tbuckley/cabot-search huggingface dataset:
Abstract 13033: Titin Mutations in IPS Cells Define Sarcomere Insufficiency as a Cause of Dilated Cardiomyopathy <i>(Best of Basic Science Abstract)</i>
Authors: J. Travis Hinson, Anant Chopra, Sandra Swist, Craig Benson, Calvin Sheng, Navid Nafissi, William Polacheck, Norbert Hubner, Wolfgang Linke, Stuart Cook, Christopher Chen, Jonathan Seidman, Christine Seidman
Journal: Circulation (2015)

Introduction: Dilated cardiomyopathy (DCM) is one of the most common cardiovascular disorders with a prevalence of 1:250 patients. Patients with DCM develop left ventricular dilation, systolic dysfunction, and ultimately heart failure. While DCM can occur due to acquired cardiovascular conditions, our group recently identified mutations in the giant sarcomere protein titin (TTN) as the most common genetic cause of DCM, occurring in 15-20% of familial or sporadic cases. Truncation mutations in the A-band of TTN are enriched in DCM cases, while truncation mutations in the I-band are less pathogenic and are commonly found in normal patients. How some mutations in TTN lead to DCM remains unclear. Hypothesis: We tested whether myocytes derived from induced pluripotent stem cells (iPS-CMs) with mutations in TTN in the A-band and I-band could recapitulate features of DCM by single myocyte and cardiac microtissue (iPS-CMT) assays. Methods &amp; Results: We engineered a panel of patient-specific iPSc’s with two truncation mutations in the A-band and a missense mutation, W976R, in the Z/I junction of TTN. TTN mutant iPS-CMTs had impaired baseline contractility and impaired response to both mechanical and adrenergic stress. In addition, isogenic iPSc lines with TTN truncation mutations in the A- and I-bands also had similarly reduced contractile function. By combining functional analyses with RNAseq, we determine that TTN truncations in the I-band are less pathogenic because I-band exons are spliced out in the adult left ventricle but are expressed in iPS-CMs. Finally, we demonstrate that mutant TTN protein in iPS-CMs leads to sarcomere insufficiency and growth factor and cell signaling deficiencies. Conclusion: iPS-CMs and iPS-CMTs with TTN mutations derived from patient-specific and CRISPR/CAS9-edited iPScs recapitulate contractility and adaptation deficiencies often identified in patients with dilated cardiomyopathy. TTN truncation mutations in the A-band may cause DCM by impaired sarcomerogenesis while I-band truncations are spliced out and are tolerated. Sarcomere abnormalities lead to failure to activate growth factor and cell signaling pathways. The iPS-CMT assay can be a powerful strategy to determine the pathogenicity of DCM mutations.
Abstract 12781: Traffic-related Air Pollution, Blood Pressure, and Adaptive Response of Mitochondrial Abundance
Authors: Jia Zhong, Akin Cayir, Letizia Trevisi, Marco Sanchez-Guerra, Xinyi Lin, Cheng Peng, Marie-Abèle Bind, Diddier Prada, Hannah Laue, Kasey Brennan, David Sparrow, Pantel Vokonas, Joel Schwartz, Andrea Baccarelli
Journal: Circulation (2015)

Introduction: Black carbon (BC) exposure - a tracer of vehicular traffic pollution - is associated with increased blood pressure (BP). Identifying biological factors that attenuate BC effects on BP can aid effective prevention. Hypothesis: We aimed to evaluate the role of mitochondrial abundance, an adaptive mechanism compensating for cellular-redox-unbalance, in the BC-BP relationship. Methods: At one or more visits among 675 older men from the Normative Aging Study (1,252 observations), we assessed BP and ambient BC levels (2-day to 28-day prior to visit, from a stationary monitor). Mitochondrial abundance was determined as blood mitochondrial-to-nuclear DNA ratio (mtDNA/nDNA) using quantitative polymerase-chain-reaction. Results: Every standard deviation (SD) increase in 28-day BC moving average (MA) was associated with 1.94 mm Hg (95%CI, 1.23-2.72; P&lt;0.0001) and 3.46 mm Hg (95%CI, 2.06-4.87; P&lt;0.0001) higher diastolic and systolic (SBP) BP, respectively. Positive BC-BP associations existed throughout all time windows. Likewise, BC MAs (5-day to 28-day) were associated with increased mtDNA/nDNA. Every SD increase in 28-day BC MA was associated with 0.12 SD (95%CI, 0.03-0.20; P=0.007) higher mtDNA/nDNA. High mtDNA/nDNA significantly attenuated the BC-SBP association throughout all time windows. The estimated effect of 28-day BC MA on SBP was 1.95-fold larger for individuals at the lowest mtDNA/nDNA quartile midpoint (4.68 mm Hg; 95%CI, 3.03-6.33; P&lt;0.0001), compared to the top quartile midpoint (2.40 mm Hg; 95%CI, 0.81-3.99; P=0.003). Conclusions: In older adults, short- to moderated-term ambient BC levels were associated with increased BP and mitochondrial abundance. Increased mitochondrial abundance may represent a compensatory response that attenuates the adverse cardiac effects of BC.
