tbuckley/cabot-search huggingface dataset:
Abstract 339: Causes and Initial Cardiac Arrest Rhythms in a National Paediatric Cohort From Norway
Authors: Inga K Kelpanides, Stephan Katzenschlager, Eirik Skogvoll, Ingvild B Tjelmeland, Guro Grindheim, Kristin Alm-Kruse, John-Petter Liberg, Thomas Kristiansen, Jan Wnent, Jan-thorsten Grasner, Jo Kramer-Johansen
Journal: Circulation (2023)

Background: Mortality following paediatric out-of-hospital cardiac arrest (POHCA) is high. Registration of any resuscitation attempt is mandated by law in the Norwegian Cardiac Arrest Registry (NorCAR), providing an opportunity to study precipitating causes from a nationwide population perspective. Research questions and aims The study set out to investigate the precipitating causes and the presenting rhythms of OHCA in children; enabling a focused approach to prevention and treatment of cardiac arrest in children. Methods: NorCAR data for children aged 0-17 years was extracted for 2016-21. Cases of perinatal resuscitation and children not receiving ongoing cardiopulmonary resuscitation by ambulance personnel were excluded. Descriptive statistics were used to create age-stratified summaries for presumed causes of POCHA and presenting rhythms. Results: In total, 308 children were included. Presumed causes of cardiac arrest included choking (n=67), cardiac aetiology (n=55), respiratory failure (n=51), sudden infant death syndrome (n=51), and drowning (n=37). The presumed causes differed substantially according to age (Figure). Non-shockable rhythms dominated (87%, 250 of 287 with available rhythm data). The proportion of shockable rhythms increased with age to 15 % (19 of 127) in the 13-17 year age group. Conclusion: The causes of POHCA were diverse and highly age dependent. This knowledge may inform both parents and caretakers, health professionals, and the whole community with respect to effective prevention, proper first aid, and focused emergency medical treatment.
Abstract 17196: Genetic and Acquired DHCR7 Deficiency Upregulates 7β-hydroxycholesterol to Drive Endothelial Apoptosis and Pulmonary Hypertension
Authors: Rashmi J Rao, Hee-Jung Kim, Siyi Jiang, Yi-Yin Tai, Bing Wang, Ying Tang, Wadih El Khoury, Anna Kirillova, Yassmin Al Aaraj, Annie Watson, Ankit X Sharma, Jeffrey McDonald, Kevin Francis, Sriganesh Ramachandra Rao, Steven J Fliesler, Thomas Bertero, Wei Sun, Lloyd D Harvey, Stephen Y Chan
Journal: Circulation (2023)

Introduction: Pulmonary hypertension (PH) is a fatal disease without a cure, in which endothelial dysfunction drives pathologic remodeling of the pulmonary vasculature. Individuals with Smith-Lemli-Opitz syndrome (SLOS) develop PH, but the underlying mechanisms remain undefined. SLOS is an autosomal recessive disorder of cholesterol synthesis, resulting from loss-of-function mutations in 7-dehydrocholesterol reductase (DHCR7)-the terminal enzyme in the de novo synthesis of cholesterol- that leads to accumulation of 7-dehydrocholesterol (7-DHC) and cytotoxic oxysterol species. The role of DHCR7 in PH, however, is unknown. Hypothesis: Elevated cytotoxic oxysterols resulting from genetic or acquired DHCR7 deficiency promotes endothelial dysfunction and the development of PH. Methods &amp; Results: DHCR7 mRNA and protein expression was decreased in pulmonary artery endothelial cells (ECs) in cellular (P=0.0089), rodent, and human PH models, mirroring DHCR7 reduction in SLOS. Both genetic loss of DHCR7 and hypoxia promoted a global shutdown of de novo cholesterol synthesis, resulting in an accumulation of cholesterol intermediates and increased derivative oxysterols. Specifically, 7β-hydroxycholesterol (7β-HC) was elevated in DHCR7-deficient ECs (P&lt;0.0001), and 7β-HC drove endothelial apoptosis (P&lt;0.0001) via downregulation of insulin-like growth factor 1 (IGF1) in ECs (fold change=0.101 ± 0.034, FDR=6.65E-11). Conversely, overexpression of DHCR7 upregulated IGF1 expression (P&lt;0.0007), and IGF1 delivery reversed apoptosis (P&lt;0.0001). Correspondingly, ECs derived from SLOS patient stem cells with DHCR7 mutations (p.T93M/c.964-1G&gt;C) exhibited IGF1-dependent apoptosis. Finally, EC-specific DHCR7 deletion in chronically hypoxic mice induced more severe PH in vivo (right ventricular systolic pressure 36.4 mmHg vs. 30.8 mmHg, P&lt;0.0130). Conclusions: Resulting either from hypoxic or genetic causes, DHCR7 deficiency promoted EC apoptosis and PH via 7β-HC accumulation and subsequent IGF1 downregulation. Our work is the first to define an oxysterol-dependent mechanism underlying the link between genetic and acquired DHCR7 deficiency and PH.
