tbuckley/cabot-search huggingface dataset:
Abstract 16920: Permanent Reduction of Ryr2 Improves Lv Ejection Fraction in Heart Failure
Authors: Zhiwen Ding, Ran Xu, Chunjie Yang, Jian Wu, Jie Yuan, Shijun Wang, Guoliang Jiang, Xuan Li, Yunzeng Zou
Journal: Circulation (2018)

Introduction: Ryanodine receptor type 2 (RyR-2), the main Ca 2+ release channel from sarcoplasmic reticulum in cardiomyocytes, plays an important role in regulation of myocardial contractile function and cardiac hypertrophy. Hypothesis: RyR-2 is a target of gene therapy in heart failure. Methods and Results: Two CRISPR-Cas9 gRNA targeting RyR-2 were identified: one located on the gene N terminal and the other on the C terminal. Adeno-associated virus was used to express CRISPR-Cas9 to knockdown RyR-2 in two weeks transverse aortic constriction (TAC) model of mice. After one week of administration of the virus, compared with the control, cardiac mass, heart size and fibrosis decreased and the LV ejection fraction increased significantly in the model with CRISPR-Cas9 gRNA on the RyR-2 N terminal, and the other one had a similar result but not significantly. Conclusions: Our results hint genome editing with CRISPR-Cas9 disrupts the RyR-2 in vivo with partly restore the function of the heart.
Abstract 16935: Severity of Congenital Heart Disease, Not Risk of Acute Coronary Syndrome,Drives Extent of Ischemic Evaluation for Chest Pain in the Emergency Department
Authors: Jordan Gales, Richard Krasuski, Jordan Awerbach
Journal: Circulation (2018)

Introduction: Population growth and increasing complexity of disease among adults with congenital heart disease (ACHD) has led to an increased burden on U.S. emergency services. Assessment of chest pain (CP) within this population poses a challenge to emergency department (ED) providers; and as this population ages, their cardiovascular risk profile continues to change. There is a paucity of literature describing appropriate assessment of CP among ACHD patients within the ED setting. Hypothesis: Despite very low probabilities for acute coronary syndrome (ACS), ACHD patients are likely to undergo extensive evaluations for CP within the ED, possibly correlating with ACHD complexity. Methods: Retrospective review of ED visits for primary complaint of acute CP among ACHD patients aged 18-50 years (n=182) presenting to a single tertiary center between 1/1/1998 and 4/1/2018. CP quality was classified according to Diamond-Forrester criteria and severity of ACHD according to the Bethesda Classification. Results: The mean age of the cohort was 32.8±8.7 years, 88 were women, 102 were Caucasian, 74 had simple CHD, 58 had moderate severity CHD, and 50 had high complexity CHD. Although 94.5% of patients were identified as having a low 30-day risk of major adverse cardiovascular events according to Heart Score, 86.3% had ≥1 set cardiac biomarkers drawn. Only 6 patients (3%) had an initial ECG with changes concerning for possible ischemia. 3 patients (2%) had troponin levels above the upper limit of normal and only 1 case required urgent catheterization. Among ACHD complexity groupings (simple, moderate severity, and high complexity), there were no differences seen with regard to, gender, frequency of ECG changes suggesting ischemia, chest pain quality or coronary disease risk factors (hypertension, hypercholesterolemia, diabetes, smoking, BMI or predefined cardiovascular disease). Despite this fact, complexity of ACHD was associated with increased ED length of stay (p=0.02), likelihood of an urgent echocardiogram being performed (p&lt;0.001), ordering of cardiology consultation (p &lt;0.001) and hospital admission (p =0.009), without concurrent increase in 30-day overall mortality. Conclusion: ACHD patients undergo extensive evaluation for ACS despite having low pre-test probability, with complexity of underlying congenital disease correlating with increased ED resource utilization despite similar clinical outcomes.
Abstract 16612: The Feasibility, Safety, and Value of a Virtual Cardiac Implantable Electronic Device Wound Check
Authors: Lucas N Marzec, Rebecca Guigli, Mika Hamer, William H Sauer, Martha Meyer, Connor Baringer, Mark Gritz, P Michael Ho, Lisa Sandy, Daniel Matlock, Larry A Allen
Journal: Circulation (2018)

