tbuckley/cabot-search huggingface dataset:
Abstract 16788: Anatomical Repair Can Be Facilitated by Three-Dimensional Cardiac Printing in the Patients With Double Outlet Right Ventricle
Authors: Dong-Hee Kim, Eun Seok Choi, Chun Soo Park, Tae-Jin Yun
Journal: Circulation (2018)

Introduction: Determination of optimal strategy between single ventricle palliation (SVP) versus left ventricular recruitment (LVR) as a systemic ventricle is challenging in the patients with complicated double outlet right ventricle (DORV). We sought that three-dimensionally printed cardiac models (3DM) may enables the surgeons to make an intuitive preoperative decision potentially in favor of LVR. Hypothesis: Use of 3DM can extend the candidates for LVR and improve surgical outcomes. Methods: We retrospectively reviewed the patients with DORV from Jan 2008 to Jun 2018 in single center. The patients with discordant atrioventricular (AV) connection, complete AV septal defect and atresia of AV valves were excluded. The patients without at least one of LVR precluding factors such as left or right ventricular hypoplasia, mitral valve (MV) or tricuspid valve (TV) straddling, TV interposition in potential baffle course, huge ventricular septal defect (VSD), multiple VSDs and remote VSD were excluded. All patients were divided in SVP or LVR group except two patients without clear determination of strategy. Finally, 100 patients were enrolled and since 2016, 3DM was made in the patients with LVR precluding anatomy for better consensus formation whether LVR could be feasible in 26 patients. Risk factor analysis was done for SVP and adverse outcome. Results: Thirty-five patients enrolled as SVP strategy (Fontan operation in 14, Kawashima operation in 1, interstage mortality in 12, follow-up loss in 3 and waiting scheduled operation in 5) and 65 patients enrolled as LVR strategy (complete anatomical correction in 50, one and half ventricle repair in 6 and waiting scheduled operation in 9). In multivariate analysis, LV hypoplasia ( P =0.003) and MV straddling ( P =0.015) were significant LVR precluding factors and the use of 3DM was a favorable factor for LVR ( P =0.039, OR=0.212). Risk factor for mortality were LV outflow tract obstruction ( P =0.006) and LV hypoplasia ( P =0.043). The use of 3DM did not reach statistical significance on mortality ( P =0.132). Conclusions: In DORV patients, LVR can be precluded especially with LV hypoplasia and MV straddling however, LVR can be facilitated by direct-vision driven preoperative decision about complicated features with 3DM.
Abstract 16664: Intrapatient Variability in the Brockenbrough-Braunwald-Morrow Sign and Peak Instantaneous Left Ventricular Outflow Gradients in Obstructive Hypertrophic Cardiomyopathy
Authors: Terry D Bauch, Alexandra J Smith, James A Watts, Bernard J Rubal, Joseph P Murgo
Journal: Circulation (2018)

Introduction: Although the variability in left ventricular outflow tract (LVOT) gradients in patients with hypertrophic cardiomyopathy (HCM) is well known, the value of pulse pressure (PP) changes with ectopy for predicting changes in LVOT gradient remains unreported. Hypothesis: This study examines the intrapatient variability in peak instantaneous LVOT gradients and aortic pulse pressure (PP) associated with the Brockenbrough-Braunwald-Morrow sign (BBM sign) compared with beat-to-beat variability. Methods: Variability in continuously recorded, high-fidelity left ventricular and aortic pressure waveforms were evaluated by computer-aided analysis in the resting state (N = 659 beats) and during supine exercise (N = 379 beats) in a symptomatic patient with a resting LVOT gradient &gt;30 mmHg. Results: BBM sign was observed in 92.9% (26/28) of post-PVC beats at rest and the post PVC PP decreased 11.8±8.2% (P&lt;0.001) compared with a 148.3±49.5% (P&lt;0.001) increase in the LVOT gradient. During exercise, BBM sign was noted in 84.2% (32/38) of post-PVCs beats and PP decreased 4.0±6.3% (P&lt;0.001) compared with a 74.2±37.5% (P&lt;0.001) increase in LVOT gradient. PP decreases were also noted in 89.5% (17/19) beats during sinus arrhythmia following prolonged RR intervals. Changes in pulse pressure with ectopy poorly predicted quantitative changes in the LVOT gradient (R 2 ≤ 0.198). However, component analysis of the LVOT gradient suggests that beat-to-beat variability provides information similar to ectopic provocation in characterizing gradients in HCM and that rest and exercise changes converge to a common reference value. Conclusions: Although caution is suggested when interpreting pulse pressure changes with the BBM sign as surrogate for measuring LVOT gradients, this study suggests that analysis of hemodynamic variability in HCM may prove useful in characterizing the severity of obstruction.
Abstract 16646: Inositol 1,4,5-Trisphosphate Receptor Regulation in Atrial Myocyte Microdomains
Authors: Jaime DeSantiago, Disha Varma, Lothar Blatter, Kathrin Banach
Journal: Circulation (2018)