Abstract 13055: Different Impact of Immunosuppressive Therapy on Disease Activity and Cardiac Outcome in Isolated Cardiac Sarcoidosis and Systemic Sarcoidosis
Authors: Tomoka Masunaga, Toru Hashimoto, Takeo Fujino, Kisho Ohtani, Yusuke Ishikawa, Keisuke Shinohara, Shouji Matsushima, Tomomi Ide, Yuzo Yamasaki, TAKURO ISODA, Shingo Baba, Kosei Ishigami, Hiroyuki Tsutsui, Shintaro Kinugawa
Journal: Circulation (2023)

Introduction: Sarcoidosis is a systemic granulomatous disease of unknown cause, and cardiac involvement impacts its prognosis. Isolated cardiac sarcoidosis (iCS) has increasingly been recognized; however, its prognosis and efficacy of immunosuppressive therapy remains undetermined. The aim of this study is to clarify the clinical features and outcomes of patients with iCS and systemic sarcoidosis including cardiac involvement (sCS) receiving immunosuppressive therapy. Methods and Results: We retrospectively reviewed the clinical data of 42 patients with sCS and 30 with iCS diagnosed at our institution between 2004 and 2022. We compared the characteristics, and the rate of adverse cardiac events including cardiac death, fatal ventricular tachyarrhythmia, and heart failure hospitalization between groups. The median follow-up duration was 1535 [630, 2555] days, without significant difference between groups. There were no significant differences in sex, NYHA class, and left ventricular ejection fraction between groups. Immunosuppressive agents were administered in 86% of sCS and in 73% of iCS. When analyzed only with patients receiving immunosuppressive therapy (sCS, n=36; iCS, n=21), the cardiac event-free survival was significantly lower in iCS patients than sCS patients (37% vs. 79%, p=0.002). Multivariate analysis showed that iCS was an independent determinant for predicting adverse cardiac events. We evaluated the disease activity in 26 sCS and 16 iCS patients by quantitative measures of FDG-PET including cardiac metabolic volume and total lesion glycolysis, representing accurate three-dimensional distribution and intensity of inflammation. Although iCS patients had lower baseline disease activity than sCS patients, immunosuppressive therapy did not attenuate disease activity in iCS patients in contrast to sCS. Conclusions: iCS showed poorer response to immunosuppressive therapy and worse cardiac prognosis than sCS.
