tbuckley/cabot-search huggingface dataset:
Abstract 16946: Proteomics Identifies Inflammatory, Lipid, and Cell Proliferative Pathways in Diastolic Dysfunction in HIV: A CHART Substudy
Authors: Svati H Shah, Lydia Kwee, Steven McNulty, Priscilla Hsue, Patrice Desvigne-Nickens, Sanjiv J Shah, Adrian F Hernandez, Eugene Braunwald, Javed Butler
Journal: Circulation (2018)

Background: Anti-retrovirals have shifted the epidemiology of heart failure in HIV from one of systolic dysfunction to that of diastolic dysfunction (DD), but the underlying mechanisms are incompletely understood. We hypothesized that a proteomics analysis could identify novel biomarkers of DD in HIV. Methods: The NIH-funded Characterizing Heart Function on Anti-Retroviral Therapy (CHART) study enrolled HIV-infected individuals through the Heart Failure Network (HFN) with the goal of identifying clinical, imaging, and molecular markers of DD in HIV. Using the Olink platform (proximity extension assay technology), we profiled 977 proteins in frozen plasma samples from the 195 individuals enrolled in CHART. Logistic regression was used to compare protein levels between DD cases (N=94) and controls without DD (N=101). Results: We observed differences in many proteins between DD+ and DD- including inflammation (EDA2R, TNF-R1, TNFRSF19, VSIG4), lipid metabolism (leptin, FABP4, CLMP, PON3, PLIN1), cell proliferation and cell-cell adhesion (IGFBP6, TGFBR2, NOV, INHBC), and extracellular matrix (COL18A1, PRELP, HSPG2, COL1A1) proteins (p= 1.4x10 -3 – 1.2x10 -4 ). Of these, eight met false discovery rate (FDR) adjustment (EDA2R [tumor necrosis factor receptor superfamily member], leptin, FABP4 [fatty acid binding protein 4], CLMP [cell-cell adhesion, adipocyte differentiation], IGFBP6 [IGF binding protein involved in cell proliferation], TGFBR2 [transforming growth factor binding receptor 2], NOV [cell proliferation and adhesion], INHBC [member of TGF-β superfamily involved in cell development], and adrenomedullin, all FDR p&lt;0.05). Adjustment for BMI, SBP, age, creatinine attenuated results (nominal p=0.24 – 1.3x10 -3 ). Pathway analysis identified extracellular space, TNF activated receptor activity, cytokine-cytokine receptor interaction, collagen trimer, glycosaminoglycan binding, and response to chemical stimulus pathways (FDR P=5x10 -4 - 5x10 -7 ). Conclusions: Using a high throughput proteomics platform we have identified proteins that differentiate HIV-infected individuals with DD from those without DD, highlighting potential biomarkers and molecular mechanisms mediating DD in HIV for further investigation.
