tbuckley/cabot-search huggingface dataset:
Abstract 18754: The Variants of Uncertain Significance Issue on Steroids: Determination of the Background Genetic Noise Rate Within the Known Channelopathy/Cardiomyopathy-Susceptibility Genes
Authors: Jamie D Kapplinger, Michael J Ackerman
Journal: Circulation (2013)

Background: Next-Generation Sequencing (NGS) allows for sequencing of a many genes simultaneously, leading genetic testing companies to provide sequencing of all genes associated with a particular disease in large gene test panels. For example, there are over 90 distinct genes associated with premature sudden arrhythmic death. Previous publiclations have shown a background rate of rare non-synonymous single nucleotide variants (nsSNVs) in many of these genes which may be compounded when included in large gene panels. Therefore, we hoped to determine this background rate of nsSNVs in 93 genes that comprise various sudden death genetic heart disease genetic test panels. Methods: The exomes from the 1000 Genomes Project (1kG) and the NHLBI Exome Sequencing Project (ESP) were genotyped in-silico for nsSNVs in 93 genes indentified on clinically available genetic tests available for HCM, DCM, ARVC, LQTS, SQTS, BrS, and CPVT. The number of subjects hosting an exceedingly rare and unique nsSNV was determined for each gene. Results: Strikingly, 40.8% of the 1 kG cohort (12.5% hosted &gt; 2 unique nsSNVs) and 41.9% of the ESP cohort possessed &gt; 1 rare nsSNV within the entire 93 gene panel, while the yield of rare nsSNVs in individual genes only ranged from 0.02% for PLN to 2.3% for DMD. This background rate directly correlated with the number of genes on the panel (r=0.97). When limited to only those genes that account for &gt;10% of the disease (HCM - MYBPC3, MYH7; LQTS - KCNQ1, KCNH2; ARVC - PKP2, DSG2; CPVT - RYR2; BrS - SCN5A), at least 7% of the subjects in both cohorts had at least one nsSNV. Thus, nearly 90% of the background rate is contained within the minor disease-susceptibility genes. Conclusions: Despite not being enriched for the presence of genetic channelopathies and cardiomyopathies, two out of every 5 subjects within these cohorts hosted at least 1 ultra-rare nsSNV within the 93 known channelopathy/cardiomyopathy-susceptibility genes. Despite the anticipated transition from disease-specific genetic testing to whole exome genetic testing, great caution must be exercised to glean the true pathogenic mutation amidst this very daunting burden of background genetic noise. If handled poorly, false positive genetic test results and misguided cascade screens will increase.
Abstract 13502: Statins Buffer the Vasoconstricting, Pro-Inflammatory and Pro-Oxidant Effects of Experimental Venous Congestion in Patients With Systolic Heart Failure on Stable Medical Regimen
Authors: Paolo C Colombo, Ka Yuk Wong, Duygu Onat, Yacki Hayashi, Ante Harxhi, Myra Ahmad, Serge Cremers, Hani N Sabbah, Thierry H Le Jemtel, Ryan T Demmer
Journal: Circulation (2015)

Background: In heart failure (HF), statins decrease hospitalizations for acute decompensation, which are primarily due to venous congestion (VC). The reason is unknown. We tested whether statins buffer the vasoconstricting, pro-inflammatory and pro-oxidant effects of VC in an established human model of this condition. Methods: We studied 41 pts, NYHA class II-III, LVEF &lt;40%, euvolemic and on stable medical therapy. To experimentally model VC, venous arm pressure was increased to 30 mmHg above baseline by inflating a pressure cuff around the dominant arm. Blood was sampled from test and control arm (lacking an inflated cuff) before and after 90 minutes of VC. Plasma endothelin-1 (ET-1), interleukin-6 (IL-6), and vascular cell adhesion molecule 1 (VCAM-1) were measured by ELISA; isoprostane by LC-MS. Results: Age was 53±2 years, 32% were female, 29% had an ischemic etiology, LVEF was 22±1%, 56% were treated with a statin. Experimental VC increased plasma isoprostane, ET-1, VCAM-1 and IL-6. However, the use of a statin greatly influenced the rate of this response: the increase in isoprostane (marker of oxidative stress) was four-fold higher among nonstatin vs statin users (62.3±11 vs 15.4±11.2 pg/ml, p=0.01); ET-1 (marker of vasoconstriction and inflammation) increased 50% more among nonstatin users (1.83±0.23 vs 1.21±0.21 pg/ml, p=0.05); VCAM-1 (marker of endothelial activation) increased 80% more among non-statin users (62.5±15.1 vs 33.6±13.3 pg/ml, p=0.16). Changes in IL-6 (marker of inflammation) did not differ in the two groups (1.2±.08 vs 1.1±0.08 pg/ml, p=0.78). Of note, the effects of statins on ET-1 was dose-dependent. Conclusions: We provide the first evidence that statins (particularly at high dose) partially buffer the vasoconstricting, pro-inflammatory and pro-oxidant effects of experimental VC. Future studies are warranted to address whether short-term high dose statins have an adjunctive role in the treatment of acute decompensation in HF pts.
Abstract 13061: Right Atrial Strain Combined With Ve/vco <sub>2</sub> in Early Detection of Systemic Sclerosis Pulmonary Vascular Involvement
Authors: Ailia Giubertoni, Miriam Gravellone, Jacopo Zanaboni, Cristina Piccinino, Paolo N Marino
Journal: Circulation (2016)