Abstract 16465: Cardiovascular Disease Burden in the Middle East and North Africa Region
Authors: Laith Alhuneafat, Omar Al Taani, Tala Altarawneh, Adee Elhamdani, Abdallah Naser, Rand Al-Adayleh, Majd Al Ahmad, Fares Ghanem, Saed Alnaimat, ahmad jabri
Journal: Circulation (2023)

Introduction: Cardiovascular disease (CVD) remains the leading cause of death globally, including the Middle East and North Africa (MENA) region. However, limited research has been conducted on the burden of CVD in this region. Hypothesis: Our study aims to investigate the burden of CVD and related risk factors (RFs) in the MENA. Methods: We used data from the Global Burden of Disease (GBD) 2019 to examine CVD prevalence in 21 MENA countries. Prevalence, mortality, and incidence were analyzed using Bayesian regression tools, demographic methods, and mortality-to-incidence ratios. Disability-adjusted life years (DALYs) were calculated, and RFs were evaluated under the GBD's comparative risk assessment framework. Results: Between 1990 and 2019, CVD prevalence in the MENA increased by 140.9%, while age-standardized (AS) prevalence slightly decreased (-1.3%). CVD mortality rose by 78.3%, but AS death rates fell by 28.01%. Ischemic heart disease remained the most prevalent condition, with higher rates in men, while women had higher rates of CVA. All-age DALYs increased by 53.3%, but AS DALYs decreased by 32.54%. DALY rates varied across countries and were consistently higher in males. Leading RFs included HTN, high LDL, dietary risks, and elevated BMI. Conclusions: The ongoing impact of CVD in the MENA region necessitates targeted interventions that address country-specific variations, including socio-economic factors, healthcare infrastructure, and political stability. To effectively reduce the burden of CVD in MENA, it is crucial to focus on targeting risk factors and implementing effective strategies.
Abstract 15137: microRNA-132 Inhibition Improves Cardiac Function and Reduces Remodeling in Patients With Heart Failure With Reduced Ejection Fraction (HFrEF): An Exploratory Subgroup Analysis of the CDR132L First-in-Human Study
Authors: Jorg Taubel, Wilfried Hauke, Steffen Rump, Janika Viereck, Johann K Bauersachs, Scott Solomon, Thomas Thum
Journal: Circulation (2023)

Background: The CDR132L first-in-human (FiH) study examined safety, tolerability, pharmacokinetic, and exploratory pharmacodynamic effects of different ascending doses of the novel antisense oligonucleotide CDR132L targeting microRNA-132-3p (miR-132) in patients with stable heart failure (HF) of ischemic origin receiving standard-of-care (n=28). The study population was not stratified according to their left-ventricular ejection fraction (LVEF), and therefore heterogenous, but equally distributed among heart failure with reduced or preserved ejection fraction (HFrEF or HFpEF). Research question: In an exploratory post-hoc analysis of pharmacodynamic parameters we specifically focused on patients with HFrEF (with a LVEF&lt;45% at baseline, n=14) and, based on our predictive PK/PD modeling, categorized patients into ‘non-pharmacodynamically active’ (non-PD active; placebo and 0.32 mg/kg CDR132L group) and 'pharmacodynamically active' (PD active; patients receiving 1, 3, or 10 mg/kg CDR132L). Results: The PD active group showed a significant median reduction in NT-proBNP by 37.1% between baseline and study endpoint (day 112) while this HF biomarker was increased by 17.7% in the non-PD active group (p=0.0152, Mann-Whitney U test). CDR132L treatment provoked a trend towards 6.1% improvement in LVEF. For the non-PD active group only +1.4% were noted. An additional biomarker related to HF and cardiac fibrosis, lipocalin-2 (NGAL), tended to decrease in the PD active, but not in the non-PD active group. Conclusion: Analysis of the HFrEF subgroup in this FiH trial, although limited by the small patient numbers, indicatively underlines the encouraging benefits of CDR132L, a novel antisense drug, on LV function and cardiac remodeling as established in previous large animal HF models.
