tbuckley/cabot-search huggingface dataset:
Abstract 12226: Combined Impact of Acute Kidney Injury and Chronic Kidney Disease on In-hospital Mortality in Patients With Acute Myocardial Infarction
Authors: Shotaro Kuji, Masaharu Ishihara, Masashi Fujino, Hisao Ogawa, Koichi Nakao, Satoshi Yasuda, Teruo Noguchi, Yukio Ozaki, Satoru Suwa, Kazuteru Fujimoto, Yasuharu Nakama, Takashi Morita, Wataru Shimizu, Yoshihiko Saito, Atsushi Hirohata, Yasuhiro Morita, Teruo Inoue, Atsunori Okamura, Masaaki Uematsu, Kazuhito Hirata, Kengo Tanabe, Yoshisato Shibata, Mafumi Owa, Seiji Hokimoto, Kunihiro Nishimura, Yoshihiro Miyamoto, Masami Kosuge, Kazuo Kimura
Journal: Circulation (2015)

Introduction: Renal dysfunction such as acute kidney injury (AKI) as well as chronic kidney disease (CKD) is associated with poor outcomes after acute myocardial infarction (AMI). We examined the combined impact of AKI and CKD on in-hospital clinical outcomes in patients with AMI. Hypothesis: Both CKD and AKI, i.e., acute-on-chronic kidney injury, might amplify the increased risk of mortality and morbidity after AMI. Methods: J-MINUET is a prospective, multicenter registry that enrolled consecutive AMI patients who were admitted within 48 h after symptom onset between July 2012 and March 2014 at 28 hospitals in Japan. We studied serum creatinine (Cr) on admission and for the following 48 h in 2987 patients of this registry. CKD was defined as estimated glomerular filtration rate on admission &lt;60 ml/min/1.73m2, and AKI was defined as Cr increase ≥0.3 mg/dl or ≥50% within 48 h. Results: The incidences of CKD and AKI were 41.0% and 10.5%, respectively. AKI developed more frequently in CKD patients than non-CKD patients (21.0% vs 3.1%, p&lt;0.001). Both CKD and AKI were associated with in-hospital mortality (1.9% and 11.7% for non-CKD and CKD patients, p&lt;0.001; 3.8% and 24.3% for non-AKI and AKI patients, p&lt;0.001) and major adverse cardiac events (MACE) (9.3% vs 30.5% for non-CKD and CKD patients, p&lt;0.001; 14.4% vs 49.2% for non-AKI and AKI patients, p&lt;0.001). Multivariate analysis showed that both CKD and AKI were independent predictors of in-hospital death (CKD, odds ratio [OR] 2.02, 95%CI 1.18-3.45, p=0.010; AKI, OR 3.72, 95%CI 2.29-6.02, p&lt;0.001) and MACE (CKD, OR 2.19, 95%CI 1.66-2.87, p&lt;0.001; AKI, OR 2.30, 95%CI 1.62-3.25, p&lt;0.001). When a combination of these 2 variables was analyzed, a stepwise increase in in-hospital death and MACE was observed (Figure). Conclusions: Both CKD and AKI were independent predictors of in-hospital mortality and MACE, and combined evaluation of these 2 variables enhanced the ability to predict in-hospital clinical outcomes in patients with AMI.
