tbuckley/cabot-search huggingface dataset:
Abstract 16201: Use of Cardiac Computed Tomography (CT) Imaging Biomarker Variables for the Prediction of Incident Heart Failure: Multi-Ethnic Study of Atherosclerosis
Authors: Aditya Mehta, Angelo De La Rosa, Spencer Hansen, Robyn McClelland, Alain G Bertoni, Matthew J Budoff
Journal: Circulation (2023)

Introduction: Several predictive heart failure (HF) models exist to determine incident HF. We aimed to create a model that uses cardiac CT imaging biomarkers to improve discrimination scores of incident HF. Hypothesis: Cardiac CT variables increase predictive abilities of the Pooled Cohort Equations to Prevent HF (PCP-HF) score (a validated 10-year risk of new-onset HF prediction model) in all HF, HFrEF, and HFpEF. Methods: MESA participants aged 45-84 years old and free of clinical CVD who completed a cardiac CT were included for study analysis. The outcome of interest was new-onset HF. Clinical risk factors were obtained. Cardiac CT variables analyzed included left ventricular size index (LVSi) and calcifications of coronary arteries (CAC), aortic valve (AVC), mitral valve (MVC), and thoracic aorta (TAC). Results: Among 6,667 MESA study participants who underwent cardiac CT, 426 events of new-onset HF occurred during the follow-up period. Among the 426 events, 173 (40.6%) were categorized as HFrEF, 193 (45.3%) were categorized as HFpEF, and 60 (14.1%) had missing ejection fraction data. The reported data is based on the Cox model adjusted for all CT variables in one model with log(PCP-HF). For all incident HF (preserved and reduced), CAC (HR 1.10 95% CI 1.05-1.15, p&lt;0.001) and LVSI (HR 1.14 95% CI 1.10-1.18, p&lt;0.001) were statistically significant with an improvement in c-stat from .773 to .805. For HFpEF, CAC (HR 1.07 95% CI 1.01-1.14, p&lt;0.025), AVC (HR 1.08 95% CI 1.00-1.16, p&lt;0.037) and MVC (HR 1.12 95% CI 1.05-1.19, p&lt;0.001) were statistically significant with an improvement in c-stat from .782 to .800. For HFrEF, CAC (HR 1.15 95% CI 1.08-1.23, p&lt;0.001) and LVSI (HR 1.28 95% CI 1.23-1.34, p&lt;0.001) were statistically significant with an improvement in c-stat from .751 to .815. Conclusions: Current HF prediction models, including PCP-HF model, are based on clinical risk factors. As evidenced by this model CAC, AVC, MVC and LVSi have statistical significance with improvement in c-statistics of the PCP-HF model when adjusted for CT variables. HFpEF and HFrEF have different CT variables with enhanced predictive ability.This study emphasizes the need to study the utility of cardiac CT imaging biomarkers in the development of an incident HF predictive model.
