tbuckley/cabot-search huggingface dataset:
Abstract 4945: Eptifibatide is Non-inferior to Abciximab in Acute Coronary Syndromes: Results From the Swedish Coronary Angiography and Angioplasty Registry (SCAAR)
Authors: Axel Akerblom, Stefan K James, Michael Koutouzis, Bo Lagerqvist, Ulf Stenestrand, Bodil Svennblad, Jonas Oldgren
Journal: Circulation (2009)

Introduction: Glycoprotein IIb/IIIa inhibitors are recommended by international guidelines with high level of evidence in patients with Acute Coronary Syndromes (ACS) undergoing treatment with percutaneous coronary interventions. No prospective randomized trial comparing abciximab and eptifibatide has been published. Hypothesis: We hypothesized that eptifibatide is non-inferior to abciximab. Methods: We included all ACS patients in Sweden undergoing percutaneous coronary interventions receiving either eptifibatide or abciximab during 2004 to 2006 from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). The primary endpoint was death and myocardial (re-)infarction during one year follow-up with adjustment for baseline differences with a multivariable logistic regression analysis including propensity score. The pre-specified non-inferiority margin was set to 1.29. Results: ACS patients were stratified in two treatment groups (eptifibatide n=3703 and abciximab n=10252) which showed similar baseline characteristics with mean age of 65 years, female representation of 27% and diabetes in 20.5% respectively 19.4%. The eptifibatide cohort had a lower proportion of ST-elevation myocardial infarctions (45.8% vs. 67.6%). The combined endpoint occurred in 543 (14.7%) and 1607 (15.7 %) of eptifibatide and abciximab treated patients respectively. The unadjusted odds ratio (95 %CI) for eptifibatide versus abciximab was 0.92 [0.83 – 1.03]. Multivariable adjustment (n=13882) showed non-inferiority with an odds ratio of 1.07 [0.95 – 1.19]. In patients with ST-elevation myocardial infarctions the non-inferiority remained with adjusted odds ratio of 1.03 [0.89 – 1.20] (n=8598). Conclusions: This large scale registry study shows that eptifibatide is non-inferior to abciximab as adjunctive therapy in invasively managed ACS patients with respect to death or myocardial infarction during one year, justifying its broad use in clinical practice.
Abstract 4865: Detection of Basal and Transient Myocardial Ischemia-Induced Cardiac Troponin Release Into Coronary Circulation by Highly Sensitive Assay
Authors: Masaaki Konishi, Seigo Sugiyama, Eichi Akiyama, Keisuke Ohba, Toshimitsu Nozaki, Kenji Sakamoto, Hitoshi Sumida, Hisao Ogawa
Journal: Circulation (2009)

Background: Cardiac troponin is well established as a specific biomarker for cardiomyocyte necrosis in acute coronary syndromes but not in angina pectoris. However, troponin release from coronary circulation during transient ischemic attack by angina remains to be determined because of lower sensitivity of traditional troponin assay. We assessed the basal and angina-induced occurrence of troponin release using highly sensitive troponin T (TnT) assay before and after acetylcholine-induced coronary spasm. Methods and Results: Serum cardiac TnT levels sampled from peripheral vein (PV), aortic root (Ao), and coronary sinus (CS) were measured by highly sensitive assay in 108 consecutive patients (57% men, 67±10 years) suspected of stable coronary artery disease (CAD). TnT in PV was detectable in 91.4% of the patients [9.8 (7.1, 14.7) pg/mL for median (25 th , 75 th percentile)]. At the baseline condition, there was significant increase in TnT levels from Ao [9.6 (6.9, 14.3) pg/mL] to CS [10.9 (7.9, 17.3) pg/mL, p&lt;0.001] in 92.5% of patients and the difference was 1.2 (0.6, 2.5) pg/mL, which reflects basal transcardiac release of TnT. The cardiac release of TnT positively correlated with PV levels (r=0.21, p&lt;0.05). In univariate logistic regression analysis, male gender (odds ratio [OR]; 3.65, 95% confidence interval [CI]; 1.58 – 8.47, p&lt;0.01), presence of heart failure (OR; 3.18, 95% CI; 1.11–9.15, p&lt;0.05), and presence of organic CAD (OR; 2.40, 95% CI; 1.05–5.47, p&lt;0.05) were significantly correlated with elevated transcardiac TnT release (above median). Furthermore, there was significant increase in transcardiac TnT release after acetyocholine provocation test in patients with positive result of coronary spasm [7.2 (−1.8, 11.5) pg/mL, p&lt;0.05] but not in 19 patients with negative result [0.0 (−0.5, 0.5) pg/mL, p=0.95]. Conclusions: Basal TnT release in coronary circulation was observed in most of patients suspected of CAD and the transcardiac TnT values were significantly correlated with the peripheral levels. Presence of heart failure or CAD significantly contributed to the elevated TnT release in stable states. This sensitive assay detected angina like transient myocardial ischemia-induced significant increase in transcardiac troponin release.
Abstract 191: Analysis Of Conduction Block During Ventricular Fibrillation In Langendorff Perfused Explanted Human Hearts.
Authors: Rajesh Dhopeshwarkar, Stephane Masse, Elias Sevaptsidis, John Asta, Heather Ross, Vivek Rao, Robert Cusimano, Diego Delgado, Nimalan Thavandiran, Kumaraswamy Nanthakumar
Journal: Circulation (2006)

