tbuckley/cabot-search huggingface dataset:
Abstract 13643: Impact of Aortic Valve Repair and Valve-sparing Procedures on the Mitral Annular Geometry Assessed by 3-dimensional Transesophageal Echocardiography
Authors: Maude Page, Maxime Laflamme, Christophe De Meester, Mihaela Amzulescu, Laurent De Kerchove, Gebrine El Khoury, Agnès Pasquet, Jean-Louis Vanoverschelde
Journal: Circulation (2015)

Background: Annular non-planarity, the "saddle-shape" of the mitral valve (MV) annulus, plays a role in minimizing leaflet stress and preserving valve function. Aortic valve (AV) repair/sparing procedures are increasingly used to treat aortic regurgitation (AR). The impact of these procedures on MV geometry and function is unknown. Methods: 2D and 3D transesophageal echocardiography (TEE) of the MV was acquired pre-operatively and immediately after surgery in 30 patients with severe AR and/or aortic root dilatation (Group 1 (n=10): bicuspid AV undergoing AV repair and valve-sparing root replacement with AV reimplantation; Group 2 (n=10): tricuspid AV undergoing AV repair and AV reimplantation; Group 3 (n=10): isolated AV cusp repair) and in 10 controls (Group 4). MV morphology was assessed by dedicated quantification software (fig. 1). Results: Comorbidities were similar in all groups. Groups 1, 2 and 3 had increased LV end-diastolic volumes compared to group 4 (214±90, 193±56, 180±55 vs. 86± 28ml for groups 1, 2, 3 and 4, respectively; p&lt;0.001); LVEF was similar (59.5 ± 6.2%). The baseline dimensions of the ventriculo-aortic junction and sinuses of Valsalva were larger in groups 1 and 2 vs. groups 3 and 4 (p&lt;0.0001). AV and MV parameters are summarized (table). Pre-operative MV parameters did not differ from those of normal subjects. The annular height and annular height to commissural width ratio (AHCWR) significantly decreased after surgery in groups 1 and 2, as did the tenting area. Significant changes in the coaptation depth and mitro-aortic angle were only found in group 1. Conclusions: AV repair/sparing procedures alter the MV geometry, including the non-planarity of the annulus and the depth of coaptation of the leaflets, especially among patients with a bicuspid AV undergoing AV reimplantation. These alterations could have long-term implications on MV function.
Abstract 12983: mtDNA Damage in Concert With PCSK9 Expression Induces Apoptosis in Vascular Smooth Muscle Cells
Authors: Zufeng Ding, Shijie Liu, Jawahar L Mehta
Journal: Circulation (2016)

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in inducing hypercholesterolemia and associated cardiovascular diseases. Autophagy is considered a protective and adaptive mechanism to promote cell survival, while apoptosis represents cell death program designed to remove injured cells. Exposure of vascular smooth muscle cells (SMCs) to noxious stimuli such as LPS or ox-LDL induces PCSK9 expression and apoptosis. Methods and Results: Treatment of human primary vascular SMCs to 20 ng/ml LPS significantly induced both mtDNA damage and PCSK9 expression. mtDNA damage induction with the autophagy inhibitor 3-methyladenine enhanced PCSK9 expression, whereas mtDNA damage inhibition with the autophagy inducer rapamycin reduced PCSK9 expression, indicating an interplay between autophagy, mtDNA damage and PCSK9. Inhibition of DNase II (siRNA) for reduced the extent of mtDNA damage and PCSK9 expression confirmed the role of mtDNA damage in PCSK9 expression. Next, we investigated the role of PCSK9 in the development of apoptosis. We observed that PCSK9 upregulation by hPCSK9 treatment induced and PCSK9 inhibition by siRNA transfection reduced apoptosis of SMCs (measured as TUNEL staining and expression of Bax, Bcl2 and cleaved caspase-3). Conclusions: These observations provide a compelling evidence for the role of mtDNA damage in PCSK9 release. Both collectively induce SMC apoptosis during inflammatory states characteristic of cardiovascular diseases, such as atherosclerosis.
