tbuckley/cabot-search huggingface dataset:
Abstract 16610: A New Left Ventricle Vortex Formation Time for Clinical Assessment of Diastolic Filling Efficiency Based on Direct Mechanical Ventricular-Vascular Coupling: Evaluation in Heart-Failure and Healthy Cohort
Authors: Coskun Bilgi, Ben A Lin, Niema M Pahlevan
Journal: Circulation (2023)

Introduction: The mechanical coupling of the left ventricle (LV) and aorta creates the apical motion of the atrioventricular plane (AVP), resembling a piston-cylinder system, impacting early diastolic filling (J Am Heart Assoc. 2017;6:e004903). Furthermore, several clinical studies have suggested the vortex formation time (VFT) as an indicator of LV diastolic function (Eur. Heart J. Cardiovasc. Imaging. 2012;13(5):385-93). However, conflicting results exist in previous clinical studies, potentially due to deviations from the original fluid dynamics definition of VFT in a piston-in-cylinder setting. In this study, we propose a new VFT approach to assess LV diastolic filling performance based on direct mechanical ventricular-vascular coupling. Methods: Cardiac MRI was used on 69 healthy individuals and 19 heart failure (HF) patients. The clinical cohort (37% women) had a mean age of 46 [± 17.5] years and BMI of 24.8 [±4.5]. LV valvular diseases were excluded. VFT was assessed using the original L/D definition, where L represents ascending aortic recoil motion (piston displacement) and D represents the mitral valve orifice. Aortic displacement was measured on the three and four-chamber MRI scans by tracing the AVP. Mitral valve orifice was determined as the average of commissure distance (short-axis images) and the leaflet tip distance (three-chamber view). Results: The new VFT approach yielded a mean[± std.] of 4.73[±0.89] for the healthy group, and considerably lower values (3.24±0.83) for the patients with HF (figure 1). Conclusions: The proposed VFT based on the mechanical ventricular-vascular coupling and original fluid dynamic formulation, demonstrates a theoretical optimal value of approximately 4 in healthy individuals, while significantly lower in HF. This novel VFT has the potential to address existing discrepancies regarding the clinical significance of VFT and establish it as a promising indicator of left ventricular filling efficiency.
Abstract 14771: Chronotropic Incompetence and Response to Exercise Training by HIV Status in the Exercise for Healthy Aging Study
Authors: Matthew S Durstenfeld, Melissa P Wilson, Catherine Jankowski, Grace L Ditzenberger, Chris T Longenecker, Kristine M Erlandson
Journal: Circulation (2023)

Background: People with HIV (PWH) have lower exercise capacity compared to HIV-uninfected peers. Chronotropic incompetence (CI), the inability to increase heart rate during exercise, may contribute to reduced exercise capacity. We hypothesized that PWH would have lower adjusted heart rate reserve (AHRR=(HR peak -HR rest )/(220-Age-HR rest ), a measure of chronotropy, normal &gt;80%) and that AHRR would improve with exercise training. Methods: The Exercise for Healthy Aging Study included sedentary adults ages 50-75 with (PWH) and without HIV (controls) recruited for a 24-week exercise training program. Participants exercised at moderate intensity for weeks 1-12 and were then randomized to continue moderate or advance to a higher intensity of exercise for weeks 13-24. We compared prevalent CI on treadmill cardiopulmonary exercise testing by HIV. We compared AHRR and change in AHRR from baseline to 12 and 24 weeks by HIV status using mixed effects models. Finally we explored whether improved chronotropy could explain the greater benefit of exercise observed among PWH. Results: Among 32 PWH and 37 controls (median age 56, 7% female, mean BMI 28 mg/m 2 ), 9/31 (29%) with HIV compared to 4/38 (11%) controls had CI (p=0.07). At entry, AHRR was lower among PWH (91 vs 102%; difference 11%, 95%CI 2.5-19.7; p=0.01). At week 12, AHRR normalized among 27 PWH (+8%, 95%CI 4-11; p&lt;0.001) and sustained at week 24 (+5, 95%CI 1-9; p=0.008) compared to no change among 31 controls (95%CI -4 to 4; p=0.95; p interaction =0.004). Accounting for AHRR, the greater benefit of exercise observed among PWH at 12 weeks (peak VO 2 +1.5 ml/kg/min more than controls, 95%CI 0.1 to 2.9, p=0.04) was attenuated (0.4 ml/kg/min independent of AHRR, 95%CI -0.9 to 1.8; p=0.53). After 24 weeks of exercise, only 4/26 (15%) PWH met the definition for CI compared to 3/29 (10%) of controls (p=0.70). Conclusions: Chronotropic incompetence may contribute to reduced exercise capacity among PWH and improve with exercise training.
