tbuckley/cabot-search huggingface dataset:
Abstract 18334: Altered in-vivo Placental Microstructure Predicts Adverse Neurodevelopmental Outcomes in Toddlers With Congenital Heart Disease
Authors: Yao Wu, Nickie Andescavage, Kushal Kapse, Mary T Donofrio, Melissa Liggett, Anushree Kapse, Madison Myers, Adré J du Plessis, Catherine Limperopoulos
Journal: Circulation (2023)

Introduction: Pregnancies complicated by fetal congenital heart disease (CHD) are at risk for disrupted placenta function; placental insufficiency, in turn, is a risk factor that may adversely impact offspring neurodevelopment. However, the relationship between altered in-vivo placenta function and infant neurobehavioral outcomes in CHD is unknown. Hypothesis: We hypothesized that altered in-vivo placenta microstructural diffusion in CHD would be associated with impaired infant neurodevelopment. Methods: We prospectively recruited women with pregnancies complicated by CHD diagnosis and low-risk pregnancies. Women underwent an MRI on a GE 1.5T scanner at 20-39 gestational weeks. T2w sequence and pulsed gradient spin echo were acquired for placenta volume and diffusion kurtosis measures. Bayley-III and Infant-Toddler Social and Emotional Assessment were completed at around 18 months. Generalized estimating equation was used to examine the association between placenta measures and infant outcomes, adjusting for potential confounders. Results: We enrolled 236 mother/baby dyads (111 CHD; 125 controls) who underwent 394 MRIs (175 CHD; 219 controls). Forty-seven had single-ventricle (SV) CHD and 64 had two-ventricle (2V) CHD. In CHD, 32 subjects died, and 71 infants had neurodevelopment testing at a mean age of 20 months. Placenta diffusion coefficient (dki_d), reflecting tissue cellularity, was higher in CHD vs controls (p=0.009). In CHD, placenta diffusional kurtosis (dki_k), reflecting tissue heterogeneity, was lower in neonates who died pre-operatively vs those who survived (p=0.05). Compared to 2V CHD, pregnancies with SV fetuses had lower placenta dki_k and trending higher placenta dki_d. In CHD, higher placenta dki_d was associated with poorer language skills (p=0.05) while lower placenta dki_k was associated with higher behavioral dysregulation (p=0.03). Conclusions: We report for the first time disturbances in placenta microstructural diffusion in CHD. We also demonstrate that altered placenta diffusion was associated with impaired language and behavioral dysregulation in CHD toddlers. These data suggest that altered placenta microstructure may be an important biomarker for later neurodevelopmental dysfunction in CHD.
Abstract 18714: Myocardial Infarction With Non-Obstructive Coronary Artery Disease in a Young Woman - The Cardinal Role of Coronary Reactivity Testing in Unveiling the Underlying Etiology
Authors: Amie M Kolimas, Joshua K Beverly, Mohammad Kashif, Tushar Acharya, Adarsh Vangala, Michel T Corban
Journal: Circulation (2023)

43-year old female presented to the emergency department with substernal chest pain. She had similar symptoms years ago without obstructive CAD on coronary angiogram and was diagnosed with myocarditis. Presenting ECG revealed new anterolateral T wave inversions (Fig 1), and high-sensitivity troponins peaked at 322 ng/L consistent with NSTEMI. TTE was significant for global hypokinesis of the left ventricle with a reduced ejection fraction of 35 to 40%. Invasive coronary angiogram showed no obstructive CAD or spontaneous coronary artery dissection however there was reduced flow in the mid to distal LAD raising suspicion for endothelial and microvascular dysfunction. Contrast-enhanced cardiac MRI showed myocardial edema in the anterior and anteroseptal walls with elevated myocardial T1 and T2 values, and early enhancement post gadolinium administration showed an acute LAD territorial infarct (Fig 2). Findings were consistent with myocardial infarction with non-obstructive coronary artery disease (MINOCA). She was started on carvedilol for empiric treatment of coronary artery spasm and microvascular dysfunction, along with aspirin and atorvastatin. Losartan was added for heart failure management. Outpatient invasive coronary reactivity testing showed severe epicardial (70% vasoconstriction) and microvascular (80% decrease in coronary blood flow) endothelial dysfunction in response to acetylcholine (Fig 3 and Fig 4) as underlying etiology of recent MINOCA. CFR was normal. L-arginine (NO precursor) was added to the medical regimen. Patient has not had recurrence of chest pain or ACS at 1 year follow-up and LVEF normalized on repeat echocardiogram. This case shows the importance of cardiac MRI in confirming the diagnosis of MINOCA in patients with no obstructive CAD, and the crucial role of coronary reactivity testing in diagnosing and treating severe coronary endothelial dysfunction, which is aligned with the AHA/ACC MINOCA consensus document.