Introduction: InsP 3 receptor type 2 (InsP 3 R2) is up-regulated in patients with atrial fibrillation (AF) and InsP 3 -induced Ca release (IICR) is linked to an increase in premature atrial contractions (PACs). Nevertheless, knowledge of the physiological and pathophysiological relevance and regulation of InsP 3 Rs in the atria is limited. Hypothesis: We hypothesized that InsP 3 R and NADPH oxidase 2 (NOX2) form a functional signaling domain where NOX2 derived reactive oxygen species (ROS) regulate InsP 3 R agonist affinity and contractile strength. Method: Atrial myocytes (AM) were isolated from wild type and NOX2 (gp91 phox-/- ) deficient mice. Changes in cytoplasmic Ca concentration [Ca] i ; fluo-4/AM) or ROS (2’,7’-dichlorofluorescein, DCF) were monitored by confocal microscopy. Results: We demonstrate for the first time in AMs that agonist angiotensin II (AngII) induced IICR and PACs depend on ROS production in a signaling domain of InsP 3 R and NOX2. Superfusion of AMs with AngII (1 μM) significantly increased diastolic [Ca] i (ΔF/F 0 , Ctrl 20’ : 1.0±0.01, AngII 20’ : 1.2±0.03; n=7; p&lt;0.05), the field stimulation induced Ca transient amplitude (ΔF/F 0 , Ctrl: 2.0±0.17, AngII: 2.39±0.22, n=7; p&lt;0.05), and spontaneous Ca releases resulting in PACs (Ctrl: 0 s -1 , AngII: 0.15±0.05 s -1 ; n=7; p&lt;0.05). These effects, were suppressed by InsP 3 R2 blocker 2-aminoethoxydiphenyl-borate (2APB; 1 μM)) and phopholipase C inhibitor, U73122 (10 μM), demonstrating their dependence on IICR. Simultaneously, AngII induced an increase in ROS production that was sensitive to the NOX2 specific inhibitor gp91ds-tat (1 μM). In AMs deficient for NOX2 (gp91 phox-/- ) AngII failed to increase [Ca] i and to induce PACs indicating a sensitization of InsP 3 R by NOX2/ROS. In saponin (0.005%) permeabilized AMs InsP 3 (5 μM) induced spatially defined Ca release events (sparks) that increased in frequency in presence of exogenous ROS (tert-Butyl hydroperoxide: tBHP: 5 μM; InsP 3 : 9.65±1.44 sparks*s - 1 (100 μm -1 ); InsP3 + tBHP: 10.77±1.5 sparks*s -1 (100 μm -1 ), n=5, p&lt;0.05). The combined effect of InsP 3 + tBHP was entirely suppressed by 2-APB suggesting a ROS dependent sensitization of the ryanodine receptor through IICR. Conclusion: Our data show a novel mechanism of InsP 3 R regulation in the atrial muscle that consisting of a functional signaling domain where InsP 3 R and NOX2 closely interact. This mechanism could have relevance in a stretch dependent increase in atrial contractile force.
Abstract 16589: First Demonstration That Small Lp(a) Particles, With Kringle IV Repeats of 24 or Less, but Not Large Lp(a) Particles (More Than 24 Kringle IV Repeats), Are Atherogenic
Authors: Gustavo Vazquez, Brad Brown, Idean B Marvasty, Etienne Guillot, Phillip Janiak, Anthony Muslin, Aruna Bansal, Harry Davis, Roger S Newton, Szilard Voros
Journal: Circulation (2018)

