tbuckley/cabot-search huggingface dataset:
Abstract 10951: Clinical Outcome of Maze Procedure for Atrial Fibrillation Combined with Mitral Valve Disease and Tricuspid Regurgitation
Authors: fumio yamana, Keitaro Domae, Noriko Kodani, Keiwa Kin, Masatoshi Hata, Takafumi Masai
Journal: Circulation (2021)

Introduction: The surgical strategy for atrial fibrillation (AF) combined with mitral valve (MV) disease are still controversial whether biatrial or left atrial maze procedure should be performed concomitantly. Hypothesis: Our retrospective study aimed to evaluate the long-term results of two kinds of maze procedure combined with MV surgery and identify the factors involved in AF recurrence. Methods: We enrolled 88 patients from January 2010 to December 2020 who underwent MV surgery with maze procedure concomitantly. The patients were divided into two groups; biatrial maze, group F: n=42 and left atrial maze, group L: n=46). Primary endpoint was AF recurrence and we also evaluated early and late complication and preoperative and operative factors related to AF recurrence. The average follow-up term was 2.8 years. Results: Preoperative factors of long-standing AF and TR grade were significantly higher in group F than group L (P=0.004, 0.02, respecively). Consequently, tricuspid annuloplasty (TAP) was performed significantly frequent in group F than group L (P=0.002). We encountered 2 hospital deaths (4.4%) due to postoperative cerebral hemorrhage and AMI in group L. There was 1 case (2.2%) required pacemaker implantation (PMI) during hospitalization in group L and 3 cases (7.1%) requiring PMI in Group F in late-period. The AF recurrence rates at 1 and 5-year follow-ups between Group F and Group L were not significantly different (24.4% and 28.4% vs. 22.9% and 32.4%, P =0.79). However, the AF recurrence rate in group L with TAP is significant high than those of the other groups (group F 24.4% and 28.4%, group L with TAP 44.3% and 56.7%, and group L without TAP 7.7% and 14.3% at 1 and 5 years, respectively p =0.005). Subject with group L with TAP were associated with a high risk of AF recurrence, with an adjusted OR of 2.4 (95% CI: 1.31-4.45, P =0.005). Conclusions: Our study demonstrated that both concomitant maze procedure was effective for preventing AF recurrence. However, it is also revealed that left atrial maze with TAP significantly increased AF recurrence. It was suggested that preoperative right atrial load was involved in primary occurrence of AF and left atrial maze alone might not control AF recurrence in such situation.
Abstract 10338: A Junctophilin-2-Mitofusin-2 Interaction Links T-Tubule Remodeling to Mitochondrial Dysfunction in Pulmonary Arterial Hypertension-Mediated Right Ventricular Failure
Authors: Sasha Z Prisco, Megan Eklund, Lynn Hartweck, Ann QUICK, Satadru K Lahiri, Xander H Wehrens, Kurt W Prins
Journal: Circulation (2021)

Introduction: Junctophilin-2 (JPH2) plays a crucial role in t-tubule structure/function and gene regulation in cardiomyocytes. In addition, JPH2 downregulation causes mitochondrial dysfunction and mitofusin-2 (MFN2) dysregulation, but the link between JPH2 and mitochondria is undetermined. Here, we investigated the hypothesis that a direct JPH2-MFN2 interaction is important for mitochondrial regulation and subsequent right ventricular (RV) function in pulmonary arterial hypertension (PAH). Methods and Results: Confocal microscopy revealed JPH2 and MFN2 colocalized at t-tubules in isolated cardiomyocytes. Immunoprecipitation demonstrated JPH2 and MFN2 interacted in RV extracts. Pulldown experiments showed JPH2 directly bound MFN2, and that the MFN2 binding domain was localized to the N-terminal third of JPH2. To probe the importance of the JPH2-MFN2 interaction for RV function, we compared the effects of treatment with AAV9-JPH2 to AAV9-GFP in monocrotaline-induced PAH. Consistent with its known role in t-tubule homeostasis, AAV9-JPH2 normalized RV t-tubule architecture. Interestingly, transmission electron microscopy showed AAV9-JPH2 corrected RV mitochondrial morphology. Immunoblots of RV extracts demonstrated AAV9-JPH2 increased JPH2 and MFN2 expression, which may underlie the restoration of mitochondrial morphology. At the organ level, AAV9-JPH2 reduced RV cardiomyocyte hypertrophy and RV fibrosis. AAV9-JPH2 increased tricuspid annular plane systolic excursion and RV free wall thickening as quantified by echocardiography. Pressure-volume loop analysis showed AAV9-JPH2 augmented RV ejection fraction and right ventricular-pulmonary arterial coupling and lowered RV end diastolic pressure and tau. Importantly, the improvements in RV systolic and diastolic function were independent of altering PAH severity as RV systolic pressure, effective arterial elastance, and pulmonary arterial small vessel remodeling were not altered with AAV9-JPH2. Conclusions: Disruption of the JPH2-MFN2 interaction may link altered t-tubule structure to mitochondrial dysfunction in the compromised RV. Strategies to increase JPH2 expression could have therapeutic value for RV failure.