Abstract 16681: Echocardiogram-Based Screening and Prevalence of Rheumatic Heart Disease in Children and Adolescents From Endemic Areas: A Systematic Review and Updated Meta-Analysis
Authors: Antonio Mutarelli, Alexandre Negrao Pantaleao, Wilson Nogueira, Marco Antônio Smiderle Gelain, Fábio Augusto Pinton, Pedro Melo, Maria C Nunes
Journal: Circulation (2023)

Background: Rheumatic heart disease (RHD) is the leading cause of cardiac death in children, posing a significant burden to health systems, particularly in developing countries. Echocardiogram is a sensitive tool to identify early RHD patients, who may benefit from secondary prevention. Therefore, we performed an updated meta-analysis to determine the prevalence of latent RHD using echocardiogram-based screening performed in endemic regions across the globe. Methods: PubMed, Embase, Cochrane, and Lilacs databases were searched for cross-sectional studies reporting the prevalence of RHD in individuals aged 5-20 years, through echocardiogram-based screening programs in endemic areas. Studies with screening based on auscultation were excluded. Echocardiography-detected RHD was considered as borderline or definite by World Heart Federation (WHF) criteria and possible, probable or definite by World Heart Organization (WHO) criteria. We used random-effects models to assess the prevalence of RHD according to the geographic distribution. Results: A total of 57 studies were included, with a total of 224,100 screened subjects. WHF criteria for RHD echocardiographic diagnosis were used in 46 studies, WHO criteria in 6, and others in 3. The overall prevalence of echocardiography detected RHD was 23 per 1,000 individuals (95% CI 18 to 29 per 1,000), with a pooled prevalence of definitive RHD of 9 per 1,000 individuals (95% CI 7 to 12 per 1,000). Analysis of the prevalence of echocardiography detected RHD in different continents yielded an overall prevalence of 21 per 1,000 (95% CI 14 to 31 per 1,000) in Africa, 28 per 1,000 (95% CI 18 to 42 per 1,000) in Oceania, 21 per 1,000 (95% CI 15 to 30 per 1,000) in Asia, and 22 per 1,000 (95% CI 6 to 76 per 1,000) in Latin America. Conclusion: Screening programs incorporating echocardiography found a significant prevalence of RHD, in the range of 20 to 30 per 1,000 children and adolescents screened in endemic areas across different continents.
