tbuckley/cabot-search huggingface dataset:
Abstract 16914: Structural and Functional Investigation of Myocardial Fiber Architecture in Genetic Mouse Models of Heterodoxy and Situs Inverses Totalis
Authors: Yijen L Wu, Xiaoqin Liu, Yu Chen, Nathan Salamacha, Joyce Han, Daniel B Ennis, Sameh Tadros, Cecilia Lo
Journal: Circulation (2018)

Introduction: Heterotaxy (HTX) patients with congenital heart disease have higher risk of post-surgical complications and increased morbidity and mortality. Given HTX involves disruption of left-right patterning, this suggests laterality disturbance may drive the poor outcome in CHD patients with HTX. To investigate this, we used mouse models with laterality defects. Although HTX mutant mice invariably die prenatally/neonatlly from complex CHD, many mutations causing HTX also giive rise to mice that are adult viable with situs inversus totalis (SIT), or situs solitus (SS) without CHD. Hence, our goal is to delineate myocardial fiber architecture in the SIT and SS mutant mice to gain insights into possible functional deficits associated with HTX. Hypothesis: Disturbance in specification of laterality results in abnormal myocardial fiber architecture that can cause cardiac dysfunction and make the heart more vulnerable to stress. Methods: Diffusion tensor imaging (DTI) was used to delineate the myocardial fiber organization in SIT and SS mutant mice, and wild-type (WT) control mice. Cardiac MRI and echocardiography were used to evaluate cardiac function with or without dobutamine stress. Results: Echocardiography showed no significant differences in global systolic function in the SIT and SS mutant hearts, but they displayed compromised strain rates under dobutamine stress. SIT and SS hearts also exhibited reduced rotation and torsion, suggesting altered myocardial fiber organization. Myocardial tractography by DTI (Fig.A-D) showed less coherent myocardial fiber organization (Fig. G-I) and more diverse helix angles (Fig. K&amp;M) in SIT mutant hearts. Overall, our data showed the mutant SS and SIT hearts have disrupted myocardial fiber architecture resulting in abnormal torsion, rotation, and strain when stressed. Conclusions: These findings suggest abnormal myocardial architecture may contribute to the poor clinical outcome in HTX patients with CHD.
Abstract 12372: Acute Supplementation of <i>Lactobacillus plantarum 299v</i> Improves Vascular Endothelial Function in Adults With Stable Coronary Artery Disease (CAD)
Authors: Benjamin C Hofeld, Venkata K Puppala, Elise Nelton, Amberly Anger, Rachel A Schneider, Molly Pfeffer, Michael E Widlansky
Journal: Circulation (2021)

Introduction: We have shown that dietary supplementation of L. plantarum 299v (Lp299v) over a six-week period in men with stable CAD improves endothelial function and reduces systemic inflammation. Prior ex vivo work with human resistance vessels suggests that this effect is at least partially mediated by non-genomic actions of post-probiotic supplementation plasma constituents. Whether acute supplementation with Lp299v favorably impacts in vivo endothelial function is not known. We investigated the impact of Lp299v on acute changes to endothelial function in individuals with stable CAD or CAD risk factors and hypothesized that endothelial function would improve within 24 hours. Methods: 9 adult subjects with stable CAD or at least one traditional CAD risk factor were recruited. Baseline dietary information was collected. Subjects consumed 3 oz. of Lp299v (20x10^9 CFU) after an overnight fast, and brachial artery flow mediated dilation (FMD) was used to measure vascular endothelial function at baseline, 2 hours, and 24 hours following supplementation. Lipids, glucose, and insulin levels were obtained at these timepoints. Data were analyzed using paired t-tests and chi square tests as appropriate. Results: No significant changes were seen in blood pressure, heart rate, lipid levels, or insulin at the 2-hour or 24-hour timepoints, compared to baseline. A nonsignificant trend of improved brachial artery FMD from the 0 to 2-hr timepoints (3.57±0.62% to 4.04±0.71%, p=0.63, n=9) persisted to the 24-hour timepoint (3.57±0.62% to 5.01±0.85%, p=0.23, n=9). There was a statistically significant decrease in glucose at the 2-hr timepoint (p=0.04), likely related to continued fasting, which was not seen at a 24hr timepoint (p=0.72). Conclusions: A single dose of Lp299v supplement did not result in a statistically significant improvement of endothelial function within the first 24 hours. However, the number of subjects tested was small and the FMD data at 24 hours suggests that Lp299v could improve endothelial function through non-genomic mechanisms. This could be more definitively determined with a larger study.