Abstract 16577: Unraveling T-cell and Macrophage Chemokine Crosstalk in Immunotherapy-Induced Myocarditis
Authors: Yuhsin V Huang, Daniel Lee, Corynn Branche, Zachary Lin, Emma Wang, Natasha Banga, Joel Neal, Holden T Maecker, Ronald M Witteles, Patricia K Nguyen, Pilar Alcaide, Gerald J Berry, Sean M Wu, Han Zhu
Journal: Circulation (2023)

Introduction: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate immunity against tumor cells but can cause immune related adverse events such as myocarditis, a rare but serious side effect with up to 40% mortality. Hypothesis: Macrophages contribute to recruitment of cytotoxic T-cell subsets to the heart in the setting of ICI, causing myocarditis. Methods: To study the role of macrophage depletion on ICI myocarditis, we treated MRL/Pdcd1-/- mice with liposomal clodronate. To identify timing of immune infiltration, we performed serial single cell T-cell receptor and RNA sequencing of CD45+ cells from the hearts/blood of MRL/Pdcd1-/- myocarditis mice at 1, 2, and 4 weeks of age. We treated MRL mice with anti-PD1/CTLA4 to induce myocarditis and assessed if anti-CXCR3 could decrease effector CD8+ T-cell cardiac infiltration and mitigate myocarditis. We studied the effects of in vitro CXCR3 blockade on CXCR3+ T-cell migration in a transwell assay. Results: Serial single-cell TCR sequencing/scRNA-seq of immune cells from MRL/ Pdcd1-/- vs. MRL control hearts showed infiltration of CXCL9/10+ macrophages ( Fig. 1, A ) along with progressive clonal expansion of CXCR3+ effector CD8+ T-cells in the heart starting at 2 weeks of age, prior to clinical onset of myocarditis. Macrophage depletion with liposomal clodronate reduced myocarditis and improved survival in MRL/ Pdcd1-/- mice ( Fig. 1, B-C) . CXCR3 blockade with anti-CXCR3 antibody reduced myocarditis, decreased CXCR3+ CD8+ T-cell infiltration, and improved survival in mice treated with anti-CTLA4/anti-PD1 antibodies (Fig. 1, D-E) . CXCR3 blockade in transwell assay also reduced migration of CD8+CXCR3+ T-cells towards the macrophage compartment (Fig. 1, F) . Conclusions: CXCL9/10+ macrophages likely play a critical role in development of ICI myocarditis through the recruitment of CXCR3+ effector T-cells into the heart, making this pathway an attractive therapeutic target.