Introduction: It has been demonstrated using statistical methods that smaller lipoprotein (a) [Lp(a)] particles are more strongly associated with atherosclerosis. However, the exact relationship between Lp(a) size (defined by the number of kringle IV repeats) and atherogenicity has not been elucidated. Hypothesis: We hypothesized that smaller, but not larger, Lp(a) particles are atherogenic, with a clear size cut-point. Methods: We determined Lp(a) levels and precise isoform size (defined by number of kringle IV repeats) in 340 subjects in the GLOBAL clinical study (NCT01738828). Atherosclerosis was quantitatively phenotyped using cardiovascular computed tomography angiography, analyzed in central core laboratory. We generated cumulative incidence curves (CIC) to assess relationship between isoform size, concentrations and atherosclerosis. Once we determined cut-point for small vs. large Lp(a), we compared levels by Mann-Whitney test; p&lt;0.05 was significant. Results: Mean age was 56.2±0.72; 49% were male. Lp(a)-mass, particle number and Lp(a)-cholesterol were significantly higher in those with atherosclerosis (Table). In 12 patients who had single isoform only, there was sharp stepdown in atherogenicity with &gt;24 kringle IV repeats (Figure; A); median isoform size was 26 vs. 16 in Controls vs. Atherosclerosis (p&lt;0.05) (Figure; B). Small Lp(a) (24 kringle IV repeats or less) levels were significantly higher in Atherosclerosis; large Lp(a) levels were not different (Figure; D). Increasing levels of small, but not large, Lp(a) particles was associated with atherosclerosis (Figure; E, F). Conclusions: We demonstrated for the first time that 24 kringle IV repeats represent a sharp demarcation between small/atherogenic and large, non-atherogenic Lp(a) particles in humans.
Abstract 16697: Predictive Value of Cardiopulmonary Exercise Testing Parameters for 1-Year Adverse Outcomes in Ambulatory Advanced Heart Failure
Authors: Anuradha Lala, Donna M Mancini, Angiza Shahim, Keyur Shah, David Lanfear, M.D. Lanfear, Jennifer Thibodeau, Maryse Palardy, Amrut Ambardekar, M.D., Dennis McNamara, J.Timonthy Baldwin, Neal Jeffries, Lynne W Stevenson, Shokoufeh Khalatbari, Catherine A Spino, Blair Richards, Douglas L Mann, Garrick C Stewart, Keith D Aaronson
Journal: Circulation (2018)

Introduction: Maximal and submaximal cardiopulmonary exercise (CPX) parameters predict heart failure (HF) outcomes, yet the best predictors in advanced ambulatory HF are not known. Hypothesis: We examined the discriminative value of maximal CPX parameters including peak oxygen consumption (peak VO2), VO2 pulse, circulatory power (CP, peak systolic BP x peak VO2), and end tidal pressure CO2 (PetCO2), as well as submaximal parameters of ventilatory efficiency (VE/VCO2 slope), VO2 at anaerobic threshold (VO2AT) and oxygen uptake efficiency slope (OUES) on the combined outcome of LVAD, UNOS 1 transplant or death at 1 year. Methods: REVIVAL enrolled systolic HF pts in INTERMACS profiles 4-7 despite optimal medical therapy and CRT, of whom 273 performed CPX; 64 did not exercise (26 too ill, 38 for non-cardiac issues). ROC curves display the discriminative power of each parameter using censored c-statistics. The best multivariable model was identified by Cox regression. Results: At 1 year, there were 53 events (10 transplants,19 deaths; 24 LVADs). Pts with and without events were comparable for age (61 vs 60 yrs), LVEF (27 vs 29%), and BMI (31 vs 32 kg/m 2 ).) Peak VO2, VO2AT, OUES, PetCO2, and CP were higher in the no event group (all p &lt;0.001), whereas VE/VCO2 slope was lower (p&lt;0.0001); respiratory exchange ratio was not different. Among the 26 pts too sick for exercise, the event rate was 15/26 (58%) compared to 38/273 (14%) in those exercising (HR=6.7, p&lt;0.0001). Figure displays ROC curves and c-indices for CPX parameters. VO2 pulse (HR 1.18, p=0.017), CP (HR 0.86, p=0.005) and VE/VCO2 slope (HR 1.1, p=0.0001) were significant predictors in the multivariable analysis (model c-statistic=0.80). Conclusions: In ambulatory advanced HF, the inability to perform exercise due to being too ill predicts adverse outcome and for those who can exercise, VE/VCO2 slope is the most robust submaximal CPX parameter, while CP was the strongest maximal parameter to predict death, transplant or LVAD at 1 year.
Abstract 16615: A Rare <i>MEGF8</i> Variant is Involved in the Genetic Risk for Transposition of the Great Arteries
Authors: Anne Moreau de Bellaing, Kylia Williams, Sally Li, Abha S Bais, Cullen B Young, Cecilia W Lo
Journal: Circulation (2018)