Abstract 18485: Transgenic Expression of a Kir6.1 Gain-of-Function Mutation in the Mouse Heart Results in Av Nodal Conduction Abnormalities
Authors: Haixia Zhang, Mark Levin, Keita Uchida, John W Verbsky, Colin G Nichols
Journal: Circulation (2013)

While consensus exists that Kir6.2 gives rise to the pore forming subunit of KATP channels in mouse heart, there is growing evidence that Kir6.1 is also present in mouse cardiomyocytes. Furthermore, Kir6.1 gain-of-function mutation (GOF) is associated with Early Repolarization (ERS) and Brugada Syndromes. It is unclear, however, whether the consequences of the Kir6.1 GOF result from abnormalities in cardiomyocytes, or other cell types in the heart. To assess the consequence of Kir6.1 GOF in cardiomyocytes, we generated Kir6.1[G343D] (GOF) mice under α-myosin heavy chain promoter. Patch-clamp data shows decreased sensitivity to ATP inhibition in GOF myocytes (EC50 = 43.5 ± 6.1 μM in GOF, 8.3 ± 3.1 μM in WT; p = 0.0007), with no significant change in peak current density (WT: 128 ± 23 pA/pF; GOF: 103 ± 24 pA/pF, p = NS). In vivo electrophysiology testing using programmed electrical stimulation (PES) shows slowed sinus cycle length (SCL, ms) (WT:120 ± 8.7; GOF: 134.0 ± 19.7, p = 0.04), and prolonged atrioventricular interval (AVI, ms) for GOF (WT: 38.0 ± 4.3; GOF: 46.7 ± 4.3, p = 0.02). Kir6.1 GOF mice show prolonged atrioventricular effective refractory period (AVERP, ms) (WT: 49.2 ± 6.6; GOF: 65.7 ± 8.4, p = 0.0001) and diminished anterograde AV node conduction, as seen by right atrial (RA) pacing resulting in 1:1 capture (pacing cycle length, ms) (WT: 73.0 ± 8.4, GOF: 85.0 ± 5.0, p = 0.02), Wenckebach (WT: 68.0 ± 8.4; GOF: 79.3 ± 6.1, p = 0.049) and 2:1 capture (WT: 54 ± 4.2; GOF: 63.6 ± 6.3, p = 0.049). However, the Kir6.1 GOF mice did not show any differences in either atrial refractory period (AERP, ms) (WT: 37.5 ± 2.7, GOF: 37.1 ± 10.75, p = NS) or ventricular refractory period (VERP, ms) (WT: 45 ± 9.4, GOF: 44.2 ± 7.36, p = NS). In summary, Kir6.1 GOF mice display significant AV nodal conduction abnormalities, providing a potential model of Kir6.1-dependent ERS.
Abstract 18363: Activation of the Hippo Pathway, Associated With Suppression the Canonical Wnt Signaling, Contributes to the Pathogenesis of Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Suet Nee Chen, Priyatansh Gurha, Raffaella Lombardi, Alessandra Ruggiero, James Willerson, Ali J Marian
Journal: Circulation (2013)

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an enigmatic disease characterized by excess fibro-adipocytes in the heart, cardiac arrhythmias and heart failure. Molecular genetic studies have identified mutations in several desmosome proteins as causes of ARVC. Our objective is to delineate the molecular links between the desmosomes and fibro-adiposis in ARVC. Expression levels and localization of plakophilin 2 (PKP2), plakoglobin (JUP), desmocollin 2 (DSC2), desmosome proteins and connexin 43 (GJA1), a member of Gap junction, in the human hearts with ARVC, were reduced. To test whether molecular remodeling of the junctions affected signaling pathways, we analyzed the Hippo kinase pathway, which is regulated by cell-cell contact and known to suppress the canonical Wnt signaling, the latter implicated in the pathogenesis of ARVC. Accordingly, Merlin, an upstream regulator of the Hippo kinase cascade, was activated and YAP, the downstream effector was inactivated by phosphorylation. To gain mechanistic insights, expression of Pkp2, the most common causal gene for ARVC, was stably knocked down using shRNA in the HL-1 cells. Transcriptome analysis showed reduced mRNA levels of the canonical Wnt and Hippo targets including Ctgf, an inhibitor of adipogenesis. KD of PKP2 was associated with a dramatic reduction in pPKC-α level, in accord with the known function of PKP2 as a platform for phosphorylation of PKC-α. Reduced pPKCα, an inhibitor of Merlin through phosphorylation, was associated with activation of Merlin and cascade phosphorylation of MST1, LATS1/2 and YAP, constituents of the Hippo pathway. Consequently, signaling through TEAD, the transcription factor of the Hippo pathway, was reduced and sequestration of pβ-catenin in the cytoplasm was increased, leading to suppression of the canonical Wnt signaling and enhanced adipogenesis. KD of pLAT1/2 using shRNAs partially rescued the molecular phenotype. Thus, human ARVC is characterized by molecular remodeling of the intercalated discs, which results in inactivation of PKCα, phosphorylation of the Hippo kinases, suppression of the canonical Wnt signaling and enhanced adipogenesis. The findings implicate the Hippo pathway in the pathogenesis of ARVC.