Abstract P498: Polycystin-1 Regulates Excitation-contraction Coupling In Atrial Cardiomyocytes
Authors: Troy Hendrickson, William Perez, Vincent Provasek, Francisco J Altamirano
Journal: Circulation Research (2021)

Patients with Autosomal Dominant Polycystic Kidney disease (ADPKD) have multiple cardiovascular manifestations, including increased susceptibility to arrhythmias. Mutations in polycystin-1 (PC1) encoding gene accounts for 85% cases of ADPKD, whereas mutations in polycystin-2 (PC2) only accounts for 15%. In kidney cells, PC1 interacts with PC2 to form a protein complex at the primary cilia to regulate calcium influx via PC2. However, cardiomyocytes are non-ciliated cells and the role of both PC1 and PC2 in atrial cardiomyocytes remains unknown. We have previously demonstrated that PC1 regulates action potentials and calcium handling to fine-tune ventricular cardiomyocyte contraction. Here, we hypothesize that PC1 regulates action potentials and calcium handling in atrial cardiomyocytes independent of PC2 actions. To test this hypothesis, we differentiated human induced pluripotent stem cells (iPSC) into atrial cardiomyocytes (iPSC-aCM) using previously published protocols. To determine the contribution of PC1/PC2 in atrial excitation-contraction coupling, protein expression was knocked down utilizing specific siRNA constructs, for each protein, or a universal control siRNA transfected using lipofectamine RNAiMAX. We measured action potentials using the potentiometric dye FluoVolt and intracellular calcium with Fura-2 AM or Fluo-4. Changes in fluorescence were monitored using a multiwavelength IonOptix system. iPSC-aCM were paced at 2 Hz to synchronize the beating pattern using field electrical stimulation. Our data shows that PC1 ablation significantly decreased action potential duration at 50% and 80% of repolarization, by 24% and 23%, respectively. Moreover, we observed that PC1 knockdown significantly reduced calcium transient amplitude elicited by field electrical stimulation without changes in calcium transient decay. Interestingly, PC2 knockdown did not modify calcium transients in atrial cardiomyocytes (iPSC-aCM). Our data suggest that PC1 regulates atrial excitation-contraction coupling independent of PC2 actions. This study warrants further investigation into atrial dysfunction in ADPKD patients with PC1 mutations.