Abstract 18604: The Prognostic Value of Diuretic Dose in Stable Chronic Heart Failure Patients
Authors: Marco Triggiani, Alessandra Manerba, Laura Lupi, Silvia Suardi, Annalisa Pizzuto, Nicolò Dasseni, Arnaud Romeo Mbadjeu Houndjeu, Bruno Mario Cesana, Mihai Gheorghiade, Savina Nodari
Journal: Circulation (2013)

Background: High daily diuretic dose (DDD) in chronic heart failure (HF) patients (pts) is related to cardiac and renal dysfunction but its relationship with outcomes in this population is still not completely understood. The aim of this study was to evaluate the prognostic implications of DDD in pts with chronic HF. Methods: Retrospective analysis of pts with HF and reduced Left Ventricular Ejection Fraction (LVEF&lt;45%), followed at our outpatient HF clinic. Inclusion criteria were optimized therapy and clinical stability (neither events nor therapeutic changes) in the previous 3 months. Hypervolemic or euvolemic status was defined according to the sodium retention score (NaRS). We considered DDD as a continuous variable. Patients were followed prospectively for the occurrence of the composite endpoint cardiovascular (CV) death and hospitalizations for HF or CV causes after one- year follow-up. Results: A total of 528 pts (mean age 66.9 ± 13 years, 82% male) were enrolled. Overall, at one-year follow-up, the composite endpoint occurred in 151 pts (28.6%). In table 1 are summarized clinical, laboratory and echocardiographic characteristics that at Univariate analysis were significantly correlated with the occurrence of the composite endpoint. In multivariable model, only LVEF (OR 0.97; CI 0.94-0.99; p = 0.029), DDD (OR 1.002; CI 1.0005-1.004; p = 0.011) and NaRS (OR 2.58; CI 1.52-4.39; p &lt;0.001), were independently associated with events. Conclusion: In chronic stable HF patients, DDD appears to have an independent prognostic value. Additional analyses are needed to determine if high DDD may have the same independent predictive value after adjustment for the clinical congestion status of pts.