Purpose Rotors in Ventricular Fibrillation (VF) are known to occur in distinct domains identified by dominant frequency (DF). It has been postulated that VF is driven by these domains of excitation with fibrillatory propagation to adjacent domains with conduction blocks. If the dominant domain hypothesis is applicable to human VF, we postulated that minimally during VF, areas blocks in a DF map should localize at boundaries of DF domains. Methods Explanted hearts from 4 patients undergoing cardiac transplant were perfused with Krebs-Henseilet solution. The epicardial and endocardial mapping was constructed with 112 electrodes disposed on an extensible sock and balloon array. The electrodes were organized in 14 rows of 8 electrodes disposed radially around the apex. 12 episodes of VF from the 4 hearts were analyzed. Fast Fourier Transformation (FFT) analysis was performed with a resolution of 0.25 Hz. DF domain was defined as a region on the DF map with uniform DF. Double peak (DP) an estimate of conduction block, was identified at a time point if a secondary peak was present in the power spectrum of an FFT that was within a maximum separation of 80% of the dominant (highest) peak frequency and that had an amplitude of at least 20% of the amplitude of the dominant peak. Results The average DF was 4.64±1.20 Hz. The mean percentage of blocks was 26.13±12.19 %. The average number of domains per DF map were 9.25±3.77. The mean percent block per domain was 2.95±1.27.The number of domains per map correlated significantly to areas with blocks. (r = 0.49, p=0.014). When the hearts were individually analyzed, the correlation was greater than when analyzed together. Higher occurrence of block is seen with increasing number of DF domains. Conclusions During human VF, areas of blocks in a DF map localize at boundaries of DF domains.
Abstract 4164: Decreased Skeletal Muscle Mitochondrial DNA in Patients on High-Dose Simvastatin Therapy
Authors: Brian Schick, Hélène C Côté, Reijo Laaksonen, Hannu Päivä, Terho Lehtimäki, Jiri Frohlich
Journal: Circulation (2006)