Abstract 16709: Multicenter Assessment of Wearable Cardioverter Defibrillator Use in Patients at Risk of Sudden Cardiac Death: France National Experience
Authors: Eloi Marijon, Nicolas Combes, Daniel Gras, Nicolas Sadoul, Laurence Guedon-Moreau, Christophe Leclercq, Fabrice Extramiana, Nicolas Lellouche, Pascal Defaye
Journal: Circulation (2018)

Hypothesis: The wearable cardioverter defibrillator (WCD) has been shown to be useful during transient periods of high sudden cardiac death risk. This Registry was designed to provide real-world data on WCD use in France, in terms of compliance, potential adverse events, as well as efficacy. Methods: Multicenter evaluation (WEARIT FRANCE Registry) was conducted in France between January 2017 and March 2018. Overall, 1013 patients with complete data sets were analyzed: 834 with ischemic heart disease (82%, including 577 patients after myocardial infarction), 111 after ICD explant (11%), and 68 pre-transplant (7%). The median age was 61 years; the median ejection fraction was 25.4%. Results: Median WCD wear time was 61 days, with median daily use of 23.4 hours. Less than 1% of patients did not wear WCD at least 4 hours per day. During follow-up, a total of 35 sustained ventricular tachyarrhythmias (VT/VF) occurred in 30 patients, of whom 56.7% (n=17) received appropriate WCD shocks, giving an incidence of appropriate therapy of 1.7% . The rate of all VT/VF episodes were 2.9% among patients with ischemic cardiomyopathy (n=24/834) versus 3.3% for the others (n=6/179). Of the ischemic patients wearing beyond 30 days (N=657), 7 received appropriate therapy. Overall shock survival was 100%. Supra-ventricular tachycardia occurred in 6 patients. At the end of the WCD period, 564 patients (55.7%) were implanted with an implantable cardioverter defibrillator. Among the patients who had an ejection fraction below 35% at baseline, and were not implanted with an implantable cardioverter defibrillator (N=416), 351 (82%) had an improvement in ejection fraction to &gt;35%. Five patients (0.49%) received inappropriate WCD shocks. Conclusions: In this multicenter nationwide WCD evaluation, 3% of patients presented with sustained VT/VF with 40% of those patients developing VT/VF after 30 days. The incidence of inappropriate therapy was low. These data suggest that the WCD, when worn appropriately, may be helpful in the arsenal to protect high-risk patients against SCD, especially in case of transient risk situations.
Abstract 16902: The Effect of Kidney Function on Antithrombotic Regimen Among Patients With Atrial Fibrillation and Acute Myocardial Infarction: Insights From the National Cardiovascular Disease Registry’s Acute Coronary Treatment and Intervention Outcomes Network Registry
Authors: Jonathan M Wong, Jennifer A Rymer, Anita Y Chen, Tracy Y Wang, Richard E Shaw
Journal: Circulation (2018)

Introduction: The impact of kidney function in selecting antithrombotic therapy at hospital discharge for patients with atrial fibrillation (AF) who survive an acute myocardial infarction (AMI) is uncertain. Hypothesis: We hypothesized that kidney dysfunction is associated with decreased oral anticoagulant (OAC) use in AF patients who survive AMI. Methods: We studied 30,308 AF patients at 791 hospitals who survived AMI and were hospitalized between January 2015 and December 2017 (Acute Coronary Treatment and Intervention Outcomes Network Registry). We separated patients into 4 mutually exclusive groups: triple antithrombotic therapy (TAT), dual-antiplatelet therapy (DAPT), dual antithrombotic therapy excluding DAPT (DAT), and single therapy. Logistic regression was used to explore the trend for each antithrombotic strategy across CKD stage. Results: Of the 30,308 patients included in this analysis, 6,618 were on TAT (22%), 12,920 on DAPT (43%), 6,148 on DAT (20%), and 4,622 were on single therapy (15%). Overall, 46% of patients were discharged on an OAC (warfarin 22%; apixaban 14%; rivaroxaban 8%; dabigatran 2%). Patients with higher CHA 2 DS 2 -VASC scores (≥4) were more likely to be discharged on oral anticoagulation, except patients with GFR &lt; 15 ml/min/1.73m 2 . Compared to patients with normal kidney function, patients with GFR &lt; 30 ml/min/1.73m 2 had lower rates of TAT use (23% vs. 18%) despite higher warfarin use (20% vs. 27%). Within each antithrombotic discharge strategy, there was no significant trend across GFR strata among patients with in-hospital PCI ( Figure ). Conclusion: Significant heterogeneity in antithrombotic discharge strategy was seen among AF patients who survived AMI, however, the trend of each strategy across CKD stage was not significant among patients with in-hospital PCI. More research is needed to understand whether a particular antithrombotic strategy has improved outcomes in this population.
