tbuckley/cabot-search huggingface dataset:
Abstract 17104: Characterization of a Novel, Clinically Relevant Mouse Model of Peripartum Cardiomyopathy
Authors: Veronica Andre, Anthony W Ashton
Journal: Circulation (2023)

Pregnancy requires significantly increased cardiac output (~30%) achieved through peripheral vasodilation and increased stroke volume, due to increased end-diastolic volume. Most women resolve these physiological changes within 6 months of delivery; however, some women progress to heart failure late in pregnancy or in the immediate post-partum period. Peri-partum cardiomyopathy (PPCM) is a rare condition of largely unknown etiology which, at its most-severe and life-threatening, requires cardiac transplantation. Pre-eclampsia occurs at much higher rates in the PPCM population (~40%) compared with the generally pregnant population (~2-5%). We have previously shown that transgenic mice expressing the human-specific isoform of the TBXA2R gene (TPβ) spontaneously develop pre-eclampsia accompanied by all the associated hallmarks expected from the human disease. We now show TPβ transgenic (TPβ-Tg) mice are a model of PPCM. Using trans-thoracic echocardiographic imaging, TPβ-Tg mice had no basal phenotype; however, unlike C57/Bl6J (WT) mice that resolved the pregnancy-induced cardiac remodeling, TPβ-Tg mice had exaggerated cardiac dilatation at term (E18.5; P&lt;0.01) which increased in severity over the subsequent 6 months (P&lt;0.005). In addition, TP-Tg mice exhibited reduced ejection fraction (22±13% vs 67% in WT), significant LV wall thinning (1.12±0.16 mm vs 1.6±0.17 mm WT), and loss of LV mass (66.55±9 mg vs 95±11mg WT). Analysis of myocardium of human PPCM patients undergoing heart transplant (n=12) compared to healthy myocardium from non-diseased donors (n=42) by RT-PCR and IHC showed highly expressed TPβ in PPCM patients. In human PPCM samples, there was a significant (p&lt;0.01) dysregulation of genes associated with circadian rhythm as determined by RNAseq analysis. Quantitative PCR analysis of hearts from non-pregnant (WT=8; TPβ-Tg=4) and pregnant (WT=10; TPβ-Tg=13) mice found similar dysregulation of multiple genes associated with circadian rhythm compared to WT mice (p&lt;0.01). This indicates that PPCM may be associated with failure to terminate CLOCK signaling as a result of TPβ activation. Our results support dysregulation of TBXA2R splicing as part of the pathogenesis of PPCM and identify new therapeutic targets for this condition.
Abstract 16351: Reference Equations for Pulmonary Artery Size and Pulsatility Using Echocardiography in Pulmonary Arterial Hypertension
Authors: shadi P bagherzadeh, Bettia Celestin, Everton Santana, Michael Salerno, Roham Zamanian, Francois Haddad
Journal: Circulation (2023)

Background: A main pulmonary artery (MPA) diameter&gt;25 mm on echocardiography is supportive of the diagnosis of pulmonary hypertension according to the most recent European Society of Cardiology guideline. [1]. The size of the pulmonary artery may however vary according to body size, age and sex and these considerations may be important for diagnostic purposes. Objectives: (1) to derive reference equations for MPA and right pulmonary artery (RPA) size on echocardiography that consider the effect of body size, age and sex; (2) to determine which measure of PA size better classifies pulmonary arterial hypertension (PAH) when compared to controls. Method: 248 healthy males and females were recruited as part of Stanford aging study and 200 patients with PAH have been retrospectively included from the Stanford Adult PH Program. The diameters of the MPA and RPA were measured from the parasternal short axis. The RPA diameter, area, and pulsatility index were measured from the supra sternal notch view. MedCalc Version 20.2018 statistical software program was used for modeling and assessing the variance function. Results: Multivariate regression analysis was used to derive PA size reference equations that consider sex, age, and height. Age retained in all the models and height was the second most influential variable. Using a Z score threshold of 1.96, for the diastolic MPA diameter size yielded an area under the ROC curve (AUC) of 0.91, 87.15% sensitivity and 95.19% specificity to detect PAH. In comparison, the AUC for absolute MPA size &gt;25 mm during diastole and systole yields 0.87 and 0.67, respectively which was significantly different from the z score AUC (Figure-1). Conclusion: Our study develops echocardiography reference equations for PA size accounting for the influence of age, height, and sex that can potentially refine PAH diagnostic algorithms if further validated.
Abstract 14488: Male Predominant Cardiac Phenotype in Cardiac-Specific Gpd1-l Knockout Mice
Authors: Haider Mehdi, Alexander Greiner, Jason Dierdorff, Jin-Young Yoon, Kyle Current, William J Kutschke, Diana Colgan, Barry London
Journal: Circulation (2023)