Abstract 18867: A Novel Light-Sensitive Ex-Vivo Rat Atrial Anatomical Model for Studying Atrial Arrhythmias and Cardioversion
Authors: Shany Glatstein, Matteo Ghiringhelli, yehuda wexler, Lilac Haimovich-Caspi, Irit Huber, Lior Gepstein
Journal: Circulation (2023)

Introduction: Atrial arrhythmias, including atrial fibrillation (AF), contribute to significant morbidity and mortality. However, the lack of suitable tissue models in small animals hampers our understanding of the underlying mechanisms. Optogenetic actuators offer precise and reversible stimulation with high spatiotemporal resolution, presenting a unique opportunity to investigate atrial arrhythmias. Hypothesis: Our aim was to develop a light-sensitive ex-vivo anatomical model in rats for studying atrial arrhythmias and to utilize this model for optimizing optogenetic stimulation and cardioversion strategies. Methods: We injected purified AAV particles containing the transgenic light-sensitive channel (CoChR) into 5-day-old Wistar rats, followed by an 8-10 week period for atrial growth. The atria were then isolated, flattened, and affixed to a custom-made silicon plate. Superfusion with oxygenated Tyrode's solution and loading with Di-4-ANBDQBS allowed for high-resolution optical mapping. Atrial arrhythmias were induced through targeted tachypacing combined with carbamylcholine treatment. Additionally, we compared different optical and pharmacological treatment strategies to evaluate their efficacy in modulating atrial arrhythmias. Results: Immunostaining confirmed atrial expression of CoChR. Optical mapping revealed a functional syncytium with sinus node activation and propagation throughout the atria. Pacing at increasing frequencies resulted in a relatively flattened action potential duration restitution curve. Successful induction of reentrant arrhythmias was achieved. Additionally, we demonstrated the feasibility of optogenetic actuators for atrial pacing, modulation of spontaneous activity, and optical termination of arrhythmias. Conclusions: The developed optogenetic superfused atria model provides a valuable platform for studying atrial electrophysiology and modeling reentrant arrhythmias. Furthermore, it enables the optimization of optogenetic stimulation and cardioversion strategies. This integrated approach enhances our understanding of atrial arrhythmias and holds promise for the development of novel therapeutic interventions.
Abstract 18592: Association of Lactation Duration With Blood Pressure Recovery at One Year Postpartum in Overweight and Obese Individuals With a Hypertensive Disorder of Pregnancy
Authors: Renee Hart, Janet M Catov, Alisse Hauspurg
Journal: Circulation (2023)

Introduction: Hypertensive disorders of pregnancy (HDP) are associated with an increased risk of maternal cardiovascular (CV) disease. Lactation is associated with favorable metabolic and CV profiles, but its impact on blood pressure (BP) recovery following a HDP is less clear. Hypothesis: Longer lactation duration is associated with lower systolic and diastolic BP throughout the first year postpartum (PP). Methods: We utilized data from a randomized clinical trial of overweight and obese individuals with a HDP diagnosis and no pre-pregnancy hypertension. BP was assessed in triplicate along with self-reported lactation status at enrollment (6 weeks to 6 months PP) and follow up (8-12 months PP). Hypertension was defined as ≥130/80 mmHg or the use of anti-hypertensive medications. PP BPs were also obtained daily using home BP monitoring for the first six weeks, then one week per month for the remainder of the first year PP. We compared demographic and cardiometabolic outcomes by lactation status at both study visits using two-sample t-tests and chi-squared tests. We utilized multivariable logistic regression models to assess the relationship of lactation with hypertension and repeated BP measurements were fit to mixed-effects linear regression models by lactation status to assess BP recovery. Results: Data from 129 individuals included 14,177 home BPs. Overall, 81% of participants initiated lactation and mean lactation duration was 5.8 ± 4.0 months PP. At follow up (10.9 ± 2.1 months PP), both systolic (p=0.004) and diastolic (p=0.008) BP were lower in individuals who lactated compared to those who did not. Each month of lactation was associated with a 12% (aOR 0.88; 95% CI 0.78-0.98) decreased odds of hypertension at one year PP with adjustment for age, race, education, BMI. Lactating individuals had a healthier BP recovery profile (p&lt;0.01 for systolic and diastolic BP) in the first year PP. Conclusions: In overweight and obese individuals with a HDP, lactation is associated with a statistically and clinically significant reduction in systolic and diastolic BP at one-year PP. This study emphasizes the need to address barriers to lactation to improve long-term CV health.