Abstract 18373: Arterial Stiffness (Pulse Wave Velocity) is Higher in Single Ventricle Patients With Reconstructed Aortas as Compared to Those Without: A Cardiac Magnetic Resonance Phase Contrast Study
Authors: Mark A Fogel, Christine Li, Marc Keller, Matthew Harris, Kevin Whitehead
Journal: Circulation (2013)

Background: Pulse wave velocity (PWV) is a measure of arterial stiffness and has been associated in adults with cardiovascular risk for morbidity and mortality including the association with atherosclerosis. Single ventricle patients who undergo an aortic to pulmonary anastomosis via the Norwood procedure have non-compliant patch material inserted into the vessel, possibly affecting PWV. The purpose of this study is to determine if PWV in these patients differs from single ventricle patients who did not undergo aortic reconstruction. Methods: We retrospectively reviewed 40 single ventricle pts from 2012 to the present, matched for age, who underwent cardiac magnetic resonance anatomic imaging and phase contrast evaluations at the neoartic valve (AoV) and the descending aorta at the level of the diaphragm (DAo). 20 had undergone Norwood reconstruction (recon) of the aorta while 20 had not (Nl). PWV was calculated as the distance from the AoV to the DAo, traced on the candycane view of the aorta, divided by the difference in time to reach 50% peak flow on the flow-time diagrams between AoV and DAo. See images below. Significance was a P &lt; 0.05. Results: PWV in Recon were significantly higher than in Nl (3.9 +/- 1.7 m/s vs 3.0 +/- 1 m/s, P=0.01). There was no statistically significant difference in ages (4.1 +/- 4.2 vs 5.1 +/- 5.7 years), body surface area (0.61 +/- 0.3 vs 0.7 +/- 0.4 meter2) or cardiac index (4.9 +/- 1.5 vs 5.2 +/- 1.7 liters/minute/meter2) between Recon and Nl respectively. Conclusion: PWV in single ventricle patients undergoing the Norwood procedure with resulting recon is higher than single ventricle patients who do not. This implies a higher arterial stiffness and may pose an additional cardiovascular risk as the patient grows; future studies should monitor PWV in these patients for clinical outcome. Other biomaterials may potentially be used in the future to moderate PWV if clinical outcome is adversely affected.
Abstract 12575: Cellular Basis of C-Type Natriuretic Peptide Produced Augmentation on Left Ventricular Systolic and Diastolic Functional Performance in Heart Failure
Authors: Zhi Zhang, Xiaowei Zhang, Tiankai Li, Heng-Jie Cheng, Peng Zhou, Che Ping Cheng
Journal: Circulation (2016)

Background: In addition to its well-known vasodilating and natriuretic actions, C-type natriuretic peptide (CNP), has been viewed as an endogenous inhibitor of the renin-angiotensin system, but its direct cardiac effects remain controversial. In heart failure (HF), circulating and myocardial CNP levels are increased, which may alter LV functional response to CNP. However, the alterations and cellular mechanisms of CNP-induced cardiac response in HF remain unclearly defined. We assessed the hypothesis that in HF, CNP might produce enhanced positive modulation on myocyte [Ca 2+ ] i transient ([Ca 2+ ] iT ) and L-type Ca 2+ current (I Ca,L ) and improve LV and myocyte functional performance. Methods: We assessed LV systolic and diastolic function and compared myocyte contractile, [Ca 2+ ] iT , and I Ca,L responses to a clinically relevant dose of CNP (2 μg/kg bolus plus 0.4 μg/kg/min, iv, 10 min) in 12 normal (N) and 12 age-matched adult rats with isoproterenol (ISO)-induced HF (2 months after 170 mg/kg, sq, for 2 days). Results: In normal rats, CNP caused leftward shifts and increased slopes of P ES -V ES relations (E ES ) (14%, 1.17 vs 1.04 mmHg/μl) with decreased LV time constant relaxation (τ, 19%, 9.0 vs 11.1ms). In HF rats, versus normal, CNP produced a significantly greater increase in E ES (37%, 0.81 vs 0.59 mmHg/μl) and a decrease in τ (31%, 11.0 vs 15.9 ms), indicating enhanced increases in LV contractility and the rate of LV relaxation. Consistently, in isolated myocytes, superfusion of CNP (5x10 -7 M) caused improved cell contraction and relaxation in both normal and HF myocytes. In HF myocytes, CNP resulted in significantly greater increases in the peak velocity of shortening (dL/dt max , 18%, 167.4 vs 141.9; 39%, 103.9 vs 74.9 μm/sec) and relengthening (dR/dt max , 19%, 134.7 vs 113.2; 71%, 92.1 vs 53.8 μm/sec) accompanied by significantly larger increases in [Ca 2+ ] iT (9.5%, 0.23 vs 0.21; 29%, 0.22 vs 0.17) and I Ca,L (12%, 9.1 vs 8.1; 28%, 5.9 vs 4.6 pA/pF). Conclusions: CNP produces positive modulation on cardiac performance in both normal and HF rats. In HF, CNP caused greater improvement of LV and myocyte contraction, and relaxation with further augmentation of increased [Ca 2+ ] iT and I Ca,L. These findings support the usefulness of CNP as a new therapeutic option for HF.