Introduction: We reported that a mutation in Glycerol-3-Phosphdate Dehydrogenase-1 Like (GPD1L-A280V) is linked to Brugada Syndrome (BrS). This mutation increases acetylation and reduces surface expression of Nav1.5, and reduces inward Na+ current (INa) in HEK293 cells and rat neonatal cardiac myocytes. Global homozygous knockout of Gpd1-l in mice (Gpd1l-/-) was usually lethal, though we noted increased Nav1.5 acetylation, decreased INa, and pharmacologically inducible arrhythmias in Gpd1l+/- heterozygotes. Cardiac-specific deletion of Gpd1l (cGpd1l-/-) led to ventricular arrhythmias, contractile dysfunction, and a BrS-like ECG phenotype in males. Here, we extend our study to female cGpd1l-/- mice. Methods: cGpd1l -/- mice were generated by crossing floxed (Gpd1l fl/fl ) mice with αMHC-Cre expressing mice. ECGs and echocardiograms (echos) were recorded at 6 and 9 months of age in cGpd1l -/- mice and Gpd1l fl/fl littermate controls. Results: At 9 months of age, male cGpd1l-/- mice compared to Gpd1lfl/fl controls had increased end diastolic and end systolic volumes (EDV, 108±67 vs 27±3 μL, p=0.02; ESV; 80±66 vs 6±2 μL; p=0.03), and markedly reduced ejection fractions (EF, 33±18% vs. 77±7%, p=0.001). Female cGpd1l-/- mice, on the other hand, had no changes to EDV, ESV, or EF (Figure A). The echo changes in male mice were minimal at 6 months. ECG recordings of ~9-month-old cGpd1l-/- male mice compared to Gpd1lfl/fl controls showed prolonged PR interval (52±1.1 vs. 40±2.7 ms; p=0.05) and QRS duration (17.8±1.5 vs. 15.2±1.1 ms; p=0.01) with no change in heart rate (Figure B). ECG parameters were also unchanged in cGpd1l-/- female mice. Conclusions: Cardiac-specific disruption of Gpd1l causes ventricular dysfunction, conduction abnormalities and arrhythmias in male but not female mice. Further investigation into the mechanisms underlying the sex-dependent phenotype of Gpd1l-/-mice and whether this impacts the male predominance of BrS in humans is warranted.
Abstract 17521: Esmolol-Associated Skin Necrosis: An Uncommon Adverse Reaction
Authors: Ekendilichukwu Nnadi, Nazima Khatun, Scherly Leon, Suzette Graham-Hill
Journal: Circulation (2023)

Background: We report a case of a patient admitted to the cardiac care unit for evaluation of a non-ST-elevation myocardial infarction (NSTEMI) in the setting of atrial flutter (2:1) who developed a bullae and skin necrosis secondary to esmolol infusion. Case presentation: A 48-year-old male with a past medical history of hypertension presented with exertional chest pain with associated shortness of breath and palpitations and was being evaluated for NSTEMI. Vitals were significant for blood pressure of 191/115 and heart rate of 125. Labs were significant for troponin I of 33.16 (&lt;=0.15 ng/mL), which peaked at 38.24, and creatinine of 2.5. Electrocardiogram demonstrated atrial flutter 2:1 conduction with a rapid ventricular response. While in the cardiac critical unit, he was placed on an esmolol drip for rate control. Twenty-four hours after administration of the esmolol through a peripheral intravenous line (PIV), the patient began to feel pain with moderate edema around the site of the injection. The PIV was removed, and cold compresses were applied. Approximately 5-7 hours later, the patient developed multiple ring-like bullae around the injection site. Physical examination was noted for cold and tenderness to palpation with paresthesias. General surgery was consulted for compartment syndrome, which was ruled out. The cutaneous changes progressively worsened through admission, persisting in size and appearance with rupture and ulceration, and necrosis one week later (see image 1). Conclusion: Although rare, esmolol can lead to skin necrosis and early identification is necessary for appropriate intervention including cessation of the culprit agent.
Abstract 13600: LDL Levels and Lipid Lowering Management Across Age Groups in Mexican Population. Analysis From the Mexican Registry of Cardiovascular Diseases (REMECAR)
Authors: Manuel O De Los Rios, Jose L Leiva-Pons, Marco A Alcocer Gamba, Jorge Cortes Lawrenz, Ricalde Alejandro, Luis R Virgen-Carrillo, Abel A Pavia-Lopez, Leslie M Lugo-Gavidia
Journal: Circulation (2023)