Abstract 18588: Baseline Neutrophil/Lymphocyte Ratio Predicts Recurrences After Radiofrequency Catheter Ablation: Results From Prospective Study on Paroxysmal Atrial Fibrillation
Authors: Chintan Trivedi, Luigi Di Biase, Sanghamitra Mohanty, Prasant Mohanty, Rong Bai, Pasquale Santangeli, Francesco Santoro, Richard Hongo, Salwa Beheiry, Rodney Horton, Javier Sanchez, J. David Burkhardt, Andrea Natale
Journal: Circulation (2013)

Introduction: Inflammation and atrial fibrillation (AF) are often associated. Whether Neutrophil Lymphocyte Ratio (NLR) affects the radiofrequency catheter ablation outcome is unknown. The aim of this study is to evaluate baseline NLR as the inflammatory predictor of ablation outcome in Paroxysmal AF (PAF) patients. Method: One hundred seventy five PAF patients undergoing radiofrequency catheter ablation were selected for the study and baseline hematological parameter were evaluated with differential cell count one day prior to ablation. All the patients underwent pulmonary vein antrum isolation and extensive follow-up. Result: Out of 165 patients with paroxysmal AF, 44 (25.1%) patients develop recurrence after average follow-up of 16 ± 8 months. Baseline NLR was high in recurrence patients. (NLR=3.2 ±0.6 vs. 2.59 ± 0.8, p&lt;0.001). After adjusting for age,gender,coronary artey disease , LA Size and high blood pressure, baseline NLR was found to be a significant predictor of recurrence [HR =1.99 (1.33, 2.96), p=0.001]. Using the cut-off value of 3.08, baseline NLR predicts the recurrence with sensitivity of 72.5% and specificity of 78.6%. Conclusion: This prospective study shows that baseline NLR is useful inflammatory marker in predicting the recurrence of PAF and in patients with more than 3.08 baseline NLR have high chance of recurrence.
Abstract 18560: Defective Ca <sup>2</sup> + Homeostasis Contributes to Arrhythmia in Transgenic Rabbit Model of LQT2 Syndrome
Authors: Dmitry Terentyev, Leroy Cooper, Weiyan Li, Yichun Lu, Radmila Terentyeva, Xuwen Peng, Gideon Koren
Journal: Circulation (2013)

Introduction: Loss-of function mutations in HERG potassium channels in Long QT2 syndrome are associated with sudden cardiac death triggered by sympathetic surge. In various models of cardiac disease changes in calcium (Ca) homeostasis, associated with upregulated plasmalemmal Na/Ca exchanger (NCX) and/or hyperactive ryanodine receptors (RyRs), have been linked to increased risk of arrhythmia. Methods and Results: The aims of this study were to investigate possible changes in Ca homeostasis in cardiomyocytes derived from from the hearts of LQT2 rabbits and to determine whether similar changes contribute to the triggering of early afterdepolarizations (EADs) characteristic of LQT2 myocytes under β-adrenergic stimulation. Parameters of Ca handling were measured in ventricular myocytes enzymatically isolated from LQT2 and littermate control hearts using confocal Ca imaging and whole cell patch clamp. Ca imaging revealed no changes in amplitude of Ca transients in intact myocytes and sarcoplasmic reticulum (SR) Ca content assessed by measuring amplitude of transients evoked by rapid application of caffeine. A two-fold increase in rate of decay of caffeine-induced Ca transients in LQT2 myocytes vs. controls indicated increased NCX activity. Experiments in saponin-permeabilized cells using a SR-entrapped low-affinity Ca indicator revealed ~2-fold increase in RyR-mediated SR Ca leak in LQT2 myocytes in comparison with controls. In contrast to controls, current-clamped LQT2 myocytes exposed to β-adrenergic agonist isoproterenol exhibited prolonged plateau of action potentials (AP) at -10 - 0 mV accompanied by aberrant Ca releases and phase 3 EADs. Importantly, complete exhaustion of SR [Ca] by incubation of LQT2 cells with SERCA inhibitor thapsigargin or 10 mM caffeine, shortened APD and completely abolished EADs. Conclusion: Functional changes in RyR and NCX underlie preserved systolic Ca transients in LQT2 myocytes under basal conditions and may contribute to stress-induced arrhythmia by maintaining the plateau of AP at voltages ideal for reactivation of plasmalemmal Ca channels and generation of EADs.