Abstract 16855: Endothelial Dysfunction Through MAPK Signaling in Cardiac Hypertrophy and Failure
Authors: Irinna Papangeli, Saejeong Park, Katharine R Clapham, Takaomi Adachi, Jianqiang Hu, Hyung J Chun
Journal: Circulation (2018)

Heart failure (HF) is the most frequent cause of hospitalization in people over 65 years. Endothelial dysfunction correlates with worse outcomes in HF, and although it has been observed in both preserved (HFpEF) and reduced (HFrEF) ejection fraction patient populations, it has been intensely studied predominantly in the latter group, due to challenges in diagnosis, limited human tissue samples and lack of animal models of HFpEF. Here, we present a novel mouse model of endothelial dysfunction caused by loss of the Mitogen Activated Protein Kinase (MAPK) Erk5, which develops cardiac hypertrophy and a HFpEF phenotype. Tamoxifen inducible endothelial specific deletion of Erk5 (Erk5 ECKO ) is lethal within 25 days. Serial echocardiograms showed that Erk5 ECKO mice develop dramatic left ventricle hypertrophy, characterized by increased heart/body weight ratios, increased cardiomyocyte size and extended fibrosis. The ejection fraction was remarkably preserved, while blood pressure was unaffected. Erk5 ECKO mice presented with increased expression of HF biomarkers and fibrotic genes, as well as increased proliferation of cardiac endothelial cells. Knockdown of ERK5 in endothelial cells resulted in dysregulation of multiple homeostatic genes, including decreased phosphorylation and subsequent degradation of YAP, a pro-proliferative Hippo pathway effector. Increased protein levels of Yap were identified both in Erk5 ECKO mouse hearts and in a subset of human HF left ventricle samples. Finally, using tamoxifen inducible, endothelial specific knockout mice of both Erk5 and Yap we show that endothelial loss of Yap improves left ventricle hypertrophy and normalizes HF biomarker expression in Erk5 ECKO mice. Our findings provide critical mechanistic knowledge on the role of endothelial dysfunction in HFpEF, downstream of impaired MAPK signaling, while setting forth new biomarkers and therapeutic candidates for diseases involving endothelial dysfunction.
Abstract 13661: Low Organ Perfusion Pressure Indexed To Body Surface Area <i>Predicts Poor Sur</i> vival Even After Heart Transplantation If The Right Atrial Pressure Is High
Authors: RAVIKUMAR RATNAGIRI, KOMARAKSHI R BALAKRISHNAN, Suresh Rao K G, T Muralikrishna, Ramanan Veena
Journal: Circulation (2021)

Introduction: Increased Right Atrial pressure (RAP) is associated with impaired renal function and mortality in patients with heart failure. Reduced renal perfusion pressure is associated with deranged renal function. Hypothesis: The effect of high RAP on survival may persist even after heart transplantation if the organ perfusion pressure indexed to body surface area (OPPI) is low. OPPI is more sensitive than organ perfusion pressure (OPP) in predicting survival. Methods: 277 patients who had a heart transplant between October 2012 to march 2020 were included in the study . OPP was calculated as : Mean arterial pressure (MAP) - RAP . OPPI was calculated as : (MAP-RAP) / body surface area . Results: There was a more significant negative correlation between OPPI and creatinine (r = -0.4015,p =0.000) than OPP and creatinine (r = -0.0335,p = 0.6187) (fig 1a) . The effect of OPPI on MELD score was also more significant than OPP.( r = -0.2973, p = 0.000 vs r = -0.0335, p = 0.6187). The 90 day mortality after transplantation was more with higher RAP (23.5 % vs 11.5 %, p ~ 0.012 RAP &gt; &amp; &lt; 15) , but not if OPPI was &gt; 40.