Abstract 16643: Clinical Implications of Identifying Pathogenic Variants in Aortic Dissection Patients With Whole Exome
Authors: Bo Yang, Brooke Wolford, Whitney E Hornsby, Dongchuan Guo, Wei Zhou, Maoxuan Lin, Linda Farhat, Jennifer McNamara, Anisa Driscoll, Xiaoting Wu, Ellen Schmidt, Chad Brummett, Himanshu J Patel, Kim A Eagle, Dianna M Milewicz, Jacob Kitzman, Cristen J Willer
Journal: Circulation (2018)

Introduction: Aortic dissection is a life threatening condition due to associated complications, such as aortic rupture, end-organ malperfusion and failure with high mortality of surgical treatment. It is not known how to manage family members of patient’s that suffer from aortic dissection, and routine cascade genetic screening of first-degree family members is not regularly practiced. Hypothesis: Clinical genetic testing for patients and cascade screening would identify pathogenic variants facilitating the management of patients with aortic dissection and families. Methods: From August 2012 to December 2015, 265 patients with aortic dissection had whole exome sequencing (WES), including Stanford type A and B or rupture, at Michigan Medicine with age-, sex-, and ancestry-matched controls (n=265). After quality control, 249 non-trauma dissection cases and 258 controls were retained. Annotation of variants in 11 known genes lead to heritable thoracic aortic disease (HTAD) was performed by experts in the field blinded to sample’s case or control status. Non-pathogenic variants were identified in 223 patients and pathogenic variants were in 26 patients. Results: Twenty-four pathogenic variants across 6 genes ( COL3A1, FBN1, LOX, PRKG1, SMAD3, TGFBR2 ) were identified in 26 patients representing 10% of aortic patients and 0% of controls. Compared to non-pathogenic group, the pathogenic group was significantly younger (41 vs 57 years, 77% younger than 50 years old), more root aneurysm (54% vs 29%), less hypertension (15% vs. 57%) and smoking history (19% vs. 47%), and more incidence of TAAD in parents, siblings and children. (all p’s&lt;0.05) Conclusion: We recommend clinical genetic testing of known HTAD genes in patients of aortic dissection with subsequent cascade screening of family members, especially the age of onset of aortic dissection younger than 50 years old, with aortic root aneurysm, no history of hypertension and smoking, as well as family members of patients whose causative variants have been identified. If the patient and families are found to have the known pathologic HTAD genes, then surgeons should be more aggressive to perform prophylactic operation on those patients to prevent aortic dissection.
Abstract 16900: Predictors of Cardiovascular Health Trends in College Students
Authors: Nabil Alshurafa, Jayalakshmi Jain, Bonnie Spring, Angela Pfammatter
Journal: Circulation (2018)

Introduction: The American Heart Association (AHA) Life’s Simple 7 (LS7) is a metric that is known to predict cardiovascular disease. What is unknown are the factors that predict cardiovascular health (CVH) scores over time, and what patterns of CVH scores are most common. Machine learning algorithms can identify these patterns using a data-driven approach. Our objective was to identify most common risk patterns over time and assess smartphone usage statistics to identify their predictors. Methods: We recruited 303 Northwestern University undergraduates and cluster randomized them to one of two health intervention groups. The intervention group focused on cardiovascular health behaviors (n=130) were provided with an app that delivered an intervention targeting the LS7 metrics smoking, physical activity, fruit and vegetable consumption, and weight. All participants reported levels of four behaviors weekly. Health scores were calculated as the sum of metrics meeting ideal criteria; CVH behaviors scored per the AHA LS7. Behavioral patterns over time used in the K-means unsupervised clustering algorithm include the mean, slope and variance of trends. K-Silhouette was used to determine optimal number of clusters, and predictors from the CVH intervention app use data were examined to determine which contributed to distinguishing between clusters. Results: We identified four clusters using K-silhouette criteria (Figure 1). Of the smartphone meta-data collected, 2 were significantly different between clusters. We observed greater number of interactions/week (p &lt; .0001) and greater number of app-use days/week (p &lt; .0001) for both “healthy-steady” and “improvers” as compared with “decliners” and “unhealthy-steady” clusters. Conclusions: Our findings suggest that frequency and consistency in health behavior monitoring predict healthier trends over time. These usage behaviors may be targets for behavioral interventions. Further work will investigate if these factors meaningfully predict CVH at the end of a 2 year intervention. In the future, predictors could be used as signals that an individual needs behavioral intervention.