Abstract 12624: Therapeutic Lymphangiogenesis Improves Diastolic Function by Limiting Cardiac Edema and Fibrosis After Myocardial Infarction
Authors: Orianne Henri, Mahmoud Houssari, Chris Pouehe, Ludovic Galas, Lionel Nicol, Florence Edwards-Lévy, Jean-Paul Henry, Anais Dumesnil, Damien Schapman, Christian Thuillez, Vincent Richard, Paul Mulder, Ebba Brakenhielm
Journal: Circulation (2015)

Little knowledge exists on how cardiac lymphatics respond to myocardial infarction (MI). We investigated the impact of MI on cardiac lymphatic structure and function during the development of chronic heart failure (CHF). We hypothesized that 1) insufficient cardiac lymph drainage may contribute to the deleterious cardiac remodeling post-MI; and 2) therapeutic stimulation of lymphatic growth, or lymphangiogenesis, may reduce chronic myocardial edema and inflammation in this setting. MI was modeled in Wistar rats by coronary occlusion (45 min) followed by reperfusion. Lymphangiogenesis-selective VEGF-C was delivered intramyocardially using slow-release albumin-alginate microparticles. Animals were divided into: sham (n=19), control MI (n=64), and treated MI, receiving low (1.5 μg; n= 54) or high (5 μg; n=26) dose of VEGF-C upon reperfusion. Cardiac function, lymphatics, edema, and levels of infiltrating immune cells were evaluated at 3 and 8 weeks post-MI. We found that control rats displayed lymphatic remodeling with increased lymphatic capillary density but rarefaction of epicardial pre-collector and collector vessels, leading to cardiac lymphatic dysfunction. In accordance with insufficient lymph drainage, chronic myocardial edema and low grade inflammation were found at both 3 and 8 weeks post-MI as determined by gravimetry, MRI T2 imaging, and immunohistochemistry, respectively. VEGF-C treatment led to a dose-dependent increase in lymphatic capillary density (sham, 255±16; con, 267±25; VEGF-C, 362±22 lymphatics/mm 2 ; p&lt;0.05) and reduced rarefaction of pre-collectors and collector vessels. As a consequence, myocardial edema (sham, 75.5±0.1; con, 77.9±0.2; VEGF-C, 77.3±0.1% water content; p&lt;0.05) and macrophage infiltration levels were both significantly reduced. Further, cardiac interstitial fibrosis was completely prevented by 8 weeks, even by low dose VEGF-C (con, 6.0±0.6; VEGF-C, 3.3±0.1% fibrosis; p&lt;0.001), leading to reduced diastolic dysfunction (LVDPVR, LV end-diastolic pressure-volume relation: sham, 0.8±0.1; con, 2.0±0.2; VEGF-C, 1.1±0.1; p&lt;0.001). In conclusion, our data suggest that therapeutic lymphangiogenesis may represent a new therapeutic target in CHF.
Abstract 18566: V1A Receptor Overexpression in the Murine Heart Depresses the Inotropic Response to Catecholamines
Authors: Larry A Barr, Weizhong Zhu, Valerie D Myers, Douglas G Tilley, Arthur M Feldman, Steven R Houser
Journal: Circulation (2013)

Background: — Circulating levels of arginine vasopressin (AVP), a vasoconstrictor, are elevated in patients with heart failure. In the heart, AVP induces effects through the V1A receptor. The goal of this study was to better define the role of AVP in cardiac contractile dysfunction in the diseased heart. We utilized an inducible, cardiac-specific V1A receptor overexpression (V1A-OE) mouse model to explore the effects of AVP signaling in cardiac myocytes. Methods and Results: — Isolated WT and V1A-OE hearts were studied using a Langendorff apparatus. A fluid-filled balloon was inserted into the LV to record isovolumic ventricular pressure. Each heart underwent a 20min equilibration period, followed by administration of ISO or IBMX for 3min each. ISO [10 -5 ] had significantly smaller inotropic effects in V1A-OE (n=8) compared to WT hearts (n=5) (LVDP% V1A-TG: 129±14.04% increase vs. WT: 191.5±20.80%). WT hearts (n=4) pretreated with exogenous AVP [10 -9 ] also had significantly smaller inotropic responses to ISO [10 -5 ] (LVDP% WT+AVP: 118.8±12.30). The phosphodiesterase inhibitor IBMX [10 -5 ] had enhanced contractility in WT (n=5) significantly more than in V1A-OE (n=5) (LVDP% V1A-OE: 99.40±6.61 vs. WT 149.4±8.135). Western blot analysis showed reduced levels of phospholamban (PLB) phosphorylation at Serine-16, a PKA phosphorylation site, in the V1A-OE+IBMX compared to WT+IBMX. Conclusions: — These results suggest that V1A overexpression reduces myocardial inotropic regulation by inhibiting PKA-induced phosphorylation of Ca 2+ regulatory proteins that are involved in β-adrenergic regulation of cardiac contractility. Increased AVP signaling plays a role in the depression of cardiac contractility in heart failure and AVP antagonists may improve heart function by enhancing cardiac contractility reserve.
