpoint than those with low PMADL-8 scores both in HFrEF (≥16 defined by ROC analysis, AUC 0.590[0.503-0.676]; adjusted hazard ratio: 2.20 [95%CI 1.08-4.48], 43% vs 25%, p=0.03) and HFpEF (≥25 defined by ROC analysis, AUC 0.617 [0.528-0.707]; adjusted hazard ratio: 1.95 [95%CI 1.04-3.66], 50% vs 29%, p=0.04). Conclusion: FL evaluated based on PMADL-8 was associated with poor prognosis in ADHF patients with both HFrEF and HFpEF.
Abstract 17750: Impact of Ventricular Assist Device Use on Pediatric Heart Transplant Outcomes in a Linked Cohort of the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) and Pediatric Heart Transplant Society (PHTS) Databases
Authors: Scott R Auerbach, Kristin Anton, Neha Bansal, Carmel Bogle, Katerina Boucek, Ryan S Cantor, James K Kirklin, David N Rosenthal, Muhammad Farrukh Shezad, Simon Urschel, Kae Watanabe, Hong Zhao, Matthew J O'Connor
Journal: Circulation (2023)

Purpose: Pediatric ventricular assist devices (VAD) improve waitlist mortality. We aimed to compare outcomes after heart transplant (HT) based on pre-HT support in patients (pt) &lt;18 years (yr) at listing. Methods: Prospectively collected VAD and post-HT data were linked between ACTION and PHTS databases, respectively (4/1/2018-6/30/2022). Support groups were defined as medical (MG) and VAD (VG), device groups as paracorporeal pulsatile (PP), paracorporeal continuous (PC), and intracorporeal continuous (IC), and device types as LVAD, BiVAD, RVAD, and systemic VAD (SVAD). Standard descriptive statistical methods were used. The Kaplan Meier Method and log rank test analyzed for univariable graft loss post-HT. Results: The 1360 pt included VG=405 and MG=955. At HT, VG pt were younger (6.7 ± 6.2 vs 7.7 ± 6.4 yr; p=0.008) and waited less time for HT 0.35 +/- 0.9 vs 0.5 +/- 0.82 yr (p=0.0036). More VG pt required mechanical ventilation (15.3% vs 11.0% (p=0.03) and intensive care (67% vs 51% p&lt;0.0001). Proportions of congenital heart disease (CHD) and cardiomyopathy (CM) were different between groups (MG: 64.8% CHD and 32.6% CM vs VG: 35.1%CHD and 65.2% CM; p&lt;0.0001). VG device group and type were PP n=184 (LVAD 62.0%, SVAD 22.3%, BiVAD 15.2%), IC n=154 (LVAD 77.3%, SVAD 12.3%, BiVAD 10.4%), PC n=50 (LVAD 26.0%, SVAD 38%, BiVAD 12%), and other n= 17 (41.2% LVAD, 47.0% unknown, 11.8% BiVAD). Overall, graft survival was similar between MG vs VG (p=0.17). There were significant differences in graft survival when stratified by device group ( Figure 1A, IC 95.5%, PP 78.8%, and PC 65.9% p&lt;0.0001), support group and diagnosis ( Figure 1B MG-CM 95.7%, VG-CM 88.0%, MG-CHD 86.5%, and VG-CHD 82.7% at 3 yr, p=&lt;0.0001), and by device type (LVAD 90.3% vs SVAD 80.0, and BiVAD 70.7% at 3yr; p=0.014). Conclusion: Graft survival varies by pre-HT dx and device type and group. CHD, PC, and BiVAD pt may be at higher risk of graft loss. These may be risk factors to consider for risk stratification in post-HT management.
Abstract 16628: Threshold for Ascending Aorta Diameter for Clinical Management: An Assessment of the UK Biobank Population Based on Z-Scores
Authors: Nikhil Paliwal, Albert Henry, Chris Finan, Rhodri Davies, Tom Lumbers, Alun Hughes, Bryan Williams, Aaron Hingorani
Journal: Circulation (2023)

Introduction: Ascending aortic diameter (AAoD) is commonly monitored to manage patients at risk of aortic dissection. Z-scores have also been proposed to identify at risk aortas, adjusting AAo for age, gender, and body surface area (BSA). Despite improved imaging and proven association of AAoD with age, sex and BSA, cutoff remains at 4.5 cm for monitoring and 5.5 cm for surgery in guidelines. However, studies like International Registry of Acute Aortic Dissection found that most aortic dissection had AAoD&lt;5.5 cm. Aim: Identify AAoD in the UK Biobank population and compare current 4.5 cm cutoff with Z-scores to classify cases with dilated ascending aortas. Methods: Using cardiac magnetic resonance images of participants in the UK Biobank, we applied a pre-trained neural network to segment and quantify the AAoD. We also obtained demographics and clinical covariates for the participants with AAoD. Two common Z-scores were calculated using published equations including: (1) age, height, and sex (Z-HAS) and (2) age, BSA and sex (Z-BAS). We identified participants with AAoD&gt;4.5 cm and compared them with Z&gt;2 cutoff value that might require imaging follow-up for managing their dilated aortas. Results: AAoD diameter was calculated for 44,799 participants (22,983 females and 21,816 males). Common demographics in both groups are listed in the Table. Average AAoD was 3.15±0.32 cm in females and 3.44±0.35 cm in males. Diameter cutoff of 4.5 cm identified 15 females and 110 males with dilated aortas. On the other hand, Z-HAS classified 862 females and 674 males, while Z-BAS classified 583 females and 405 males (orange dots in the top and bottom panels of Figure, respectively) with higher aortic diameter that might require regular follow-up imaging. Conclusion: Z-Score might identify more people at dilated aortas as compared to the hard cutoff. Future work is needed to define whether Z scores are more sensitive means of identifying patients who might be at increased risk of aortic dissection.