tbuckley/cabot-search huggingface dataset:
Abstract 17013: CTX320: An Investigational in vivo CRISPR-Based Therapy Efficiently and Durably Reduces Lipoprotein (a) Levels in Non-Human Primates After a Single Dose
Authors: Phuong Khanh Morrow, Sanjay D'Souza, Tess Wood, Vivek Gowda, Nicolette Lee, Maria Lei Zhang, Jeremy Pandji, Laura Serwer, Keith Steiger, Erisa Sula, Erin Thorstensen, Kayla Urbaez, Jacob Usadi
Journal: Circulation (2023)

Background: Genetic and epidemiological studies have identified elevated levels of lipoprotein (a) (Lp(a)) as a direct cause of atherosclerosis and related diseases. CTX320™ is an investigational in vivo CRISPR/Cas9 gene editing therapy designed to knock out the apolipoprotein (a) component of Lp(a) in the liver. CTX320 contains Cas9 mRNA and guide RNA (gRNA) formulated for efficient encapsulation into LNPs for in vivo administration . Here we assessed the efficacy, safety, and durability of CTX320 in primary human cells and non-human primates (NHPs). Methods: For in vitro studies, primary human hepatocytes were plated and dosed with CTX320 one day later. Cells were harvested after three days and analyzed via Sanger and next-generation sequencing. For NHP studies, cynomolgus monkeys were dosed with either vehicle control or CTX320 at doses ranging from 0.5 to 3 mg/kg. Baseline levels of plasma Lp(a) were established via ELISA prior to dosing and plasma Lp(a) levels were measured at multiple intervals after dosing until the end of each study. Results: In primary human hepatocytes, potent, dose-dependent editing of up to &gt;80% was observed with CTX320. In NHPs, dose-dependent editing in the liver of ~10%, ~45%, and ~65% at the 0.5, 1.5, and 3 mg/kg doses, respectively, was observed after treatment with CTX320. Plasma Lp(a) levels were reduced by ~20%, ~80%, and ~90% from baseline in each of these respective groups. These reduced Lp(a) levels were attained by Day 15 and lasted for the duration of the study (Day 84). As is commonly observed with LNP delivery, transient elevation in liver enzymes was observed and resolved within 14 days without intervention. In a separate durability study in NHPs, a single infusion of CTX320 at 2 mg/kg led to significant and durable decreases in plasma Lp(a) levels. By Day 14, plasma Lp(a) levels had decreased by an average of 94% from baseline, which persisted through Day 224. The study is ongoing. Conclusion: CTX320 was well-tolerated in NHPs and resulted in high levels of editing in the liver that led to long-lasting reduction in plasma Lp(a). This data suggests CTX320 could be used to reduce plasma Lp(a) levels in humans.
Abstract 18901: Critical Role of Endothelial Injury in the Initiation of Aortic Dissection
Authors: Chen Zhang, Lin Zhang, Laxman Devkota, Yanming Li, Vela Deborah, Yang Li, Abhijit Chakraborty, Kimberly Rebello, Samantha Xu, Hernan G Vasquez, Ketankumar B Ghaghada, Scott A Lemaire, Ying H Shen
Journal: Circulation (2023)