Abstract 15254: Temporal Assessment of Clinical Outcomes in Patients With ST-Elevation Myocardial Infarction and Non-ST-Elevation Myocardial Infarction
Authors: Kyung Hoon Cho, Seok Oh, Yongwhan Lim, Joon Ho Ahn, Seung Hun Lee, Dae Young Hyun, Min Chul Kim, Doo Sun Sim, Young Joon Hong, Juhan kim, Young Keun Ahn, Jang Hoon Lee, Chang-hwan Yoon, Sang Rok Lee, Joo-Yong Hahn, Jin-Ok Jeong, Weon Kim, Jinyong Hwang, Myung Ho H Jeong
Journal: Circulation (2023)

Background: Limited data exist regarding the temporal progression of outcomes in patients with ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI). Research Questions: Are there any significant differences in the occurrence of cardiovascular events over time between patients with STEMI and NSTEMI in the modern era of percutaneous coronary intervention? Aims: We aimed to compare the incidence rates of major cardiovascular events over time between patients with STEMI and NSTEMI using the Korea Acute Myocardial Infarction Registry-National Institutes of Health database. Methods: We analysed the data of 13,056 patients diagnosed with STEMI or NSTEMI between 2011 and 2015 (median age, 65 years [interquartile range {IQR}, 54-74]). We calculated yearly, monthly, weekly, and daily time-point event rates after admission, considering the number of events during the specific periods divided by the number of event-free patients just before those periods. The primary outcome measure was all-cause mortality. Results: During the 3-year follow-up (median, 1095 [IQR, 1044-1095] days), 12.4% of patients (1589/12,836) died from any cause. Patients with STEMI had a significantly higher mortality rate in the first week of admission than that of patients with NSTEMI (4.54% [283/6235] vs 1.76% [120/6823], P &lt; 0.001), but this difference was not observed in the second week (0.59% [35/5952] vs 0.67% [45/6703], P = 0.635). Subsequently, higher mortality rates were observed in patients with NSTEMI than in those with STEMI for all time points. Daily outcome analysis revealed a gradual decrease in the difference in mortality rates in patients with STEMI versus NSTEMI from the first to the ninth day, followed by an inversion on the tenth day: STEMI: 2.39% (149/6235) vs NSTEMI: 0.59% (40/6823) on the first day; 0.13% (8/5942) vs 0.10% (7/6694) on the ninth day; and 0.03% (2/5934) vs 0.13% (9/6687) on the tenth day. Conclusions: This analysis of temporal outcomes from a nationwide Korean registry demonstrated that patients with STEMI initially had higher mortality than patients with NSTEMI, but this difference gradually decreased and subsequently inverted during the second week, specifically after the ninth day.
Abstract 14687: Altered Left Ventricular Hemodynamic Forces as an Early Indicator of Disease Progression in Duchenne Muscular Dystrophy
Authors: Sarah E Kollar, Francesco Capuano, Jonathan H Soslow, Yue-Hin Loke, Christopher Spurney
Journal: Circulation (2023)

Introduction: Duchenne muscular dystrophy (DMD) patients develop progressive cardiomyopathy. Cardiac magnetic resonance (CMR) imaging can identify global/regional dysfunction and myocardial fibrosis, although left ventricular (LV) biomechanics are not conventionally assessed. Thus, we investigated hemodynamic force (HDF), a novel measurement of the intraventricular pressure gradient, as potential biomarker for myocardial dysfunction in DMD. Methods: Prospective, multi-center study of DMD patients and age-matched controls. Feature-tracking (Qstrain, Medis) performed on short/long-axis cine to capture LV wall motion. Novel diffeomorphic mapping used to generate kinematic models and calculate HDF components (apical-basal, lateral-septal, anterior-posterior) throughout the cardiac cycle ( Figure 1A ). HDF was correlated to conventional CMR parameters. Results: Thirty-six DMD and 10 controls included with LV ejection fraction (LVEF) 51±6% vs 56±6% (p = 0.037). DMD patients with normal LVEF had altered HDF across multiple points in each axis compared to controls ( Figure 1B ). Twenty-one DMD patients (58%) with LVEF &lt; 55% had lower apical-basal (p = &lt; 0.001), lateral-septal (p = 0.001), and anterior-posterior (p = 0.005) root mean square (RMS) HDF compared to DMD with normal LVEF (Figure 1C) . All components of HDF correlated with LV volumetric/strain parameters ( Table 1 ). Conclusions: Cine-derived HDF are altered in DMD patients. Decreased systolic HDF and delay to peak diastolic HDF may be an early indicator of myocardial dysfunction compared to conventional CMR testing. Future studies will investigate HDF as a biomarker of disease progression.