(10.8 % vs 9.4 %,p ~ 0.817). The 90 day survival was worse with lower OPPI but improved with lower venous pressures.(Fig 1b) The effect of RAP on medium term survival was significantly worse for RAP &gt; 15 (p = 0.0143).(Fig 1c). The effect was absent if OPPI was &gt; 40.(Fig 1d). Survival at 5 years was worse if the OPPI was low . This effect was absent if the RA pressure was low.(1 e,f). Medium survival for mean pulmonary artery pressure more than 40 mm hg was worse but not if OPPI &gt; 40.(Fig 1 g,h). Conclusions: Short and medium term survival after transplantation are worse with high RAP if OPPI is low. OPPI ,a hemodynamic parameter easily measurable, is more sensitive in predicting survival than OPP . OPPI &lt; 40 appears to be deleterious. With high RAP, excessive vasodilatation must be avoided
Abstract 16734: Coronary Artery Calcium as a Predictor of All-Cause, Cardiovascular and Coronary Heart Disease Mortality in Asian Americans: The Coronary Artery Calcium Consortium
Authors: Olusola A Orimoloye, Sandeep Banga, Zeina Dardari, S M Iftekhar Uddin, Daniel S Berman, Michael D Miedema, John A Rumberger, Khurram Nasir, Matthew J Budoff, Michael J Blaha, Mohammadhassan Mirbolouk
Journal: Circulation (2018)

Introduction: Although coronary artery calcium (CAC) has been shown in multiple populations to be predictive of risk, very few studies have assessed its predictive value in Asian-Americans. We therefore assessed the value of CAC for cardiovascular and all-cause mortality risk prediction in Asian-Americans using data from the CAC Consortium, the largest observational cohort of clinical CAC scoring yet assembled. Methods: We included 1,621 Asian Americans from the CAC consortium. CAC was modeled in categorical (CAC 0; CAC 1 - 99; CAC 100 - 399; CAC ≥ 400) and continuous forms. Participants were followed over a median of 12 ± 4 years for all-cause mortality, cardiovascular disease (CVD) mortality and coronary heart disease (CHD) mortality. The predictive value of CAC for individual outcomes was assessed using multivariable-adjusted Cox proportional hazards regression models adjusted for traditional cardiovascular risk factors. Results were reported as hazard ratios (95% confidence intervals). Additionally, cubic spline graphs centered at CAC = 100 were generated for graphical presentations of CHD and CVD mortality hazards with increasing CAC score. Results: Mean (SD) age of the population was 54 (11.2) years and 64% were men. Approximately 49% had a CAC score=0. A total of 59 deaths, 16 CVD-specific deaths and 8 CHD-specific deaths were recorded over the duration of follow-up. Of a total of 794 participants in the CAC=0 group, only 9 deaths were recorded (0.93 per thousand person-years). There were no CVD or CHD deaths in the CAC=0 group over the duration of follow-up. Individuals with CAC ≥ 400 had approximately 3 times the multivariable-adjusted hazards of all-cause mortality compared against a reference of CAC=0. (Hazard ratio 3.3 (1.3 - 8.6)). Similarly, we noted statistically significant increases in risk of CHD (HR 2.6 (1.5 - 4.3)) and CVD (HR 2.3 (1.8 - 2.9)) mortality per unit increase in log (CAC + 1). Conclusion: Similar to more extensively studied race/ethnic groups, CAC is strongly predictive of all-cause and cardiovascular mortality in Asian Americans. These findings may help address the existing knowledge gaps for cardiovascular risk prediction in Asian Americans as recent guidelines have little data-driven advice for risk prediction in this population.