Abstract 12989: Attenuation of Renal Fibrosis and Inflammation in <i>Npr1</i> Haplotype Mice by Retinoic Acid and Sodium Butyrate via Interactive Modulation of STAT1, HDACs and NF-κB
Authors: Prerna Kumar, Ramu Periyasamy, Venkateswara R Gogulamudi, Kailash N Pandey
Journal: Circulation (2016)

Introduction: Mice lacking functional guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene ( Npr1 ) exhibit hypertension, kidney disease, and heart failure. In this study, we investigated the effect of butyric acid, a histone deacetylase (HDAC) inhibitor and all-trans retinoic acid (ATRA) hybrid drug (ATRA-BA) on the attenuation of renal inflammation and fibrosis in Npr1 haplotype mice. Methods and results: Adult (18-20 week old) male Npr1 haplotype (1-copy; Npr1 +/-; n=10), wild-type (2-copy; Npr1 +/+ ; n=10), and gene-duplicated (3-copy; Npr1 ++/+ ; n=10) mice were treated with ATRA-BA (1.0 mg/kg/day) by intraperitoneal injections for 2-weeks. A significant decrease in systolic blood pressure was observed in ATRA-BA-treated Npr1 +/- mice (treated, 113.3 ± 1.5 vs. control, 130.4 ± 1.9; p &lt; 0.01; n=10). Treatments with ATRA-BA showed a marked reduction in tubulo-interstitial fibrosis (50%, p &lt; 0.001) and a decrease in renal col 1α levels (treated, 25.9 ± 1.2 vs. control, 57.2 ± 2.9, p &lt; 0.001) in Npr1 +/- mice. Significant reduction was observed in renal IL-6 (55%, p &lt; 0.001) and MCP-1 (61%, p &lt; 0.01) protein levels in ATRA-BA-treated Npr1 +/- mice compared with untreated controls. There was significantly increased renal NF-κB (p65) protein expression and activity in Npr1 +/- mice; however, reduced levels were observed in Npr1 +/++ mice compared with wild-type mice. Renal NF-κB (p65) activity decreased (52%, p &lt; 0.01) in drug-treated Npr1 +/- mice compared with controls. Treatment with ATRA-BA facilitated dissociation of HDAC1/2 from STAT1 protein complex and enhanced STAT1 acetylation. Furthermore, acetylated STAT1 formed complex with NF-κB (p65), thereby inhibiting its activity. Higher urinary albumin creatinine ratio and urinary protein was detected in Npr1 +/- mice compared with Npr1 +/+ mice and a complete reversal was observed in drug-treated Npr1 +/- animals. Conclusions: The present results demonstrate that ATRA-BA reduces blood pressure and repairs the abnormal renal pathology in haplotype Npr1 +/- mice by modulating STAT1, HDAC1/2, NF-κB (p65) interactions. The findings will be important in developing the strategies for treating the hypertension and renal pathological conditions.
Abstract 13691: Extracorporeal Cardiopulmonary Resuscitation for Nonshockable Rhythms
Authors: Eisuke Kagawa, Keigo Dote, Masaya Kato, Shota Sasaki, Yasuki Kihara
Journal: Circulation (2015)

Introduction: In cardiac arrest patients, patients with shockable rhythms have more favorable outcomes than those with non-shockable rhythms. Recently, alternative cardiopulmonary resuscitation (CPR) using extracorporeal membrane oxygenation (ECMO) has shown the potential to improve the outcomes of patients who are unresponsive to conventional CPR. Hypothesis: We assessed the hypothesis that initial shockable rhythms are associated with improved outcomes in extracorporeal CPR (ECPR) using ECMO. Methods: Patients who were treated with ECPR were enrolled in this study. Patients were divided into 2 groups according to the whether the initial recorded rhythms were shockable (shockable group) or not (nonshockable group). Baseline characteristics and 90-day survival were assessed. We constructed 90-day survival curves using the Kaplan-Meier method. A P &lt; 0.05 was defined as statistically significant. Results: The study patients in the shockable and nonshockable groups were similar in terms of age, witnessed to arrest, bystander initiated CPR, collapse to CPR, collapse to initiation of ECMO. Patients in the shockable group were more likely than those in the nonshockable group to undergo immediate coronary angiography (91% vs. 66%, P &lt; 0.001), subsequent coronary revascularization (55% vs. 37%, P = 0.02), and targeted temperature management (56% vs. 49%, P = 0.37). The rates of return of spontaneous heart-beat (88% vs. 91%, P = 0.58) and weaning from ECMO (48% vs. 40%, P = 0.25) were similar between groups. The 90-day survival curves are shown in the figure. Cox proportional hazard regression suggested that the initial shockable rhythm was not an independent predictors of 90-day survival. Conclusions: Unlike in conventional CPR, the initial nonshockable rhythm is not necessarily associated with an adverse outcome. However, none of the patients with an initial asystole rhythm survived up to 90 days.