Abstract 18568: Normal Angiographic Appearance of the Coronary Arteries is Common in Antiphosopholipid Syndrome Patients Presenting With Acute Coronary Syndrome
Authors: Eliany Mejia Lopez, Neeraja Yedlapati, Daniel M Spevack
Journal: Circulation (2013)

Background: Antiphospholipid syndrome (APLS) is known to be associated with Acute Coronary Syndrome (ACS) due to coronary artery thrombosis or embolism. Because individual cases of ACS with normal angiographic appearance of the coronary arteries have been reported in this population, we aimed to determine the prevalence of this presentation amongst patients with known APLS at our institution. Methods: Our institutional database was queried for all patients testing positive for antiphospholipid antibodies (n=575) between 2000 and 2012. From this sample, we identified 46 patients having cardiac catheterization. ACS (n=32) was defined as the presence of angina chest pain, ECG with ST segment or T-wave abnormalities and troponin-I &gt; 0.1 mg/dL. Results: Normal appearing coronary arteries, without evidence of atherosclerosis or embolism, were found in 8 patients (52±7 years, 5 female) with APLS (lupus anticoagulant n=5; anti-cardiolipin n=5; anti-B2-GP1 n=3) presenting with ACS. All 8 patients had history of prior arterial (stroke n=5) or venous thrombosis (n=3). Median troponin-I was 0.30 mg/dL [range 0.15, 0.50]. One subject was found to have diffuse coronary artery spasm, which reversed following administration of intra-coronary nitroglycerine. One patient had a regional wall motion abnormality in a single territory and another patient had global ventricular dysfunction. Median left ventricular ejection fraction was 60% [range 30, 60]. Conclusions: A high proportion of patients with APLS presenting with ACS did not have evidence of either coronary thrombosis or embolism on angiography. This clinical presentation is suspicious for either coronary artery spasm or myopericarditis.
Abstract 12451: Pulmonary Artery Stiffness is an Independent Predictor of Right Ventricular Mass and Function
Authors: Timothy Dawes, Ajay Gandhi, Antonio S de Marvao, Rui Buzaco, Pawel Tokarczuk, Marina Quinlan, Giuliana Durighel, Tamara Diamond, Laura Monje-Garcia, Alain De Cesare, Stuart Cook, Declan O’Regan
Journal: Circulation (2015)

Background: Right ventricular (RV) mass is independently associated with cardiovascular risk in the general population, but the underlying causes are not known. Objectives: We used cardiac magnetic resonance (CMR) imaging to determine if there was a relationship between pulmonary (PA) stiffness and measures of RV function and mass. Methods: 156 healthy volunteers underwent 1.5T cardiovascular magnetic resonance imaging. Pulmonary pulse wave velocity (PWV), derived from phase-contrast imaging, was used to assess vascular stiffness. RV performance was assessed using feature-tracking to derive peak systolic strain and strain rate, as well as peak early-diastolic strain rate (PEDSR). RV volumes, ejection fraction (RVEF) and mass (RVM) were measured from the cine images. The association of pulmonary PWV with RV function and mass was quantified by univariate linear regression. Results: Pulmonary PWV and RV ejection fraction (RVEF) both increased with age (R = +0.32, p &lt; 0.001; R = +0.17, p = 0.04 respectively). Adjusting for the effects of age, body surface area and gender, pulmonary PWV showed an independent association with increased RVEF (R = +0.17, p = 0.03), RVM (R = +0.26, p=0.001), RV radial strain (R = +0.36, p = 0.005) and strain rate (R = +0.38, p &lt; 0.001) and reductions in radial (R = -0.45, p = 0.002), longitudinal (R = -0.42, p = 0.008) and circumferential (R = -0.45, p = 0.003) PEDSR. Conclusions: In subjects with no known cardiovascular disease, PA stiffness increases with age and is independently associated with both RV mass and diastolic dysfunction. These findings suggest that prognostically adverse changes in RV function and morphology are associated with age-related changes in PA stiffness.