Introduction: Systemic sclerosis (SSc) is at risk of developing pulmonary vasculopathy (PV) leading to pulmonary arterial hypertension (PAH), right heart failure and death. Early detection of this life-limiting complication may allow timely therapy and improve patients’ survival. Nevertheless, standard non-invasive screening tests are not fully adequate to identify milder degrees of vascular disease and right heart catheterization is reserved to hemodynamic confirmation. An integrating strategy including reliable specific echocardiographic and CPET parameters may identify “pre-clinic” PV and better characterize patients that warrant further attention. Hypothesis: The aim of this study was to test the value of right atrial (RA) two-dimensional strain echocardiography (2D-STE) combined with VE/VCO2 slope in the early detection of PV in SSc patients. Methods: We recruited 57 asymptomatic, consecutive, SSc patients without previous diagnosis of PAH, referred to our specialized out-patients clinic from April 2015 to March 2016. Six patients were excluded because unsuitable for CPET. The remaining 51 patients (48 female and 3 male - mean age 61±11years) had normal resting pulmonary function, chest X-ray, BNP, blood routine test and standard echo parameters. RA 2D STE was assessed by averaging all segments in dedicated 4-chamber view. During an incremental CPET we analyzed: minute ventilation, workload, peak oxygen uptake, oxygen pulse, anaerobic threshold, ventilatory reserve and VE/VCO2 slope. We also studied 11 matched controls. Results: Despite normal standard CPET parameters, we found that SSc patients had higher VE/VCO2 slope (mean 31,4±5,1 vs. 24,3±3,7; p &lt;0.001) and lower RA strain (mean 21,4±9.0% vs. 27,5±6.0%; p=0,01) than controls. Moreover, VE/VCO2 slope, but not traditional parameters as BNP, RA area, PAPs and TAPSE, showed a significant correlation with RA strain (r=-0.32 p&lt; 0.002). In particular, patients with VE/VCO2 slope &gt;34 had lower strain than patients with VE/VCO2 slope ≤34 (mean 15,6±3,8% vs. 23,8±9,5%; p&lt;0,001). Conclusions: In asymptomatic SSc patients, combined approach with VE/VCO2 slope and RA strain could unmask milder forms of PV, improve SSc patients’ characterization and minimize diagnosis delay.
Abstract 13036: Relations of Metabolically Healthy and Unhealthy Obesity and to Digital Vascular Function in Three Community-based Cohorts: A Meta-Analysis
Authors: Luisa C Brant, Na Wang, Francisco M Ojeda, Michael LaValley, Sandhi M Barreto, Emelia J Benjamin, Gary F Mitchell, Ramachandran S Vasan, Joseph N Palmisano, Thomas Munzel, Stefan Blankenberg, Philip S Wild, Tanja Zeller, Antonio L Ribeiro, Renate B Schnabel, Naomi M Hamburg
Journal: Circulation (2016)