Abstract 18260: Association of Physical Activity History With Disease Penetrance in a Disease-Based Cohort Does Not Replicate in a Healthcare-Based Genomic Screening Population
Authors: Eric D Carruth, Weijia Wang, Catherine Pendleton, Christopher D Nevius, Rachel Keefer, Crystal Tichnell, Brittney Murray, Cynthia A James, Christopher M Haggerty
Journal: Circulation (2023)

Background: Physical activity (PA) restriction is a recommended intervention for patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), due to strong associations of PA history with disease, and the known risk of arrhythmic events in affected patients from tertiary referral centers. However, in patients with secondary findings of genetic risk for ARVC, the association of PA exposure with disease expression is unknown. Hypothesis: Among individuals with incidentally identified pathogenic or likely pathogenic (P/LP) variants in desmosome genes (PKP2, DSP, DSG2, DSC2), clinical evidence of disease will be associated with higher pre-diagnostic PA exposure. Methods: The MyCode (MC) cohort included individuals with P/LP variants in desmosome genes, discovered via population genomic screening of 175,000 individuals; the Johns Hopkins (JH) disease-based cohort included ARVC probands and family members with single P/LP variants enrolled in the JH ARVC Registry. The ARVC task force criteria (TFC) status of each patient was defined based on most recent clinical evaluation. Recreational PA history from age 10 to time of diagnosis (TFC+) or survey (TFC-) was self-reported through structured phone interview and each activity was assigned a metabolic equivalent score. Results: The MC cohort was older, more female-predominant, had a lower proportion of PKP2 variants, and had less disease than the JH cohort (Figure; all p&lt;0.001). As expected, MET-hrs/year of exercise prior to presentation was significantly higher in affected vs. unaffected patients in the JH cohort. In contrast, no association between PA history and disease expression was observed in MC (p=0.42). Conclusions: The MyCode cohort demonstrated both a paucity of clinically evident disease and a lack of obvious association of exercise with disease expression. These findings may be seen as reassuring in the management of patients with secondary ARVC genetic findings, but additional data are needed.
Abstract 18258: Leucine Supplementation Improves Myocardial Function in a HFpEF Rat Model
Authors: Antje Schauer, Paula Ketilly Nascimento Alves, Antje Augstein, Maria Elisa Prieto Jarabo, Anselmo S Moriscot, Axel Linke, Volker Adams
Journal: Circulation (2023)

Introduction: We previously documented that leucine supplementation protects from skeletal muscle atrophy by increasing skeletal muscle mass and force during hind limb immobilization. One of the proposed underlying mechanisms was the suppression of HDAC4 protein expression and increased nuclei accretion. Hypothesis: The present study aimed to examine whether the protective effects of leucine supplementation are also observed in the myocardium in an animal model of heart failure with preserved ejection fraction (HFpEF) and to assess the role of HDAC4 modulation. Methods: Female ZSF1 lean (control, con) and obese (HFpEF) rats were randomized at an age of 20 weeks to one of three groups: lean rats receiving standard chow (con), obese rats receiving standard chow (HFpEF), and obese rats receiving leucine-supplemented chow (3% w/w) for 12 weeks (HFpEF/leu). All animals underwent echocardiography at baseline and after 6 and 12 weeks. Prior to organ harvest left ventricular (LV) hemodynamics were measured invasively, blood samples were taken, cardiac mitochondrial function was assessed and LV tissue was collected for molecular and histological analyses. Results: Assessment of diastolic function revealed a 20% reduction of E/é in the HFpEF/leu group compared to untreated HFpEF. While no alterations of left ventricular hemodynamics were observed between the groups, stiffness factor β was significantly reduced in leucine-treated rats. Left ventricular mRNA levels of Collagen type I a1 and matrix metalloproteinase 2 were reduced by 25% and 22%, respectively. Assessment of mitochondrial oxidative phosphorylation revealed a significant improvement of complex-I- and complex-II mediated respiration in leucine-treated rats compared to HFpEF. Finally, HDAC4 protein expression levels were reduced by 40% in the HFpEF/leu group compared to HFpEF. Conclusions: This study presents beneficial effects of leucine supplementation on cardiac function, remodeling, and metabolic parameters in an HFpEF rat model. These benefits may be attributed to suppressed HDAC4 expression.