Abstract 12381: Clinical Implications of <i>SCN5A</i> and <i>SCN10A</i> Loss of Function Variants in 169,610 Exomes Representing the General Population
Authors: Christian Paludan-Mueller, Simon Larsen, Gustav Ahlberg, Laura Andreasen, Jesper Hastrup H Svendsen, Jorgen K Kanters, Morten S Olesen
Journal: Circulation (2021)

Background: Genetic variation in the genes SCN5A and SCN10A has previously been associated with cardiac disease and conduction velocity through genome-wide association studies (GWAS) and rare variant analyses. The two neighboring genes constitute the much-investigated SCN5A-SCN10A locus, and it has been challenging to determine the region’s function as GWAS often identifies variants in non-coding regions. The cardiac function of SCN5A is well established whereas the role of SCN10A in cardiac conduction and disease remains disputed. The study focuses on SCN10A while SCN5A was included for comparative analyses. Methods and Results: We accessed the UK Biobank database, which contains data on &gt;500,000 individuals. The recent exome release provides whole-exome sequencing data on 169,610 unrelated European individuals while resting ECGs are available on 44,987 individuals. We identified 668 individuals harboring LOF-variants (leading to early stop codon, frameshift or splice site disruption) in SCN10A and SCN5A with a MAF &lt;1%. Among the 668 individuals, 543 individuals carried SCN10A variants, whereas 125 individuals held a variant in SCN5A . There were 88 and 37 different variants in SCN10A and SCN5A , respectively. From these individuals, we obtained 69 ECGs in sinus rhythm and 55 of these were recorded on individuals with a SCN10A LOF-variant and 14 ECGs were recorded on individuals with a SCN5A LOF-variant. Linear regression analyses established an association between SCN5A LOF-variants and prolongation of the PR-interval as carrying a variant corresponds to an average PR prolongation of 25.1 milliseconds (P = 0.001). There were no statistically significant alterations among other ECG parameters. Furthermore, we could not determine correlations of ECG parameters for SCN10A LOF-variants. A burden test on SCN10A and SCN5A LOF-variants could not establish a relationship with atrial fibrillation (P = 0.26 and P = 0.41, respectively) and heart failure (P = 0.92 and P = 0.17, respectively). Remaining possible disease associations could not be properly established due to low number of cases. Conclusion: These findings confirm the significance of SCN5A in cardiac conduction while questioning the function of SCN10A in human cardiac conduction and disease.
Abstract 16604: Recombinant Tafazzin Enzyme Replacement Therapy Rescues Metabolic and Functional Defects in a Mouse Model of Barth Syndrome
Authors: Junya Awata, Corinne J Thomas, Ana A Dinca, Wei-Ming Chien, Robert Blanton, Mark Aronovitz, Gregory L Martin, Lauren Richey, Douglas Strathdee, Michael T Chin
Journal: Circulation (2018)

Barth syndrome (BTHS) is an X-linked autosomal recessive disease caused by mutations in the tafazzin (TAZ) gene. These mutations lead to hypotonia, cyclic neutropenia, 3-methyglutaconic aciduria, and the most common cause of mortality in patients, cardiomyopathy. The TAZ gene encodes an enzyme that generates mature cardiolipin (CL) from monolysocardiolipin (MLCL)in the mitochondrial membrane, which is essential for normal mitochondrial morphology and function. Currently, there is no effective therapy for BTHS. In this study, we test an enzyme replacement therapy for BTHS in myocardial-specific TAZ conditional knockout mice which model the cardiomyopathy of BTHS. Serial echocardiograms showed that the BTHS mice developed increased septal wall thickness at 5 weeks of age. The BTHS mice were treated for 12 weeks with either vehicle or recombinant human TAZ fused to a cell penetrating peptide (hTAZ-CTP) to facilitate tissue uptake. During the treatment period, septal wall thickness in the vehicle-treated mouse continued to increase, whereas it remained stable in those treated with hTAZ-CTP . Pressure-volume (PV) loop analysis indicated that heart function was impaired in the vehicle-treated BTHS mouse while the protein-treated mice were shown to have PV loops similar to normal mice. The ratio of MLCL/CL, a direct measure of TAZ enzymatic activity, was measured in heart mitochondria isolated from BTHS and control floxed allele mice after treatment. The MLCL/CL ratio in the vehicle treated BTHS mouse was 20.4, consistent with a BTHS phenotype, whereas the MLCL/CL ratios in protein-treated and control mice were 0.01, indicating that injection of hTAZ-CTP successfully rescued the function of TAZ in BTHS mice. Histological observation of liver, spleen, kidney, and heart did not show any sign of toxicity for hTAZ-CTP injection. These results indicate that TAZ enzyme replacement therapy has great potential as a future treatment for BTHS.