Abstract 12634: Amplified P2x <sub>3</sub> Pathway Activity in IB4 Positive Muscle DRG Neurons and Exercise Pressor Reflex Regulation in Hindlimb Ischemia-Reperfusion
Authors: Lu Qin, Qin Li, Jianhua Li
Journal: Circulation (2023)

Background: Hindlimb ischemia-reperfusion (IR) represents one of the most prominent pathological conditions observed in peripheral artery disease (PAD). Arterial blood pressure response (BP) during exercise, partly driven by the exaggerated exercise pressor reflex (EPR), is associated with an elevated risk of cardiovascular events in PAD patients. However, the precise underlying mechanisms leading to this exaggerated BP response are poorly elucidated. The purinergic P2X 3 signaling pathway, which plays a key role in modifying the EPR, was the focus of the present study. Objectives: To examine the regulatory role of P2X 3 on the EPR in a rat model of hindlimb IR, which was induced by 6 hours’ ischemia followed by 18 hours’ reperfusion (referred to as IR rats). Results: We found that, in IR rats, there were: 1) upregulation of P2X 3 protein expression in the L4-6 dorsal root ganglion (DRG) (1.48±0.16 in IR rats/n=8 vs. 1.00±0.41 in sham rats/n=9; P&lt;0.05), which was localized in IB4 positive DRG neurons by the method of immunohistochemistry, 2) amplified P2X currents in isolated muscle DRG neurons (P2X transient currents: 1281.64±776.74 pA in IR rats/n=25, vs. 717.91±556.2 pA in sham rats/n=9, P&lt;0.05; and sustain currents: 466.94±168.68 pA in IR rats/n=11, vs. 271.49±200.90 pA in sham rats/n=8, P&lt;0.05); 3) amplification of P2X-mediated BP response (29±8 mmHg in IR rats/n=12 vs. 21±4 mmHg in sham rats/n=7; P&lt;0.05); and 4) alleviation of the exaggerated BP response induced by static muscle contraction (18±8 mmHg in IR +A317491/n=8, vs. 29±11 mmHg in IR/n=7, P&lt;0.05) and P2X-mediated BP response by α, β-me-ATP injection (15±4 mmHg in IR+A317491 /n=6 vs. 23±7 mmHg in IR/n=4, P&lt;0.05) following the inhibition of muscle afferents’ P2X 3 receptor by A-317491. We further verified that both A-317491 and siRNA knockdown of P2X 3 significantly decreased the activity of P2X currents in the isolated muscle DRG neurons (all P&lt;0.05 vs. their respective controls). Conclusion: With the above evidence from multiple approaches, we concluded that the P2X 3 signaling pathway activity is amplified following hindlimb IR via the enhancing expression and activity of P2X 3 receptors in IB4 positive muscle DRG afferents. This contributes to the exacerbated EPR responses in PAD.
Abstract 14481: Engineered Cardiac-Specific AAV Capsids From a Novel Next-Generation Platform (next-CAP) With Cross-Species Selection for Cardiac-Targeted Gene Therapy
Authors: Jörg Schweiggert, Gregor Habeck, Rabea Hinkel, Dorothea Kehr, Kristin Cimen, Xenia Kramp, Marc Lerchenmueller, Hugo Katus, Patrick Most, Martin Busch
Journal: Circulation (2023)

Background: Adeno-associated virus (AAV) based gene therapy bears the potential to transform future clinical care of hereditary and acquired heart failure. However, the broadly used AAV9 serotype exhibits fatal liver toxicity in clinical studies and requires long-term immunosuppressive therapy when used systemically e.g., for LAMP2 gene-associated cardiomyopathy. Hypothesis: AAVs with genetically-engineered cardiac tropism are key for safe and efficient delivery of therapeutic gene replacement, silencing or editing systems to the diseased heart with minimized off-target organ transduction after a simple systemic administration. Technology &amp; Results: We developed novel cardiac-specific AAV capsids by a next-generation experimental-bioinformatic AAV capsid development platform (next-CAP) employing mouse, farm pig and non-human primate models. A highly diverse capsid library with more than 100 million variants was generated from novel mammalian heart AAV isolates integrating DNA shuffling and peptide display approaches and underwent a two-step cross-species in vivo evolution. Implementing a unique molecular identifier strategy eventually allowed for combined long- and short-term sequencing to capture 77 novel AAV capsid variants displaying highest enrichment in hearts over all other organs, including the liver with superior patterns to AAV9. Subgroups of the top heart-AAV capsid portfolio displayed an overall sequence homology of up to 99.5% identity highlighting the presence of novel cross-species conserved heart-homing motifs. As producibility was another inherent screening criteria, our cardiac-specific AAV capsid portfolio already provides scalable manufacturing characteristics for in vivo indications. Conclusion: Our proprietary portfolio of novel heart-specific AAV capsids now enables the systematic development of optimal therapeutic capsid-promoter-transgene ensembles for further dose-expression, -efficacy and -toxicity assessments for various hereditary and acquired HF indications in suitable model systems. In summary, we developed an efficient and versatile platform for the generation of next-generation AAV capsids for heart-specific gene therapy of yet uncurable rare and common cardiac diseases.