Abstract 18234: The Fast and the Furious, A Rare Case of RCA Dissection Following a Car Accident in a Male Patient
Authors: Valentina N Saracino, Catherine Kelly, Michael Mitchell
Journal: Circulation (2023)

Introduction: Coronary artery dissection is a rare, but potentially lethal, etiology of chest pain in the emergency department. Dissection is defined as a spontaneous, traumatic, or iatrogenic disruption of the tunica intima, causing blood to accumulate in a false lumen. Coronary artery dissection reportedly has a 0.1% incidence in the general population, occurring most commonly in the LAD, and less commonly in the RCA. Acute myocardial infarction (AMI) following blunt chest trauma has an age predominance of 82% being less than 45 years of age. With a low incidence and abnormal age presentation, an electrocardiogram must be included in the work-up of blunt chest trauma to assess for coronary artery dissection. Case: A 44-year-old male with a history of polysubstance abuse, obesity, and hypertension presented with left hip pain following a motor vehicle accident. The patient had been operating a small motorcycle when he struck a stationary vehicle. He was wearing a helmet but was ejected from the motorcycle, landing on his back. The patient eventually began to experience both right-sided chest pain as well as right-sided neck pain while in the. An electrocardiogram was performed that showed inferior ST-segment elevation with reciprocal ST-segment depression in the lateral leads. Troponins were 42ng/L, 1,465ng/L and 8,170ng/L. Cardiac catheterization revealed a spiral dissection of the RCA extending from the ostium to the mid-segment with TIMI 1 flow. The patient remained on medical management of aspirin, clopidogrel, and heparin and was monitored in intensive care for 48 hours prior to home discharge. Conclusion: Blunt force cardiac injury is an uncommon cause of chest pain and myocardial infarction, and rarer still is RCA dissection. This case highlights the distinct importance of electrocardiograms as a pivotal part of the trauma and chest pain diagnostic reasoning process.
Abstract 18306: Race, Natriuretic Peptides, and Physiological Perturbations
Authors: Naman S Shetty, Nirav Patel, Mokshad Gaonkar, Nehal Vekariya, Yuxin Chu, Min Xie, Niklaus Evitt, Kiran Musunuru, Garima Arora, Pankaj Arora
Journal: Circulation (2023)

Introduction: Racial differences in natriuretic peptide (NP) levels among young adults are uncharacterized. Race-based differences in NP response to physiological and pharmacological perturbations are unknown. Methods and Results: A population-level study in healthy young individuals (18-40 years) with NT-proBNP measurements from the 1999-2004 National Health and Nutrition Examination Survey cycles was conducted. In this study of 3055 individuals, Blacks [34.3% (29.3-38.9%)] had lower NT-proBNP levels compared with Whites. Healthy participants were recruited in 2018-23 in a mechanistic trial to assess the racial differences in NP response to standardized exercise and 6 weeks of metoprolol (started at 50 mg/day and doubled every 2 weeks). MR-proANP was measured pre- and post-exercise, before starting metoprolol and then every 2 weeks till study completion. Among 72 young adults [39 (54.2%) White, 37 (51.4%) females], the increase in MR-proANP levels was higher in Whites [49.0% (38.2-60.6%) compared with Blacks [35.9% (25.2-47.6%)] after exercise (p int : 0.004). With metoprolol, MR-proANP levels increased by 36.3% (23.3-50.8%) in Whites and 28.3% (15.0-43.0%) in Blacks (p int :0.42). To assess the mechanism of ANP increase, iPSC-CM (3 controls and 3 experiments) were treated with metoprolol to assess the change in NPPA expression. miR-425 (negative regulator of ANP) levels were measured at the abovementioned time points. The expression of NPPA in iPSC-CM did not change on treatment with metoprolol. With metoprolol, the relative expression of miR-425 reduced by ~10% at the end of 6 weeks. Conclusion: Using multiple lines of evidence, this study established that healthy young Blacks have lower NP levels and have a blunted NP response to exercise compared with Whites. ANP protein levels differed but no changes in ANP expression were noted with metoprolol. Further work is needed to elucidate pathways underlying miR-425 expression responsiveness with metoprolol.