Background: Statins are used widely to treat dyslipidemia. Statin-induced myopathy (SIM) is a well-recognized side effect that decreases quality of life and complicates patient management. A reliable and convenient method of diagnosing SIM is needed, as patient self-report and creatinine kinase levels are unreliable and light microscopy of skeletal muscle is inconvenient. Statins have been associated with mitochondrial toxicity, which may be related to mitochondrial DNA (mtDNA) levels; mtDNA levels could be a useful marker of SIM. We studied the effect of high-dose statin treatment on mtDNA levels in human skeletal muscle. Method: Skeletal muscle mtDNA to nuclear DNA (nDNA) ratios were measured retrospectively in 86 biopsies obtained from an earlier randomized, double-blind, placebo-controlled trial. Forty-three hypercholesterolemic subjects aged 31 to 69 years were randomly assigned into 3 treatment groups and received placebo (n=14), atorvastatin 40mg/d (n=15), or simvastatin 80mg/d (n=14) for 8 weeks. Biopsy specimens were acquired at baseline and 8 weeks. mtDNA was quantified by extracting total DNA from muscle homogenates then quantifying a nuclear gene (ASPG) and a mitochondrial gene (CCOI) with real-time PCR. Results are expressed as the mtDNA/nDNA ratio. Differences within groups were assessed by the paired t -test and differences between groups by ANOVA with repeated measurements. Results: mtDNA significantly decreased (47%; P =0.0020) in the simvastatin group. Non-significant decreases of 12% occurred in the atorvastatin ( P =0.24) and placebo ( P =0.20) groups. Average baseline ratios of the three groups did not differ significantly ( F =0.655). Conclusion: High-dose simvastatin therapy significantly decreased skeletal muscle mtDNA. mtDNA may be a useful marker of mitochondrial toxicity in statin users, but the clinical relevance of our findings needs to be further investigated.
Cardiomyocyte Protein Kinase G Activation by Phosphodiesterase-5 Inhibition Suppresses Canonical Transient Receptor Potential (TRPC) Channel 6 Expression/Activity and Cardiac Hypertrophy Signaling
Authors: Norimichi Koitabashi
Journal: Circulation (2009)

Abstract #3087 Norimichi Koitabashi, Takeshi Aiba, John Hopkins Medical Inst, Baltimore, MD; Geoffrey G Hesketh, Univ of Cambridge, Cambridge, United Kingdom; Manling Zhang, Gordon F Tomaselli, David A Kass, John Hopkins Medical Inst, Baltimore, MD Norimichi Koitabashi, 2009 Finalist and Presenting Author
Abstract 564: Xenograft of Human Mesenchymal Stem Cells to Canine Myocardial Infarction Model with or without Epicardial Pacing has no Immune Rejection, But Proarrhythmia and Sympathetic Nerve Sprouting
Authors: Hui-Nam Pak, Jin Seok Kim, Yong Hu Fang, Gwang Il Kim, Hong Euy Lim, Ji Yeon Ryu, Byung Soo Kim, Chun Hwang, Peng-Sheng Chen, Young-Hoon Kim
Journal: Circulation (2006)

Background Cardiac resynchronization therapy reduces morbidity and mortality in patients with heart failure, and mesenchymal stem cells (MSC) transplantation has a potential for the improvement of ventricular function, especially in acute stage of myocardial infarction. However, the safety of combined left ventricular (LV) epicardial pacing (EpiP) and MSC transplantation in acute myocardial infarction (AMI) has not been studied. Methods and Results We explored the safety of human MSC (hMSC) transplantation in 15 canine model of with or without AMI or LV EpiP. AMI was made by ligation of proximal left circumflex coronary artery in open chest canine model, and positioned EpiP electrode on the peri-infarct zone (DDD mode, 3.5 V, minimal AV delay 150 ms). Implantable cardioverter defibrillator (ICD) was implanted in right ventricular endocardium to monitor ventricular arrhythmia. hMSC (1x10 7 in 1 mL, 5 sites) were injected subepicardially 15 mm separated from pacing electrode. We compared hMSC+EpiP+AMI (n=5), hMSC+EpiP (n=5), hMSC only (n=5), and sham operation (n=1) by ICD egm analysis and immunohistochemistry after 4 weeks of survival. Results: 1. 80% of hMSC+EpiP+AMI group, 60% of hMSC+EpiP group, 40% of hMSC only group, and none of control revealed spontaneous ventricular tachyarrhythmia (VT) episodes in stored ICD egm, and 60%, 40%, 20%, and 0% of each group died suddenly at 5.3±6.6 days after surgery. 2. Human nucleolin positive hMSC with vimenting positive meosdermal differentiation were observed at the subepicardial peri-infarct zone without any evidence of immune rejection. 3. The hMSC transplanted hearts expressed higher density of tyrosine hydroxylase positive cardiac nerves compared with control dog. Conclusion Although hMSC xenograft to canine AMI and EpiP model showed successful engraftment of hMSC without immune rejection, VT and sudden death with sympathetic hyper-innervation happened frequently.
Abstract 578: Urotensin-II Upregulation in Human Heart Failure: Direct Effects on Contractility and Sarcoplasmic Reticulum Calcium Load
Authors: Michael P Quaile, Kenneth B Margulies
Journal: Circulation (2006)