Introduction: Obesity and metabolic risk factors induce microvascular dysfunction, a marker of early vascular disease that predicts cardiovascular events. Whether obese individuals with a metabolically healthy profile have impaired microvascular function remains unclear. Objectives: The aim of this study was to evaluate the relation of obesity phenotypes stratified by metabolic status to microvascular function. Methods: We meta-analyzed aggregate data from 3 large cohorts (Brazilian Longitudinal Study of Adult Health, the Framingham Heart Study and the Gutenberg Heart Study; N= 16830 participants, age range 19-90, 48.7% women). Regression slopes between cardiovascular risk factors and microvascular function, measured by peripheral arterial tonometry (PAT), were calculated for each cohort. Individuals were classified as normal-weight, overweight or obese by body mass index (BMI) and further stratified by healthy or unhealthy metabolic status based on metabolic syndrome defined by the ATP-III criteria. Results: Male sex, BMI and the presence of metabolic risk factors were associated with more impaired PAT measures ( P &lt;0.0001 for baseline pulse amplitude, P &lt;0.01 for PAT ratio). There was stepwise impairment of vascular measures from normal weight to obesity in both metabolic status strata (all P &lt;0.0001). Metabolically healthy obese had more impaired vascular function than metabolically healthy normal-weight individuals (baseline pulse amplitude 6.12±0.017 vs. 5.61±0.010; PAT ratio 0.58±0.008 vs. 0.76±0.005, respectively, all P &lt;0.0001). Within the same BMI category, metabolically healthy individuals had better vascular function than their metabolically unhealthy counterparts (all P &lt;0.0001). Conclusion: Metabolically healthy obese individuals have impaired microvascular function, though the degree of impairment is less marked than in metabolically unhealthy obese individuals. Our findings suggest that obesity is detrimental to vascular health irrespective of metabolic status.
Abstract 13704: Leisure Activity is Associated With Prognosis in Heart Failure With Preserved Ejection Fraction - Results From the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial
Authors: Sheila M Hegde, Amil M Shah, Brian Claggett, Inder S Anand, Sanjiv J Shah, Nancy K Sweitzer, Marc A Pfeffer, Scott D Solomon
Journal: Circulation (2015)

Background: Leisure-time physical activity is inversely associated with cardiovascular (CV) outcomes in healthy populations but the impact of leisure activity in heart failure with preserved ejection fraction (HFpEF) is unknown. We hypothesized that poor leisure activity predicts CV outcomes in HFpEF patients. Methods: The baseline self-reported physical activities of 1751 subjects from the Americas region of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial were categorized as poor, intermediate, or ideal by American Heart Association (AHA) criteria. Leisure activity was related to the primary composite outcome (heart failure [HF] hospitalization, CV mortality, or aborted cardiac arrest), its components, and all-cause mortality using multivariable Cox models. Results: The mean age was 71.5 ± 9.7 years. Few patients met AHA criteria for ideal activity (11.0% ideal, 14.0% intermediate, 74.9% poor). Over a median follow-up of 2.4 years, the primary composite outcome occurred in 519 patients with a total of 397 HF hospitalizations, 222 CV deaths, and 6 aborted cardiac arrests. Compared to those with ideal activity, poor baseline activity was associated with a greater risk of the primary outcome (HR 1.53; 95% CI, 1.10-2.13), HF hospitalization (HR 1.65; CI, 1.12-2.44) (Figure), CV mortality (HR 1.38; CI, 0.86-2.23), and all-cause mortality (HR 1.70; CI, 1.16-2.50) after multivariable adjustment for potential confounders. A dose-response relationship was also present such that those with the least activity demonstrated highest risk of the primary composite outcome, HF hospitalization, and all-cause mortality (p for trend all ≤ 0.01). Conclusions: In patients with HFpEF, poor baseline leisure activity is associated with higher risk of HF hospitalization and mortality.
Abstract 18863: Emerging Role of Cytoglobin in Cardiovascular Function and Regulation: Evidence From Cytoglobin Knockout Mice
Authors: M A Hassan Talukder, Raed S Ismail, Mohamed A El-Mahdy, Le T Thuy, Norifumi Kawada, Jay L Zweier
Journal: Circulation (2013)

Cytoglobin (Cygb), a recently identified globin protein, is reported to play an important role in O 2 -dependent nitric oxide (NO) removal, nitrite reduction and NO production; and it is thought to be involved in vascular function. However, there is no report on the effect of Cygb in cardiovascular (CV) function. Recently, a genetically modified mouse model with global absence of Cygb was developed. Therefore, to investigate the role of Cygb in CV function and regulation, we utilized this mouse model to explore the role of Cygb for in vivo (echocardiography) and in vitro (isolated perfused hearts) cardiac hemodynamics. Tail-cuff BP measured in conscious animals was &gt;20 mmHg lower in Cygb-knockout (Cygb-KO) mice than in age-matched (6-months) wild-type (WT) mice. Importantly, echocardiographic parameters in Cygb-KO mice were markedly different from WT mice (Table). Cardiac chambers in Cygb-KO mice were significantly larger with increased end-systolic and end-diastolic volumes; however, there was septal hypertrophy with large stroke volume, but no differences in heart rate or fractional shortening. In isolated hearts, coronary flow was significantly higher in Cygb-KO hearts, but other parameters were comparable (Table). Thus, the absence of Cygb results in marked hypotension, ventricular chamber dilatation and dysfunction yet with preserved cardiac contractile function. Collectively, these data from both in vivo and in vitro studies provide direct evidence that Cygb plays a critical role in CV pathophysiology, and its absence during stressful conditions may lead to progressive high output cardiomyopathy or heart failure that warrants in-depth investigation.
Abstract 18748: High Resolution Structure Determination and Small Molecule Inhibitor Identification of NPP4, a Procoagulant Enzyme Localized to Brain Vascular Endothelium
Authors: Demetrios Braddock
Journal: Circulation (2013)