Introduction: In-person wound checks are standard of care for patients implanted with cardiac implantable electronic devices (CIEDs), which include pacemakers and implantable cardioverter-defibrillators. However, in-person wound checks burden patients, providers, and health systems. A virtual wound check may be a safe alternative, but the feasibility, safety, and costing savings of a virtual CIED wound check are unknown. Methods: We performed a single-center pilot study of a virtual wound check following CIED implantation. Eligible patients included those implanted with a CIED and scheduled for an in-person wound check at our center, and who had a smartphone or digital camera and internet access. Virtual wound checks consisted of 1) patients taking and uploading a digital photograph of their wound, and 2) a phone conversation with a CIED nurse regarding signs and symptoms of wound complication. The safety of a virtual wound check as compared to an in-person wound check was assessed by examining the agreement between virtual and in-person wound checks regarding wound abnormalities detected and recommended treatments. The value of a virtual wound check was assessed with time-driven activity-based costing (TDABC), a micro-costing approach in which time is assigned to each task in both the virtual and in-person wound checks. Results: We enrolled 67 of 76 (88.2%) eligible patients, of whom 50 (74.6%) completed a virtual wound check. No abnormality was seen in either virtual or in-person checks for 42 (62.7%) patients. An abnormality was seen in the virtual but not in-person wound check in 5 patients, and in the in-person but not virtual wound check in 5 patients. Pocket swelling was detected in 6 patients during virtual wound checks, and 7 during in-person wound checks. Erythema was detected in 1 patient during an in-person wound check that was not detected during a virtual wound check. The overall agreement was 71.4%. All complications that led to a clinical action (i.e. prescription of antimicrobial drugs, placement of pressure dressing) were detected in both the virtual and in-person wound checks. TDABC analysis demonstrated virtual visits used an average of 5 minutes less of provider time, and a total cost savings of $153. Conclusions: A virtual CIED wound check is feasible, safe, and associated with cost-savings to health systems. Further work is needed to improve the processes of care for virtual CIED wound checks.
Abstract 16786: ADP Ribosylation Factor 6 Modulates the Cell Surface Expression of the Acetylcholine Activated Inward Rectifier Potassium Current
Authors: Michelle Reiser, Bojjibabu Chidipi, Sami Noujaim
Journal: Circulation (2018)

Introduction: The ADP ribosylation factor 6 (Arf6), a GTP binding protein, is suggested to play a role in the trafficking of potassium inward rectifiers. We investigated the effects of Arf6 on the cell surface expression of Kir3.1 and Kir3.4, the molecular correlates of the acetylcholine activated inward rectifier potassium current (I KACh ). Hypothesis: The GDP and GTP bound forms of Arf6 modulate the surface expression of I KACh proteins. Methods: We used human embryonic kidney cells stably expressing Kir3.1 and Kir3.4 (GIRK cells). Cell surface I KACh proteins were labeled with TertiapinQ ATTO488, visualized with confocal microscopy, or quantified using flow cytometry in the GIRK cells transiently transfected with Arf6WT (wild type), dominant negative Arf6T44N (GDP bound), or constitutively active Arf6Q67L(GTP bound). Patch clamp was used to quantify the effects of Arf6 on the barium sensitive I KACh current, and coimmunoprecipitation in human atrial tissue was used to probe the interaction between Kir3.1, Kir3.4 and Arf6. Results: In confocal microscopy, Arf6WT, and Arf6T44N localized mainly to the cell membrane, while Arf6Q67L localized to intracellular vesicles. In flow cytometry, Arf6T44N significantly decreased channels expression at the cell surface compared to Arf6WT. Arf6Q67L did not affect cell surface expression compared to Arf6WT. Patch clamp showed that I KACh current density was significantly smaller in Arf6T44N compared to WT and Q67L, consistent with the flow cytometry experiment. Kir3.1, Kir3.4 and Arf6 coimmunoprecipitated in whole cell lysates form human atrial tissue samples. Conclusion: Expression of the I KACh proteins at the cellular membrane is in part modulated by an Arf6-dependent pathway. Constitutive interference with Arf6 cycling between GDP- and GTP-bound forms leads to changes in the cell surface expression of the I KACh proteins.
Abstract 16599: Mutations In KCNE1 Alters Multiple K <sup>+</sup> Channels To Cause APD Instability And Polymorphic Ventricular Tachycardia (PVT) In Transgenic Long QT Syndrome Type 5 Rabbits
Authors: Tae Yun Kim, Anatoli Kabakov, Dmitry Terentyev, Radmila Terentieva, Karuppiah Arunachalam, Yichun Li, Katja Odening, András Varró, Zsuzsanna Bosze, Gideon Koren, Bum-Rak Choi
Journal: Circulation (2018)