Abstract 12981: Long-term Efficacy of Balloon Pulmonary Angioplasty in Patients With Inoperable Chronic Thromboembolic Pulmonary Hypertension
Authors: Shunsuke Tatebe, Koichiro Sugimura, Tatsuo Aoki, Saori Yamamoto, Nobuhiro Yaoita, Katsuya Kozu, Haruka Sato, Kimio Satoh, Hiroaki Shimokawa
Journal: Circulation (2016)

Background: Balloon pulmonary angioplasty (BPA) has been shown to markedly improve both exercise capacity and pulmonary hemodynamics in patients with inoperable chronic thromboembolic pulmonary hypertension (CETPH). Since 2009, we have adopted BPA as a first-line treatment strategy for inoperable CTEPH. The aim of this study was to evaluate the long-term efficacy of BPA in patients with inoperable CTEPH. Methods and Results: From 1992 to 2014, we treated a total of 110 patients with inoperable CTEPH at our Hospital. Among them, we excluded 11 patients from the present analysis due to advanced cancer or multiple organ failure at admission. We divided the remaining 99 patients into 2 groups; the historical control (HC) group (N=35; mean age, 62 years; M/F = 30/5) who were admitted from 1992 to 2008 and the BPA group (N= 64; mean age, 64 years; M/F= 49/15) who were admitted from 2009 to 2014. We compared baseline characteristics, hemodynamics and long-term survival between the 2 groups. There was no significant difference in baseline parameters, including age, sex, WHO functional class or serum BNP levels between the 2 groups. Regarding hemodynamic parameters, the BPA group had significantly higher pulmonary capillary wedge pressure compared with the HC group (9±0.4 vs. 7±0.6 mmHg, P&lt;0.01). The median follow-up period was 53 months (IQR 26-80 months) for the HC group and 23 months (IQR 13-39 months) for the BPA group. Kaplan-Meier analysis showed that the survival rate was significantly better in the BPA group compared with the HC group (log-rank P=0.02), with the estimated 5-year survival probability of 98% for the BPA group and 73% for the HC group ( Figure ). The multiple Cox hazard analysis showed that both age (hazard ratio 1.07, P=0.02) and the HC group (hazard ratio 9.2, P=0.01) were independent predictor of mortality. Conclusions: These results indicate that BPA has a beneficial impact on long-term survival in patients with inoperable CTEPH.