Abstract 16606: Utilization of the Genome Aggregation Database, In Silico Tools, and Heterologous Expression Patch Clamp Studies to Identify and Demote Previously Published Type 2 Long QT Syndrome-Causative Variants From Pathogenic to Likely Benign
Authors: Connor L Mattivi, Dan Ye, David J Tester, Daniel J Clemens, Wei Zhou, John R Giudicessi, Michael J Ackerman
Journal: Circulation (2018)

Introduction: Loss-of-function (LOF) variants in the KCNH2 -encoded Kv11.1 potassium channel cause type 2 long QT syndrome (LQT2). To date, hundreds of KCNH2 missense variants (MVs) have been published as “disease-causative”. However, it has been suggested that 10% of rare LQTS variants in the literature may be "false positives”. Objective: To determine previously published KCNH2 variants that are likely false positives and warrant demotion to at least likely benign status. Methods: A list of all case-derived LQT2-associated MVs from six large published compendia was compiled. The frequency of each MV within the Genome Aggregation Database (gnomAD, n = 141,352 individuals) was recorded. Eight in silico variant assessment tools were used to grade each MV. Variants (n=8) absent in gnomAD but predicted “benign” by all 8 tools were considered potential false positives, despite being ultra-rare, and were characterized functionally using whole-cell patch clamp. Results: Overall, 339 KCNH2 MVs were identified among LQTS cases. Of these, 13 (4%) were seen at a minor allele frequency (MAF) &gt; 0.0004 in gnomAD. This MAF cut-off is derived from the frequency of R176W-KCNH2, a well-established albeit weakly penetrant (i.e. &lt; 20%) LQT2-causative MV. Variants seen at MAF &gt; R176W-KCNH2 are unlikely to be LQT2-contributing. However, 253 MVs (75%) were absent in gnomAD. Of these, 8 (4%) MVs (I96V, G187S, A203T, P241L, H254Q, G314S, P935S, and P963T) were predicted by all 8 in silico tools to be benign and had never been characterized functionally. Patch clamp studies did not demonstrate any LOF perturbation for these 8 MVs. Conclusion: This study offers compelling evidence for the demotion from LQT2-causative status to likely benign status for 21 (6%) of the 339 previously published LQT2 MVs based either on i) gnomAD MAF unacceptably high for a 1:8000 disorder (LQT2) for 13 MVs or ii) ultra-rarity (never seen in gnomAD) but in silico variant assessment tools predicting benign impact of the amino acid substitution and in vitro functional validation studies devoid of LOF for 8 additional MVs. This meticulous “pruning” exercise must be conducted for all published variants previously implicated as the monogenic cause for LQTS in particular and all genetic heart diseases in general.