Background and Aims: Age is a major determinant of cardiovascular (CV) risk. While younger people are more likely to have lower CV risk they may have other risk factors that can impact the long-term development of cardiovascular disease. Among them, dyslipidemia has a crucial role in the development of atherosclerotic disease (ASCVD). Objective: This analysis aimed to compare LDL levels and lipid lowering management in patients with dyslipidemia across different age groups Methods: The REMECAR registry is a prospective, multicentre, observational study of patients attending to outpatient cardiovascular clinics for diagnostic, and clinical management of cardiometabolic diseases. Patients were classified according to their age group. Results: A total of 6,138 patients with a previous diagnosis of dyslipidemia were included in the analysis. The prevalence of ASCVD and comorbidities progressively increased with older age, while younger patients presented higher proportions of modifiable risk factors (Alcohol consumption, Smoking). Younger patients had significantly higher cholesterol, LDL-c, and triglycerides levels compared with groups &gt;60 years (Figure 1A). Most of the patients &lt;40 did not have any established lipid-lowering therapy (73.4%). This same group also showed higher proportions of patients with LDL&gt;190mg/dL (6.3%) and with triglycerides&gt;500mg/dL (4.8%). Low/Moderate Statin was the most frequent treatment, high-intensity statins were used in less than 20% of all groups despite the increasing prevalence of ASCVD (Figure 1B). Conclusions: A stepwise therapy escalation is reasonable in young patients, as the risk of CV events is not immediately perceived. However, this also prolongs long-term exposure if proper management is not established on time, leading to the progression of the disease. Our results underline the urgent need to improve population awareness, proper follow-up, and optimization of lipid-lowering management.
Abstract 17686: Safety and Efficacy of Drug-Eluting Stents for Patients at High Risk of Bleedings: A Network Meta-Analysis
Authors: Federico Giacobbe, Eduardo Valente, Marco Nebiolo, arianna morena, Giuseppe Giannino, Lucrezia Falorni, Mattia Troncone, Ludovica Carmagnola, Emanuele Ravetti, umberto di vita, Ovidio De Filippo, Francesco Bruno, Fabrizio D'Ascenzo, Gaetano Maria De Ferrari
Journal: Circulation (2023)

Introduction: Among different coronary stents implanted in High Bleeding Risk (HBR) patients with an indication for short antiplatelet therapy, no comparisons in terms of efficacy have been provided. Methods: A Network Meta Analysis was performed including all Randomized Controlled Trials comparing different coronary stents evaluated in HBR patients. Major Adverse Cardiovascular Events (MACEs) as defined by each included trial were the primary end point, whereas TLR (target lesion revascularization), TVR (target vessel revascularization), stent thrombosis and total and major (BARC3-5) bleedings were the secondary ones. Results: A total of 4 studies (ONYX ONE, LEADERS FREE, SENIOR and HBR in BIO-RESORT) including 6637 patients were analyzed with different kind of stents and DAPT length (1 or 6 months) on 12 months follow-up. About one third of these patients were defined HBR due to indication for oral anticoagulation. All Drug Eluting Stents (DESs) reduced risk of MACE compared to Bare Metal Stents (BMSs) when followed by a 1-month DAPT. At SUCRA analysis, Orsiro was the device with the highest probability of performing best. Rates of TLR and TVR were significantly lower when using Resolute Onyx, Synergy and BioFreedom stents in comparison to BMS when followed by 1-month DAPT, with Synergy ranking best. Synergy also showed a significantly lower number of stent thrombosis compared to BMS (RR 0.28, 95%CI 0.06-0.93), while Orsiro and Resolute Integrity showed the highest probability of performing best. Conclusion: In HBRs patients, all DESs were superior to BMSs in terms of efficacy and safety. Among DESs, Orsiro was the one with the highest ranking in terms of MACE, mainly driven by a reduced incidence of repeated revascularization and stent thrombosis
Abstract 13928: Targeted Atrial Inhibition of Galphaq Signaling With Inhibitory Peptides Attenuates Fibrosis and Inducibility of Atrial Fibrillation in a Canine Heart Failure Model
Authors: Anna Pfenniger, David Johnson, Wenwei Zhang, Justin Ng, Julia Swanson, Aleksei Mikhailov, Shin Yoo, William Marszalec, Rod S Passman, Bradley P Knight, Rishi Arora
Journal: Circulation (2023)