Abstract 15049: Combinatorial Immune Checkpoint Blockade Increases Myocardial Secretion of H-FABP, NT-Pro-BNP, NLRP-3 Inflammasome, Interleukin-1β and Interleukin-6: Biochemical Implications in Cardio-Immuno-Oncology
Authors: Nicola Maurea, Margherita Passariello, Irma Bisceglia, Andrea Paccone, Alessandro Inno, Carlo Maurea, Domenico Gabrielli, Alessia Merola, Martina Iovine, Marino Scherillo, Rapuano Lembo, Lorenzo Manna, Paolo Antonio A Ascierto, Claudia De Lorenzo, Vincenzo Quagliariello
Journal: Circulation (2023)

Background: Immune checkpoint blockade alone or in combination with chemotherapy or radiotherapy or other immune checkpoint blocking agents have become an integral part of oncology in recent years. Monoclonal antibodies against CTLA-4 or PD-1 or PDL-1 are the most studied ICIs in randomized clinical trials, however, more recently, an anti-LAG3 (Lymphocyte activation gene-3) human monoclonal antibody, Relatlimab, has been approved by FDA for combinatorial treatment with Nivolumab for metastatic melanoma. Moreover, anti PD-L1blocking agent Atezolizumab is actually under study in association with Ipilimumab as innovative thearpy for metastatic lung cancer. Cases of cardiotoxicity such as myocarditis, vasculitis and endothelitis are rarely observed in these patients on monotherapy, however new combination therapies and the use of new targets in immunotherapy could expose patients to more adverse cardiovascular events. Methods: human cardiomyocytes co-cultured with human peripheral blood lymphocytes (hPBMCs) were exposed to monotherapy and combinatorial ICIs (PD-L1 and CTLA-4 or PD-1 and LAG-3 blocking agents, at 100 nM) for 48 h. After treatments, cardiac cell lysis and secretion of biomarkers of cardiotoxicity (H-FABP, NT-Pro-BNP), NLRP3-inflammasome and Interleukin 1 and 6 were determined through colorimetric and enzymatic assays. Results: Both combinations of immune checkpoint inhibitors exert more potent cardiotoxic side effects compared to monotherapies against human cardiac cells co-cultured with human lymphocytes. LDH release from cardiac cells was 43% higher in PD-L1/CTLA-4 blocking agents, and 35.7% higher in PD-1/LAG-3 blocking agents compared to monotherapies. Biomarkers of cardiotoxicity, such as NT-Pro-BNP and H-FABP, were also strongly increased in combination therapy with respect to monotherapies. NLRP3 inflammasome, IL-6 and IL-1β levels were also increased by PDL-1/CTLA-4 and PD-1/LAG-3 combined blocking agents compared to untreated cells and monotherapies. Conclusions: Data of the present study, although in vitro, indicate that combinatorial immune checkpoint blockade, induce a pro- inflammatory phenotype.