Abstract 16655: Impact of Age, Race, and Arterial Stiffness on Ambulatory Heart Rate-Stroke Volume Counter-Regulation
Authors: Sherif M Elsayed, Kalaimani Elango, Rahil Ahmed, Sajeer Bhura, Peter J Osmond, Joseph L Izzo
Journal: Circulation (2018)

Background: We have previously reported a strong negative correlation between stroke volume index (SVI) and heart rate (HR) within and between normal and hypertensive individuals and have defined the slope of the SVI-HR relationship as an index of the efficiency of rate-volume counter-regulation. SVI-HR slope may also reflect the efficiency of diastolic filling (Starling forces). Objective: To investigate whether SVI-HR slope is influenced by demographic or hemodynamic variables. Design and method: 24 hr. ambulatory pulse wave analysis (PWA, Mobil-O-Graph, IEM, Stolberg, DE) with a 20-minute sampling interval was performed in a convenience sample of 94 normal and hypertensive subjects. Systolic (S) and diastolic (D) blood pressure (BP), pulse pressure (PP), HR, cardiac index (CI), SVI (= CI/HR) and the slope of the SVI-HR regression line were calculated in each subject. Group data were analyzed using IBM SPSS software with Pearson linear regression and stepwise multiple linear regression methods. Results: Characteristics of the cohort were (mean ± SD): age 57±17 years, weight 82.5±19 kg, 59% women, 62% Caucasians, BP 135±20/80±14 mm Hg, and HR 69±12 beats/min). There was a strong negative correlation between individual SVI and HR values (r = -0.53; p &lt; 0.001). Slope correlated with age (r=0.268), race (greater in Blacks), and PP (r=0.222) (all p&lt;0.05). Stepwise multiple linear regression modeling yielded the following relationship: SVI-HR Slope = - 0.31 race + 0.227 PP - 0.535 (multiple r = 0.381, p&lt;0.001); excluded variables were: age, gender, height, weight, 24 hr. SBP, MAP and DBP. Conclusions: There is a strong negative correlation between HR and SVI; the slope of this relationship is affected by age and PP (lower slope in older people or with wide PP) and race (greater slope in Blacks). In a multiple regression model, age was replaced by PP but age and PP are closely related to arterial stiffness. Lower SVI/HR slope with age may signify a parallel increase in “cardiac stiffness” or diastolic dysfunction. Why blacks exhibit more effective rate-volume counter-regulation is unknown.
Abstract 16613: Stories to Save Lives: A Qualitative Assessment to Identify Opportunities for Prevention of Sudden Unexpected Death
Authors: Mojtaba Mirzaei, Paul Mihas, Elham A Masoudi, Rachel F Seidman, Neil P Patel, Ross J Simpson
Journal: Circulation (2018)

Introduction: Despite significant reduction in cardiovascular mortality, the incidence of sudden unexpected death (SUD) has not decreased substantially. Risk management by doctors and community health workers has the potential to reduce SUD in rural communities. We performed a qualitative assessment to understand behavioral constructs that might aid their efforts. Methods: The archives of the Southern Oral History Program (SOHP) contain about 6000 interviews. Using keywords related to SUD prevention, we selected 171 interviews. Stratified purposeful sampling identified information-rich cases from rural areas. We coded transcripts based on both predetermined and emerging codes and wrote memos for each transcript. A final code report synthesized information from these memos into themes. Results: We assessed 23 interviews with people of diverse ethnicities (42% African-Americans) who were mainly farmers (46%) or textile workers (29%). Four themes emerged from the interviews: "sense of surrender", "social support", "instrumental doctor-patient relationship" and "lack of proactivity". (Table 1) The "sense of surrender" emerged when people talked about the heightened period of symptoms, often characterized by limited health knowledge and preparation. "Social support" among neighbors and family was strong and evident during hardship. The "instrumental doctor-patient relationship" highlights a shift to one-way communication of absolute diagnoses and recommendations. The "lack of proactivity" emerged when people did not take ownership of their health to modify risk factors and waited for serious conditions before seeking medical help Conclusion: We found that even individuals showing proactivity in work and home life often have a sense of surrender in their relation to their health. Our findings can guide interventions on how doctors and community health workers can promote partnerships for prevention of sudden unexpected death in rural communities.