Abstract 12511: Left Ventricular Hypertrophy by Electrocardiogram versus Cardiac Magnetic Resonance Imaging as a Predictor for Stroke: The MESA Study
Authors: Abdullahi O Oseni, Valery S Effoe, Hooman Kamel, Veit Sandfort, Rebecca F Gottesman, Joao A Lima, David A Bluemke, Elsayed Z Soliman
Journal: Circulation (2016)

Background: Left ventricular hypertrophy (LVH) is an established risk factor for stroke and is a component of the Framingham Stroke Risk Score (FSRS). It is unknown, however, if LVH detected by the electrocardiogram (ECG-LVH) is equally predictive of stroke as LVH detected by cardiac magnetic resonance imaging (MRI-LVH). Methods: We analyzed 4716 participants (mean age 61±10 years, 53.4% women, 38.2% whites) from the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of cardiovascular disease at baseline (2000-2002). ECG-LVH was defined as values &gt; 95 th percentile of left ventricular mass (LVM) derived from an established race- and sex-specific ECG model for estimating LVM indexed to weight. MRI-LVH was obtained from LVM by cardiac MRI using the 95th percentile cut-off value of observed LVM/predicted LVM calculated as 1.31. Multivariable Cox regression was used to examine the association between 1-standard deviation (SD) increase in estimated ECG-LVM and MRI-LVM as well as ECG-LVH and MRI-LVH, separately, with incident ischemic stroke. Harrell’s C-index was used to estimate the predictive ability of the FSRS model when either ECG-LVH or MRI-LVH was included. Results: Over a median follow-up of 11.2 years, 119 participants developed stroke. In a model adjusted for demographics and components of the FSRS, ECG-LVM and MRI-LVM as well as ECG-LVH and MRI-LVH were all predictive of stroke with ECG-LVM and MRI-LVH showing stronger associations with stroke in terms of hazard ratios but with wider confidence intervals (Table). However, the ability of FSRS model to predict stroke was slightly better when MRI-LVH (C-index 0.748, 95% CI: 0.514-0.829) was used as one of the FSRS components instead of ECG-LVH (C-index 0.739, 95% CI: 0.503-0.823), likelihood ratio test p 0.008. Conclusion: In asymptomatic cardiovascular disease-free individuals, both ECG-LVH and MRI-LVH are predictive of stroke. Using MRI-LVH slightly improves the predictive ability of the FSRS model.
