tbuckley/cabot-search huggingface dataset:
Abstract 18442: Long-Term Prognostic Value of Cardiac Magnetic Resonance and Echocardiography After Reperfusion Therapy in ST-Segment Elevation Myocardial Infarction
Authors: Susan H Kwon, Kwang J Lee, Selma F Mohammed, Gregory W Barsness, Malcolm R Bell, David Larsen, James Glockner, Jae K Oh
Journal: Circulation (2013)

Background: The aim of this study was to determine whether adding DE-CMR and/or TTE based parameters beyond known clinical factors provides incremental improvement of predicting long-term outcomes in STEMI patients who undergo acute reperfusion therapy. Methods and Results: One hundred twenty patients with first time STEMI who underwent PCI (74%), fibrinolysis (3%), and both (19%), were studied by both delayed enhancement cardiac magnetic resonance (DE-CMR) and transthoracic echocardiogram (TTE) during the acute phase of myocardial infarction. The primary endpoint was major adverse cardiac events (MACE). There were 28 events (6 deaths, 13 recurrent ischemia, and 9 heart failure) over a median follow-up of 4 years. We defined incremental increase in prognostic value by increase in Cox proportional hazards global chi square (χ 2 ) and/or increase in c-index with the addition of TTE and/or CMR parameters after adjusting for clinical variables. Among the clinical data, heart rate (HR: 1.02, p=0.047) and troponin (HR: 1.13, p=0.013) predicted MACE (χ 2 : 12.4, P=0.002; C index 0.69). After adjusting for these clinical factors, adding TTE parameters (left ventricular end systolic volume index [HR: 1.05, p&lt;0.0001] and mitral valve deceleration time [HR: 0.99, p=0.036]), increased the global χ 2 to 24.6 and C index to 0.74 (p&lt;0.0001). When CMR parameter (infarct size [HR: 2.92, p&lt;0.0001]) was added to the clinical data alone, there was greater increase in global χ 2 to 36.8 and C index to 0.83 (p&lt;0.0001). Addition of DE- CMR to clinical data combined with TTE measures showed significant incremental value with increased χ 2 difference of 17.6 (p&lt;0.0001). There was no significant incremental value of adding TTE to clinical data combined with DE-CMR (p&gt;0.05). Conclusion: DE-CMR provides significant incremental value for prognosticating adverse cardiac events over clinical data alone (or when in combination with TTE) in STEMI patients who undergo reperfusion therapy.
Abstract 18687: Obesity is Associated With Increased Mortality and Hospitalization in Patients Supported With a Continuous-Flow Left Ventricular Assist Device
Authors: Ramsey M Wehbe, Brian C Jensen, Patricia P Chang, Amanda Bowen, Sarah B Waters, Aparna Veeramachaneni, Brett C Sheridan, Jason N Katz
Journal: Circulation (2013)

Background: Greater body mass index (BMI) is associated with poor prognosis following cardiac transplantation, but little is known about the influence of BMI on outcomes after mechanical circulatory support (MCS). In particular, no data exists describing either serial changes in BMI or the impact of baseline obesity on morbidity or mortality in “real-world” patients supported with a continuous-flow LVAD (CF-LVAD). Methods: We reviewed records for all consecutive patients implanted with a CF-LVAD at our institution from 2008-2012. BMI was recorded prior to surgery, and at 1, 3, 6, and 12-months post-implant. Obesity was defined as a BMI ≥ 30 kg/m 2 . Serial BMI measurements were analyzed for significance, and Cox proportional hazards analysis was used to identify any associations between pre-implant BMI, or BMI changes, and survival or all-cause hospitalization. Results: Ninety-eight patients were included - 79 as bridge-to-transplant (BTT) and 19 as destination therapy (DT). Median follow-up was 256d, during which 24 patients died, 31 were transplanted, and 43 remained on MCS. At baseline, median BMI was 27.1 kg/m 2 (IQR 23.6, 30.9) and 27% were obese. Obesity rates were similar in BTT and DT cohorts. Non-obese patients exhibited a mean weight gain from pre-implant to 12 months of 11.7 ± 1.4 kg (p&lt;0.001), while obese patients showed no significant changes in weight. Pre-implant obesity was associated with increased mortality at 90d (31% vs 6% non-obese, HR 6.0, p=0.002) and with decreased hospitalization-free survival (HR 1.7, p=0.04). Neither absolute nor relative changes in BMI after CF-LVAD were significantly associated with the evaluated outcomes. Conclusions: Obese patients have a significantly increased risk of death and hospitalization within the first 90d after the implantation of a durable CF-LVAD. This is the first study to demonstrate a mortality liability associated with obesity in patients implanted with these contemporary devices. Similar to clinical trial cohorts, non-obese patients gained a significant amount of weight during LVAD support, while obese patients neither gained nor lost weight. Serial changes in BMI did not influence outcomes. Future analysis will focus on mode of death and causes of morbidity for these obese patients.
Abstract 11917: Muscarinic Stimulation Facilitates SR Ca <sup>+2</sup> Release by Increasing PKG Phosphorylation of RyR2 at Ser-2808 and Decreasing CaMKII Phosphorylation at Ser-2814
Authors: Hsiang-Ting Ho, Andriy E Belevych, Bin Liu, Ingrid M Bonilla, Przemyslaw B Radwanski, Héctor H Valdivia, Karsten Schober, Cynthia A Carnes, Sándor Györke
Journal: Circulation (2016)