Abstract 12152: The Association of Improvement in Left Ventricular Ejection Fraction With Outcomes in Patients With Heart Failure With Reduced Ejection Fraction - Data From CHAMP-HF
Authors: Adam D Devore, Anne Hellkamp, Laine E Thomas, Nancy M Albert, Javed Butler, J Herbert H Patterson, John Spertus, Fredonia Williams, Xian Shen, Adrian F Hernandez, Gregg C Fonarow
Journal: Circulation (2021)

Background: Among patients with heart failure with reduced ejection fraction (HFrEF), improvements in left ventricular EF (LVEF) are associated with better outcomes in select populations. How changes in LVEF are associated with outcomes in routine clinical practice is not clearly defined. Methods: CHAMP-HF was a prospective registry of US outpatients with HF and an LVEF &lt; 40%. Enrolled patients completed the Kansas City Cardiomyopathy Questionnaire 12-item questionnaire (KCCQ-12) at regular intervals and were followed as part of routine care for assessments of LVEF and clinical outcomes. We analyzed all patients with baseline and &gt; 1 LVEF assessment during follow-up, and we assessed for associations between improvements in LVEF ( &gt; 5%) over time and concurrent changes in KCCQ-12 and subsequent risk of HF hospitalization or all-cause death. Results: Among patients enrolled in CHAMP-HF, 2092 had a baseline and follow-up LVEF assessment. The median age was 67 years (25 th , 75 th percentile 58, 75), 29% were female, 64% had concomitant coronary disease, and the median duration of HF was 2.7 years (0.6, 6.8). The median baseline LVEF was 30% (23, 35) and 1032 (49%) patients had a &gt; 5% improvement in LVEF over time. Patients that had an improvement in LVEF over time had a significant simultaneous improvement in KCCQ-12 overall summary score compared with patients with no improvement (change from baseline: +6.8 vs +3.0, adjusted effect estimate 3.8 [95% CI 1.8 to 5.7]) ( Table ). Similarly, subsequent HF hospitalization or all-cause death occurred in 14% in the LVEF improvement group vs 27% in the no LVEF improvement group (adjusted hazard ratio 0.52, 95% CI 0.43 to 0.63). Conclusions: In a large cohort of outpatients with chronic HFrEF, improvements in LVEF were common and associated with improvements in health status and clinical outcomes. These data underscore the importance of changes in LVEF as a treatment target for medical interventions for patients with chronic HFrEF.
Elucidating the Importance and Regulation of Key Enhancers for Human MEIS1 Expression
Authors: Xining Yang, Ping Xiang, Leo Escano, Ishpreet Dhillon, Edith Schneider, Jack Clemans-Gibbon, Wei Wei, Jasper Wong, Simon Xufeng Wang, Gregg Morin, Pamela A Hoodless, Martin Hirst, Aly Karsan, Florian Kuchenbauer, R. Keith Humphries, Arefeh Rouhi
Journal: Blood (2021)
Abstract 11848: Biomarkers of Glucose-Insulin Homeostasis, Randomized Treatment With Omega-3 and Vitamin D Supplementation, and Incident Type 2 Diabetes: Prospective Analysis From the Vitamin D and Omega-3 Trial (VITAL)
Authors: Frank Qian, Yanjun Guo, Heike Gibson, Natalya Gomelskaya, Yanyan Liu, Olga Demler, Nancy R Cook, I-min M Lee, Julie E Buring, Julia A Larsen, Jennifer Boring, Michael J Mcphaul, Joann E Manson, Aruna D Pradhan, Samia Mora
Journal: Circulation (2021)

Introduction: Insulin resistance is central to the development of type 2 diabetes (T2D). Association between specific biomarkers of glucose-insulin homeostasis and T2D have been inconsistent. Whether vitamin D or omega-3 fatty acids (n-3 FA) can modify these associations is also unclear. Hypothesis: We hypothesized that higher insulin, C-peptide, insulin resistance score (IRS), and HbA1c are each associated with higher T2D risk, and that these associations would be attenuated among participants who received vitamin D or n-3 FA. Methods: VITAL Diabetes (NCT01633177) was a pre-specified ancillary 2x2 factorial study in the VITAL RCT to assess whether vitamin D (cholecalciferol, 2000 IU/d) or n-3 FA (EPA + DHA, 1 g/d) could prevent T2D. Subjects without baseline reported T2D and with HbA1c &lt;6.5% were included. Incident cases were matched 1:1 on age and sex to healthy controls (N=359 pairs). Conditional logistic regression models with adjustment for demographics, risk factors including BMI, and randomized treatment were used to estimate the adjusted odds ratio (aOR) and 95% CI between baseline measurements of insulin, C-peptide, IRS (Insulinх0.0265+C-peptideх0.00511+Creatinineх-3.2641), HbA1c, and T2D. Interaction was tested between each biomarker and treatment groups (placebo vs vitamin D or n-3 FA). Results: Mean age of participants was 66 years, approximately 45% were female, and 16% were African American. Each of the glucose-insulin homeostasis biomarkers was associated with T2D risk ( Table 1 ), aOR (95% CI) per SD increment, insulin: 1.46 (1.10, 1.94), C-peptide: 1.72 (1.28, 2.31), IRS: 1.59 (1.26, 2.01), and HbA1c: 80.43 (25.90, 249.77). Biomarker associations did not differ by randomized treatment ( P interaction &gt;0.05). Conclusions: In VITAL Diabetes, insulin, C-peptide, IRS, and HbA1c were each associated with an increased risk of T2D, independent of other risk factors. Randomization to either vitamin D or n-3 FA did not modify these associations.