Abstract 12780: Impact of Target Vessel on the Procedural Techniques and Outcomes of Chronic Total Occlusion Percutaneous Coronary Intervention
Authors: Spyridon Kostantinis, Athanasios Rempakos, Bahadir Simsek, Judit A Karacsonyi, Salman S Allana, Michaella Alexandrou, Khaldoon Alaswad, Mir B Basir, Rhian Davies, Stewart Benton, Oleg Krestyaninov, Dmitrii Khelimskii, Wissam Jaber, Stephane Rinfret, William Nicholson, Jarrod Frizzell, Farouc A Jaffer, Jaikirshan Khatri, Paul Poommipanit, James Choi, Raj H Chandwaney, brian jefferson, Taral Patel, Karim M Al-azizi, Srini Potluri, Nazif Aygul, Ahmed M Elguindy, Nidal Abi Rafeh, OMER GOKTEKIN, Olga Mastrodemos, Bavana V Rangan, Yader Sandoval, M Nicholas Burke, Emmanouil S Brilakis, sevket gorgulu
Journal: Circulation (2023)

Introduction: There is limited information on the impact of the target vessel on the procedural techniques and outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI). Methods: We analyzed the baseline clinical and angiographic characteristics and procedural outcomes of 11,580 CTO PCIs performed between 2012 and 2022 at 44 centers. Results: The most common CTO target vessel was the right coronary artery (RCA) (53.1%) followed by the left anterior descending artery (LAD) (26.0%) and the left circumflex artery (LCX) (19.8%). RCA CTO lesions were longer and more complex with higher J-CTO score compared with LAD or LCX CTO lesions. Technical success was higher among LAD (88.8%) lesions when compared with RCA (85.7%) or LCX (85.8%) lesions (p&lt;0.001). The incidence of major adverse cardiovascular events (MACE) was overall 1.9% (n=220) and was similar among target vessels (p=0.916). There was a tendency towards more frequent utilization of the retrograde approach for more proximal occlusions in all three target vessels. When compared with all other RCA lesions combined, distal RCA lesions had higher technical success (87.7% vs. 85.3%; p=0.048). Technical success was similar between various locations of LAD CTOs (p=0.704). First/second/third obtuse marginal branch had lower technical success when compared with all other LCX lesion locations (82.7% vs. 86.8%; p=0.014). There was no association between MACE and CTO location in all three target vessels. Conclusions: LAD CTO PCIs had higher technical and procedural success rates among target vessels. The incidence of MACE was similar among target vessels, and also among various locations within the target vessel.
Abstract 15732: Chronic Mavacamten Treatment Has Opposing Effects on Contractility in Engineered Heart Tissue Models of Severe vs. Mild Hypertrophic Cardiomyopathy
Authors: Willem J De Lange, Angeela Gauchan, Natalie A Nelson, Emily T Farrell, John C Ralphe
Journal: Circulation (2023)

Many hypertrophic cardiomyopathy (HCM) causing mutations result in myocardial hypercontractility by increasing the number of myosin crossbridges in the disordered relaxed (DRX) state, or by sensitizing the sarcomere to the effects of Ca 2+ . Mavacamten (Mava) recently became the first FDA-approved treatment of obstructive HCM that directly targets hypercontractility by reducing the number of DRX cross bridges. Mava improves outcomes in patients with obstructive HCM but has not been approved in children or adults without obstructive HCM. The efficacy of chronic Mava treatment at preventing phenotype development in asymptomatic HCM mutation carriers remains largely unexplored. We recently showed that ablation of cardiac myosin binding protein-C (cMyBP-C -/-) in engineered heart tissue (EHT) causes rapid phenotype development in a dish. Initial hypercontractility progresses to hypocontractility with impaired relaxation, mediated by Ca 2+ mishandling. Here we investigate whether chronic Mava administration prevents phenotype progression. cMyBP-C +/+, +/- and -/- EHT were treated with 100nM Mava starting on day 7 of EHT culture. Serial twitch force (TF) measurements were performed weekly for 5 weeks, using the Mantarray platform. At day 7, prior to Mava treatment, +/- and -/- produced significantly more TF than +/+ EHT (392 ± 9 μN vs. 390 ± 15 μN vs. 199 ± 13 μN). At day 14, Mava treatment reduced TF by 31% (p &lt; 0.001) in +/+ EHT, 30% (p &lt; 0.001) in +/- EHT and 12% (p = 0.115) in -/- EHT. After an additional 4 weeks, chronic Mava treatment reduced TF by 54% (p &lt; 0.001) in +/+ EHT, 65% (p &lt; 0.001) in +/- EHT but increased TF by 23% (p = 0.034) in -/- EHT.These data show that chronic Mava treatment prevents/slows maladaptive remodeling in -/- EHT, but depresses contractility in +/+ and +/- ECT, suggesting that chronic Mava treatment may be detrimental to patients with mild HCM. Our ongoing studies are assessing the effect of chronic Mava treatment on other EHT models of HCM and on Ca 2+ -handling.