Introduction: Endothelial dysfunction, a hallmark of heart failure (HF), is closely associated with atrial fibrillation (AF). However, the precise role of endothelial dysfunction in creating an atrial arrhythmogenic substrate is unknown. Endothelin-1 (ET-1) and its downstream Gα q signaling are significantly upregulated in the atria of patients with HF. We therefore hypothesized that ET-1-Gα q signaling contributes to adverse structural remodeling in the atria in the setting of HF. Hypothesis: Inhibition of atrial ET-1-Gα q signaling with Gα q inhibitory peptides (Gα q -ct) will attenuate the development of atrial fibrosis and AF inducibility in a HF model. Methods: Plasmids expressing Gα q -ct were injected and electroporated in the left atria of 4 dogs. LacZ or scrambled plasmids were used in 8 control dogs. HF was induced by ventricular tachypacing (VTP) at 240 bpm for 3 weeks. At terminal EP study, left atrial conduction vectors were recorded with high-density mapping and AF inducibility assessed. Left atrial fibrosis was quantified by Masson Trichrome. Results: All animals developed clinical HF (prolonged capillary refill time, ascites, reduced activity level) and LV systolic dysfunction by echocardiogram (LVEF 17.5±8.3% in Gα q -ct, 13.7±3.1% in controls, p=0.55). Conduction inhomogeneity was reduced in Gα q -ct animals (example of posterior left atrium recordings in Fig. A). AF was less inducible in Gα q -ct than control animals (4.8% of pacing attempts Vs 17.8%, p&lt;0.001, Fig. B) and AF episodes were shorter (5.6±0.9 sec Vs 63.8±11.9 sec). Left atrial fibrosis was significantly attenuated in Gα q -ct animals Vs controls (Fig. C). Conclusions: Gα q signaling contributes to atrial fibrosis and subsequent AF susceptibility in VTP-induced HF, thereby highlighting an important role for ET-1 signaling in HF-related atrial remodeling. Future optimization of gene therapy targeting ET-1 signaling may lead to novel, mechanism-guided treatments for AF in the context of HF.
Abstract 16188: Fibrosis-4 Index in the Evaluation of Non-Ischemic Myocardial Injury in the Emergency Department
Authors: Michele Golino, matteo morello, Federico Blasi, Carlo A Oliva, Martina Zappa, Fabio Angeli, Roberto De Ponti
Journal: Circulation (2023)

Introduction: Fibrosis-4 (FIB-4) is a recognized score of liver fibrosis that is associated with ischemic heart disease and cardiac death. The relationship between FIB-4 index and non-ischemic myocardial injury (ni-MI) has not yet been investigated. Hypothesis: There is an association between FIB-4 index and ni-MI in patients admitted to an emergency department (ED). Methods: This retrospective study included consecutive patients presenting at the ED within a six months’ timeframe, with at least one high-sensitivity cardiac troponin T (hs-cTnT) value and without acute coronary syndromes diagnosis. The cohort with ni-MI was compared with the group with normal hs-cTnT values (control group, CG). FIB-4 index was calculated by: {age [years]хAST [U/L]/ [platelet count (10 9 /L)хALT (U/L) 1/2 ]}. Results: A total of 3,853 patients were enrolled, 1,950 (51%) males, 64 [48-78] years, 1,372 (35.6%) with ni-MI. FIB-4 index was higher in the cohort with ni-MI compared to the CG (1.90 [1.28-2.78] vs. 1.01 [0.64-1.49]; p&lt;0.001), with no sex differences (see Figure 1) . After adjustment for other covariates, FIB-4 index was independently associated with ni-MI in overall population (OR 1.468, 95% CI:1.195-1.803; p&lt;0.001), and separately in both males and females (OR 1.385, 95% CI:1.054-1.822; p=0.02 and OR 1.407, 95% CI:1.017-1.946; p=0.039, respectively). FIB-4 index was positively correlated with hs-cTnT (Rho= +0.536, p&lt;0.001), NT-proB-type Natriuretic Peptide (Rho= +0.280, p&lt;0.001) and negatively with estimated glomerular filtration rate (Rho= -0.510, p&lt;0.001). AUC of FIB-4 index for predicting ni-MI in the overall population was 0.790 (optimal cutoff: ≥1.46, sensitivity: 71.9%, specificity: 73.2%). Conclusions: FIB-4 index is independently associated with ni-MI in ED, without sex differences, and positively correlated with the grade of cardiac injury, volume overload and renal dysfunction.
Abstract 16322: Role of Spleen Tyrosine Kinase in Pathomechanism of Aortic Dissection
Authors: RYO SHIBATA
Journal: Circulation (2023)