Abstract 16647: Loss of Reversibility in Flow-Induced Pulmonary Arterial Hypertension is Associated With a Senescent Vascular Phenotype and Can Be Rescued by Targeted Senolysis
Authors: Diederik van der Feen, Lysanne M Jorna, Jan Renier Moonen, James Chappell, Francesco Vallania, Michele Donato, Marco Demaria, Rudolf A de Boer, Marlene Rabinovitch, Rolf M Berger, Beatrijs Bartelds
Journal: Circulation (2018)

Introduction: Patients with congenital heart disease (CHD) are at risk of developing progressive pulmonary arterial hypertension (PAH). Timely hemodynamic unloading (HU) by surgical shunt correction usually reverses the arteriopathy, but the timepoint when or reason why PAH becomes irreversible remains elusive. Methods: PAH was created in syngeneic rats by monocrotalin (MCT) injection and an aorto-caval shunt. For HU at different PAH stages, the left donor lung with PAH was transplanted into healthy recipients at t14/t21/t28. Recipients were sacrificed 21days after transplantation. Results: MCT+Shunt induced medial neomuscularization from t14, and neointimal lesions from t21, causing arteriolar occlusion and PAH. HU normalized the vascular morphology in all t14 rats and in 7/10 t21 rats, whereas no reversal or progressive occlusion occurred in 3/10 t21 and all t28 rats. RNA-sequencing revealed that activated pro-proliferative/regenerative, pro-apoptotic and DNA-repair pathways were associated with reversal after HU. This was confirmed immunohistochemically by increased vascular-specific Ki67, Caspase3 and Rad51 protein expression. In contrast, irreversibility was associated with deactivation of latter pathways and activated pro-survival, pro-senescence and pro-inflammatory pathways, as confirmed by increased Survivin, p16 ink4A , p21 cip1 , TNFα, IL6 and MMP2. These findings were also confirmed in human PAH-CHD explant tissue. Finally, we report that the senolytic BCL2 antagonist ABT263 selectively targets rat endothelial cells made senescent by irradiation. Moreover, low-dose ABT263 treatment from t25 to t32 in MCT+Shunt rats significantly improved pulmonary hemodynamics and relieved PAH symptoms. Conclusions: Similar to clinical observations in PAH-CHD, this study showed that HU reverses PAH only in an early stage, and describes a zone of no return. We characterized the mechanistic basis for (loss of) reversibility, showing a distinct switch from increased proliferation/regeneration, apoptosis and DNA-repair, to a growth arrested, apoptosis-resistant and intrinsically pro-inflammatory phenotype, suggesting a role for senescence. Reversal of this phenotype by targeted senolysis also reversed PAH beyond the zone of no return.
Abstract 16611: Higher Total Ultrafiltration Volume During Infant Cardiac Surgery is Associated With Acute Kidney Injury
Authors: Dominic B Zanaboni, Roopa Seshadri, J. William Gaynor, Molly Dreher, Joshua J Blinder
Journal: Circulation (2018)

Introduction: Many congenital heart centers use intraoperative ultrafiltration (UF) for fluid removal during and after infant cardiopulmonary bypass (CPB) surgery to reduce fluid overload. Excessive UF may result in intravascular hypovolemia. Postoperative acute kidney injury (AKI) is multifactorial, but little is understood about the role of UF on hypovolemia and postoperative AKI. Methods: This is a single center, retrospective review of infants receiving UF associated with CPB surgery. Patients requiring ECMO were excluded. UF volume (ml) was indexed to weight (kg). AKI was determined using the serum creatinine ‘Kidney Disease Improving Global Outcome (KDIGO)’ criteria or neonatal KDIGO (≤ 30 days of age) criteria. Multivariable logistic regression was used to adjust for multiple covariates associated with AKI. Results: From 6/2013 to 4/2015, 532 subjects &lt;1 year of age underwent CPB-assisted congenital heart surgery with UF. Sixty-four (12%) subjects developed postoperative AKI. No patients required renal replacement therapy. Higher total indexed UF volume was associated with AKI (median 119 ml/kg [IQR 92-164 ml/kg] versus 97 ml/kg [72-128 ml/kg], p=0.001). Other univariate associations with AKI are listed in table 1. After adjusting for multiple covariates, higher indexed total UF volume was associated with increased AKI risk (OR 1.1, CI 1.03 - 1.17, p=0.005) for each additional 10 ml/kg UF volume. The only additional independently associated factor with AKI was higher vasoactive inotrope score on post-operative day 2 (OR 1.1, [1.04-1.17], p&lt;0.001). Conclusions: While few patients developed postoperative AKI, higher intraoperative UF volume is associated with AKI risk. Postoperative hypovolemia due to excessive UF may be a modifiable AKI risk factor. Judicious use of postoperative UF may reduce AKI risk.