Abstract 18774: Electromechanical and Scar-Mediated Interactions in Cardiac Resynchronization Therapy Based on Cardiac Magnetic Resonance
Authors: Kenneth C Bilchick, Sujith Kuruvilla, Yasmin Hamirani, Raghav Ramachandran, Katherine M Parker, Samantha A Clarke, Andrew E Darby, Pamela Mason, John D Ferguson, J M Mangrum, Rohit Malhotra, John P DiMarco, Jeffrey Holmes, Michael Salerno, Christopher M Kramer, Frederick H Epstein
Journal: Circulation (2013)

Background: Mechanical dyssynchrony (MD), left ventricular (LV) lead electrical timing relative to QRS onset (QLV, or normalized for QRS width as LVLED), percent LV scar volume (PSV), and scar at the LV lead position (LP-SCAR) are important determinants of the response to cardiac resynchronization therapy (CRT), but their interactions are not well understood. Objective: We sought to determine these electrical, mechanical, and scar-mediated interactions in a clinical CRT cohort. Methods: Patients undergoing CRT first had cardiac magnetic resonance (CMR) with cine DENSE (displacement encoding with stimulated echoes) and late gadolinium enhancement (LGE), echocardiography, and cardiopulmonary exercise testing, followed by repeat testing at 6 months. Factors influencing CRT response (defined as a 15% reduction in LVESV) and clinical events up to 5 years after CRT were analyzed using logistic and Cox proportional hazards regression, respectively. Results: The 70 patients studied (66 ± 13 years old, 26% F) had an LVEF of 22.0 ± 8.2%, and 51% had positive LGE (PSV 10.0% [IQR 6.3%-16.7%]). 36 (51%) were CRT responders, 16 (23%) died during follow-up, 24 (34%) had the combined endpoint of heart failure hospitalization (HFH) or death, and 10 (14%) had sustained ventricular tachycardia (VT). Predictors of CRT nonresponse included CURE ≥ 0.70 (OR 73.2, 95% C.I. 8.8-605.8), QLV ≤ 90 ms (OR 9.0 [2.6-31.0]), and LP-SCAR (OR 2.9 [1.1-7.6]). The logistic model with these 3 covariates was highly predictive of CRT nonresponse (AUC 0.933; p &lt; 0.001). Electromechanical factors also predicted clinical events. The best Cox model for death consisted of CURE ≥ 0.70 (HR 3.88 [1.38-10.88]) and LVLED ≤ 0.50 (HR 5.12 [1.79, 14.69]), while LVLED ≤ 0.50 also predicted the combined endpoint of HFH or death (HR 3.64 [1.57, 8.46]). Of note, LP-SCAR and CURE influenced VT events (p=0.07). Conclusions: The clinical course after CRT-D implantation reflects complex interactions between electrical, mechanical, and scar-mediated factors that can be understood well with CMR. A model combining CMR-derived mechanical and scar-mediated factors with electrical parameters accurately predicts both CRT nonresponse and adverse clinical events, such as heart failure hospitalization and death.
Abstract 14173: Pharmacologic and Activated Fibroblast-Specific Gβγ-GRK2 Inhibition is Protective Following Ischemia Reperfusion Injury
Authors: Joshua G Travers, Fadia A Kamal, Michelle L Nieman, Burns C Blaxall
Journal: Circulation (2015)

Heart failure is a devastating disease characterized by chamber remodeling, interstitial fibrosis and reduced ventricular compliance. Cardiac fibroblasts are largely responsible for extracellular matrix homeostasis, however upon injury or pathologic stimulation, these cells transition to a myofibroblast phenotype and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation induces excess signaling through G protein βγ subunits and ultimately results in pathologic G protein-coupled receptor kinase 2 (GRK2)-mediated β-adrenergic receptor downregulation. We hypothesized that Gβγ-GRK2 inhibition plays an important role in the cardiac fibroblast to attenuate pathologic myofibroblast differentiation, interstitial fibrosis and the overall progression of heart failure. To investigate this hypothesis, mice were subjected to ischemia/reperfusion injury and treated with the small molecule Gβγ-GRK2 inhibitor gallein for 4 weeks. Animals receiving vehicle demonstrated severe cardiac dilatation and deterioration in overall cardiac function as measured by percent fractional shortening and ejection fraction. Remarkably, mice treated with gallein exhibited nearly complete preservation of cardiac function, along with reduced scar formation and fibrotic marker expression, suggesting a direct effect within the cardiac fibroblasts. To further explore possible mechanisms, activated fibroblast-restricted GRK2 knockout mice (GRK2fl x PeriostinMCM) were subjected to 4 weeks of ischemia/reperfusion injury. These animals displayed preserved myocardial function and reduced eccentric hypertrophy and collagen deposition compared to GRK2fl littermate controls. Finally, systemic Gβγ-GRK2 inhibition by gallein may not confer further protection over activated fibroblast-specific GRK2 ablation alone. In summary, these findings suggest a potential therapeutic role for Gβγ-GRK2 inhibition in limiting pathologic myofibroblast activation, interstitial fibrosis and heart failure progression. We believe this fibroblast-targeted approach will lead to the refinement of existing targets and compounds, and possibly the generation of novel therapeutics for the treatment of heart failure.