Abstract 13046: Lysophosphatidic Acid Activates Spinal TRPV1 Signaling and Contributes to Myocardial Ischemia/Reperfusion Injury
Authors: Chao Wu, Meiyan Sun, Muge Qile, Shufang He
Journal: Circulation (2023)

Introduction: Lysophosphatidic acid (LPA) has been shown to directly activate transient receptor potential vanilloid 1 (TRPV1) on primary nociceptors via the binding site of K710 to produce acute pain. However, it is unclear whether LPA participates in myocardial ischemia/reperfusion (I/R) injury by activating TRPV1 receptors. Hypothesis: We hypothesize that LPA contributes to myocardial I/R injury by acting on TRPV1 receptors in the spinal cord, and that blocking the interaction between LPA and TRPV1 could exert cardioprotective effects. Methods: Wild type male C57BL/6 mice underwent myocardial I/R injury, and LPA levels in cerebrospinal fluid (CSF) were measured. LPA synthesis inhibitor HA-130 or exogenous LPA were intrathecally administrated during myocardial ischemia. Additionally, CRISPR/Cas-9 edited TRPV1K710N knock-in mice and a peptide V1-Cal targeting the K710 region were utilized to block the interaction of LPA with TRPV1. Results: The levels of LPA in CSF of the I/R group were found to be 1.5-fold higher than those of the sham group (Fig.1B, p=0.0001). Intrathecal administration of HA130 reduced infarct size (Fig.1C, p=0.0021) and CSF LPA levels (Fig.1D, p=0.0018). The CSF LPA levels were positively correlated with infarct size (Fig.1E, p&lt;0.0001). Intrathecal administration of LPA caused a 1.4-fold rise in infarct size relative to I/R group in wild type mice (Fig.1F, p&lt;0.0001), but not in TRPV1K710N mice (Fig.1F, p&gt;0.9999). LPA treatment enhanced the activation of spinal TRPV1 receptors following I/R injury in wild type mice, but not in TRPV1K710N mice (Fig.1 G-I). Further, the V1-Cal peptide reduced myocardial I/R injury, as well as the protein levels of TRPV1 and pTRPV1 in spinal cord (Fig.1 J-M). Conclusions: Our results suggest that LPA activates spinal TRPV1 signaling and contributes to myocardial I/R injury. Blockade of the interaction between LPA and TRPV1 in spinal cord may be a promising therapeutic approach for myocardial ischemic injury.
Abstract 13214: Arrhythmic Burden After Bruton's Tyrosine Kinase Inhibitor Initiation and Major Cardiovascular Events
Authors: John A Gambril, Sanam Ghazi, Stephen Sansoterra, Mussammat Ferdousi, Onaopepo Kola-Kehinde, Patrick Ruz, Adam Kittai, Kerry Rogers, Michael Grever, Seema Bhat, Tracy Wiczer, John Byrd, Jennifer Woyach, Daniel Addison
Journal: Circulation (2023)

Background: Bruton’s tyrosine kinase inhibitors (BTKi) have dramatic efficacy against B cell malignancies. BTKi’s also cause cardiotoxic arrhythmias, including atrial fibrillation (AF) and ventricular arrhythmias (VA). Yet, the true burden and long term effects of arrhythmias after BTKi therapy are unknown. Research Question: In patients with suspected BTKi related arrhythmias, what is the relative AF burden? Does it prognosticate future events? Methods: Leveraging a cohort of consecutive B cell malignancy patients initiated on BTKi from 2009-2020, we identified patients with available ambulatory rhythm monitors. The primary outcome was AF burden after BTKi initiation. Secondary outcomes included VA burden, conduction blocks, and other arrhythmias of probable or definite BTKi association. Observed incident AF rates and burden with next generation BTKi’s were compared to ibrutinib. Multivariable regression and survival analysis were used to define factors associated with AF related hospitalizations and major adverse cardiac events (MACE), as well as the relationship between AF burden and mortality. Outcomes were stratified by high (≥5%) vs low (&lt;5%) AF burden. Results: Of 890 BTKi treated patients, 98 wore ambulatory rhythm monitors, including 38 on next generation BTKi’s [age 67.7 years, 24.2% prior AF]. Median duration BTKi use was 34 months. Among next generation BTKi treated patients, 8.7% developed incident AF compared to 25.5% with ibrutinib ( P =0.048). Ten patients (26.3%) developed symptomatic or &gt;1% PVCs, at a mean burden of 7.1% compared to eight patients (13.3%) with mean burden 9.4% on ibrutinib. In a multivariable model accounting for traditional CV risk factors, prior AF associated with increased post BTKi AF burden. In follow up, high AF burden associated with increased MACE (HR 3.49, P =0.001) and mortality (HR 3.2, P =0.002); Figure . Conclusions: In BTKi treated patients, cardiotoxic AF burden prognosticates future MACE and mortality.