Abstract 18247: Society for Cardiovascular Angiography and Intervention Shock Staging is Associated With Outcomes in Patients With an Impella 5.5 Temporary Left Ventricular Assist Device
Authors: Jean-Luc A Maigrot, Randall C Starling, Edward G Soltesz, Nicholas G Smedira, Michael Tong, Shinya Unai, Pavan Bhat, David Moros, Eugene H Blackstone, Aaron J Weiss
Journal: Circulation (2023)

Introduction: Surgically implanted microaxial ventricular assist devices (VAD) such as Impella 5.5 are increasingly used as temporary mechanical circulatory support (tMCS) in patients at risk for and with cardiogenic shock (CS). Understanding the associations between CS severity and outcomes in patients supported with Impella 5.5 may optimize patient selection and prevent futile interventions. Hypothesis: Increasingly severe Society for Cardiovascular Angiography and Intervention (SCAI) SHOCK stages in patients supported with Impella 5.5 are associated with worse outcomes. Methods: From 2019-2022, retrospective review of perioperative characteristics, SCAI SHOCK stage and outcomes in patients supported with an Impella 5.5. Results: In total, 228 Impella 5.5s were implanted in 226 patients; 28% (63) SCAI SHOCK stage A, 4% (10) stage B, 14% (31) stage C, 46% (104) stage D and 9% (20) stage E. Stage A and B patients more often had elective Impella 5.5s for tMCS-assisted interventions (cardiac surgery, PCI, VT ablation) (30%, 69/228) while stage C-E patients primarily had Impella 5.5 placement for acute MI (AMI), chronic cardiomyopathy and postcardiotomy CS (60%, 136/228) (p&lt;0.01). Death on Impella support by SCAI SHOCK stage was: A 3.2%, B 10%, C 13%, D 27%, E 37% (p&lt;0.01). The transition to durable VAD or heart transplant by SCAI SHOCK stage was: A 1.6%, B 0%, C 48%, D 35%, E 16% (p&lt;0.01). Conclusions: Patients supported with Impella 5.5s presented in varying degrees of CS as defined by SCAI SHOCK stage. Patients with AMI, chronic cardiomyopathy, and postcardiotomy CS more commonly presented in higher SCAI SHOCK stages than those who underwent planned Impella 5.5-assisted cardiac interventions. Patients in stage E at implant had the highest mortality while patients in stage C and D were more likely to be bridged to durable VAD or heart transplant.
Abstract 16749: Influence of Dual-Specificity Protein Phosphatase 5 on Structural and Mechanical Properties of Rat Middle Cerebral Artery
Authors: Chengyun Tang, Huawei Zhang, Jane J Border, Xing Fang, Richard J Roman, Fan Fan
Journal: Circulation (2023)

Dual-specificity protein phosphatase 5 (DUSP5) is a multifunctional phosphatase that modulates signaling cascades by catalyzing the dephosphorylation of both threonine and tyrosine residues. We recently reported that KO of Dusp5 enhances cerebral and renal hemodynamics and cognitive function. This effect is associated with increased pPKC and pERK1/2 levels in arteries and arterioles of the brain and kidneys. Further, we found that KO of Dusp5 contributes to the regulation of arteriolar passive mechanical properties with higher myogenic tones, better distensibility, greater compliance, and less stiffness. The present study focuses on the structural and mechanical properties of rat middle cerebral artery (MCA) to evaluate whether it contributes to enhanced vascular and cognitive function in Dusp5 KO rats. Vascular smooth muscle cell layer numbers and collagen content in the wall of the MCA are similar in Dusp5 KO and control rats. While external elastic lamina was absent in the MCA in both strains, internal elastic lamina was thicker in the MCA of Dusp5 KO vs. control rats (2.33 ± 0.02 vs. 1.85 ± 0.03 μm) and associated with higher autofluorescence intensity (953.76 ± 10.03 vs. 737.31 ± 64.88 au), smaller fenestrae areas (51.31 ± 3.62 vs. 70.46 ± 2.24), and fewer number of fenestrations (138.19 ± 8.86 vs. 374.73 ± 17.02 μm 2 ). Even though the myogenic tone is enhanced in Dusp5 KO vs. control rats (52.37 ± 1.65 vs. 44.87 ± 2.00%), other passive mechanical properties (wall thickness, cross-sectional area, wall-to-lumen ratio, wall tension, distensibility, incremental distensibility, circumferential wall strain, circumferential wall stress, and elastin modulus) of the MCA of Dusp5 KO rats do not exhibit significant changes. The findings suggest that while Dusp5 KO has a limited impact on changing the structural and mechanical properties of the MCA, its role in enhancing hemodynamics and cognitive function is primarily attributed to its enzymatic function.