Autonomic regulation of SR Ca +2 release is critical for modulating cardiac performance to match physiologic demand. During heart failure (HF), autonomic balanced shifts to a dominant sympathetic state to increase fractional SR Ca +2 release. Although intended to be compensatory, this increase in sympathetic input causes increases in the frequency of proarrhythmic spontaneous SR Ca +2 release events. Interestingly, parasympathetic augmentation was recently shown to alleviate HF phenotypes by shifting autonomic balance away from sympathetic dominance. While the effects of sympathetic stimulation and mechanism behind their action on cardiomyocyte Ca +2 handling are relatively well established in health and disease, the modes of action and mechanisms of parasympathetic modulation of SR Ca +2 release are poorly defined. To address this question, we investigated the effects of the cholinergic agonist, carbachol (CCH), on Ca +2 handling (Fluo-4 FF AM) and protein phosphorylation levels in cardiomyocytes using a combination of pharmacological approaches and genetic mouse models. In settings of reduced SR Ca +2 load, exposure to the parasympathetic agonist CCH increased fractional Ca +2 release without affecting Ca +2 spark frequency in cardiomyocytes. Immunoblot measurements showed that this “efficient” mode of excitation-contraction (EC) coupling involves reciprocal changes in the phosphorylation state of RyR2. Specifically, CCH treatment of cardiomyocytes increased Ser-2808 phosphorylation, mediated by muscarinic receptor subtype 2 and activation of PKG. Conversely, CCH treatment was associated with dephosphorylation at Ser-2814 through activation of muscarinic receptor subtype 3 and decreased ROS-dependent activation of CaMKII. We further demonstrate that parasympathetic stimulation improved Ca +2 cycling efficiency in cardiomyocytes isolated from failing hearts by restoring altered RyR2 phosphorylation balance. These results suggest that parasympathetic stimulation initiates a novel mode of EC coupling in cardiomyocytes that enhances the efficiency of cardiac SR Ca +2 store mobilization during systolic Ca +2 release, while inhibiting pathologic diastolic Ca +2 leak.
Abstract 18660: A Potential Role of TRPM2 Mediated Inflammation in Heart Disease
Authors: Zhichao Yue, Jianyang Du, Jia Xia, Xin Qin, Yanhui Zhang, Yanlin He, Daniel Fusco, Bruce Liang, Lixia Yue
Journal: Circulation (2013)