While studies have reported that Urotensin II (UII) is upregulated in failing (F) hearts, the pathophysiologic implications of increased UII on cardiac function is incompletely understood. We investigated the direct effects of exogenous UII on in vitro contractile performance and sarcoplasmic reticulum (SR) Ca 2+ load in F and non failing (NF) human myocardium. Methods: Isometric force was measured in F (n=11) and NF (n=6) right ventricular trabeculae (0.5 Hz, 37°C) before and after bath application of UII (UII; 0.1, 1.0, 10, 100, 1000 nM). Single and paired rapid cooling contractures (RCCs) were employed to define SR Ca 2+ load and the balance between SERCA and the NCX. Results: UII induced increases in developed tension (DT) in NF trabeculae and dose-dependent decreases in DT in F trabeculae. UII did not alter resting tension in either group. RCC amplitude increased during graded increases in UII in NF trabeculae, suggesting increases in SR calcium load, but remained stable in F trabeculae. In NF trabeculae, UII did not alter the RCC2/RCC1 ratio at any concentration, but in F trabeculae the RCC2/RCC1 ratio increased at 0.1 nM UII then exhibited dose-dependent decreases at higher concentrations. Conclusion: In contrast to the positive inotropic response elicited in NF hearts, UII is a negative inotrope in ventricular trabeculae obtained from F human hearts. Based on the RCC data, UII has little effect on SR Ca 2+ load in F myocardium suggesting that negative inotropic responses reflect decreases in myofilament Ca 2+ sensitivity. The paired RCC data suggests that U-II also affects the functional competition between SERCA and NCX differently in F and NF human hearts.
Abstract 4928: Coronary Flow Reserve is Reduced in Pulmonary Arterial Hypertension Patients
Authors: Osamu Yamada, Etsuko Tsuda, Hideo Ohuchi
Journal: Circulation (2009)

Background: Pump function of the right ventricle, which is a major determinant of prognosis in pulmonary arterial hypertension (PAH), is much influenced by coronary perfusion. Acute studies in animals exhibited paradoxical coronary flow decrease under excessive pressure overload. However, little is known about human or chronic coronary flow reserve (CFR) in PAH. Methods: Coronary flow measurement with pulse Doppler was performed for 19 PAH consecutive patients (right ventricular systolic pressure RVSP 89.7±22.7 mmHg; age 22.0±5.5 year; 10 females, data are mean±SD). The control state blood velocity was recorded in distal right coronary artery (RCA). The maximal blood velocity was recorded at the same site, on continuous infusion of adenosine triphosphate (150ng/kg/min). CFR was defined as the ratio of peak adenosine/baseline flow velocity. RVSP was adopted from the most adjacent catheterization. Coronary arterial lesions were excluded with coronary angiogram. Results: RCA flow signals were achieved in 17/19. Systolic flow signals were observed in 2/17. RCA diastolic peak velocity in basal condition was somewhat higher than reported in normal subjects (29.9±11.4 cm/sec) and positively correlated with right ventricular systolic pressure (RVSP) with significance (R^2 = .236; p&lt;0.05). CFR of RCA ranged 1.55– 4.16 (2.46±0.82) and was below 2.0 in 7/17. It negatively correlated with RVSP (R^2 = .383; P &lt; 0.01). Conclusion: Peak flow velocity of RCA in PAH correlated with RVSP, in reply to greater energy demand of RV. CFR of RCA was low and negatively correlated with RVSP, which may suggest poor energy supply reserve in PAH patients.
Abstract 4166: Clinical Significance of HDL-c Levels among Patients with LDL-c less than 60 mg/dl
Authors: Emil M deGoma, Nicholas J Leeper, Paul A Heidenreich
Journal: Circulation (2006)