Introduction: Endothelium forms a protective barrier and maintains vascular hemostasis. However, the role of endothelial injury in aortic aneurysms and dissections (AAD) remains poorly understood. Receptor-interacting protein kinase 3 (RIP3)-mediated necroptosis and gasdermin D (GSDMD)-mediated pyroptosis trigger necrotic cell death. We hypothesize endothelial cell (EC) death induced by necroptosis and pyroptosis contributes to AAD formation. Methods: Endothelial integrity and gene expression were examined in ascending aortic tissues from ascending thoracic aortic aneurysm (ATAA) patients (n=9) and organ donor controls (n=8) by single-cell transcriptome analysis. Effects of EC death on AAD formation were determined in EC-specific Rip3 knockout (EC-Rip3 -/- , n=26), EC-specific Gsdmd knockout (EC-Gsdmd -/- , n=21), and necroptosis/pyroptosis inhibitor necrosulfonamide (NSA) treated mice (n=15) in sporadic AAD models induced by angiotensin II (Ang II) infusion. Evans blue staining and nanoparticle-mediated contrast-enhanced CT (n-CECT) detected endothelial hyperpermeability Results: Single-cell transcriptome and immunostaining analyses revealed significant upregulation of pro-death genes (e.g., RIP3 and GSDMD), but downregulation of cell junction genes (e.g., TJP1 and GJA1) in ECs of ATAA patients compared with controls. In the mouse AAD model, endothelial injury and hyperpermeability were detected 2-5 days after Ang II infusion and were associated with intramural nanoparticle accumulation, elastic fiber fragmentation, and macrophage infiltration. Importantly, EC-Rip3 -/- mice and EC-Gsdmd -/- mice showed preserved EC barrier function, reduced nanoparticle accumulation and elastic fiber fragmentation, and reduced AAD incidence (including aneurysm, dissection, and rupture) compared to their littermate controls (EC-Rip3 -/- mice: 52% vs 23.1%, P=0.033; EC-Gsdmd -/- mice: 52.6% vs 14.3%, P=0.01). Blocking necroptosis/pyroptosis by NSA treatment reduced the incidence (65% vs 27%; P=0.04) and severity of AAD. Conclusions: Endothelial injury and subsequent barrier dysfunction and infiltration are key features of AAD formation. Prevention of EC necrotic cell death can be a potential AAD therapeutic target.
Abstract 17229: Atrioventricular Conduction System Changes During Transcatheter Aortic Valve Replacement (TAVR)
Authors: John-Ross D Clarke, Bharath Rathakrishnan, Marie-France Poulin, Roger J Laham, Beattie Ultimo, Kim Guibone, Duane S Pinto, Katherine Kiernan, Alexandra Medline, Alice Haouzi, Wally Omar, Mark Tuttle, Tyler Hardy, Jonathan W Waks, Alfred E Buxton
Journal: Circulation (2023)

Introduction: Transcatheter aortic valve replacement (TAVR) is complicated by atrioventricular (AV) conduction disturbance in 8-15% of cases. Prior studies have not utilized complete electrophysiology studies (EPS) with continuous recording during TAVR. We sought to better understand the potential utility of intraprocedural electrophysiologic study to identify patients at risk for developing high-grade AV conduction disturbances after TAVR. Hypothesis: Intraprocedural EPS has the potential to identify patients at risk of developing AV conduction block after TAVR. Methods: We conducted a prospective study of TAVR patients at BIDMC between 5/2021-3/2023, excluding those with pre-existing pacemakers/defibrillators. We performed EPS in the cath lab prior to and after valve replacement: atrial pacing to AV block, recording His bundle electrogram (HBE) and RV pacing to assess VA conduction. When possible we recorded the HBE continuously during valve implant. Results: We studied 400 consecutive patients. Forty-three patients (10.8%) received permanent pacemakers (PPMs). Patients receiving PPM had significantly longer post-HV intervals, greater change in HV interval as well as longer AV Wenckebach cycle length after valve replacement. There were no differences in pre-TAVR AV Wenckebach cycle length or VA conduction. Twenty patients (46.5% of all PPMs) were implanted for AV block post discharge, and after adjustment for age, gender, and baseline HV interval, the only predictor of need for post-discharge PPM was peri-TAVR change in HV interval with an adjusted OR of 1.19 per each 10 ms increase. Conclusions: In contrast to prior studies, we have found that EPS at the time of TAVR may have utility in predicting AV conduction disturbances. Larger increases in HV interval and AV block CL were associated with need for PPM. Measuring the peri-TAVR change in HV interval may be useful in predicting late AV block.
Abstract 16611: The Feasibility of Artificial Intelligence in Interpretation of the Treadmill Test
Authors: Yoo Ri Kim, Kihong Lee
Journal: Circulation (2023)