Introduction: LQT5 is caused by mutations in KCNE1, an accessory subunit of slowly activating delayed rectifier K + channel (I Ks ), and is associated with polymorphic ventricular tachycardia (pVT) and sudden cardiac arrest. Methods: Optical mapping of intact heart and single myocyte voltage clamp were used to investigate arrhythmia mechanism in LQT5 rabbit hearts. Results: LQT5 rabbits show slight prolongation of APDs as compared to littermate control (LMC) (179±12 vs. 165±10 ms at 350 ms pacing, p&lt;0.05). APD restitution in LQT5 rabbits was non-monotonic and steeper at longer diastolic interval compared to LMC rabbits (τ=24±3 vs.16±2 ms), accompanying by APD alternans. Isoproterenol (ISO, 140 nM) alone did not induce pVT but the sudden acceleration of heart rate (HR) with S1S2S3S4 stimulation in the presence of ISO induced pVTs (n=9/11 in LQT5 vs. 0/5 LMC hearts (panel A). The mapping of pVT initiation showed that the sudden HR acceleration produced large APD oscillations (red line) and progressively increased APD dispersion of S2S3S4 beats (blue line, panel B), which is associated with triggered focal activity (stars, panel C) to form reentry. Patch clamp data showed that transient outward K + current (I to ) in LQT5 myocytes is markedly altered with slow inactivation (τ=14 and 99 ms for double exponential curve fit) and slow recovery from inactivation kinetics (τ=217 and 3100 ms for I to,f and I to,s , respectively). These results suggest that in addition to I Ks , KCNE1 mutation also modifies I to thereby cause large APD oscillations and increase APD dispersion particularly during abrupt heart rate acceleration, resulting in pVTs in LQT5 rabbit. Conclusion: KCNE1 mutation in LQT5 affects multiple K + channels including I to , causing large APD variation and dispersion that trigger pVTs during sudden HR acceleration.
Abstract 16961: KLF15 Regulates the Circadian Susceptibility to Ischemia Reperfusion Injury in the Heart
Authors: Le Li, Hui Li, Chih-Liang Tien, Rongli Zhang, Xudong Liao, Mukesh K. Jain, Lilei Zhang
Journal: Circulation (2018)

The onset and the injury of heart attacks show a circadian rhythmicity with a peak during the sleep to active transition. Studies using cell type specific clock mutant demonstrated the intrinsic varying susceptibility of the cardiomyocytes to the ischemia reperfusion (I/R) injury, however, the molecular mechanisms remain unclear. Recently, we show that transcription factor KLF15 coordinates the diurnal expression of catabolic genes in the heart during the active phase. Here we show that cardiomyocyte specific KLF15 deficient mice have exaggerated I/R injury in vivo during the sleep to active transition but not the active to sleep transition, demonstrating its critical role in governing the circadian rhythmicity of myocardial injury. We found acute KLF15 deficiency in the primary cardiomyocytes is associated with increased ROS and exaggerated susceptibility to oxidative stress, which can be rescued by a MnSOD mimetic Tempol. We further demonstrate that KLF15 deficiency in the cardiomyocytes in vitro and in vivo are both associated with increased acetylation of MnSOD K122 , which leads to reduced MnSOD activity. There is no change in mitochondrial sirtuin SIRT3 level, the main deacetylase for MnSOD K122 , however its co-enzyme NAD + level and NAD + /NADH ratio are drastically reduced with KLF15 deficiency. We show that NAD + precursor NMN rescues the increased susceptibility to ROS in KLF15 deficient cardiomyocytes in vitro in a SIRT3 dependent fashion and rescues the increased cardiac I/R injury of KLF15 deficient mice specifically at ZT14. We show that KLF15 directly regulates nicotinamide phosphoribosyltransferase (NAMPT), the rate limiting enzyme of NAD + salvage pathway and the NAD + determinant in the heart. We found a strong circadian rhythmicity of NAD + level and mitochondrial acetylation in the heart. The beginning of the active phase is associated with increased expression of KLF15, NAMPT, NAD + , and reduced acetylation at MnSOD K122 . Collectively, our results demonstrate that KLF15 coordinates cardiac metabolism and ROS clearance in a circadian fashion through mitochondrial NAD + ; loss of KLF15 expression in ischemic cardiomyopathy likely contributes to an enhanced susceptibility to additional I/R insult in a time-of-the-day dependent fashion.
Abstract 16665: Tead1 - a Novel Cell-Autonomous Regulator of Mitochondrial Function in Cardiomyocytes
Authors: Ruya Liu, Rajaganapathi Jagannathan, Feng Li, Jeongkyung Lee, Vijay K Yechoor, Mousumi Moulik
Journal: Circulation (2018)