Abstract 16620: Left Ventricular Ejection Time is an Independent Predictor of Cardiovascular Morbidity and Mortality Following Acute Coronary Syndrome
Authors: Alia Saed Alhakak, Kristoffer G Skaarup, Allan Iversen, Philip Brainin, Peter G Jørgensen, Jan S Jensen, Tor Biering-Sørensen
Journal: Circulation (2018)

Background: Color Tissue Doppler imaging M-mode through the mitral leaflet is an easy and precise method to obtain the cardiac time intervals including the left ventricular ejection time (LVET). The aim of this study was to investigate whether the LVET can be used to predict cardiovascular morbidity and mortality following acute coronary syndrome (ACS). Methods: We retrospectively studied 390 patients with ACS (mean age 64 ±12 years, men 74%, STEMI 81%, mean LVEF 41±11%, mean LVET 256±35ms) who underwent echocardiography, following percutaneous coronary intervention. The LVET was measured. The primary endpoint was major adverse cardiac events (MACE) and consisted of heart failure, myocardial infarction and cardiovascular death. The secondary endpoint was all-cause mortality. Patients with prevalent HF were excluded. Results: During a median follow-up of 3 years, 180 patients (46%) reached the composite endpoint MACE, and 77 (20%) suffered from all-cause mortality. LVET was significantly associated with risk of MACE (HR 1.13; 95% CI (1.08-1.18), p&lt;0.001) with a 13% increase in risk per 10ms decrease in LVET (figure ). The association remained significant after adjusting for age, sex, hypertension, diabetes, body mass index, previous ischemic heart disease, STEMI, multivessel culprit lesions, left ventricular ejection fraction, left ventricular mass index, E/e’, E/A and deceleration time (HR 1.10; 95% CI (1.03-1.17), p=0.002 per 10ms decrease). Additionally, the LVET predicted all-cause mortality and the association remained significant even after multivariable adjustment (HR 1.11; 95% CI (1.01-1.21), p=0.032 per 10ms decrease). Conclusion: In patients with ACS the LVET provides novel and independent prognostic information on the risk of cardiovascular morbidity and mortality.