Introduction: The treadmill test (TMT) is commonly used as a screening test to identify myocardial ischemia. The sensitivity of the TMT in diagnosing obstructive CAD was approximately 50%, with a specificity of approximately 90%. However, the challenge with TMT is the variability in interpretation. Hypothesis: We aimed to develop an Artificial intelligence (AI) to interpret TMT. The primary endpoint was the accuracy comparison between the initial assessment (of AI or cardiologist) for obstructive CAD. Methods: Out of a total of 800 TMTs performed on adults for any clinical indications in 2018-2020, Of these, we used 500 as training data, 200 as validation data, and 100 as test data. A one-dimensional convolutional block was applied to each of the 12 leads of the TMT, and then all the leads were concatenated to apply a dense layer, which was then trained to predict the presence of obstructive coronary artery disease. This deep learning model was developed based on convolutional neural networks (CNNs) using TensorFlow (Google, Mountain View, CA, USA) and Keras packages based on the Python language. TMT were simultaneously interpreted by an AI algorithm or by the cardiologist. This assessment was subsequently reviewed by blinded interventional cardiologist who provided a final report of obstructive coronary artery disease (CAD) with coronary compute tomography. Results: The mean age was 58.1 (20-78) years, 68% were male, and 33% had obstructive coronary artery disease (≥70% stenosis in at least one vessel). The performance of AI was compared with that of conventional TMT. Accuracy of AI model was comparable to cardiologist (0.720 vs. 0.680, p =0.845) F1 score was also similar between AI and cardiologist (0.440 vs. 0.384. p =0.845) Conclusions: Artificial intelligence is comparable to a cardiologist in the initial interpretation of the treadmill test. These approaches might be applicable to data obtained from wearable electrocardiography technologies during exercise.
Abstract 18738: 3D Speckle Tracking Echocardiography in Radiation-Associated Cardiac Disease and Associated Mortality Outcomes
Authors: Joseph El Dahdah, Tahir Kafil, Larisa G Tereshchenko, Alaa Alashi, Susan Ospina, Samantha Xu, eoin donnellan, Shinya Unai, Grant W Reed, Samir R Kapadia, Brian P Griffin, Milind Y Desai
Journal: Circulation (2023)

Introduction: The 2D echocardiographic features of radiation-associated cardiac disease (RACD) are well-described including aorto-mitral curtain thickness. However, the 3D speckle tracking echocardiographic strain patterns and their predictive risk for all-cause mortality are not well known in RACD. Methods: We studied 441 patients with RACD (63.7 ± 13.4 y; 62.4% female) seen in our institution. Echocardiographic strain patterns of their initial echocardiograms were reviewed. 3D strain analysis using TOMTEC was performed for left ventricle (LV), right ventricle (RV), and left atrium (LA). Primary outcome was all-cause mortality. We constructed 3 Cox regression models: (1) unadjusted; (2) minimally adjusted for age and sex; (3) adjusted for 42 covariates including CV risk factors, cancer history, cardiac treatments, and cardiac function. Results: During a median 6.8 (95%CI 5.7-7.4) years follow-up, 245 patients died. In the unadjusted model, all LV, RV, and LA strain metrics (except for RV free wall strain) were significantly associated with all-cause death. After comprehensive adjustment for 42 covariates, the strain metrics (except for left atrial contraction strain) remained significantly associated with mortality. The strongest predictor for mortality was reduced LV GLS (HR 0.93, 95%CI 0.89-0.96; p &lt;0.001). Conclusions: Abnormal strain patterns in patients with RACD were associated with increased all-cause mortality independently from other known risk factors. Abnormal strain is a distinct feature of radiation-induced cardiac disease, possibly indicating the mechanism of radiation associated cardiac disease. (JED and TSK are first Co-authors)
Abstract 16374: Perm1 Regulates Mitochondrial Energetics Through O-Glcnacylation in Cardiomyocytes
Authors: KARTHI SREEDEVI, Amina James, Shreya Yedla, Sara Do, sumaita arowa, Riyan Shah, Breanna Goode, Sydney Bui, Katia Olmos, Alexey Zaitsev, Junco S Warren
Journal: Circulation (2023)