Introduction: Transposition of the great arteries (TGA) is one of the most common neonatal heart defects with a prevalence of 0.2 per 1,000 live births. Although some studies have suggested laterality genes and environmental factors are involved, the pathogenesis of this outflow defect is still unclear. The majority of TGA are sporadic, arguing for a polygenic etiology. Methods: Whole exome sequencing (WES) analysis was conducted on 104 unrelated subjects with isolated or complex TGA. Variants in 20 human and mouse genes previously reported with TGA were recovered using frequency filter of 1%. These were compared to those on 120,000 subjects of the Genome Aggregation Database (GnomAD). Results: Among variants recovered in the 20 selected genes, we observed 14 (13.5%) patients with rare variants in MEGF8 . Four patients shared the same MEGF8 rare variant (0.26% in GnomAD) causing missense of a conserved amino acid (p.Val2502Ile). This variant is significantly overrepresented in the TGA cohort (OR=7.6, p =0.002). MEGF8 encodes a type I transmembrane protein shown to play a role in laterality specification in zebrafish and mice. It also has been shown to negatively regulate Hedgehog (Hh) signaling. Interestingly, recessive MEGF8 mutations are associated with Carpenter’s syndrome characterized by multiple congenital malformations and skeletal dysplasia. Unlike Carpenter’s mutations mostly distributed at the MEGF8 protein N-terminus, the variant we highlight is at the C-terminal extremity. Also of note, all TGA patients were heterozygous, except for one patient with cleft palate who had compound heterozygous MEGF8 mutations. Interestingly, 10 of the TGA patients also had rare variants in at least one other TGA-associated gene, supporting a complex genetic model of disease for TGA. Using fibroblasts from TGA patients with this variant and also Megf8 mutant mice with TGA, we are assaying Hh signaling pathway to confirm its role in TGA pathogenesis. Conclusions: We identified MEGF8 as a gene significantly associated with TGA, especially a rare variant localized at the C-terminus. The co-occurrence of rare variants in other laterality genes supports a multigenic etiology for TGA and points to the involvement of laterality defects in TGA pathogenesis.
Abstract 13804: True Anemia in Heart Failure Patients: Peripheral Hematocrits Lack Sensitivity and Specificity as a Predictor of Measured Red Blood Cell Volumes in a Mixed-LVEF Cohort
Authors: Marc A Silver, John E Strobeck, Jonathan A Feldschuh
Journal: Circulation (2021)

Introduction: Anemia is a common and serious co-morbidity of heart failure (HF) that is undertreated, impacting outcomes for HF patients and the overall economics of HF. Studies have shown that anemia is associated with worse outcomes in HF, but to date interventional studies aimed at treating anemia in HF have failed to demonstrate conclusive outcome improvements. A common feature of past studies is that they generally defined anemia via a threshold of peripheral Hct (or via Hemoglobin, which has a direct linear relationship to Hct). Methods: In a recently published study of a mixed-LVEF cohort of 245 HF patients, red cell volume status relative to patient norms was quantified using direct blood volume analysis (BVA, Daxor, Oak Ridge, TN). We evaluated the suitability of a Hct for detecting true anemia (as measured by BVA) in this group. Although Hct was somewhat correlated (R 2 =0.43) with red cell volume (RCV) deviation from ideal (as measured directly by BVA), actual RCV status was heterogeneous. We performed an analysis of the specificity and sensitivity of Hct as an indicator of true anemia, defined as RCV &lt; 90% of normal value. Results: The distribution of true anemia is shown in Figure 1. Visual inspection shows mixed anemia status across a broad range of Hct values. We examined three Hct thresholds for determining true anemia. Two thresholds were defined based on deviations from normal Hct (M=45, F=40); a third threshold was chosen at 24 for both genders, corresponding to a common transfusion trigger. Using a moderate 10% deviation threshold yielded a sensitivity of 96%, but a specificity of only 50%, due to a False Positive (dilutional anemia) rate of 19%. Using a more extreme 25% deviation threshold yielded a specificity of 90%, but a sensitivity of only 62%, due to a False Negative (FN) rate of 23%. The transfusion trigger had a FN rate of 61%. Conclusions: Hct lacks sensitivity and specificity for detecting true anemia. Interventions for anemia in HF would benefit from BVA.
Abstract 16666: Comparison of Wall Stresses After Ross Procedure Using Ex-Vivo Pulmonary Autograft vs in-vivo Autograft Imaging
Authors: Yue Xuan, Zhongjie Wang, Shalni Kumar, Ismail El-Hamamsy, Francois Pierre-Mongeon, Richard Leask, Liang Ge, Elaine Tseng
Journal: Circulation (2018)