Abstract 14849: Impact of Intravenous Heparin Bolus on Outcomes of Leadless Pacemaker Implantation
Authors: Jingwen Huang, neal bhatia, Michael S Lloyd, Stacy Westerman, Anand Shah, Miguel A Leal, David B Delurgio, Anshul Patel, Christine Tompkins, Angel R Leon, Mikhael F El-Chami, Faisal M Merchant
Journal: Circulation (2023)

Background: During Micra leadless pacemaker (LP) implantation, continuous heparin is infused to prevent thrombus within the sheath and on the device. Early guidance from the manufacturer (Medtronic) recommended an initial systemic heparin bolus to further prevent thrombus formation. However, systemic heparin may increase the risk of implant complications. Thus, many operators have moved away from routine boluses. However, there is a paucity of data on the impact of heparin bolus on outcomes. Methods: We reviewed all Medtronic Micra LP implants at our institution from 9/2014 to 9/2022. The decision to bolus with heparin was at the operator discretion. Results: Among 621 LP implants, 326 received a heparin bolus, 243 did not, and 52 patients had unknown bolus status. In the cohort, 50.4% were men. Mean age at implant was 76.8 ± 14.9 years. Mean follow up was 1.7 ± 1.4 years. There were no significant differences in device electrical parameters (R wave sensing, impedance, and capture thresholds), right ventricular pacing burden (RVP), or left ventricular ejection fraction (LVEF) comparing heparin bolus vs. no bolus at both initial interrogation and long-term follow up (Figure). There was no difference between groups in the number of attempted device deployments per implant procedure (1.42 ± 0.81 vs 1.31 ± 0.66, p=0.15). Implant-related adverse events were also similar between bolus and no-bolus groups: access-site hematoma (5 vs 7, p=0.99), pseudoaneurysm (1 vs 1, p=0.99), cardiac perforation (1 vs 1, p=0.99), 30-day re-hospitalization (15 vs 21, p=0.98) and 30-day all-cause mortality (14 vs 16, p=0.57). There was 1 additional non-fatal cardiac perforation in a patient with unknown bolus status. Conclusion: Routine systemic bolus of heparin can be safely omitted in appropriately selected patients undergoing LP implant. Heparin bolus may still be considered in long cases requiring multiple device deployments or in patients with high risk for thrombotic complications.