O-GlcNAcylation is a post-translational modification of proteins that plays an important role in cellular homeostasis and stress responses. Two enzymes regulate O-GlcNAcylation: O-GlcNAc transferase (OGT) that adds O-GlcNAc to proteins; O-GlcNAcase (OGA) that removes O-GlcNAc from proteins. While O-GlcNAcylation is necessary to respond to ischemia/reperfusion injury, chronic activation of O-GlcNAcylation in the heart has adverse effects, and excessive O-GlcNAcylation leads to the development of heart failure. However, there is currently no therapy for heart failure that targets O-GlcNAcylation. Perm1 is a striated muscle-specific regulator of mitochondrial bioenergetics. We previously demonstrated that Perm1-knockout mice exhibit reduced cardiac function and myocardial energy reserve, in association with excessive O-GlcNAcylation and upregulation of OGT. Here, we hypothesized that Perm1 maintains mitochondrial energetics by suppressing O-GlcNAcylation. We found that adenovirus-mediated overexpression of Perm1 in cardiomyocytes significantly decreased O-GlcNAcylation (Figure 1A-B) and increased the basal and maximal respiration and ATP production rates as compared with control in Cell Mito Stress Test using a Seahorse 96x flux analyzer (orange vs. green, Figure 1C-D). Furthermore, the increased levels of O-GlcNAcylated proteins (215% of control, p&lt;0.05) via silencing OGA (si-OGA) in cardiomyocytes significantly decreased the basal and maximal respiration capacity and ATP production rates as compared with control (green vs. purple, Figure 1C-D), all which were completely rescued by Perm1 overexpression (blue, Figure 1C-D). These results suggest that Perm1 positively regulates mitochondrial energetics, in part, via suppressing O-GlcNAcylation and that Perm1 might be a new therapeutic target of heart failure that maintains mitochondrial function through preventing excessive O-GlcNAcylation under pathological stress.
Abstract 16826: A Rare Case of an Emergent Third Valve in Valve Intervention
Authors: Sara Godil, Basharat AHMAD, Abdallah Masri, Cole Thompson, Mihail Paxos
Journal: Circulation (2023)

Introduction: Bioprosthetic valves are prone to structural degeneration due to an average lifetime of 10-15 years. Valve in Valve (VIV) TAVR has become an alternative to the high-risk surgical patients as the growing number of successful bioprosthetic valve placements and the deteriorations over time. Emergent VIV intervention effectiveness with prior multiple artificial valves is less studied. Hypothesis: We report a case of a 54-year-old male presenting with obstructive shock with history of substance abuse and bicuspid aortic valve status post bioprosthetic aortic valve with aortic root repair at age of 15(1983), aortic stenosis requiring repeat surgical bioprosthetic Aortic Valve Replacement (SAVR) (25 mm) at age 42(2011). Recalcitrant cardiogenic shock despite vasopressor. Emergent Heart catheterization showed mild coronary artery disease (CAD) and severe cardiomyopathy, Left Ventricle ejection Fraction 15-20%. Aortic valve Gradient was 80 mmHg. Transesophageal Echocardiography (TEE) ruled out endocarditis. Impella CP and Swan-Ganz catheter were placed for hemodynamic support and monitoring. Methods: The Heart Team approach was followed. Patient was at high risk of mortality and operative complications with redo sternotomy. He subsequently underwent valve in valve TAVR with self-expanding 26 mm valve. Prior surgical valve did not require fracturing post implantation. Results: Post Trans Aortic Valve Replacement (TAVR) the mean gradient on echocardiogram decreased to 10 mmHg and LVEF recovered to 55-60%. The patient was successfully weaned off Vaso-pressors and eventually discharged home. Conclusion: Most common cause of transcatheter bioprosthetic valve failure is stenosis from calcification and thrombosis. VIV TAVR in recent studies has proven to be safe with favorable outcomes. Our patient had already undergone two surgical valve interventions, presented with critical bioprosthetic valve stenosis requiring salvage TAVR for cardiogenic shock. After the Heart team approach, TAVR was opted as a more favorable option for the patient. Although, the life of a bioprosthetic valve results in multiple interventions but overall valve in Valve technique has been proven to provide expected results in emergent high-risk patients.
Abstract 15431: Barriers to Percutaneous Coronary Intervention in Sub Saharan Africa: A Call to Action
Authors: Ikponmwosa G Ebengho, Osaivbie E Irorere, Oseiwe 'Benjamin' B Eromosele, Judith O Ebengho
Journal: Circulation (2023)