Background: Aortic dissection (AD) is a fatal aortic disease of which molecular pathogenesis has not been elucidated. In our previous studies, we found that systemic inhibition of Syk, spleen tyrosine kinase, exacerbates AD leading and sudden death in model mice. However, cell type-specific role of the AD pathogenesis is unknown. Subject: How does Syk contribute to the pathogenesis of AD. And what cells in the aorta contribute to the pathogenesis of AD. Methods and results: Mouse AD model was created by continuous infusion of β-aminopropionitrile and angiotensin II (BAPN+AngII) for 14 days as previously reported. Iba1 and αSMA, markers of activated macrophage (Mϕ) and smooth muscle cell (Sm), respectively, were double-stained with p-Syk in the mouse AD model. As a results, we found that both Mϕ and Sm are activated in the same region as Syk. This suggests that Syk contributes in some way to Mϕ and Sm in the pathogenesis of AD. Mϕ-specific Syk knockout mice were generated using the Cre-LoxP system. Phenotype effects were compared in the controls and Mϕ-specific Syk knockout groups, but there were no significant differences in AD lesion length and mortality. Sm-specific Syk knockout mice were generated using the tamoxifen-induced CreERT2 system to avoid alteration of aortic phenotypic at the baseline. Ten-week-old mice with loxP sequences at both ends of the Syk gene in Sm were injected with 1 mg/day of tamoxifen for 5 days, and In Situ Hybridization showed that p-Syk was reduced in the aortic tunica media after 2 weeks. Phenotypic comparisons with controls what did not receive tamoxifen showed no significant differences in AD lesion length and mortality. These results differ from previous findings that systemic Syk inhibition increases AD. Conclusions: We found that systemic inhibition of Syk exacerbates the pathogenesis and mortality of AD, and that Syk has some activation in Mϕ and Sm. However, deletion of Syk in Mϕ or Sm alone had no apparent effect on the pathogenesis of AD. These results suggest that the action of Syk in AD pathogenesis is not solely due to Mϕ and Sm, but is due to a more complex mechanism involving multiple cells interactions.
Abstract 18017: Sex Based Disparities in Cardiac Arrest Related Outcomes: The National Inpatient Sample Analysis
Authors: Thatiana Schulze Goni, Amro Taha, Sagar Dabbara, Lalitsiri Atti, Sanchit Duhan, Fadi Khir, Shafaqat Ali, Varun Victor, Mohammed H Hussein, Sami Hussein, Talal Almas, Shehzad Ali, M Chadi C Alraies
Journal: Circulation (2023)

Introduction: Despite the lower incidence of cardiac arrest in women, their rates of survival to hospital discharge are poorer compared to men. To further examine this disparity in outcomes following cardiac arrest, we assessed the differences in outcomes among patients hospitalized after successful resuscitation. We utilized data from the National Inpatient Sample Database (NIS) for this evaluation. Methods: We conducted a query of the NIS spanning the years 2015 to 2019 to identify patients who experienced cardiac arrest. Subsequently, we categorized the sample based on gender. The primary outcome measured was in-hospital mortality. To calculate the adjusted odds ratios (aOR) of in-hospital outcomes, we employed multi-logistic regression analysis using STATA v.17. Results: Among the 874,745 weighted hospitalizations related to cardiac arrest, 56.91% were men and 43.09% were women. After adjusting for confounding factors, we observed that women who were successfully resuscitated from cardiac arrest had significantly higher rates of adverse outcomes compared to men. These outcomes included in-hospital mortality (aOR 1.092, 95% CI 1.07-1.10, p&lt;0.001), stroke (aOR 1.19, 95% CI 1.14-1.24, p&lt;0.001), pericardial effusion (aOR 1.14, 95% CI 1.09-1.18, p&lt;0.001), and pacemaker placement (aOR 1.20, 95% CI 1.15-1.25, p&lt;0.001). However, major bleeding occurred less frequently in women (aOR 0.93, 95% CI 0.90-0.96, p&lt;0.001). Although the total cost of hospitalization was higher for men ($172,021 ± 267,161 vs $149,718 ± 241,244), the length of stay was similar for both groups. Conclusions: Our study highlights significant gender-based disparities in post-cardiac arrest patients, with women experiencing poorer overall outcomes. Future qualitative studies should focus on identifying risk factors and improving post-resuscitation care specifically for women, with the aim of reducing gender-based differences in clinical outcomes.