Abstract 15308: NLRP3 Activation and Calcium-Dependent Contractile Function in Rat Right Ventricle Cardiomyocytes (RVCMs) Are Sexually Dimorphic and Controlled by 17β-Estradiol-via Estrogen Receptor-α
Authors: Rafael Sobrano Fais, Christopher Hoffer, Liliana Moreno Vinasco, Avram Walts, Todd Cook, Amanda Fisher, Andrea L Frump, KC Woulfe, Tim Lahm
Journal: Circulation (2023)

Introduction: NLRP3 inflammasome activation promotes right ventricle (RV) contractile dysfunction in pulmonary hypertension (PH). However, the role of NLRP3 signaling in RVCMs has not been studied. 17β-estradiol (E2) improves RVCM function in PH. Hypothesis: E2, via estrogen receptor-α (ERα), prevents RVCM NLRP3 inflammasome activation and contractile dysfunction in experimental PH. Methods: RV failure in male and female Sprague Dawley rats were induced with monocrotaline (MCT). Co-localization of NLRP3 and its partner ASC was assessed. RVCMs isolated from healthy male or female wildtype (WT) or ERα loss of function mutant (ERα mut ) rats were treated with NLRP3 activators lipopolysaccharide (LPS 1 μg/mL, 4 h) and ATP (2 mM, 10 min) ± E2 (1 nM, 24 h) or NLRP3 inhibitor MCC950 (1 μM, 30 min). RVCM contractility and Ca 2+ levels were evaluated via IONOPTIX system. Protein levels of NLRP3 and its targets were assessed. ERα binding to the NLRP3 promoter was assessed by immunoprecipitation. RNA-seq was performed in RV tissues from male and intact or ovariectomized female rats with RV failure. Results: RNA-seq demonstrated that transcripts involved in NLRP3 activation are E2-regulated. RVCMs from male, but not female, MCT rats showed increased NLRP3 and ASC co-localization/activation (p&lt;0.05). In addition, male MCT rats RVs exhibited increased activation of NLRP3 downstream mediators caspase-1 and IL-1β (p&lt;0.05). Cultured male RVCMs treated with LPS+ATP demonstrated more pronounced NLRP3 activation and decreased contractility and Ca 2+ levels than female RVCMs (p&lt;0.05). NLRP3 activation in RVCMs from male rats resulted in reduced contractility; this was abolished with NLRP3 inhibition (p&lt;0.05). E2 treatment in male RVCMs reduced NLRP3 and ASC interaction and increased contractility Ca 2+ levels in male WT but not in ERα mut RVCMs (p&lt;0.05). IP demonstrated ERα binding to the NLRP3 promoter. Conclusion: NLRP3 signaling in RVCMs from MCT-PH rats is sexually dimorphic, with more pronounced activation and contractile dysfunction in males. E2 prevents RVCM NLRP3 activation and contractile dysfunction in an ERα-dependent manner, likely mediated by ERα binding to the NLRP3 promoter. NLRP3 activation may be therapeutically targetable in PH patients of either sex.