Abstract 18802: Endothelial-Mesenchymal Transition (EndMT) of the Atrial Endocardial Endothelial Layer: A Potential Contributor to Atrial Pathological Remodeling?
Authors: Ian D Greener, Cody A Rutledge, Samuel C Dudley
Journal: Circulation (2013)

Introduction: Atrial fibrosis is a major contributor to the atrial fibrillation substrate but the mechanisms underlying its formation remain poorly understood. One major molecule implicated in enhanced fibrosis in response to atrial stress is Angiotensin II. EndMT describes the process of endothelial cell (EC) transformation into a myofibroblast - the major extracellular matrix synthesizing cell. Methods &amp; Results: Atria of 4-6 week old angiotensin converting enzyme overexpressing mice (ACE88) were compared to ACE wild-types (WT). qPCR demonstrated significantly increased Col1A2 (11.5+/-0.7vs2.7+/-0.7; p=7.3E-6) and FN1 (2.7+/-0.1vs0.86+/-0.16 ; p=7.3E-6) transcripts in ACE88 compared to WT. Interestingly, collagen I &amp; CD31 immunolabeling revealed a more complex transmural fibrotic pattern: intra-atrial collagen I was increased as expected, but a strong increase in collagen I intensity was also detected in the endothelial layer enveloping atrial fascicles and lining the endocardial free wall. CD31 immunolabeling of ACE88 atria revealed a “rugged” lining of atria endocardial free-walls &amp; fascicles compared to the finely demarcated WT counterparts. Significantly increased intra-atrial uptake of Evan’s Blue dye in ACE88 vs WT (0.15+/-0.01vs 0.04+/-0.006; p=&lt;0.002) confirmed a disruption of endothelial barrier function. In addition, atria of 16-week old mice with myocardial infarction (MI) were studied at 2 &amp; 4 weeks postMI. Similar to ACE88 mice, mRNAs for Col1A2 (0.91+/-0.1vs1.5+/-0.2 ; p=0.06) and FN1 (0.9+/-0.2vs1.3+/-0.1; p=0.052) showed a strong tendency for upregulation 4 weeks post-MI compared to aged-matched c57 atria (c57). Surprisingly, strongest collagen I post-MI labeling localized in proximity to CD31 labeling at 2 weeks, with little change in intra-atrial collagen I content. Significantly increased collagen I intensity was detected in the endocardial EC layer 4 weeks post-MI compared to c57 (31+/- 3vs45+/-3; p=0.009). Conclusions: These data suggest the endocardial EC layer may be an early sensor to increased atrial stress; endocardial EndMT may be an early event during the atrial remodeling process and perhaps contributes to global intra-atrial remodeling through altered paracrine and/or permeability mechanisms.