Abstract 12121: Right Ventricular Free-Wall Longitudinal Speckle-Tracking Strain in Patients With Pulmonary Arterial Hypertension Under Specific Treatment
Authors: Hatice S Kemal, Meral Kayikcioglu, Levent Can, Sanem Nalbantgil, Ozcan Vuran, Nesrin Mogulkoc, Hakan Kultursay
Journal: Circulation (2015)

Introduction: Pulmonary arterial hypertension (PAH) is a devastating disease of pulmonary vascular remodelling, right heart failure and limited survival. Although right ventricular (RV) dysfunction is a major determinant of outcome in patients with PAH, the optimal measure of RV function is poorly defined. Hypothesis: The objectives of this study were to test the utility of RV free wall speckle-tracking strain (RV-free) as an assessment tool for RV function in patients with PAH who are already under specific medical treatment compared with conventional echocardiographic parameters and to investigate the relationship of the findings obtained with RV-free with hemodynamic parameters of RV performance. Methods: Prospective RV- free measurement was performed on 92 PAH patients of different etiologies (49 PAH associated with congenital heart disease, 21 idiopathic PAH, 11 PAH associated with connective tissue disease and 11 chronic thromboembolic pulmonary hypertension) who were on PAH spesific treatment for at least 3 months. RV-free was calculated by averaging each of 3 regional peak systolic strain values. The mean follow-up was 222±133 days. Conventional echocardiographic parameters-RV FAC, TAPSE and Tricuspid S-, hemodynamic parameters -functional class, 6-min. walking distance, and NT-proBNP- were also studied. Results: The mean age was 41± 16 years and 67.4% were female. Mean RV- free of the study population was %-13.16 ± 6.3. There was a significant positive correlation between RV-free and functional class (r=0.312, p=0.01), NT-proBNP (r=0.423, p=0.0001), whereas negative correlation with FAC (r=-0.637, p=0.0001), TAPSE (r=-0.524, p=0.0001), Tricuspid S (r=-0.450, p=0.0001), 6-min. walking distance (r=-0.333, p=0.002). RV-free significantly correlated with all follow-up adverse events, death and clinical right heart failure (p=0.04, p=0.03, p=0.02, respectively). According to the ROC analysis, the cut-off value for the development of clinical right heart failure was -13.8% (sensitivity: 71%, specificity: 60%) for RV-free. Conclusions: Assessment of RV-free is a feasible, easy to perform method and maybe used as a predictor of right heart failure, clinical deterioration and mortality in patients under PAH specific treatment.