Abstract 16753: Effectiveness of Guideline-Endorsed Low-Density Lipoprotein Cholesterol Reduction Rates in Patients With Prior Percutaneous Coronary Intervention
Authors: Yu Jung Jung, Jong Il Park, Byung-ju Son, Hong-ju Kim, KANGUN CHOI, Jong-Ho Nam, Jang-Won Son, Jong-Seon Park, Dong Gu Shin, Ung Kim, Jun-Chang Jeong, Yu-Hyum Cho, Yeong-Hui Bae, Song Ji-Hyun, Sun Oh Kim
Journal: Circulation (2023)

Background/Objective: Low-density lipoprotein cholesterol (LCL-C) should be treated by guideline directed management which is more than 50% reduction of initial LDL-C and less than 55mg/dL LDL-C level in patients with prior percutaneous coronary intervention (PCI). However, there is no direct comparative evidence on target reduction rate and target goal LDL-C level. Therefore, we investigated the clinical influence of &gt;50% reduction from baseline LDL-C in patients with prior PCI. Methods: A total of 3,104 patients with prior PCI were retrospectively enrolled from 2014 to 2020 at Yeungnam University Medical Center. The primary endpoint was 3-year major adverse cardiovascular events (MACE which was defined as a composite of cardiovascular death, nonfatal myocardial infarction, target-lesion revascularization, hospitalization for heart failure, or non-fatal stroke. And the secondary endpoints were individual components of the primary endpoint. Results: Among all patients, the achievement rate of target LDL-C &lt; 55 mg/dL and more than 50% reduction from baseline was 17.2%. There was no significant difference between the LDL &lt; 55 mg/dL group and the LDL ≥ 55 mg/dL group in the risk for MACE (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.84-1.43; P = 0.502) after propensity score matching. However, the group that achieved ≥ 50% reduction of LDL-C from baseline LDL-C level showed a significant reduction in the occurrence of MACE in the subgroup of LDL-C level ≥ 55 mg/dL (HR, 0.34; 95% CI, 0.16-0.74; P= 0.004), compared to the group with &lt; 50% reduction of LDL-C. Conclusion: More than 50% reduction from the baseline LDL-C reduced the incidence of MACE in the LDL-C ≥ 55 mg/dL
Abstract 17245: Statin Induced Necrotizing Autoimmune Myositis
Authors: Humail Patel, Michael Vaysblat, Suhwoo Bae, Andrew Flescher, Matthew Federbush
Journal: Circulation (2023)

Description of Case: A 64 year old female with hypertension, hyperlipidemia, and type 2 diabetes presented to the emergency room for 3-4 months of progressively worsening bilateral lower extremity weakness with associated edema, but without any reports of pain. The patient had significant impairments in her daily function and now required a cane to ambulate. The patient was found to have significantly impaired strength in the bilateral lower extremities with particular involvement of the proximal thigh muscles. The patient was noted to have a markedly elevated creatine phosphokinase (CPK) to 16,000 and a moderate transaminitis. The patient underwent evaluation with an MRI which revealed several areas of bilateral necrotizing myositis. The patient’s autoimmune markers were remarkable for a positive HMG-CoA reductase antibody and a diagnosis of statin induced necrotizing autoimmune myositis was made. The patient was started on pulse dose steroids without much improvement in her weakness and functional ability. The patient was therefore started on intravenous immunoglobulin with a rapid improvement in her symptoms. The patient was discharged on long term glucocorticoid therapy with appropriate prophylactic medications. Discussion: Statin induced necrotizing autoimmune myositis (SINAM) is a very rare form of autoimmune myopathy that is characterized by rapidly progressive proximal muscle weakness along with other potential extramuscular manifestations in the setting of statin use. SINAM should be suspected in any patient on a statin, regardless of duration of treatment, who presents with proximal muscle weakness and a markedly elevated CPK, often &gt; 1000. Treatment, like other forms of autoimmune myopathies, is often centered around immunomodulatory therapies such as high dose glucocorticoids, intravenous immunoglobulin, and long term immunosuppressants. Despite rapid initiation of aggressive treatment, severe forms of the disease have a high mortality as there may be involvement of the respiratory musculature leading to respiratory failure. Given the rarity of this condition, along with the variability in presentation related to the onset of statin therapy, diagnosis and treatment of this entity remains poorly understood.