Abstract 15845: Unraveling Postoperative Atrial Fibrillation at the Single-Cell Level
Authors: Sameeksha Tiwari, Daniel DeLaughter, Azam Yazdani, Joshua Gorham, Sary Aranki, Lorenzo pesce, Christine E Seidman, Jonathan G Seidman, Barbara Stranger, Danny J Muehlschlegel
Journal: Circulation (2023)

Background: Postoperative atrial fibrillation (poAF) is one of the most common complications after cardiac surgery. It increases the length of stay in the ICU and hospital, increases the risk of stroke, and leads to death. Several clinical factors, including age, obesity, and co-occurring conditions such as prior atrial fibrillation, hypertension, kidney disease, etc., are associated with poAF. We hypothesize that the atrial transcriptome differs between patients who remain in sinus rhythm following surgery and those who develop poAF, allowing the identification of genes, pathways, and cell types necessary for the understanding and treatment of poAF. Methods: Single-cell RNA sequencing (scRNA-seq) was performed to gain insights into the heterogeneous cell populations of the left atrium. It provided an in-depth view of the variability in the cellular response to poAF through the molecular changes within cells, allowing for identifying biomarkers and therapeutic targets. Changes in gene expression associated with poAF were modeled, including batch, sex, age, atrial size, and history of atrial fibrillation and covariates. Results: sc-RNA-seq data of thirty-one human left atrium samples were analyzed. The samples included 14 females and 17 males aged 35-86 years. Cell clusters were identified after the quality check, preprocessing, and normalization. Nine distinct cell types were identified, including atrial cardiomyocytes, fibroblasts, endothelial cells, smooth muscle cells, adipocytes, pericytes, myeloid, lymphoid, and neuronal cells. The atrial cardiomyocytes and fibroblasts were the most abundant identified cell types. The enrichment of these cell types and significant changes in many marker genes in the disease condition suggest their crucial role in their response to the disease. Conclusion: The comprehensive analysis revealed distinct gene expression patterns and cellular heterogeneity. It provided valuable insights into the cellular landscape and transcriptional alterations in poAF. By shedding light on the molecular mechanisms, the findings pave the way for developing targeted interventions to mitigate the impact of poAF.