Abstract 11011: Comparison of Prognostic Value of Liver Dysfunction Scores and Serum Cholinesterase Level in Acute Decompensated Heart Failure Patients with Preserved Left Ventricular Ejection Fraction: Insights from Pursuit-hfpef Registry
Authors: Takehiro Kogame, Masahiro Seo, Takahisa Yamada, Masamichi Yano, Takaharu Hayashi, Akito Nakagawa, Yusuke Nakagawa, Shunsuke Tamaki, YOSHIO YASUMURA, Shungo Hikoso, Yohei Sotomi, Yasushi Sakata
Journal: Circulation (2021)

Background: Cardiohepatic interactions have been a focus of attention in heart failure. Liver dysfunction scores such as Fibrosis-4 (FIB-4) index, albumin-bilirubin (ALBI) and nonalcoholic fatty liver disease (NAFLD) scores have been shown to be useful for predicting poor outcome in patients (pts) with heart failure. On the other hand, malnutrition is one of the most important comorbidities in patients with heart failure with preserved ejection fraction (HFpEF), and serum cholinesterase level (CHE) was reported to be associated with adverse prognosis. We sought to compare the prognostic value of liver dysfunction scores and CHE in HFpEF pts admitted for acute decompensated heart failure (ADHF). Methods and Results: Data were extracted from a prospective multicenter observational study (PURSUIT-HFpEF) in which collaborating hospitals in Osaka recorded clinical, echocardiographic, and outcome data of HFpEF pts with ADHF. We analyzed 737 pts who survived to discharge. CHE, FIB-4 index, ALBI and NAFLD scores were obtained just before the discharge. During a follow-up period of 1.8±1.0 years, 157 pts had all-cause death. At multivariate Cox analysis, CHE (p&lt;0.0001) was independently and significantly associated with all-cause death after adjustment with important baseline clinical and study characteristics, although FIB-4 index, ALBI and NAFLD scores showed the association with all-cause death at univariate analysis. Receiver-operating characteristic curve analysis showed that CHE had the largest area under the curve for the prediction of all-cause death. Kaplan-Meier analysis revealed that the pts with lower CHE (&lt;208 IU/L=median value) had a significantly higher risk of all-cause death than those with higher CHE (31% vs 11%, p&lt;0.0001, adjusted hazard ratio 3.29 [95% CI 2.31 to 4.69]). Conclusion: CHE would be a more useful and simple prognostic marker for the prediction of total mortality than liver dysfunction scores in HFpEF pts with ADHF.