Background: Inflammation underlies a variety of pathological processes leading to various types of heart disease, including chronic heart failure, arrhythmia, and ischemic cardiomyopathy. The importance of the inflammatory cascade in heart disease has been recognized and thoroughly investigated for the last three decades. However, despite the promising results from experimental studies, attempts to attenuate inflammatory injury in clinical practice have been less successful than expected. A better understanding of the biological process and mechanisms of inflammatory cascade is necessary to identify novel targets for the treatment of inflammatory heart disease. Here we tested the hypothesis that inflammasome activation mediated by the oxidative stress sensitive TRPM2 channels contributes to ischemic cardiomyopathy in I/R mouse model and in human atrial fibrillation (AF). Methods: We used both in vivo ischemia-reperfusion (I/R) mouse model and ex-vivo dissociated fibroblasts from control and AF patients. Heart function of I/R mice was assessed by echocardiograph (ECG) and P-V loop catheter. Results: We found that TRPM2 is highly expressed in cardiac fibroblasts, and that functional TRPM2 channels were readily detected by patch-clamp in cardiac fibroblasts from mouse and human. In I/R mouse heart, TRPM2 was up-regulated by myocardial infarction. In human fibroblasts, the expression of TRPM2 measured by qPCR was much higher in AF versus control patients. We found that the infarct size of TRPM2-knockout mice was much smaller than wide-type (WT) control mice in I/R mouse model. Heart function measured one week after I/R by ECG was also much better in TRPM2-KO mice than WT mice. To understand the mechanism of the protective effects of TRPM2 deletion in heart function of the I/R model, we investigated the formation of inflammasome and found that TRPM2 deletion largely reduced the inflammasome formation in I/R mouse hearts. Conclusions: Fibroblasts from AF patients showed higher expression of TRPM2 detected by qPCR. Moreover, deletion of TRPM2 seems to play an important role in heart protection in the I/R model. Our results suggest that targeting TRPM2 may serve as a potential therapeutic approach for treatment of inflammation associated heart disease.
Abstract 12715: Aortic Arch Width Adds to Coronary Artery Calcium for Prediction of Incident Adverse Cardiovascular Disease Events: The Framingham Heart Study
Authors: Michael L Chuang, Philimon Gona, Saadia Qazi, Rebecca M Musgrave, Caroline S Fox, Joseph M Massaro, Udo Hoffmann, Christopher J O'Donnell
Journal: Circulation (2015)

Introduction: Aortic arch width (AAW) is cross-sectionally associated with multiple cardiovascular disease (CVD) risk factors. We sought to determine whether AAW would add to standard Framingham risk factors (FRF) and coronary artery calcium (CAC) as a predictor of incident adverse CVD events. Methods: AAW, the distance between the centroids of the ascending and descending aorta at the level of main pulmonary artery bifurcation, was measured in 3026 Framingham Offspring and Third Generation cohort members who underwent computed tomography (CT) for CAC assessment over 2002-2005. Upper 90th percentile (P90) limits, based on sex, age and body surface area, were determined from a healthy referent group (no hypertension, diabetes, dyslipidemia, smoking; N=1471). Participants with prevalent CVD (N=119) or missing covariates (N=27) were excluded from further analysis, leaving 2880 who were dichotomized by AAW ≥P90 (high AAW) or &lt;P90. Cox proportional hazards models were used to estimate hazard ratio (HR) of high AAW on time-to-CVD (composite of: CVD death; myocardial infarction, MI; unstable angina, USA; stroke; first admission for heart failure, HF) after adjustment for FRF (listed in Table) and log(CAC+1). The category-free net reclassification improvement (NRI) metric was used to assess the effect of adding AAW to the baseline FRF+CAC model. Results: Overall prevalence of high AAW was 19.2%. There were 135 incident CVD events (6 CVD death, 49 MI, 4 USA, 42 stroke, 34 HF) over median 8.9-y follow up. High AAW was independently predictive of CVD, HR=1.55, p=0.032, and improved prediction over FRF+CAC (Table) with NRI=0.31; 95%CI=0.15-0.48. Conclusions: AAW is commonly visualized on MRI or CT of the chest and is simple to measure. High AAW adds to traditional CVD risk factors and CAC for prediction of incident CVD events among community dwelling adults. These data suggest AAW has utility for CVD risk stratification; findings remain to be replicated in other cohorts.
Abstract 12454: Mitochondrial Transcription Factor 2B as a Mediator of Mitochondrial Retrograde Signaling and Endothelial Cell Shape
Authors: Steven J Forrester, Tatsuo Kawai, Katherine J Elliot, Kunie Eguchi, Joon-Young Park, Victor Rizzo, Satoru Eguchi
Journal: Circulation (2015)

