tbuckley/cabot-search huggingface dataset:
Abstract 4137447: Length of WACA line Affects 1 <sup>st</sup> Pass Success rates in PVI
Authors: Elizabeth Belden, Caitlin Phalunas, Grace Bailey, Minesh Lathia, Amit Thosani, William Belden, Joshua Silverstein, George Shaw, Mati Friehling, Tharian Cherian, Chaojing Duan, Emerson Liu
Journal: Circulation (2024)

Background: Standard ablation for atrial fibrillation consists of wide antral pulmonary vein isolation, efficacy for which depends on a contiguous series of ablation lesions. The larger a circumference ablated around the pulmonary veins, the more challenging it may be to ensure durable isolation, due to technical and anatomic factors, which may in turn contribute to higher rates of atrial fibrillation (AF) recurrence. The relationship between WACA size and success rates may inform procedural methods and optimize outcomes. Objective: To examine the relationship between length of WACA lines and ablation success in patients that have undergone a PVI ablation. Methods: We performed a single-center, retrospective analysis of a consecutive series of 258 patients who underwent 1 st pulmonary vein isolation (PVI) for the treatment of atrial fibrillation, between 1/1/2022 and 6/30/2023. Radiofrequency ablation (RFA) was performed using 50 W with a contact-force sensing irrigated catheter. Information on acute 1 st pass success for left and right vein was recorded. The length of each WACA line was traced out manually, following the center of the ablated lesions. Follow up information consisted of AF recurrence at three, six, and twelve months. Student t-test was used for comparison of means and Chi-square test was used for categorical variables. Results: All veins were successfully isolated in all patients. WACA 1 st pass success rates were 87% in the left veins, and 83% in the right veins. Right WACA lines were generally longer. In patients with Left WACA 1 st pass success, the average length of the WACA line was 94.8cm, compared to 100.1cm in the group without 1 st pass success (p=0.025). In patients with right WACA 1 st pass success, the average length of the WACA line was 105.8cm, compared to 110.6cm in the group without 1 st pass success (p=0.07). When evaluating post PVI patients for recurrence of AF at 1year, there was a non-statistically significant association of AF recurrence with longer combined L+R WACA lines during index PVI (205.5cm vs 197.0cm, p=0.065). Conclusion: Longer WACA lines during index PVI are associated with failure of 1 st pass isolation. Further study is needed to address the mechanism by which longer WACA lines affect ablation efficacy, whether due to technical factors reflecting something intrinsic to underlying substrate.
Abstract 4135211: Children with the D801N Variant of the <i>ATP1A3-</i> Encoded Sodium-Potassium ATPase Alpha-3 Subunit Demonstrate Paradoxical QT Response to Bradycardia and Increased Ventricular Arrhythmia Risk
Authors: Meredith Srour, Minu-Tshyeto Bidzimou, Saige Mitchell, Padmapriya Muralidharan, Mary Moya-Mendez, Mohamad Mikati, Andrew Landstrom
Journal: Circulation (2024)

Introduction: Alternating hemiplegia of childhood (AHC) is a rare condition most frequently caused by mutations in ATP1A3, encoding for the alpha-3 subunit of Na + /K + -ATPase, and D801N is the most common variant. Individuals with ATP1A3-D801N have shorter corrected QT (QTc) than those with other variants and can experience ventricular arrhythmias following bradycardia; however, the mechanism of why this occurs is unknown. Goals: To analyze how QT and QTc change with heart rate in ATP1A3-D801N compared to healthy individuals. Hypothesis: Individuals with ATP1A3-D801N have increased shortening of QT and QTc at lower heart rate. Methods: In this retrospective observational study, patients seen for evaluation of AHC at Duke University Medical Center were categorized by genotype: ATP1A3-D801N, ATP1A3 non-D801N single nucleotide variant, ATP1A3 loss-of-function variant, and genotype negative. A cohort of matched healthy children was also compiled. We collected average heart rate, QT, and QTc measurements over 5-minute intervals from Holter recordings using HScribe TM software and conducted manual blinded validation to ensure accuracy. We then used linear regression to investigate the relationship between heart rate, QT, and QTc. Results: The cohort consisted of 44 patients with ATP1A3 -related phenotypes with 81 total Holter recordings (52.27% female; mean age at first Holter 8.04 years), compared to 36 healthy individuals with 57 total Holter recordings (52.78% female; mean age at first Holter 9.84 years). Patients with ATP1A3-D801N showed diminished prolongation of QT with decreasing heart rate, manifested as a reduced mean slope for heart rate vs QT compared to healthy (-0.85 ± 0.46 vs -1.52 ± 0.42, p&lt;0.0001). This blunted QT response resulted in paradoxical shortening of QTc at lower heart rate, demonstrated by an increased mean slope for heart rate vs QTc compared to healthy (0.80 ± 0.51 vs 0.22 ± 0.43, p&lt;0.0001). Further, patients with ATP1A3- related phenotypes and very short baseline QTc showed increased shortening of QT and QTc at lower heart rate compared to those with normal QTc (p=0.0025 and p=0.0013, respectively). Conclusions: Children with AHC and ATP1A3-D801N demonstrate a paradoxical shortening of QT and QTc with slowing of heart rate. The impaired prolongation of QT and resultant further shortening of QTc increase the risk of arrhythmia. We put this forward as a novel mechanism of sudden cardiac arrest in patients with ATP1A3 mutations.
Abstract 4134417: Cardiotoxicity Conundrum: Distinguishing Immune Checkpoint Inhibitor Myocarditis from Fluorouracil Cardiotoxicity in Concurrent Therapy
Authors: Vivian Hu, Ishan Naidu, Nausheen Singh, Oludamilola Akinmolayemi, GAGAN SAHNI
Journal: Circulation (2024)