Abstract 18794: More Than a Biomarker_ANP Modulates Heart Failure, Cardiac Function and Survival in Dilated Cardiomyopathy
Authors: Dong Wang, Inna P Gladysheva, T. Michael Fan, Sullivan Ryan David, Guy L. Reed
Journal: Circulation (2013)

Although atrial natriuretic peptide (ANP) is an established biomarker for heart failure, there is significant controversy whether ANP modifies or affects the progression of heart failure in patients with reduced contractile function and dilated cardiomyopathy (DCM). Therefore we examined the effects of ANP on survival, heart failure progression, fibrosis and cardiac function in a well-established model of DCM caused by the cardiac-targeted expression of a dominant negative CREB transgene. By comparison to DCM mice with normal ANP levels (DCM, ANP+/+) mice with partial ANP deficiency (DCM, ANP+/-) had reduced survival (p&lt;0.001) and, mice with full ANP deficiency (DCM, ANP-/-), had even greater reductions in survival than those with normal ANP or partial ANP deficiency (p&lt;0.001). Radiography showed that ANP-deficient DCM mice developed more severe heart failure with pleural effusions and pronounced cardiomegaly. These mice showed increased alveolar congestion (22.9±1.5% vs. 57.3±3.2%, p&lt;0.001) and increased heart weights (heart:body weight 0.54±0.04% vs. 0.95±0.05%). ANP-deficient DCM mice showed a more marked reduction in cardiac function as evidenced by decreased EF% (30.7±3.2 % vs. 16.0 ±1.5 %, p&lt;0.001) and enhanced cardiac dilation (LVIDd 4.51±0.11 mm vs. 5.85±0.10 mm, p&lt;0.001; LVIDs 3.9±0.1 mm vs. 5.0 mm±0.2, p&lt;0.001). ANP-deficient DCM mice had more severe cardiac interstitial fibrosis (4.54±0.3 % vs. 12.58±0.62%, p&lt;0.01) and perivascular fibrosis (ratio to lumen area 0.58±0.07 vs. 2.53±0.26, p&lt;0.01) as well as eccentric cardiomyocyte hypertrophy (cross sectional area 662±12 μm2 vs. 905±23 μm2, p&lt;0.001). Levels of cGMP were significantly reduced in ANP-deficient DCM mice (p&lt;0.001). We conclude that ANP profoundly modulates the progression of DCM in mice by reducing the severity of heart failure, improving contractility, reducing ventricular dilation, preventing cardiac fibrosis and extending survival. Thus ANP is not only a key biomarker, but it also modulates the progression of heart failure, cardiac function and remodeling in DCM.
Abstract 13023: Characteristics of Treatment Failure With Rate and Rhythm Control Strategies in Patients With Atrial Fibrillation: Insights From the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) Trial
Authors: Abhishek Maan, Ziling Qin, Yanbing Wang, Zheng Zhang, Samuel Dudley, Kaustubh Dabhadkar, Moussa Mansour, Jeremy Ruskin, E. Kevin Heist
Journal: Circulation (2016)

Introduction: In patients with atrial fibrillation (AF) both “rate control” and “rhythm control” therapies have distinct set of limitations. We sought to investigate the rates and reasons of crossover from an initially assigned rate control arm to rhythm control and from rhythm to rate control therapy in patients who were enrolled in the AFFIRM trial. Methods: We compared the characteristics of patients who continued in the initially assigned treatment arm versus those who crossed over to the alternative treatment strategy in both “rhythm” and “rate” control arms. Two-sample t-test and chi-squared tests were used to compare means and proportions respectively. Results: A total of 4,060 patients were enrolled in the AFFIRM trial and over a mean follow-up duration of 3.5 years, 842 of them underwent crossover from an initially assigned treatment arm. The rate of crossover from an initially assigned rhythm control arm (594/2033, 29.2%) was more frequent than the rate of crossover from rate control to rhythm control (248/2027, 12.2%, p &lt; 0.0001). In the rhythm control arm, the patients who crossed over to rate control had a significantly higher incidence of prior failure of an antiarrhythmic drug (139/594, 23.4%) than in those who continued as assigned (210/1439, 14.6%, p &lt; 0.0001). In the rate control arm, patients who crossed over to rhythm control were relatively younger (68.3 ± 8.2 vs. 69.7 ± 8.0 years in those who continued, p = 0.01). The leading reasons for crossover to rate control were failure to achieve or maintain sinus rhythm (272/594, 45.8%) and intolerable adverse effects (122/594, 20.5%). In comparison, the major reasons for crossover to rhythm control were failure to control AF symptoms (159/248, 64.1%) and intolerable adverse effects (9/248, 3.6%). The difference in crossover pattern was statistically significant (p &lt; 0.0001). Conclusions: Rhythm control was abandoned more commonly than rate control in patients who were enrolled in the AFFIRM trial. Failure of antiarrhythmic drug therapy prior to randomization was a significant factor for crossover from rhythm to rate control. Patients who crossed over from rate to rhythm control were younger than those who continued. The crossover from rhythm to rate control was driven by the occurrence of adverse effects.