Mitochondrial dysfunction, such as observed in endothelial cells, has been implicated in various cardiovascular diseases including, hypertension and atherosclerosis. Mitochondrial transcription factor 2B (TFB2M) is an essential component to maintain proper transcriptional and functional control of mitochondrial DNA. As well, elongation of endothelial cells is a characteristic of atheroprotective regions within the vasculature, and the relationship between the mitochondria and EC shape is currently unknown. Additionally, recent interest has been focused on mechanisms by which the mitochondria may signal to the nucleus to affect cell function. The aim of our study is to investigate the hypothesis that TFB2M has a novel role in enhancing endothelial function. Human umbilical vein endothelial cells (HUVECs) were harvested 72 hours after adenoviral transduction with TFB2M (100 moi). HUVECs transduced with TFB2M showed an elongated cell morphology when compared to GFP control. To further investigate the effect of TFB2M on regulating mitochondrial function and cell shape, immunoblotting was carried out for markers involved in mitochondrial function/dynamics and markers indicative of cytoskeleton reorganization. TFB2M transduction resulted in increased expression of mitochondrial biogenesis marker VDAC (2.6 fold increase), mitochondrial fusion protein MFN2 (2.1 fold increase), and phosphorylated myosin phosphatase targeting protein MYPT1 at Thr850 (2.2 fold increase, p &lt; 0.05 for all proteins). Additionally, fluorescence microscopy showed enhanced mitochondrial fluorescence in TFB2M transduced cells using mitotracker red staining (3.5 fold increase, p &lt; 0.001). These data indicate that TFB2M has a previously undiscovered function contributing to altered EC function and shape, potentially through a novel mitochondrial retrograde signaling mechanism. Further research will focus on distinguishing the exact mechanisms culminating in a protective EC phenotype and the beneficial role of endothelial TFB2M-mediated enhanced mitochondrial function in the treatment of EC dysfunction associated with various cardiovascular diseases.
Abstract 18641: Relationship Between Effective Arterial Elastance and Specific Measures of Left Ventricular Afterload
Authors: Julio Chirinos, Prithvi Shiva-Kumar, Salvatore Geraci, Sanjal Desai, Rahul Chandrashekhar, Snigdha Jain, Hassam Saif, Philip Haines, Preston Broderick, Amin Vakilipour, Deepa Rawat, Walter Witschey, Victor Ferrari, Scott Akers
Journal: Circulation (2013)

Background: Effective arterial elastance (E A ), the ratio of left ventricular (LV) end-systolic pressure and stroke volume, was proposed as a lumped parameter that incorporates pulsatile and resistive afterload and is increasingly being used in clinical studies. In conjunction with LV end-systolic elastance, it is used to assess combined “ventricular-arterial stiffening”. However, theoretical modeling studies indicate that E A is not prominently affected by arterial stiffness or pulsatile load. However, empirical data assessing the relationship between E A and specific measures of arterial load are not available. Methods: We used multiple linear regression to assess the relationship between E A and arterial load determined non-invasively from time-resolved central pressure-flow analyses performed at rest in a diverse clinical population of adults (n=133). We also investigated the sensitivity of E A to detect changes in pulsatile load induced by isometric handgrip exercise (n=72) and by the administration of 0.4 mg of sublingual nitroglycerin (n=30). Results: Measurements at rest demonstrated that Ea was essentially a function of SVR (standardized β=0.99; P &lt;0.0001), and heart rate (standardized β=0.18; P &lt;0.0001), without significant contributions from aortic characteristic impedance (standardized β=0.0001; P =0.98), total arterial compliance (standardized β=0.007; P =0.63) or reflection magnitude (β=0.02; P =0.20). Despite pronounced changes in indices of pulsatile load induced by isometric exercise and sublingual nitroglycerin, changes in E A were unrelated to changes in indices of pulsatile load in response to either intervention (all R 2 &lt;0.02). However, changes in Ea were essentially a linear function of the change in the SVR*heart rate product (isometric exercise R=0.98; nitroglycerin R=0.97; both P &lt;0.0001). Conclusions: Our empirical findings demonstrate, in agreement with modeling studies, that E A is essentially a function of resistive afterload and heart rate and is negligibly influenced by (and insensitive to) variations in pulsatile afterload. Its current interpretation as a lumped parameter of pulsatile and resistive afterload should thus be reassessed.
Abstract 18307: Intracoronary Infusion of Allogeneic Cardiosphere Derived Cells, During Acute Myocardial Infarction Delays but Eventually Does Not Limit Remodeling of the Left Ventricle
Authors: Argyrios Ntalianis, Titika Sfakianaki, Vassilis Sousonis, Evaggelos Repasos, Maria Nana, Chris Kontogiannis, Lampros Katsaros, Apostolos Papalois, John Nanas, Ioannis Terrovitis
Journal: Circulation (2013)