Abstract 15736: Coronary Angiography Alone Compared With Invasive Coronary Function Testing in Women With Ischemia and No Obstructive Coronary Artery Disease
Authors: Natasha Cigarroa, Marah J Maayah, Arshjot Khokhar, Steffne Kunnirickal, Alexandra Schwann, Nida Latif, Natalija Odanovic, Kaitlin Maciejewski, Steven Pfau, Samit Shah
Journal: Circulation (2023)

Introduction: Ischemic heart disease is a leading cause of morbidity and mortality in women. Women frequently suffer from ischemia and no obstructive coronary artery disease (INOCA) which includes phenotypes of coronary microvascular dysfunction (CMD) or coronary vasospasm (VA). Between 30-60% of women referred for invasive angiography have non obstructive coronary arteries, leaving many patients without a definitive diagnosis. Objective: We sought to determine the real-world diagnostic yield of invasive physiological testing in women with INOCA, and to describe downstream care regarding modifications to medical therapy based on the eventual diagnosis. Methods: We included 198 women who underwent either coronary angiography (CA, N=99) alone or coronary function testing (CFT, N=99) comprised of acetylcholine provocation and assessment of coronary flow reserve and the index of microcirculatory resistance. We performed a descriptive retrospective analysis of demographics, pre-procedure diagnostic testing and used logistic regression to compare the findings of angiography, post-procedure diagnosis, and changes to cardiac medications across cohorts. Results: The mean age was 62 ± 10 (CA alone) compared with 57 ± 10 years (CFT). Patients were mostly white (72% CA vs 79% CFT). An angiography-based diagnosis of normal coronary arteries was found in 21% CA alone (N=21) vs 48% in CFT (N=48) and non-obstructive CAD in 79% CA alone (N=78) vs 51% CFT (N=50), p&lt;0.001. Of the women who underwent CFT, 76% (N=75) were diagnosed with a vasomotor disorder stratified by endotype of CMD 34% (n=34), VA 22% (n=22), mixed CMD/VA 10% (N=10) or endothelial dysfunction 20% (N=20). Medications were changed after angiography in 41% in the CA alone group compared to 67% in the CFT group, p&lt;0.001; while medication changes at 30 days occurred in 22% CA alone vs 45% in the CFT group, p&lt;0.001. Conclusions: Our findings demonstrate that women presenting with suspected ischemic heart disease undergoing coronary angiography often received a diagnosis of non-obstructive coronary artery disease; whereas those undergoing CFT were diagnosed with coronary vasomotor disorders. In our institution, medication changes occurred more frequently after a CFT-confirmed diagnosis.
Abstract 16625: Frameshift Mutation in <i>LMNA</i> Gene Causes Atrial Arrhythmogenesis via Epigenetic Inhibition of <i>KCNA5</i> Expression
Authors: YUE ZHU, ZHIQIAO LIN, Yongping Lin, BINGYU ZHENG, YIKE ZHANG, Hailei Liu, WEIZHU JU, Chang Cui, Minglong Chen
Journal: Circulation (2023)

Introduction: Cardiolaminopathy is a genetic heart disease caused by LMNA mutations, often leading to atrial tachycardia, AV block, ventricular arrhythmia and eventually dilated cardiomyopathy. While performing WES on pedigrees with primary atrial myopathy, we identified that nearly half of them possess mutations on the LMNA gene. However, previous studies on laminopathy have mainly focused on ventricular lesions, leaving the mechanism of how LMNA mutation leads to the atrial myopathy yet to be elucidated. Methods: To better understand the role of the LMNA gene in atrial cardiomyopathy, we employed the CRISPR/Cas9 to establish a heterozygous KI mouse model with a frameshift mutation ( lmna c.1249delA, p.K418Sfs) identified from a pedigree of atrial cardiomyopathy. Results: The heterozygous mice displayed progressive and spontaneous atrial arrhythmia, along with increased fibrosis, without any involvement of the ventricles, which was consistent with the affected individuals in the pedigree. Electrophysiological measurements showed prolonged APD90, an increased occurrence of EAD events, and augmented atrial conduction heterogeneity compared to the control mice. Bioinformatics analysis of mouse atrium indicated KCNA5 , which specifically expressed in the atrium, was significantly down-regulated. This reduction was further corroborated through Western blotting and immunofluorescence. Additionally, ChIP qPCR analysis revealed an enhanced binding of KCNA5 with lamin A/C and reduced binding with the promoting histone H3K4me3 in the mutant atrium. Notably, the presence of atrial arrhythmia and the downregulation of KCNA5 were also observed in another lmna frameshift mutation mouse model, suggesting that these mechanisms may be universal in LMNA -related atrial cardiomyopathy. Conclusions: Laminopathy causing atrial cardiomyopathy has long been underestimated. Our study validates the pathogenicity of LMNA frameshift mutation for the atrium and highlights epigenetic changes leading to KCNA5 expression downregulation and consequential phenotypic alterations. These results broaden the current knowledge of laminopathy beyond its previous emphasis on ventricular lesions, offering potential therapeutic targets for the disease.