We recently identified the enzyme NPP4, an uncharacterized member of the nucleotide pyrophosphatase/phosphodiesterase family, as present at high concentrations on the vascular surface of the brain and promotes platelet aggregation in a dose dependent manner at physiologic concentrations of AP3A. AP3A is a small molecule stored at high concentrations in platelet dense core granules and is released upon platelet activation at high concentrations in the vicinity of the growing thrombus. Ap3A has a significantly longer lifespan in whole blood than ADP and has long been thought to promote stable thrombus formation by serving as a ‘chemically masked’ source of ADP. The goal of the present study was to determine the high-resolution three-dimensional structure of NPP4, and to identify small molecule inhibitors of NPP4 useful for the in vitro and in vivo validation of the physiologic role of the enzyme. We used X-ray crystallography to determine the high-resolution structure of the enzyme, and high-throughput small molecule screening to identify lead small molecules as lead inhibitors. The three-dimensional structure of the enzyme was determined to1.5Å resolution in the presence and absence of its enzymatic product (AMP), and high-affinity (nM) small molecule inhibitors of NPP4 were identified as lead inhibitors in high throughput small molecule screens. Structure-activity relationships (SAR) of the lead compound were explored via chemical derivatization, and three-dimensional structures of the lead compounds were obtained to assist a structure-guided approach to lead optimization. Our combined studies lay the foundation for the validation of the biological role of NPP4 in hemostasis and establishes the necessary tools and reagents for the translational application of our preliminary findings into the clinic.
Abstract 18878: Development of a Unique Mode of Cardiac Remodeling in Muscular Dystrophy Patients
Authors: Ryan C Martin, Colby R Ayers, Parag C Patel, David W Markham, Jennifer T Thibodeau, Susan A Matulevicius, Mark H Drazner, Pradeep P Mammen
Journal: Circulation (2013)

The muscular dystrophies (MD) represent an array of inherited myogenic disorders involving mutations and dysregulations of a variety of cytoskeleton or nuclear proteins. Many MD patients also develop a commitant cardiomyopathy. Despite the high incidence of end-stage cardiomyopathy in MD patients there is limited data regarding the mode of maladaptive cardiac remodeling that develops in these patients. In this retrospective study, we examined the hypothesis that MD patients with a cardiomyopathy develop a unique mode of cardiac remodeling as compared to patients with other forms of nonischemic cardiomyopathy. We examined the cardiac MRIs of 3 cohorts (N = 35 per cohort): patients with neuromuscular disorders with associated cardiomyopathy; patients with primary idiopathic nonischemic cardiomyopathy (NICM); and healthy patients from the Dallas Heart Study (DHS). The cardiac MRIs in each group were reviewed, assessing objective measurements of left ventricular ejection fraction (LVEF), mass (LVM), and end diastolic volume (LVEDV). LVM and LVEDV were indexed for body surface area. In addition, left ventricular concentricity 0.67 (LV Conc 0.67 = LVM / LVEDV 0.67 ), a surrogate marker for wall thickness known to decrease in advanced nonischemic heart failure, was computed for each patient. Despite a preserved ejection fraction in the neuromuscular cohort compared to the NICM cohort (58% vs. 30 %, p&lt;0.05), both displayed similar reduced LV Conc 0.67 (4.69 ± 1.05 and 5.16 ± 1.47) compared to the DHS cohort (7.27 ± 0.83). However, whereas the nonischemic cohort demonstrated hypertrophy with marked dilation (95.8 vs. 84.6 g/m 2 and 119.4 vs. 54.7 mL/m 2 , DHS comparison, p&lt;0.05), the neuromuscular cohort demonstrated a reduced cardiac mass (65.6 vs. 84.6 g/m 2 , p&lt;0.05) with only moderate dilation (74.5 vs. 54.7 mL/m 2 , p&lt;0.05) compared to the DHS population. In conclusion, our data suggests that MD patients develop a unique mode of cardiac remodeling and highlights that novel signaling pathways are involved in the development of cardiomyopathy in these patients.
Abstract 18739: Novel Protein Glycan Derived Marker of Systemic Inflammation is Associated With Incident Cardiovascular Disease
Authors: Akintunde O Akinkuolie, Julie E Buring, Paul M Ridker, Samia Mora
Journal: Circulation (2013)