Case Description: The patient is a 37-year-old male with metastatic gastroesophageal junction adenocarcinoma presenting with chest pain and dyspnea two days after initiation of leucovorin, fluorouracil, oxaliplatin (FOLFOX), and nivolumab therapy. He was tachycardic and hypotensive with elevated cardiac biomarkers and globally reduced left ventricular systolic function. Suspecting immune checkpoint inhibitor (ICI) myocarditis versus fluorouracil (5-FU) cardiotoxicity, he was treated simultaneously for both. After starting high-dose steroids and before uridine triacetate, he had improved symptoms, cardiac function, biomarkers, and invasive hemodynamics. Though his endomyocardial biopsy did not show inflammatory cell infiltrates, his CMR demonstrated increased T1 and T2 relaxation times consistent with myocarditis. Testing revealed normal dihydropyrimidine dehydrogenase (DPD) activity. He completed uridine triacetate and was discharged on a steroid taper. At follow-up, he remained clinically stable, tolerating oxaliplatin and docetaxel (FLOT) initiation and nivolumab rechallenge without 5-FU. Discussion: This case is challenging as the presentation does not conclusively identify a causative agent. The patient’s symptom severity suggests ICI myocarditis, while the early onset points to 5-FU cardiotoxicity. His quick recovery of cardiac function after medication cessation suggests 5-FU-associated Takotsubo cardiomyopathy. His improvement after steroids raises concern for an adverse immunologic response as in ICI myocarditis or idiosyncratic reactions to oxaliplatin with 5-FU. This patient received ICI therapy and chemotherapy, increasing his risk for cardiac immune-related adverse events. His protracted 5-FU infusion increased his risk for 5-FU cardiotoxicity, but his normal DPD activity mitigates this risk. Although his biopsy was negative, it cannot exclude ICI myocarditis. By the IC-OS 2021 consensus, he meets the criteria for ICI myocarditis presenting 48 hours after nivolumab exposure with cardiogenic shock, elevated cardiac biomarkers, decline in cardiac function, and CMR with elevated T1 and T2 relaxation times. Yet, his biomarkers remained normal with nivolumab rechallenge, arguing against ICI myocarditis and suggesting 5-FU as the culprit. Early recognition and differentiation of the culprit in concurrent therapies impact management and future treatment options. Rechallenge carries risk and requires interdisciplinary collaboration to ensure patient safety.
Abstract 4138019: eQTL Analysis of the PAH Biomarker CCN2 Identifies a Novel SNP that Associates with Survival
Authors: Carly Byrd, Raymond Benza, Amy Webb, Jennifer Schramm, Jun Yang, Megan Griffiths, Stephanie Brandal, Rachel Damico, Dhananjay Vaidya, Catherine Simpson, Todd Kolb, Michael Pauciulo, William Nichols, Dunbar Ivy, Paul Hassoun, Allen Everett, Eric Austin, Lisa Martin
Journal: Circulation (2024)