Abstract 13049: Peripheral Artery Disease In Patients Undergoing Transcatheter Aortic Valve Replacement In Northern New England
Authors: Deborah Furman, Spencer Ng, Alexander Iribarne, Stanislav Henkin, James T Devries, Michael Young
Journal: Circulation (2021)

Background: Transcatheter aortic valve replacement (TAVR) is now more common than surgical aortic valve replacement (SAVR) for severe aortic valve stenosis. In the general population, the prevalence of peripheral artery disease (PAD) in patients undergoing transfemoral TAVR is 25%, with higher risk of adverse outcomes including bleeding, readmission, myocardial infarction, and all-cause mortality. The objective of this study was to examine the prevalence of peripheral artery disease in patients undergoing TAVR at Dartmouth-Hitchcock Medical Center (DHMC). Methods: We performed a retrospective observational study of 569 patients undergoing TAVR between 1/1/2012-4/8/2020. PAD was defined as presence of aorto-iliac, femoral-popliteal, below-knee tibial, reno-vascular, mesenteric, cerebrovascular, aortic disease, or upper extremity arterial disease noted in the patient’s chart prior to TAVR. Results: Of 569 TAVR patients, 19% (n=109) had concomitant PAD. Of these, 70 patients (64%) were established with a vascular specialist and 54 (50%) had a prior intervention relating to their disease. Figure 1 characterizes the distribution and location of PAD among patients. Conclusion: In a Northern New England population, 1 in 5 patients undergoing TAVR had concomitant PAD. Cerebrovascular and peripheral vascular disease were most common. Understanding PAD epidemiology is of paramount importance with respect to vascular access and longitudinal management in a vulnerable aortic stenosis population.
RBIO-06. MECHANISM OF ACTION AND ASSOCIATED EFFECTS OF TUMOR TREATING FIELDS (TTFIELDS) ON LIVING CELLS USING SIMULATIONS
Authors: Tal Marciano, Shay Levi, Eduard Fedorov
Journal: Neuro-Oncology (2021)

Abstract Following FDA approval, TTFields treatment has become a commonly used modality for treating patients with Glioblastoma (GBM) and Mesothelioma. From the early 2000’s, extensive research has been performed in in-vitro systems for studying the effects of TTFields on living cells. These studies have shown that multiple cellular functions are affected by TTFields. However, the physical mechanism by which the fields exert effects on cells are not well understood. We propose an analytical model for predicting the geometric and electrical parameters enabling amplification of the electric field in the living cells. This amplification favors the emergence of local heating, dielectrophoretic (DEP) force, or electrostatic pressure at TTFields frequencies. This model is supported by simulations of cells in different configurations. Computational studies were performed with Comsol Multiphysics software. Cell models were constituted of cytoplasm, membrane and extracellular matrix. A field of 1V/cm was generated at different frequencies between 10kHz and 1GHz. Maximal field amplification of X20 of the applied field (@200 kHz) was observed in a model of confluent cells with 5nm intercellular distance. Such field amplification could create electrostatic pressure on the membrane potentially leading to its deformation and to stress on the cytoskeleton. Analytical calculations show the field gradient could result in DEP forces of ~10pN on the membrane. Such force could potentially disrupt the membrane or junctions. Results show that a 10nm pore in membrane would lead to a 450 times amplification in the pore’s vicinity, potentially resulting in forces of between 0.1pN and 100pN on intracellular structures. Those forces are sufficient for disrupting microtubules. Specific Absorption Rates of up to 106 W/kg were observed in the vicinity of the pore, suggesting that strong thermal effects may also explain the effect of TTFields on cells. Our generic analytical model predicts the conditions for field amplification at TTFields frequencies.