Background: Enzymatically glycosylated proteins partake in multiple cellular processes, with variations in their concentration implicated in innate immunity and chronic inflammation. In addition, most inflammatory proteins are enzymatically glycosylated. GlycA is a novel nuclear magnetic resonance (NMR) biomarker whose signal originates from the N-acetyl groups of N-acetylglucosmine and N-acetylgalatosamine moieties of protein glycans. We tested the hypothesis that GlycA is related to incident CVD and compared it with high sensitivity C-reactive protein (hsCRP) Method: Baseline GlycA was quantified by NMR spectroscopy (LipoScience, NC) in 27 649 participants of the Women’s Health Study. A total of 1 651 cases of incident CVD events occurred during a median follow up of 17 years Results: GlycA correlated with LDL cholesterol (r = 0.17), HDL cholesterol (r = -0.27), triglycerides (r = 0.47), BMI (r = 0.41) and hsCRP (r = 0.61), all p&lt;0.0001. Multivariable-adjusted Cox regression HRs (95% CIs) across increasing quartiles of GlycA for incident CVD were 1.00, 1.10 (0.92-1.30), 1.34 (1.14-1.58) and 1.64 (1.39-1.94), p trend &lt;0.0001, similar in magnitude to the association of hsCRP with CVD (Table). The association of GlycA with CVD was attenuated but remained significant after additional adjustment for lipids (p-trend=0.0006). Further adjustment for hsCRP attenuated the association which was no longer statistically significant (p trend=0.33). In joint models examining combined levels of GlycA and hsCRP, CVD risk was highest when both GlycA and hsCRP were elevated: fully-adjusted HR 1.39 (1.13-1.71), p=0.002 Conclusion: A novel protein glycan derived biomarker, GlycA, was associated with a graded increase in the risk of incident CVD events in this prospective study of initially healthy women in a manner similar to hsCRP. The association of GlycA with CVD was attenuated after adjusting for hsCRP, consistent with a possible role for protein glycans in inflammation and CVD
Abstract 12825: Feasibility of Amplitude Spectrum Area Estimation in Ventilation Pauses During Cardiopulmonary Resuscitation
Authors: Liang Wei, Chenxi Dai, Peng Gao, Weilun Quan, Yongqin Li
Journal: Circulation (2016)

Introduction: Amplitude spectral area (AMSA) calculated from ventricular fibrillation (VF) waveform not only predicts defibrillation outcome, but may also reflect effectiveness of chest compressions. However, reliable VF waveform analysis usually requires rescuers to stop compressions. In the present study, we investigated whether AMSA could be accurately estimated in ventilation pauses during cardiopulmonary resuscitation (CPR). Methods: A total of 40 out-of-hospital cardiac arrest patients with VF as the initial rhythm were included in this study. All patients received resuscitation with a 30:2 compressions to ventilation ratio. ECG data and chest compression waveforms before first defibrillation were extracted. Each episode included at least one full resuscitation cycle consisting of 30 compressions followed by a ventilation pause, further compressions, and a pre-shock pause with artifact-free VF signal. AMSA was continuously calculated using a sliding window of 2 seconds duration with sliding step size of 1 sampling point. Ventilation pauses were identified by the chest compression waveforms. Mean AMSA value during chest compression (AMSA_c) and minimal AMSA value during ventilation pause (AMSA_p) were compared with the AMSA value measured in noise-free VF (AMSA_nf) during the pre-shock pause. Results: Twenty patients received mechanical CPR and other 20 patients received manual chest compressions. The ventilation pause was 3.19±0.62 sec for mechanical CPR and 5.96±2.06 for manual CPR. AMSA_c was significantly higher than AMSA_p (32.4±30.0 mVHz vs. 6.6±3.9 mVHz, p &lt;0.01) and AMSA_nf (32.4±30.0 mVHz vs. 6.0±3.5 mVHz, p &lt;0.01). As shown in Figure 1, AMSA_nf was strongly correlated with AMSA_p (r=0.90, p &lt;0.01) but not with AMSA_c (r=0.50, p =0.11). Conclusions: AMSA could be reliably determined in ventilation pauses during CPR but not during chest compressions.