Background: We recently determined that cellular communication network factor 2 (CCN2) (also known as IGFBP8) levels associate with metrics of severity, and survival, in pulmonary arterial hypertension (PAH). While genetic variants that modify CCN2 gene expression have been described, the variants across the genome that associate with CCN2 protein levels in human circulation remain unknown. Research Question: We sought to identify genetic variants associated with circulating levels of CCN2 and to determine those variants’ relationship with clinical severity and survival. Methods: Serum CCN2 was measured by ELISA in subjects from a national sample repository, the PAH Biobank. A genome wide association study (GWAS) for CCN2 (natural log transformed) was performed in White idiopathic PAH (IPAH) PAH Biobank participants (n = 768) using Illumina OMNI5 genotypes in plink after standard quality control. Subsequent exploration of the SNP of interest was conducted in a separate dataset of 687 White PAH participants (n=360 IPAH, n=313 APAH) linked to genetic and clinical data, including REVEAL 2.0 risk score assessment (divided into low, medium, and high-risk levels) and outcomes (the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials cohort). Results: In the PAH Biobank, using GWAS, we found CCN2 levels were significantly associated with rs9493157 (p = 2.8 x10 -12 ) ( Figure A ). rs9493157 is reported in the Genotype-Tissue Expression (GTEx) portal to be an eQTL for CCN2 expression in the left ventricle. In the STRIDE cohort, the hazard ratio (HR) for death was 1.33 (99% CI 1.03 to 1.72) for participants with one or more T alleles (p=0.027; ( Figure B )). On multivariate analysis, the HR for death was 1.28 (95% CI 0.99 to 1.66; p=0.060). Among subjects with the highest REVEAL2.0 risk, those with a T allele had worse survival than those no T allele, with best survival among those with low a REVEAL2.0 score and no T allele. Conclusions: In White PAH subjects, rs9493157 associates with human levels of serum CCN2, a known biomarker for PAH. While additional studies are warranted, the T allele associates with worse survival and may enhance the prognostic value of the REVEAL2.0 risk score.
Abstract 4138014: Incidence and Association of Amyloidosis Found at Carpal Tunnel Release to Development of Cardiac Involvement
Authors: Matthew Santer, Seher Berzingi, Shahrier Amin, Brijesh Patel, Kevin Felpel, Marco Caccamo, George Sokos, Christopher Bianco
Journal: Circulation (2024)

Background: Carpal tunnel syndrome (CTS) associated with transthyretin cardiac amyloidosis (ATTR-CA) may manifest 5 to 10 years prior to cardiac diagnosis. Transthyretin amyloidosis (ATTR) identification in the tenosynovium isolated during carpal tunnel release (CTR) may facilitate earlier ATTR-CA diagnosis and treatment. Hypothesis: Amyloid discovered at CTR will be associated with, and/or serve as a precursor for, cardiac involvement. Aim: We aimed to determine the frequency and type of amyloid found at CTR as well as the incidence of cardiac involvement and/or treatment indication. Methods: A retrospective analysis was conducted on a convenience sample of adults undergoing CTR from 01/05/2021 to 03/24/2023. Biopsy specimens with confirmed amyloid via Congo red staining were analyzed using mass spectrometry (MS) for subtyping. Patients with amyloid in tenosynovial tissue were offered cardiac evaluation with history and physical, electrocardiogram, B-type natriuretic peptide, troponin-I HS, echocardiogram, and TcPYP nuclear scintigraphy. Patients with light-chain amyloidosis (AL) were referred to oncology, while patients with ATTR were offered genetic testing. Results: A total of 578 patients underwent CTR with tenosynovial sample excision. Amyloid involvement by Congo red staining was found in 43 patients (7.4%), with a definitive subtype confirmed by MS in 30 patients (5.2%). Samples were insufficient to define subtypes in 13 patients. Sole ATTR was found in 27 patients (4.7%), both AL and ATTR were found in 1 patient, and sole AL was found in 2 patients. Of the 28 ATTR patients (the patient with both ATTR and AL included), 24 pursued genetic testing, revealing all had wild-type ATTR. Of these 28 patients, 21 underwent cardiac evaluation, for which 2 had cardiac involvement on TcPYP and started tafamidis therapy. The patients with concomitant ATTR and AL or sole AL did not have evidence of cardiac involvement, however, chemotherapy was initiated as indicated. Unfortunately, 1 patient with AL on CTR did not pursue an evaluation. Conclusion: Incidental amyloid tissue found at CTR is common and associated with occult involvement warranting therapy in a minority of cases. Future cardiac involvement is unknown, and this cohort will be followed to determine future incidence. A startling number of patients were found to have occult systemic AL discovered at CTR. These incidental diagnoses may trigger lifesaving interventions, which may otherwise go undiagnosed.
Abstract 4135035: Liver kinase B1 (LKB1) loss links vascular smooth muscle cell fate switch to aortic aneurysm formation
Authors: Zhaohua Cai, Ganesh Satyanarayana, Fujie Zhao, Ben He, Ming-hui Zou
Journal: Circulation (2024)