Introduction: Myocardial infarction incidence is rising in Sub-Saharan Africa (SSA). Currently, 80% of the world cardiovascular disease mortality burden is by low- and middle-income countries. SSA countries have limited access to trained interventional cardiologists and medical centers where Percutaneous Coronary Intervention (PCI) is performed. Methods: In this review, Google Scholar and PubMed were used to search literature on PCI in SSA. Selection criteria were manuscripts published between 2013-2023, written in English language, and addressed the hurdles with PCI. Results: Between April 2010 and March 2019, patients presenting to a PCI-capable center in Abidjan, Côte d’Ivoire had a median delay of 20 hours from onset of symptoms to admission. This was 53.2 hours in Senegal, 4.35 days in Burkina-Faso, and 6.6 days in Tanzania, while it was between 2.3 to 3.6 hours in South Africa. In terms of availability of PCI-capable centers in East and Central Africa; Kenya, Ethiopia Tanzania, and Uganda 5, 3, 2, and 1 center (s) respectively. In West Africa; Nigeria, Senegal, Ghana, Côte d’Ivoire and Cameroon had 6, 4, 2, 1, and 1 center(s), respectively. The average cost of an uncomplicated PCI of a single vessel occlusion costs up to $3500 (R65,000/1,612,000). In SSA, due to limited access to medical insurance, the proportion of direct out-of-pocket payments in total health expenditure remains above 40%. Conclusions: Minimizing ST-elevation Myocardial Infarction care and PCI delay should be a public health priority, as it a matter of public health interest and global health equity. There is a need for research into understanding better ways to improve access to STEMI care in Africa.
Abstract 166: Novel Mechanism of Docosahexaenoic Acid Reducing Tissue Injury by Targeting Immune Cells and HMGB1 Release
Authors: Rishabh C Choudhary, Tai Yin, Muhammad Shoaib, Mitsuaki Nishikimi, Parmeshar S Singh, Lance B Becker, Junhwan Kim
Journal: Circulation (2023)

Introduction: Dysregulated immune blood cell response has been implicated in contributing to brain injury following cardiac arrest (CA). Specifically, increased plasma HMGB1 has emerged as a critical mediator of brain damage. However, the underlying mechanisms of the dysregulated immune response and increased HMGB1 after CA remains unclear. Moreover, limited efforts have been made to develop therapeutic interventions targeting this dysregulated immune response. Objective: To elucidate the pathologic immune response during early phase of post-resuscitation and explore this as a targeted therapeutic potential using LPC(22:6), a previously shown neuroprotective compound. Methods and Results: We examined changes in lymphocytes, neutrophils, and monocytes in blood samples obtained from human CA patients. Subsequently, we conducted a time course study in rat CA model to examine changes in these cell populations and investigate the mechanisms underlying the increased HMGB1 levels in post-CA blood with/without plasma supplementation of LPC(22:6). We observed an increase in lymphocytes and neutrophils within one-hour post-resuscitation in human patients and rats. In rats, the increased levels of lymphocytes and neutrophils were followed by an increase in plasma HMGB1 level and monocytes. We further, identified that HMGB1 was significantly upregulated in CD4-positive cells, indicating that T cell-released HMGB1 is the primary source for its elevation. Intriguingly, supplementation of LPC(22:6) prevented the overexpression of HMGB1 in CD4-positive cells, the increase in plasma HMGB1 levels, and the number of monocytes. These findings support the sequential events of dysregulated blood immune response initiated by lymphocyte activation, leading to increased HMGB1 levels and subsequent monocyte activation during early phase of resuscitation after CA. Thus, our results demonstrate the efficacy of LPC(22:6) in inhibiting the expression of HMGB1 in CD4-positive T cells, thereby mitigating this inflammatory cascade. Conclusion: These findings provide novel insights into the mechanisms underlying the dysregulated immune response after CA and highlight the therapeutic potential of targeting this immune response to improve brain function.
Abstract 14799: Temporal Trends and In-Hospital Outcomes of Patients Undergoing Leadless Pacemaker Placement: Highlights From National Inpatient Sample 2016-2020
Authors: Spandan Desai, Nicholas Roma, Bruce Ferraro, Kashyap Shah, Jovan Plamenac
Journal: Circulation (2023)