Introduction: Ross operation provides young adult and pediatric patients a living valve with excellent hemodynamics and no lifelong anticoagulation. However, autograft dilatation is a concern when it leads to aneurysm formation and autograft insufficiency requiring reoperation. Computational simulations of autograft remodeling are potentially effective to predict autograft dilatation, but require zero-pressure geometry and patient-specific material properties for accuracy. Hypothesis: We hypothesized that pulmonary autograft wall stresses estimated from computational simulations using in-vivo imaging would reasonably correlate with the gold standard, wall stresses determined computationally using ex-vivo autograft specimens at zeto-pressure. We recently showed that autograft wall stresses significantly increased immediately after the Ross operation. Our goal was to compare autograft wall stresses based on in-vivo geometry to those based on ex-vivo autografts. Methods: Magnetic resonance imaging (MRI) was obtained in pre-operative Ross patients and used to reconstruct in-vivo autograft geometry. Pre-stress (zero-pressure) geometry was determined. As controls, pulmonary autografts explanted from normal donor hearts underwent micro-computed tomography scans for reconstruction of ex-vivo geometry. Biaxial stretch testing was performed on both intraoperative tissue from Ross patients and on ex-vivo autografts to determine patient-specific material properties. Finite element simulations using LS-DYNA were performed to determine wall stresses. Results: Imaging from ex-vivo pulmonary autografts (n=6) and Ross patients (n=6) were obtained. Peak stresses were 93 kPa for ex-vivo vs. 113 kPa for in-vivo autografts at 25mmHg and 448kPa vs. 558 kPa, respectively at 120mmHg. Conclusions: Wall stresses at pulmonary and systemic systolic pressure predicted by in-vivo MRI imaging reasonably correlated with wall stresses based upon ex-vivo autograft tissue. Computational simulations using in-vivo imaging provides a suitable surrogate for the gold standard simulations using ex-vivo tissue specimens and broadens clinical applicability of computational simulations for patient-specific outcomes.
Abstract 16699: Single Cell Sequencing Reveals Changes in Monocytes in Patients With Mutations Leading to Clonal Hematopoiesis: Implications for Prognosis of Ischemic Heart Disease
Authors: Wesley T Abplanalp, David John, Birgit Assmus, Lena Dorsheimer, Tina Rasper, Christina Ortmann, Andreas Ecke, Khalil Abou-El-Ardat, Tobias Schmid, Bernhard Brüne, Sebastian Wagner, Hubert Serve, Jedrzej Hoffmann, Florian Seeger, Michael A Rieger, Andreas M Zeiher, Stefanie Dimmeler
Journal: Circulation (2018)

Background: Cardiovascular disease is the leading cause of death worldwide; the majority of these deaths are due to ischemic heart disease (IHD). Recent data suggest that inflammation causally contributes to IHD. However, the detailed characterization of the individual inflammatory status of individual cells on a cellular level is missing. Single cell sequencing provides a novel opportunity to define subsets of hematopoietic cells mediating inflammation in humans. Therefore, we determined the inflammatory burden driven by heterogeneity in monocytes in subjects with IHD. Results: We sorted circulating CD31+ cells of patients with IHD versus healthy controls (n=4 per group) and performed single-cell RNA-sequencing. Unsupervised clustering of the entire 37679 cells generated 19 clusters with unique transcriptional profiles. Cells of patients with IHD showed a strikingly different pattern and dysregulated pathways compared to healthy controls. Among the specific dysregulated genes were S100A8, interleukin 1b, thrombospondin-1 and matrix metalloprotease-1, which were confirmed by FACS and qRT-PCR in a validation cohort. Because of the profound differences in each of the individual patients, we evaluated the occurrence of somatic mutations leading to clonal hematopoiesis (CHIP), which recently was shown to be increased in patients with atherosclerosis. Indeed, two of the four patients revealed a mutation in the DNA methyltransferase DNMT3A. DNMT3A mutations were associated with a change in known DNMT3A target genes such as the pro-inflammatory genes CXCL1, CXCL2 and IL6. To determine the impact of DNMT3A mutations on prognosis, we sequenced a cohort of n=200 patients with IHD. Among these patients n=13 harbored a DNMT3A mutation. Mortality of non-CHIP carriers was 23%, but 62% for DNMT3A mutation CHIP-harboring patients (p=0.012). Conclusions: This study shows that circulating cells derived from CHIP-harboring individuals have unique phenotypes. DNMT3A mutations strongly predict increased mortality in patients with ischemic heart failure relative to subjects without CHIP mutations.