Background: Acquisition and maintenance of vascular smooth muscle cell (VSMC) fate are important for vascular development and homeostasis; however, little is known about the key determinant for VSMC fate and vascular homeostasis. Methods: Lkb1 flox/flox ; Tagln- Cre, Lkb1 flox /flox ; Myh11-Cre/ERT2 , and lineage tracing Lkb1 flox/flox ; Myh11-Cre/ERT2 ; ROSA mT/mG mice were generated to study the impact of Lkb1 on VSMC and vascular function in vivo . Single aortic cells isolated from wild-type and Lkb1 flox/flox ; Myh11-Cre/ERT2 mice were analyzed by single-cell RNA sequencing (sc-RNA seq). The dynamic changes of vascular morphology and VSMC fate were investigated using high-frequency ultrasound and various histological techniques. In addition, VSMC phenotype and molecular mechanisms were further explored by mouse arterial ring assay ex vivo , in cultured human aortic VSMC in vitro, and in human aneurysmal aortic tissues. Results: We found that SMC-specific Lkb1 ablation in Lkb1 flox/flox ; Tagln-Cre mice caused severe vascular abnormalities and embryonic lethality. SMC-specific deletion of Lkb1 in tamoxifen-inducible Lkb1 flox/flox ; Myh11-Cre/ERT2 mice spontaneously and progressively induced aortic/arterial dilation, aneurysm, rupture, and premature death. Sc-RNA seq and imaging-based lineage tracing showed that Lkb1 -deficient VSMCs transdifferentiated gradually from early modulated VSMCs to fibroblast-like and chondrocyte-like cells, leading to ossification and blood-vessel rupture. Moreover, we found that SMC-specific Lkb1 ablation resulted in decreased vascular contractility and hypotension in vivo . Mechanistically, Lkb1 regulates polypyrimidine tract binding protein 1 (Ptbp1) expression and controls alternative splicing of pyruvate kinase muscle (PKM) isoforms 1 and 2. Lkb1 loss in VSMC results in an increased PKM2/PKM1 ratio and alters the metabolic profile by promoting aerobic glycolysis. Treatment with PKM2 activator TEPP-46 rescues VSMC transformation and aortic dilation in Lkb1 flox/flox ; Myh11-Cre/ERT2 mice. Furthermore, we found that Lkb1 expression decreased in human aortic aneurysm tissue compared to control tissue, along with changes in markers of VSMC fate. Conclusions: Lkb1, via its regulation of Ptbp1-dependent alterative splicing of PKM, maintains VSMC in contractile states and sustains vascular homeostasis. Our findings have important implications for understanding the pathogenesis of aortic aneurysm.
Abstract 4137770: Development of a User-Friendly Self-Screening Tool for Assessing Metabolic Syndrome Risk in young adults from economically challenged regions
Authors: Marcus Nascimento-Ferreira, Jacqueline Xavier, Shirley Cunha, Tiago Oliveira, Kliver Marin, Augusto Cesar De Moraes
Journal: Circulation (2024)

Background: Metabolic syndrome is a cluster of conditions that increase the risk of heart disease and diabetes. Early identification and management are crucial, particularly in economically challenged regions where access to healthcare may be limited. Research Questions/Hypothesis: User-friendly self-report data accurately predict metabolic outcomes. Aims: To develop and validate nomograms for individualized estimation of metabolic syndrome risk. Methods: Data from 521 college students (60.1% aged 17-20 years; 68.7% female; 28.0% white) were collected in 2022/2023 from two Brazilian cities. These cities are located in the country's poorest states, with Gini indices of 0.56 and 0.43. The potential predictors include demographic and economic variables, school-related factors, behaviors, and body weight. Based on predictors for abdominal obesity identified through multilevel logistic regression, we created a nomogram model. We performed the Hosmer-Lemeshow test to assess model calibration and used a bootstrapping approach (B = 150) for internal validation. To evaluate external validity, we assessed metabolic syndrome in a subset of 375 students. The area under the receiver operating characteristic curve (AUROC), with a threshold of 0.70, was used to evaluate the model's discrimination accuracy. Results: We identified 114 (23.0%) college students who were abdominally obese. We found ten variables associated with the primary outcome: age, biological sex, physical education facilities, enrollment in sports competition (during elementary school); grade retention, preferred subject, physical education classes per week; enrollment in sports training (during secondary school); adherence of 24-hour movement behaviors and body weight. The proposed nomogram showed acceptable performance in the AUROC (0.94 [95% CI: 0.92-0.96). The calibration assessment indicated reasonable consistency of our model (p &gt; 0.05). In the internal validation, we observed a decreased predictive capability (AUROC = 0.86). Conclusion: The 24h-MESYN risk score offers an effective self-screening tool for college students from diverse racial and ethnic backgrounds in economically challenged regions to assess their risk of developing metabolic syndrome.
Abstract 4137939: Mosaic loss of Y chromosome is associated with increased all-cause mortality in patients with ST-segment elevation myocardial infarction
Authors: Nan Li, Hongbing Yan
Journal: Circulation (2024)