Introduction: Leadless pacemakers (LPM) were introduced to address rates of pocket and lead-related complications associated with transvenous pacemakers (TPM) and to improve clinical outcomes in those who may be at high risk for TPM placement. Limited data exists on in-hospital outcomes and temporal trends of LPM placement. Methods: National Inpatient Sample 2016-2020 was used to query pacemaker (PM) placements and these were grouped into LPM and TPM cases using appropriate ICD procedure codes. Logistic regression was used to compare baseline characteristics and in-hospital outcomes. Results: 740,240 PM placements were observed between 2016 and 2020, with 3.9% (29,015) LPM cases and 96.1% (711,225) TPM cases. As shown in Table 1, there was an increasing temporal trend in LPM placement from 2016 with an overall stable trend in TPM during the same time. The LPM group had a higher proportion of cases that underwent extraction of an old pacemaker (8.9% -vs- 6.9%, p=0.004). A majority of procedures in both groups were performed in the Southern United States and predominantly in large bedsize, urban teaching hospital systems. As shown in Table 2, LPM group had higher proportions of atrial fibrillation, CKD (stage 3 or greater), and ESRD. Length of stay (LOS, 9.7 -vs- 5.9 days) and overall mortality (5.0% -vs- 1.5%, p=0.001) were also higher in the LPM group. Conclusions: There has been a significant increase in LPM placement from 2016 through 2020 as seen with an increasing temporal trend. Use of LPM in medically complex cases or in cases that are high risk for TPM placement continues to increase. Further research needs to be performed to analyze long-term outcomes in this group.
Abstract 15882: Pulmonary Hypertension in Patients With ESRD and Arteriovenous Access Removal: A Necessary Evil?
Authors: Eric Warner, Douglas Corsi, Diana Jimenez, Yevgeniy Brailovsky, Estefania Oliveros, Rene Alvarez, Anju Bhardwaj, Indranee Rajapreyar
Journal: Circulation (2023)

Introduction: Pulmonary Hypertension (PH) is a common sequelae of arteriovenous fistulas (AVF) and grafts (AVG) due to the creation of shunt physiology and increased pulmonary blood flow. PH has been consistently associated with increased mortality but there is a paucity of data in regards to management. Methods: Using the United States Renal Data System, we identified all patients over age 18 initiated on dialysis from 2012-2019 who did not receive renal transplant. We identified a) predictors for the development of PH; b) analyzed survival for patients with PH who had their AVF or AVG removed. Results: We identified 478,896 patients initiated on dialysis from 2012-2019 of whom 27,787 (5.8%) had PH. The median age was 65 (IQR: 55-74) years and 59.1% were male. Reduced ejection fraction, any congestive heart failure, obstructive sleep apnea, and female sex were the strongest predictors of PH. AVG and AVF were also associated with an increased rate of PH relative to catheter-based dialysis (p&lt;0.001). Among patients with PH, the removal of AVF or AVG was associated with significantly improved survival (p&lt;0.001). Conclusions: Patients with AVA should be screened using echocardiography and those with PH should be strongly considered for AVA removal or revision.