Abstract 10401: Uptake and Predictors of SGLT2i in Patients with Type 2 Diabetes and Cardiovascular Disease
Authors: Aya F Ozaki, Dennis T Ko, Alice Chong, Jiming Fang, Peter Austin, Therese Stukel, Gillian Booth, Karen Tu, Jacob A Udell, Clare Atzema, David Naimark, Cynthia A Jackevicius
Journal: Circulation (2021)

Introduction: While sodium glucose cotransporter 2 inhibitors (SGLT2i) improve cardiovascular outcomes in type 2 diabetes (T2D) and cardiovascular disease (CVD), their uptake in clinical practice in this population is unclear. Therefore, we evaluated trends in SGLT2i use and identified predictors of use in patients with concomitant T2D and CVD. Methods: We conducted an observational study using population-based health data in Ontario, Canada from 4/2016-3/2020 of patients ≥65 years old with a first diagnosis of T2D plus CVD. In each yearly cohort, we estimated the prevalent use of SGLT2i (≥1 prescription) within 1 year, including by demographic and comorbidity subgroups. In the overall cohort, we used multivariable logistic regression models to identify factors associated with SGLT2i use. Results: We identified 208,303 patients with T2D and CVD [median age 74.0 years (IQR 68.0-80.0); 63.5% male]. The proportion of patients dispensed an SGLT2i increased over time, from 7.0% in 2016 to 20.1% in 2019. In 2019, use in those ≥75 years was 50% lower than those &lt;75 years (12.9% vs. 28.3%;p&lt;.0001), and use in those without chronic kidney disease (CKD) was 50% higher than those with CKD (22.0% vs. 15.0%;p&lt;.0001); although SGLT2i use increased in all groups over time. Independent factors associated with increased odds of SGLT2i use were HbA1c ≥8 vs. &lt;7 (OR 3.33, 95%CI:3.22-3.46), use of 2+ non-insulin antihyperglycemic agents (OR 2.63, 95%CI:2.56-2.71), and an endocrinologist visit in prior year (OR 1.50, 95%CI:1.45-1.55). Those &gt;75 years (OR 0.39, 95%CI:0.38-0.40), with high frailty score (OR 0.38, 95%CI:0.35-0.42), or serum creatinine 1.4-2mg/dL vs. &lt;1.4 (OR 0.55, 95%CI:0.52-0.57) were less likely to use SGLT2i. Conclusions: In a real-world population of T2D and CVD, only 1 in 5 patients used an SGLT2i, although use increased over time. Markers of worse diabetes control were associated with increased SGLT2i use, while markers of more comorbidity were associated with less use.
Abstract 13714: Stress-Related Neural Pathways Mediate the Link Between Depression/Anxiety Disorders and Cardiovascular Disease
Authors: Kenechukwu N Mezue, Hadil Zureigat, Shady Abohashem, Taimur Abbasi, Charbel Gharios, Alexander Cardeiro, rachel rosovsky, Michael Osborne, Ahmed A Tawakol
Journal: Circulation (2021)

Background: Depression and anxiety disorders are linked with a greater risk of major adverse cardiac events (MACE) via unclear mechanisms. Since heightened stress-related neural activity (SNA) associates with a greater risk of MACE, we hypothesized that the link between depression/anxiety disorders and MACE is in part mediated by increased SNA. Methods: Data were obtained from subjects in the Mass General Brigham Biobank (N=118 871). A subset (N=1520) underwent clinical 18 F-fluorodeoxyglucose positron emission tomography imaging. Stress-related neural activity (SNA) was determined as the ratio of amygdalar to regulatory (ventromedial prefrontal cortex) activity. MACE (i.e., myocardial infarction, stroke, and heart failure), depression, and anxiety disorders were defined by the International Classification of Disease codes. Results: The median age was 59 years [interquartile range (IQR) 28]; 56.2% were female. MACE occurred in 4149 subjects (4.3%) over a median follow up of 3.3 years (IQR 2.9). Depression and anxiety independently predicted incident MACE (HR [95% CI]: 1.415 [1.323-1.513], p=5.696 x 10 -24 and 1.515 [1.418-1.618], p=4.548 x 10 -35 , respectively, adjusted for cardiovascular risk factors). In the 1520 subjects with brain imaging, depression and anxiety associated with higher SNA (standardized ß [95% CI]: 0.151 [0.048-0.254], p=0.004 and 0.123 [0.022-0.225], p=0.01, respectively, adjusted for age and sex). Further, SNA associated with MACE (OR [95% CI]: 1.295 [1.163-1.443], p=3 x 10 -6 ). Using path analysis, increased SNA mediated the effect of both depression and anxiety on MACE (log OR [95% CI]: 0.036 [0.009-0.072], p&lt;0.05 and 0.030 [0.005-0.063], p&lt;0.05, respectively). Conclusion: Depression and anxiety disorders associate with greater MACE risk via a mechanism that includes heightened stress-related neural activity. Future studies should evaluate the impact of therapies on this neural pathway and downstream MACE.