Abstract 15967: Unravelling the Role of Deoxyhypusine Synthase-Mediated Hypusination of eIF5A in Pulmonary Arterial Hypertension
Authors: Sarah-Eve Lemay, Yann Grobs, Charlotte Romanet, Sandra Martineau, MABROUKA SALEM, Tsukasa Shimauchi, Sandra Breuils Bonnet, Alice Bourgeois, Charlie Theberge, Francois Potus, Steeve Provencher, Sebastien Bonnet, Olivier Boucherat
Journal: Circulation (2023)

Introduction: Pulmonary Arterial Hypertension (PAH) is characterized by progressive distal pulmonary arteries (PAs) obstruction leading to heart failure and death. PA smooth muscle cells (PASMCs) from PAH patients display a “cancer-like” phenotype that contributes to PA remodeling. Appreciation of the pivotal role of translational control in hyperproliferating diseases is steadily increasing. In this regard, eukaryotic translation initiation factor 5A (eIF5A) was shown to provide cancer cells with a competitive advantage by increasing translation of mRNAs with oncogenic proprieties. Strikingly, eIF5A is the only protein containing the unique spermidine-derived amino acid hypusine required for its function. Hypusine formation is catalyzed by the sequential actions of deoxyhypusine synthase (DHPS) and deoxyhypusine hydrolase (DOHH). We hypothesized that increased Hyp eIF5A in PAH-PASMCs is required to promote translational efficiency of a set of factors conferring a higher survival and proliferative capacity, leading to pulmonary vascular remodeling. Methods/Results: As assessed by LC-MSMS and WB, expression levels of DHPS, DOHH and both total and hypusinated forms of eIF5A were found increased in PAs and PASMCs from PAH patients and animal models. In vitro , both molecular and pharmacological inhibition of DHPS and DOHH significantly attenuated PAH-PASMCs survival (WB Survivin; Annexin V labeling) and proliferation (WB MCM2, PLK1; Ki67 labeling and EdU incorporation). Hypusine signaling promoted the expression of a broad array of proteins involved in oxidative phosphorylation, supporting the bioenergetic requirements of cell survival and proliferation (LC-MSMS, WB, Seahorse). In vivo , smooth muscle cells-targeted inactivation of one allele of Dhps conferred partial protection against the development of Sugen/Hypoxia (Su/Hx)-induced PAH in mice. Accordingly, pharmacological inhibition of DHPS using GC7 improved hemodynamics (RVSP, mPAP, CO) and vascular remodeling (EVG) in monocrotaline and Su/Hx rats with established PAH. Conclusion: We showed for the first time that hypusine signaling is implicated in PAH development and represents a new promising therapeutic target.
Abstract 13317: Current Smoking Impedes Recovery in Cardiac Rehabilitation
Authors: Sherrie Khadanga, Patrick Savage, Blair Yant, Phillip Ades, Diann Gaalema
Journal: Circulation (2023)

Purpose: Current smoking is a powerful predictor of future morbidity and mortality and those who smoke are more likely to have higher risk clinical profiles and less likely to engage in secondary prevention. Little is known about how those who smoke benefit from secondary prevention following a cardiac event, such as cardiac rehabilitation (CR). The purpose of this study was to compare improvements in fitness among those who smoke vs those who do not during CR. Methods: Data were gathered on 2208 individuals entering the University of Vermont CR program from 1/1996-12/2021. Self-reported smoking status was collected at CR entry (current vs. formerly vs. never smoking). Cardiorespiratory fitness (CRF)(peak oxygen capacity [VO2peak]) was assessed via exercise tolerance test at entry to and exit from CR. Change in Peak VO2 was compared by smoking status univariately and in a multivariate model controlling for other potential contributing variables like age, sex, entry VO2, number and severity of exercise-limiting comorbidities, BMI, and number of CR sessions attended. Results: On average patients improved by 3.26 in their CRF during the course of CR. In univariate analyses improvement by smoking status was 2.29, 3.06, and 3.55 (current, former, never smoker respectively). The final multivariate model included smoking status, CRF at intake, comorbidities, age, BMI, and interactions between smoking status and age, and BMI and age. Least square means from this model were improvements of 1.95, 3.10, and 3.53 (current, former, never smoker respectively). Conclusion: These data suggest that those who are currently smoking improve less in fitness during CR than those who formerly or never smoked and that controlling for covariates highlights that the biggest difference in the effect of smoking is truly between the current smokers and the former/never smokers. Further research should be conducted to see if successful smoking cessation can improve fitness related gains during CR.