Background: Although studies support an inverse correlation between HDL-cholesterol levels and cardiovascular risk, the clinical relevance of HDL in the context of low LDL levels remains uncertain. Methods: We identified 6,357 consecutive patients seen at the Palo Alto VA Medical Center or one of 7 community clinics with LDL levels less than 60 mg/dl. The cohort was divided into quartiles based on HDL. The combined primary outcome was myocardial infarction (defined as a Tn I &gt; 0.1 ng/ml) or hospitalization for ischemic heart disease (IHD) at one year. Odds ratios were adjusted for demographics, medical history, laboratory values (hemoglobin, creatinine, HbA1C, liver function tests, LDL, triglycerides), and statin use. Results: The cohort had a mean age of 65 years, a prior diagnosis of IHD in 42%, diabetes in 46%, hypertension in 73%, and heart failure in 15%. Mean HDL levels (mg/dl) by quartile were: Q1 - 28, Q2 - 36, Q3 - 43, Q4 - 64. The incidence of the combined endpoint of MI or IHD hospitalization at one year was higher in the low HDL quartiles (Q1 - 8.5%, Q2 - 5.8%, Q3 - 5.1%, Q4 - 3.9%, p &lt; 0.0001). The association of HDL with IHD admission and MI persisted following multivariate adjustment (Figure ). Conclusions: Low HDL-cholesterol levels are a marker for excess coronary risk among patients with an LDL less than 60 mg/dl. HDL-directed therapies may play an important role in the prevention of IHD events across all levels of LDL.
Abstract 5077: Inhibition of Smooth Muscle Myosin, a Novel Anti-Hypertensive Strategy
Authors: You-Tang Shen, Li Chen, Xin Zhao, Xiangping Qian, David J Morgans, Stephen F Vatner, Fady I Malik
Journal: Circulation (2009)

Inhibition of smooth muscle myosin is a novel mechanism to reduce vascular smooth muscle tone and may represent a new antihypertensive class. The goal of this study was to examine the effects of a smooth muscle myosin inhibitor, CK-2018448 (CK-448), in conscious dogs at baseline and in the hypertensive state. Hypertension was induced by wrapping one kidney combined with renal artery stenosis in 5 dogs instrumented with a left ventricular (LV) pressure gauge, Transonic flow probes on the ascending aorta, coronary, renal and iliac arteries, and pressure catheters in the aorta and left atrium. One week after surgery, when the dogs were still normotensive, CK-448 (2– 6 mg/kg, iv bolus) produced dose-dependent decreases in mean arterial pressure (MAP) and total peripheral vascular resistance (TPR) and increases in cardiac output, LV dP/dt and heart rate; the latter were nearly eliminated by autonomic blockade. The changes in TPR and regional vascular resistance after administration of CK-448 (6 mg/kg, iv) were compared with those of the calcium channel blocker, amlodipine (0.5 mg/kg, iv) at doses inducing similar reductions in TPR (Table ). The pattern of regional vasodilation in the kidney and limb was different for the 2 drugs; the greatest vasodilation for amlodipine was in the limb, whereas for CK-448 it was the kidney. When hypertension developed 2– 4 weeks later, baseline MAP rose from 101±4 to 158±7 mmHg and TPR from 27±3 to 100±10 mmHg/L/min. The effect of CK-448 on TPR was more than in the normotensive state and there was a similar preferential renal vasodilation with CK-448, i.e., it increased renal blood flow by 76% (t = 3 min), which was twice the increase in the iliac bed. Thus, the smooth muscle myosin inhibitor and a calcium channel blocker elicited different patterns of regional vasodilation. The renal vasodilation induced by CK-448 could have additional salutary effects in hypertension, which is often accompanied by renal insufficiency.
Abstract 569: Selective Elimination of I <sub>Ks</sub> and I <sub>Kr</sub> in Transgenic Rabbit Models of LQT1 and LQT2
Authors: Gong Xin Liu, Naveed Rana, Mohammad Hajjiri, Michael Brunner, Eduardo Folco, Ekaterina Pringa, Jason Centracchio, Malcolm Kirk, Manfred Zehender, Xuwen Peng, Gideon Koren
Journal: Circulation (2006)