Introduction: Mosaic loss of Y chromosome (LOY), a common subtype of somatic mosaicism, is characterized as loss of the entire Y chromosome in a mosaic manner and increases with age. Accumulating evidence has manifested the positive link between LOY and shorter life expectations in elderly men as well as common age-associated diseases, such as cancer and cardiovascular diseases. Experimental studies also demonstrated that hematopoietic LOY in mice induced cardiac fibrosis and led to increased mortality. However, little is known about LOY and prognosis of ST-segment elevation myocardial infarction (STEMI). Hypothesis: We hypothesized that LOY may be associated with lower survival rate of patients with STEMI. Aims: Investigating the impact of LOY in peripheral blood cells on prognosis of patients with STEMI. Methods: This study prospectively enrolled 928 males and 272 females undergoing primary percutaneous coronary intervention for STEMI. LOY was measured in 928 males using droplet digital polymerase chain reaction technique. Results: During a median follow-up of 3.99 years, 93 males (10.0%) and 45 females (16.5%) died. After adjusting for traditional cardiovascular risk factors, the risk of all-cause mortality in males with LOY ≥ 18% (the 90th percentile of LOY) increased to 2.45 (95% confidence intervals [CI]: 1.16–5.15, P = 0.018), 2.11 (95% CI: 1.11–4.01, P = 0.024), and 1.88 (95% CI: 1.02–3.45, P = 0.043) times during 1-, 2-, and 3-year follow-up, respectively, compared to males with LOY &lt; 18%. Among males without prior MI, those with LOY ≥ 18% had an increased risk of all-cause mortality compared to those with LOY &lt; 18% (adjusted hazard ratio 1.93, 95% CI: 1.01–3.67; P = 0.045); this was not observed for males with prior MI. Female patients had a 1.71-fold (95%CI: 1.04–2.81; P = 0.035) increased risk of all-cause mortality than males with LOY &lt; 18%, whereas the risk was similar to males with LOY ≥ 18%. Conclusion: LOY was associated with an increased risk of all-cause mortality in male STEMI patients, particularly in those without prior MI. Detecting LOY in STEMI patients could help further refine sex differences in prognosis and assist in identifying male patients with better prognoses.
Abstract 4137836: Association of AHA PREVENT Risk Score with Cardiovascular Mortality Across Social Determinants of Health: A Nationwide Retrospective Cohort Study
Authors: Daniel Stephens, Vibhu Parcha, Trevor McClure, Parker Cobbs, Megan Nordberg, Stephen Clarkson
Journal: Circulation (2024)

Introduction/Background: The AHA PREVENT risk calculator was recently developed to accurately predict the risk of cardiovascular disease (CVD) risk, including incident heart failure, stroke, and coronary heart disease. However, the risk prediction of this tool for CVD mortality overall and among groups with increasing social determinants of health (SDOH) burden in a multi-ethnic nationally representative cohort of American adults is unclear. Methods: This retrospective study included adult NHANES participants (age &gt; 30 years) from 1998-2018 cycles without known CVD. Individuals without data for risk estimation were excluded. AHA PREVENT risk was scored from 0 to 100. Multivariable-adjusted Cox regression models were used to estimate the risk of CVD mortality, accounting for 7 SDOH measures (employment, family income, food security, health access, health insurance, housing instability, and being married or living with partner). Population was stratified based on cumulative SDOH burden (1, 2, 3, 4, 5, &gt; 5 unfavorable SDOH markers). Model discrimination was assessed using C-statistics in these groups. Results: Among 19,887 participants (median age 53 years, 49% Female, 54% White, 19% Black), a 1% increase in AHA PREVENT Risk score calculation was associated with 13% higher risk of CVD mortality (HR adj 1.13, 95% CI: 1.12-1.14) with C-statistic of 0.91. While AHA PREVENT Risk score was predictive of CVD mortality across the SDOH burden strata, there was a decline in C-statistic from 0.91 among those without any unfavorable SDOH to 0.81 among those with &gt; 5 unfavorable SDOH measures. Conclusion: The AHA PREVENT Risk score is predictive of CVD mortality even when accounting for SDOH measures. However, the risk discrimination decreases among individuals with a higher SDOH burden. Further investigation is needed to identify means to improve CVD risk prediction among disadvantaged people with high unfavorable SDOH burden.