Abstract 18497: Attenuated Endothelial Cd39 Activity Mediates Vascular Remodeling in Pulmonary Arterial Hypertension
Authors: Mikko Helenius, Sanna Vattulainen, Anne Komulainen, Pekka Taimen, Juha Koskenvuo, Tero-Pekka Alastalo
Journal: Circulation (2013)

Occlusive intimal hyperplasia in pulmonary arterial hypertension (PAH) leads to devastating consequences in pulmonary circulation and increased mortality. A phenotypic switch in endothelial cells (EC) has been suggested to play a role in the pathobiology of occlusive vasculopathy. We hypothesized that alterations in extracellular purinergic signaling could play a role in regulating EC fate during PAH progression. Purine signaling is regulated by cell surface ecto-enzymes such as CD39 and CD73. These enzymes are powerful mediators of cellular signaling since their activity adjusts the level of extracellular purine nucleotides that are potent cell signaling molecules. By using our unique magnet bead-based ex vivo EC profiling strategy in the rat monocrotaline model of PAH we identified a major ~50% decrease (p&lt;0.001) in adenosinetriphosphate (ATP) -hydrolyzing CD39 activity at early stages of the disease. The activity of AMP-hydrolyzing CD73 was not changed during the disease course. Similar ~50% (p&lt;0.05) decrease in specific CD39 activity, leading to accumulation of ATP niche, was observed in cultured pulmonary ECs from end-stage human idiopathic PAH patients. This attenuated enzyme activity was, at least partly, mediated through down-regulation of CD39 expression on RNA (~70%, p&lt;0.05) and protein level. Immunohistochemistry on human iPAH patient lung revealed that CD39 was significantly down-regulated in arteries with intimal disease compared to arteries with normal appearance. We then showed that suppression of CD39 through RNAi or excess 2 μM ATP niche initiates an EC phenotypic switch with apoptosis resistant and hyperproliferative phenotype, identical to iPAH ECs. We also show that increased ATP niche stimulates synthesis of extracellular matrix components associated with intimal disease, such as versican. In addition, increased 2 μM ATP concentration and co culture with CD39-deficient ECs induce pulmonary artery smooth muscle cell (PASMC) proliferation (~50%, p&lt;0.005) and migration (~50%, p&lt;0.05) and, thus, could contribute to SMC pathology in PAH. We show evidence, both in rat and human, that attenuation of CD39 activity is tightly linked to vascular remodeling, EC phenotypic switch and could represent a novel target for PAH therapy.
Abstract 18342: Post Discharge and Early Clinical Benefits of Eplerenone in Patients With Systolic Nyha Ii Heart Failure: Insight From Emphasis-hf
Authors: Faiez Zannad, Timothy J Collier, Nicolas Girerd, John J McMurray, Karl Swedberg, Dirk J van Veldhuisen, Henry Krum, Stuart J Pocock, Harry Shi, John Vincent, Bertram Pitt
Journal: Circulation (2013)

Purpose: Patients with heart failure (HF) have a high adverse event rate in the early post-discharge period after hospitalization for HF. No treatment initiated during this period is proven to improve outcome. In EMPHASIS-HF, which evaluated the impact of eplerenone (epl) in patients with HF with reduced ejection fraction (HFrEF) and mild symptoms, most participants were included within 180 days following a cardiovascular hospitalization (CVH). We examined the effect of eple on outcomes early after hospital discharge. Methods: In EMPHASIS-HF, eple was compared to placebo (pbo) in 2737 patients with NYHA class II HF and LVEF ≤35%. In a first post-hoc analysis in 2338 patients randomized within 180 days of a CVH, we assessed the interaction between the time from index CVH to randomization and the primary outcome of CV death or HF hospitalization (HHF) using multivariable Cox survival models. In a second analysis, the effect of epl on 30-day outcome was assessed in the complete cohort. Results: The most common reason for CVH within 180 days was HHF (N=1496, 64.0%). The median time from index CVH to randomization was 42 days. In the &lt;42 days group, median time from the index CVH was 12 days (IQR 5-26 days). The relative risk reductions in CV death/HHF and HHF were similar (p for interaction=0.65 and 0.44) whether treatment was initiated &lt;42 days or ≥42 days after the index CVH. Because event rates were higher in the &lt;42 days group, this subgroup had higher absolute risk reductions (rate of CV death/HHF 11.4% in epl versus 17.0% in the pbo arm in the &lt;42 days group, 10.0% versus 13.6% in the ≥42 days group). In the second analysis, patients randomized to epl had a lower risk for CV death/HHF at 30 days compared to patients receiving pbo (HR=0.51, CI=0.31-0.85, p&lt;0.01). Similarly effects were observed for 30 day HHF (HR=0.44, CI=0.25-0.78, p&lt;0.01). Conclusion: These analyses show that in patients with HFrEF and mild symptoms, epl 1) improves outcome when initiated shortly after a CVH, 2) leads to a significant decrease in CV death/HFH as early as 30 days. These data suggest that initiating eple in patients with HF and mild symptoms soon after hospitalization might reduce the high event rate observed.