Introduction: Mitochondrial (mito) dysfunction occurs in most forms of heart failure (HF). We previously demonstrated that TEAD1, the transcriptional effector of Hippo pathway, plays a critical non-redundant role in adult CM homeostasis and its loss-of-function (LOF) leads to rapid-onset HF and dilated cardiomyopathy (DCM). Objective of this study was to determine requirement of TEAD1 in regulation of mito function in CMs. Hypothesis: TEAD1 is required for normal CM mito function and a loss of this regulation contributes to the rapid-onset lethal DCM with Tead1 deletion. Methods and Results: Conditional Tead1 deletion in adult CMs ( Tead1 -icKO) was achieved after 3 wks of tamoxifen (TM) diet in 6 wks old mutant mice (floxed Tead1, Tead1 F/F mice crossed with Myh6-CreER mice ) . Within 3 wks of Tead1 deletion, Tead1 -icKO mice developed acute lethal DCM with LV dilation and severe systolic dysfunction. Gene-set enrichment analysis from the Tead1 -icKO myocardial transcriptome, followed by qPCR validation, revealed mito-related genes as the top regulated gene sets. ChIP-seq, using TEAD1 antibody, in adult mouse hearts revealed that TEAD1 occupies the promoter/enhancers of multiple genes regulating mito biogenesis and function. To investigate if TEAD1 regulates OXPHOS, mito oxygen consumption rates (OCR) from mitochondria isolated from control and Tead1 -icKO mouse hearts were analyzed by Oroboros respirometry. Tead1 -icKO heart mitochondria had significantly decreased OCR with both palmitoylcarnitine and pyruvate/malate substrates. Primary neonatal CMs with ex vivo TEAD1 LOF (adenoviral-Cre transduction of Tead1 F/F neonatal CMs) showed diminished maximal OCR (Seahorse XF24 analyzer), demonstrating that TEAD1 regulation of OXPHOS in CMs is cell autonomous. (Refer to Fig) Conclusions: Taken together, our data demonstrate that TEAD1 is a direct transcriptional regulator of a large network of mitochondrial function and biogenesis related genes, is a novel cell-autonomous regulator of CM mitochondrial function and is critical for maintenance of adult CM homeostasis.
Abstract 16930: Outcomes of Transcatheter and Surgical Aortic Valve Replacement in Patients With Severe Aortic Stenosis and Pulmonary Hypertension: A Nationwide Inpatient Sample Matched Analysis
Authors: Setri Fugar, Ahmed A Kolkailah, Alexis K Okoh, Jishanth Mattumpuram, Sisir Siddamsetti, Ahmed Al-Ogaili, Ali Ayoub, Sagar Ranka, Jose Sleiman, Mark J Russo, Tania Campagnoli, Rami Doukky
Journal: Circulation (2018)

Background: Transcatheter aortic valve replacement (TAVR) has been established as a viable alternative to surgical aortic valve replacement (SAVR) in select patients with severe aortic stenosis (AS). Patients with pulmonary hypertension (PH) are at increased perioperative morbidity and mortality and thus were excluded from the major TAVR trials. We sought to compare the in-hospital outcomes after SAVR and TAVR in patients with severe AS and PH. Methods: We identified patients from the Nationwide Inpatient Sample (NIS) between 2012 and 2015 who underwent SAVR or TAVR using the ICD-9-CM procedure codes 35.21, 35.22 and 35.05, 35.06, respectively. We identified PH with codes 416.0, 416.8, and 416.9. A 1:1 propensity-matched cohort was created to examine the outcomes. Primary endpoint was in-hospital mortality. Secondary endpoints included hospital length of stay (LOS), cost, and post-procedural complications. Results: A matched pair of 670 TAVR and 670 SAVR patients were identified. The respiratory complications were less frequent with TAVR as opposed to SAVR. These included non-invasive ventilation requirement (3.3% vs. 5.8%, OR 0.55, p=0.028), pneumonia (1.5% vs. 4.3% vs. OR 0.33, p=0.003), acute respiratory failure (17.6% vs. 34.0%, OR 0.41), re-intubation (7.5% vs. 14.8%, OR 0.47), and tracheostomy (1.5% vs. 5.7%, OR 0.25), all p&lt;0.001. The non-respiratory complications were also significantly less frequent in the TAVR group, including acute myocardial infarction (3.9% vs. 11.5%, OR 0.31), bleeding requiring blood transfusion (17.0% vs. 41.3%, OR 0.29), and acute kidney injury (11.5% vs. 22.4%, OR 0.45), all p&lt;0.001. Permanent pacemaker (PPM) implantation was the only complication which was significantly higher in the TAVR group (24.6% vs. 11.8%, OR 2.43, p&lt;0.001). Lastly, TAVR was associated with a significantly reduced risk of in-hospital mortality, total median cost, and shorter LOS (4.0% vs. 6.9%, OR 0.57, p=0.024, $171,496.0 vs. $218,625.4, p&lt;0.001, and 5 vs. 12 days &lt;0.001, respectively). Conclusions: Patients with PH undergoing TAVR had lower risk of in-hospital mortality, post-operative complications, shorter LOS and reduced overall cost compared to patients undergoing SAVR. Aside from higher risk of PPM implantation, TAVR may be the preferred option in this patient population.
Abstract 12365: Association Between Liver Fibrosis and Left Atrial Remodeling in Patients With Atrial Fibrillation: The Hokuriku-Plus AF Registry
Authors: Yoshihiro Tanaka, Kenshi Hayashi, Toyonobu Tsuda, Takeshi Kato, Noboru Fujino, Kenji Sakata, Soichiro Usui, Takashi Kusayama, Keisuke Usuda, Masa-aki Kawashiri, Masakazu Yamagishi, Masayuki Takamura
Journal: Circulation (2021)