LQT1 and LQT2, the two most common inherited long QT syndromes are associated with sudden cardiac death due to due torsades the pointes (TdP). We have created two lines of transgenic rabbits overexpressing pore mutants of the human KvLQT1 (KCNQ1) and HERG (KCNH2) in the heart. Both animal models have prolonged QT interval, however, only LQT2 rabbits suffer from TdP and sudden cardiac death. To investigate the differences in the cellular phenotypes we investigated the whole cell current of acute isolated apical ventricular myocytes from LQT1 and LQT2 rabbit models using patch-clamp techniques by depolarizing to potentials between −30 to +30 mV from a holding potential of −40 mV (room temperature). I Kr and I Ks were defined as currents sensitive to E-4031 (5 μM) and chromanol 293B (30μM) respectively. Our preliminary data revealed that I Ks was selectively abolished in 8 out of 8 LQT1 cardiomyocytes, while I Kr was spared (Figure 1 ). By contrast, I Kr was selectively abolished in 13 out of 14 LQT2 cardiomyocytes while I Ks was spared. The selective elimination of I Kr resulted in a significant increase in the duration of action potential (APD 90 ) from 357±48.68ms (n=13) in control to 533.14±54.22ms (n=14) in LQT2 cardiomyoctes (P&lt;0.05), while the elimination of I ks slightly prolonged the APD 90 to 423.37± 52.31 (n=8) (P=NS). In conclusion, expression of the pore mutants resulted in specific inhibition of I Ks in LQT1 and I Kr in LQT2 rabbits, and established these models as unique genetic counterparts of the human LQT1 and LQT2 syndrome. These models will enable detailed analyses of the electrical remodeling in LQTS.
Abstract 604: Atorvastatin Activates Cycloxygenase-2 in the Heart via S-Nitrosylation by Inducible Nitric Oxide Synthase
Authors: Yochai Birnbaum, Yumei Ye, Yu Lin, Sheldon Y Freeberg, Juan D Martinez, Barry F Uretsky, Jose R Perez-Polo
Journal: Circulation (2006)

Background: Atorvastatin (AT) increases myocardial expression of phophorylated Ser-1777 endothelial nitric oxide synthase (P-eNOS), inducible NOS (iNOS) and Cycloxygenase-2 (COX2). Although AT increases the expression of COX2 in eNOS −/ − mice, there is no increase in COX2 activity as occurs in wild-type (WT) mice. In the rat, COX2 activation occurs by iNOS mediated S-nitrosylation. Aim: To investigate whether the difference in COX2 activity between the AT-treated WT and eNOS −/ − is related to S-nitrosylation. Methods: WT, eNOS −/ − , and iNOS −/ − mice received AT 10 mg/kg/d (AT+) or water alone (AT-) for 3 days. Hearts were harvested and subjected to ELISA and immunoblotting. Snitrosylation of COX2 was assessed by the “Biotin Switch” assay. To verify that the immunoprecipitates contained COX2, membranes were stripped and blots with anti-COX2 antibodies. Results: COX2 expression in the AT- groups was very low. AT increased COX2 expression in WT (4,287±104%) and eNOS −/ − (4,354±101%), but not iNOS −/ − mice (101±3%). However, myocardial 6- keto-PGF 1α levels (81.4±0.2 vs. 15.7±0.1 pg/ml; p&lt;0.001) were increased by AT only in WT mice, but not in eNOS −/ − (16.5±0.1 vs. 15.6±0.1 pg/ml) or iNOS −/ − (15.9±0.2 vs. 15.3±0.1 pg/ml) mice. The “Biotin Switch” assay shows that COX2 was S-nitrosylated only in WT mice. Although eNOS is activated by AT in the iNOS −/ − mice, there is no S-nitrosylation and activation of COX2. Conclusions : COX2 is activated by S-nitrosylation only in WT mice. Although iNOS is intact in eNOS −/ − mice, it is not activated and therefore, does not S-nitrosylate the AT-induced upregulated COX2.