Objective: In animal models, it has been shown that myocardial cells regenerate even in the adult heart at very slow rates and that regeneration is stimulated after myocardial injury. However the endogenous mechanisms of regeneration are not adequate to limit the damage produced by an acute myocardial infarction.The objective of the study was to demonstrate if remodeling of the left ventricle is attenuated by intracoronary infusion of Allogeneic Cardiosphere Derived Cells (CDCs), at the ischemic phase of acute myocardial infarction, using a chronic ischemia- reperfusion model in swine. Method: In twelve pigs, AMI was induced by occlusion of Left Anterior Descending Coronary Artery for 60 minutes. At 60 minutes of ischemia, 6 animals received 5 million allogeneic CDCs (Group 1), and 6 (Group 2) normal saline, using a catheter that crossed the occlusion site. Five minutes after cell infusion, reperfusion was allowed. The follow up period was 30 days. All animals underwent transthoracic echocardiography before and immediately after the AMI, as well as at 15 and 30 days. Left ventricular end diastolic diameter (LVEDD), end-systolic diameter (LVESD) and ejection fraction (LVEF) were measured. Results: Group 1 animals did not demonstrate statistical significant increase in LV dimensions or decrease of EF at 15 days (LVEDD from 38mm to 42.6mm, p= 0.149, LVEF from 67.66% to 56.5%, p= 0.335). In contrast, Group 2 animals experienced significant decrease of LV function (LV EF from 56.5% to 48%, p=0.014) and a significant increase of LVESD (from 22.75mm to 28.5mm p=0.005) and LVEDD (from 32 mm to 37.75mm, p=0.009). However, animal in both groups had significant remodeling at 30 days There was an equivalent % reduction of LVEF (8.3% vs 7.6%, p=0.95) and increase of LVEDD and LVESD ( 6.5% vs 9.2 % p=0.3 and 6.3% vs 8.6% p=0.6 ,respectively) in Group 1 compared to Group 2. Conclusions: Infusion of allogeneic CDCs during acute AMI was safe and well tolerated hemodynamically, but produced only a transient benefit on LV function. This result may suggest that a re-infusion of cells is necessary at later time points after the index MI, in order to achieve sustained improvement.
Abstract 18274: Under Use of Statins and LDL-C Control Among People With a Framingham 10-Year Coronary Heart Disease Risk &gt; 20%
Authors: Christopher Gamboa, Emily Levitan, Devin Mann, Huifeng Yun, Stephen Glasser, J. Michael Woolley, Robert Rosenson, Michael Farkouh, Monika Safford, Paul Muntner
Journal: Circulation (2013)

Statins reduce the incidence of coronary heart disease (CHD) in individuals with a history of CHD or risk equivalents. A 10-year CHD risk &gt;20% is considered a CHD risk equivalent but is frequently not estimated. We studied the use of statins and control of LDL-C among participants with a history of CHD or CHD risk equivalents in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study (n=30,239) The 8,812 participants with CHD or risk equivalents were categorized into four mutually exclusive groups: (1) history of CHD, (2) no history of CHD but with a history of stroke and/or aortic aneurysm, (3) no history of CHD, stroke or aortic aneurysm but with diabetes mellitus, or (4) no history of the conditions listed in (1) through (3) but with a Framingham 10-year CHD risk &gt; 20% at baseline. Lipids were measured after an overnight fast, LDL-C was calculated using the Friedewald equation, and statin use was assessed through pill bottle review during an in-home study visit. The mean age of study participants was 65 years (SD=9), 45% were women and 46% were black. In fully adjusted models, compared to those with a history of CHD, the use of statins was statistically significantly lower among people with a history of stroke/aortic aneurysm, history of diabetes, and especially 10-year CHD risk &gt; 20% (Table). Among high risk participants taking statins, the prevalence of LDL-C &lt; 100 mg/dL was similar for those with a history of CHD, a history of stroke/aortic aneurysm and diabetes, but participants with a 10-year CHD risk &gt; 20% were less likely to have an LDL-C &lt; 100 mg/dL. These data suggest many people with high CHD risk, especially those with a FRS &gt;20%, were not receiving guideline-concordant lipid-lowering therapy and quality improvement efforts should focus on this group.