Introduction: Fibrosis-4 score (FIB-4), a laboratory-based marker for liver fibrosis, is reportedly associated with increased risks for cardiovascular events and mortality in patients with atrial fibrillation (AF). However, it remains unclear whether FIB-4 is associated with cardiac remodeling in patients with AF. Hypothesis: We hypothesized that liver fibrosis might be associated with cardiac remodeling, such as left atrial dilatation and/or systolic dysfunction. Methods: The Hokuriku AF Registry is a multicenter, population-based, prospective cohort study including 1,492 AF patients aged 30-94 years from 19 affiliated hospitals. We excluded patients with valvular AF and missing variables at baseline. We conducted a cross-sectional analysis to assess the association between the severity of liver fibrosis based on the FIB-4 score and echocardiographic parameters. The severity of liver fibrosis was classified into three categories based on FIB-4 score (Mild, Intermediate, and Severe) (Table). Unadjusted and adjusted linear regression analysis was performed to compute beta coefficient with 95% confidence interval using the Mild liver fibrosis group as a referent. Results: A total of 1,139 non-valvular AF patients were analyzed after the exclusion (mean age 72 ± 10 years, male 73.0%, paroxysmal AF 38.4%). In unadjusted analysis, severe liver fibrosis was significantly associated with increased left atrial diameter (LAD) and decreased left ventricular ejection fraction (LVEF), but this association was not observed in intermediate liver fibrosis. In addition, severe liver fibrosis was independently associated with LAD, not LVEF, after adjusting for other covariates (Table). Conclusions: The present study demonstrated that severe liver fibrosis based on FIB-4 score was significantly associated with larger LAD, a surrogate marker for left atrial remodeling, in patients with AF.
Abstract 16792: Gender Differences in African Americans and Caucasians With Severe Aortic Stenosis or Bicuspid Aortic Valve
Authors: Khendi T White Solaru, Zoran Popovic, Vidyasagar Kalahasti, Eric Roselli, Benico Barzilai
Journal: Circulation (2018)

Introduction: Severe aortic stenosis (AS) is a multifactorial, progressive condition that is associated with high short-term mortality. Risk factors for mortality have been described and include male sex, hypertension, hyperlipidemia, and congenital bicuspid valve (BAV). Senile, calcific AS is thought to affect both genders equally in contrast to BAV which has a 3:1 male preponderance. It is unknown if there are gender differences in the prevalence of severe, senile AS or congenital bicuspid aortic valve in Whites compared to Blacks. Methods: 10,299 Black or White patients with severe aortic stenosis or bicuspid aortic valve treated at Cleveland Clinic with primary AVR from 1/1/2000 to 1/1/2017 were included in this study. There were 257 Black patients (2.5% of the study population). Categorical data on gender was compared using the Chi-squared test. Results: Blacks with severe aortic stenosis were significantly more likely to be female compared to Caucasians (55% vs 36%, p&lt;0.001). There were no differences in gender prevalence among patients with BAV (73% vs 74%, p=0.88). Conclusions: Our study found that Blacks with severe AS undergoing AVR are significantly more likely to be female compared to Whites. However, there were no differences in gender prevalence among Blacks and Whites with BAVs. Although Black men are the least likely demographic to access health care, they comprise the majority of the BAV group. Thus, lack of health care access does not fully explain the gender differences in the severe AS group. There may be a strong underlying genetic component accounting for the 3:1 male predominance in all BAV patients.