Abstract 12474: Nicotinamide Restores Tissue Nad <sup>+</sup> and Improves Outcomes in a Murine Model of Cardiac Arrest
Authors: Xiangdong Zhu, Jing Li, Huashan Wang, Chunpei Lee, Terry Vanden Hoek
Journal: Circulation (2016)

Introduction: Metabolic suppression in the ischemic heart is characterized by reduced levels of NAD + and ATP. Hypothesis: Since NAD + is required for most metabolic processes that generate ATP, we hypothesized that nicotinamide (NAM) restore of tissue NAD + and improve cardiac function and survival in a mouse model of cardiac arrest. Methods: Cardiomyocytes isolated from 1-2-day old C57BL6 mice were exposed to 30 min ischemia and 90 min reperfusion. Contraction recovery was measured by phase contrast imaging without and with 0.1mM NAM given at reperfusion. Adult C57BL6 mice were subjected to an established KCL-induced 8 min cardiac arrest protocol, randomly assigned to receive saline or 500 mg/kg NAM after cardiopulmonary resuscitation (CPR). Survival, MAP, ETCO 2, and continuous ECG were recorded until 4 h after successful CPR. Results: We first tested the effect of NAM on NAD + recovery in heart cells exposed to the simulated ischemia and reperfusion. NAD + content was decreased from 4.51 ± 0.03 nMol/g before ischemia (equilibration) to 2.69 ± 0.42 nMol/g at the end of ischemia. Treatment with 0.01 mM NAM completely restored the cellular level of NAD + by 15 min reperfusion (4.63 ± 0.45 nMol/g), while there was no significant recovery of NAD + in untreated cells. This rescue of NAD + depletion was associated with improved contractile recovery by 10 min reperfusion (58.1 ± 7.3% return of baseline contractile velocity vs.18.5 ± 3.7% in control cells, n=5, p &lt;0.05) that could be augmented further using isoproterenol treatment (83.3 ± 3.5% vs. 58.0 ± 2.9% in control cells. p &lt;0.05). We then tested the effect of NAM (500 mg/kg) on mouse SCA 4 h survival and cardiovascular recovery. NAM administered IV after CPR resulted in a trend toward improved mouse SCA survival, with 9/10 survival at 4 h as compared to 5/10 in the saline (NS) group. Compared to saline treated mice, NAM-treated mice displayed improved NAD + content in hearts obtained at 4 h post-ROSC compared to saline treated SCA hearts (2.4 ± 0.1 nMol/g vs. 4.5 ± 0.1 nMol/g, p &lt;0.05). Conclusions: NAM is CPR medication that can rapidly restore cardiac tissue NAD + and promote contractile recovery, with improved early survival demonstrated in a mouse model of cardiac arrest.
Abstract 12548: Expression of Let-7 Family microRNAs in Skin Correlates Negatively With Severity of Pulmonary Hypertension in Patients With Systemic Scleroderma
Authors: Yasuhiro Izumiya, Yuichi Kimura, Satoru Yamamura, Yoshiro Onoue, Shinsuke Hanatani, Satoshi Araki, Hisao Ogawa
Journal: Circulation (2015)

Introduction: Pulmonary hypertension (PH) is a serious complication in patients with systemic scleroderma (SSc), therefore it is important to identify the factors that could predict the presence and progression of PH. Skin biopsy is performed in patients with SSc to examine the type and severity of the disease. MicroRNAs (miRNAs) are potential biomarkers for various cardiovascular diseases including PH. Hypothesis: In patents with systemic scleroderma (SSc), skin miRNAs expression profiles varies depending on the presence or absence of PH. Methods and Results: We determined the skin miRNA expression profile in 15 female SSc patients with (n=6) and without PH (n=9). Plasma BNP level was significantly higher in the PH group than non-PH group, but left ventricular function and dimension were not different between the two groups. A mixture of equal amounts of miRNAs from PH and non-PH patients were prepared and used for miRNA PCR array analysis. The analysis identified 591 upregulated miRNAs and 57 downregulated miRNAs in the PH group. Of these, only miRNAs with a Ct value of less than 35 were subjected to further analysis. When a 1.5-fold difference was considered meaningful, 32 miRNAs were upregulated and 14 miRNAs were downregulated in the PH group. Interestingly, 5 out of 14 downregulated miRNAs belonged to the let-7 family. The results were validated by quantitative real-time PCR with specific primer for each miRNA, which showed significant downregulation of five let-7 family members (let-7a, -7d, -7e, -7f, -7g) in 6 PH compared with 9 non-PH skin samples. Circulating these miRNA levels were trended to decrease in PH group, but it did not reach statistically significant. The expression of let-7b and -7d correlated significantly and negatively with the estimated pulmonary arterial pressure. The expression of let-7a, -7e, -7g, -7f tended to correlate negatively with the estimated pulmonary arterial pressure, albeit insignificantly. Conclusions: The expression level of let-7 family microRNAs in skin are lower in patients with SSc with PH than those without PH. Skin miRNA is a potentially useful marker for evaluation of PH in patients with SSc. Skin biopsy can be considered in patients with collagen diseases to identify the presence and severity of PH.