Abstract 17450: Sex Influences the Gut-Lung Microbiome Composition in Schistosomiasis-Associated Pulmonary Arterial Hypertension
Authors: Ygor MarinhoFerreirados Santos, Omar Loya, Jun Sun, Suellen Darc D Oliveira
Journal: Circulation (2023)

Introduction: Pulmonary arterial hypertension (PAH) is an uncurable cardiopulmonary disease highly incident in women. Infection by the intravascular parasite Schistosoma mansoni recapitulates several aspects of widespread inflammation that leads to PAH (Sch-PAH). Our data indicate that after infection, the S. mansoni eggs translocate within the cardiopulmonary system, disturbing gut-lung microbiome and leading to severe PAH. Hypotheses: S. mansoni eggs disturb the lung microbiome, contributing to vascular inflammation and PAH in a sex-dependent manner. Methods: To test this hypothesis, we induced Sch-PAH in end-Scl.creERT2;Rosamt/mg mice by intraperitoneal sensibilization with 240 eggs/gram body weight (bw; 2 weeks) followed by intravenous injection of 175 eggs/gram bw. After 7 days, we analyzed the Right Ventricular Systolic Pressure and hypertrophy (RVSP; RVH). Lung sections were used for TUNEL stain and for microbiome analysis by shotgun metagenomics. Results: Metagenomic analysis revealed that S. mansoni egg infection disrupted the lung microbiome reducing α-diversity compared to controls. Infection also reduced the Phylum Ascomycota in the lungs, whereas the ratio Firmicutes:Bacteroidetes (F/B) remained similar between groups. No difference was observed in the Simpson and Chao index. In the guts, the infection did not alter the α-diversity or the relative abundance of Deferribacteres and Proteobacteria, but it significantly increased the ratio F/B, indicative of gut dysbiosis. In terms of sex, our preliminary data indicated female mice exhibit a lower lung α-diversity compared to male mice, characterized by a significant reduction in the Firmicutes Phylum (Mean reads: 0.013 and 0.119, respectively; reads normalized by Readcount with Children). Principal coordinate analysis identified a distance in the clustering pattern between sexes, which may account for microbiome differences in Sch-PAH. Finally, our data revealed increased RVH and presence of microvascular apoptosis in female compared to male group. Conclusion: Understanding whether the disrupted gut and lung microbiome composition contributes to the onset and progression of Sch-PAH in a sex-dependent manner opens a novel therapeutic direction.
Abstract 17665: School Electrocardiography Screening Program Prompts the Detection of Otherwise Unrecognized Atrial Septal Defect in Children in Japan
Authors: Noriko Yodoya, Hirofumi Sawada, Yoshihide Mitani, Hiroyuki Ohashi, NAOKI TSUBOYA, Kazunobu Ohya, Mami Takeoka, Masahiro Hirayama
Journal: Circulation (2023)

Background: Atrial septal defect (ASD) is a congenital heart disease that often presents without symptoms or murmurs. If left untreated, children with ASD can develop comorbidities in adulthood. In Japan, school electrocardiography (ECG) screening has been implemented for all 1st, 7th, and 10th graders. However, the impact of this program in detecting children with ASD is unknown. Hypothesis: School ECG screening program prompts the detection of otherwise unrecognized ASD in children in Japan. Methods: This is a retrospective study that analyzed consecutive patients with ASD who underwent catheterization for surgical or catheter closure at ≤18 years of age during 2009-2019 at a tertiary referral center in Japan. Results: Of the overall 116 patients with ASD (median age of 3.0 years at diagnosis and 8.9 years at catheterization), 43 (37%) were prompted by the ECG screening (Screening group), while the remaining 73 (63%) were by other findings (Non-screening group). Of the 49 patients diagnosed at ≥6 years of age, 43 (88%) were prompted by the ECG screening, with the 3 corresponding peaks of the number of patients at diagnosis. Compared with the non-screening group, the screening group exhibited similar levels of hemodynamic parameters but had a lower proportion of audible heart murmur (Levine 2/6 or higher) and coexisting diseases at catheterizarion (p=0.016), which were mainly prompted by the health care and health checkups in infancy or preschool period. Patients positive for a composite parameter (iRBBB, inverted T in V4, or ST depression in the aVF lead) accounted for 79% of the screening group at catheterization, each of which was correlated with hemodynamic parameters in the overall patients (p&lt;.05). Conclusions: The present study showed that school ECG screening detected otherwise unrecognized ASD, which prompted the diagnosis of the majority of patients at school age and &gt; one-third of overall patients in Japan. These findings suggest that ECG screening program could be valuable for detecting hemodynamically significant ASD in students, who are asymptomatic and murmurless.