Abstract 16737: Cardiopulmonary Fitness and Cardiac Reserve 12-Months Following the Completion of Anthracycline-Based Chemotherapy With or Without Concurrent Exercise Training
Authors: Erin J Howden, Steve Foulkes, Ashley Bigaran, Steve Fraser, Mark Haykowsky, Andre La Gerche
Journal: Circulation (2018)

Introduction: Anthracycline chemotherapy (AC) has been associated with reductions in cardiac function that increases long-term risk of heart failure. We have previously shown that AC is associated with a reduction in cardiopulmonary fitness (VO 2 peak) that occurs alongside a subtle reduction in the heart’s contractile response to exercise. However the degree to which these changes recover following the completion of AC is unknown. Hypothesis. We sought to determine whether change in cardiopulmonary fitness (VO 2 peak) and cardiac function persisted at 12-months post-AC completion. Methods: 28 women with breast cancer who had self-selected to undergo 12-weeks of aerobic and resistance training twice per week during AC (ET; n=14) or usual care during AC (UC; n=14) were followed up at 12-months from AC completion. Prior to AC and at 12-months, participants completed a cardiopulmonary exercise test (VO 2 peak) and cardiac MRI with exercise to assess the stroke volume (SV), heart rate (HR) and cardiac output (CO) response to exercise (measured at rest, and during high-intensity supine cycling). Results: Seventeen women (UC: n=8; ET: n=9) have completed follow-up evaluation. AC was associated with reductions in fitness at 12-months in both the UC (22.4±6.8 to 19.1±6.9 ml/kg/min; 15%) and ET (28.5±6.0 to 26.5±5.4 ml/kg/min; 6%, P&lt;0.01), and these declines were not attenuated by ET (interaction, P=0.42). Peak CO was reduce by 13% as compared with pre-AC values (14.0 ± 2.5L/min vs 12.2 ± 2.6 L/min, P&lt;0.01). The reduction in CO was due to a 14% reduction in the SV response to exercise (98.3 ± 12.1 ml vs 84.6 ± 14.5 ml, P&lt;0.01), whereas the HR response was similar (146 ± 16 bpm vs 151 ± 17bpm, P=0.70). No differences were found between resting CO and SV from pre-AC to 12-months (P=0.25 and P=0.27 respectively). Conclusion: Cardiopulmonary fitness reductions persisted 12-months following AC-based chemotherapy, which was not attenuated by exercise during AC. Reductions in fitness coincided with reductions in peak cardiac output during exercise.
Abstract 16982: Adenylyl Cyclase Isoform 1 Plays a Critical Role in Beta-Adrenergic Response of Pacemaking Cells in Sinoatrial Node
Authors: Lu Ren, Phung N Thai, Valeriy Timofeyev, Hannah A Ledford, Padmini Sirish, Claudia Moreno Moreno, Richard Q Ngo, Luis Fernando Santana, Michael I Kotlikoff, Yang K Xiang, Vladimir Yarov-Yarovoy, Xiaodong Zhang, Nipavan Chiamvimonvat
Journal: Circulation (2018)

Introduction: Sinoatrial node (SAN), the primary pacemaker region of the heart, is the main determinant of heart rate, which is tightly regulated by β-adrenergic receptor (β-AR) signaling. Adenylyl cyclase (AC) is a key enzyme in the β-AR signaling pathway. There are 10 known AC isoforms but it is unclear which AC isoforms are predominant in the SAN. Furthermore, their functional roles in regulating the pacemaking activity of the heart is not well understood. Hypothesis: We hypothesize that distinct AC isoforms are preferentially expressed in SAN and serve specialized function compared to atrial and ventricular myocytes. Methods: Regional distribution of AC isoforms in the heart was determined using single-cell RT-PCR and single molecule fluorescence in situ hybridization. Transgenic mice expressing GCaMP8 under HCN4 promoter was used to identify SAN cells. To determine the role of AC isoforms in the SAN, CRISPR/Cas9 gene editing was used to generate SAN specific knockout (KO) mice. Electrocardiogram was performed to determine heart rate during basal condition and after β-AR stimulation with isoproterenol (ISO). Analyses of Ca 2+ and pacemaking currents as well as local Ca 2+ release were performed in single isolated SAN cells from the KO mice with and without β-AR stimulation. Results: Single-cell RT-PCR showed that in the SAN, AC I is the most abundant isoform, followed by AC VI , AC VII , AC III and AC IV . In contrast, AC VI was the most abundant isoform in both atria and ventricles. CRISPR/Cas9-mediated gene silencing of AC I resulted in a decrease in heart rate with blunted response to ISO (Figure 1). In contrast, AC V /AC VI double KO mice exhibited similar heart rate responses to ISO compared to WT mice, suggesting that AC V /AC VI isoforms do not play critical roles in controlling the SAN firing frequency. Conclusions: Our study suggests AC I plays a critical role in β-AR response of pacemaking cells in SAN and may offer unique therapeutic opportunities to directly modify pacemaking cells without interfering with ventricular myocytes.