tbuckley/cabot-search huggingface dataset:
Abstract 19472: Clinical and Angiographic Factor for the Mismatch Between Myocardial Perfusion Imaging and Pressure-Derived Fractional Flow Reserve
Authors: Tomoyuki Yamaguchi, Takashi Kubo, Yasutsugu Shiono, Yasushi Ino, Takashi Tanimoto, Hiroko Nakanishi, Hiromichi Sougawa, Makoto Orii, Kunihiro Shimamura, Takashi Yamano, Kohei Ishibashi, Kumiko Hirata, Toshio Imanishi, Takashi Akasaka
Journal: Circulation (2012)

Background: Myocardial perfusion imaging (MPI) with single-photon emission computed tomography (SPECT) is well-established modality to detect myocardial ischemia noninvasively. But it has been reported that MPI can underestimate ischemic region of myocardium, particularly in patients with multivessel coronary artery disease or previous myocardial infarction. Method: We analyzed the records of MPI and pressure-derived fractional flow reserve (FFR) retrospectively, and investigated what is the clinical and angiographic factor of discordance between MPI and FFR result. Myocardial ischemia is defined by an FFR≤0.75. Adenosinse or exercise Thallium 201 scintigraphy was underwent within 3 months before the FFR study. The clinical and angiographic features were compared with the patients who have myocardial ischemia identified by both MPI and FFR (concordance group). Result: Two hundred and sixty-three vessels in 220 patients were enrolled. Thirty-nine vessels in 37 patients were FFR-positive (i.e.FFR≤0.75), but MPI-negative (discordance group). Thirty patients (81.1%) in discordance group have multivessel coronary artery disease, and 18 patients (37.8%) have previous myocardial infarction. To compare with concordance group (40 vessels in 37 patients), there were no significant differences in basic characteristics, angiographic lesion complexity, and minimum lumen diameter. Two groups have same frequency of history of infarction (discordance group 46.2% vs. concordance group 42.5%; p=ns), but non-infarct-related-arteries were more often included (and misdiagnosed) in discordance group than concordance group (83.3% vs. 50%; p&lt;0.05). Conclusion: In patients with previous myocardial infarction, MPI may underestimate myocardial ischemia. MPI should be carefully interrupted in these patients, and the measurement of FFR should be considered to evaluate myocardial ischemia accurately.
Abstract 19629: Expression and Role of TRPC Channels in Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells
Authors: Hairuo Wen, Charelle Allen, Nadezhda Fefelova, Lai-Hua Xie
Journal: Circulation (2012)

Store-operated Ca 2+ entry (SOCE) is a mechanism for increasing cytosolic Ca 2+ (Ca i 2+ ) load after the SR/ER Ca 2+ depletion in many cell types. Our previous study has implicated SOCE, which is at least partially mediated by transient receptor potential canonical (TRPC) channels, exists in adult mouse ventricular myocytes, and contributes to the generation of spontaneous SR Ca 2+ release and triggered arrhythmias. However, it is unclear if this mechanism also exists in human cardiac myocytes. In the present study, we investigate the expression and role of TRPC channels in cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) (purchased from Cellular Dynamics). Abundant distributions of TRPC3 and 6 channels were detected in the plasma membrane of hiPSC-CMs using immunocytochemical staining. Ca i 2+ was imaged in fluo-4-AM loaded cells. A SOCE (F/F 0 = 1.75 ± 0.08, n = 47) was observed in hiPSC-CMs when the external Ca 2+ concentration ([Ca 2+ ] o ) was switched from 0 to 1 mM after SR Ca 2+ was completely depleted by caffeine (20 mM) and thapsigargin (10 µM). The SOCE was inhibited by non-selective TRPC blockers gadolinium (F/F 0 = 1.05 ± 0.03, n = 13) and SKF-96265 (F/F 0 = 1.04 ± 0.03, n = 17), respectively, compared to control (p&lt;0.05). Whereas, the SOCE in hiPSC-CMs was significantly reduced only by pretreatment with anti-TRPC6 antibody (F/F 0 = 1.38 ± 0.06, n = 15, p&lt;0.05), but not with anti-TRPC1 (F/F 0 = 1.93 ± 0.19, n = 8) or anti-TRPC3 antibodies (F/F 0 = 1.49 ± 0.05, n = 14), indicating TRPC6 channels are essential for SOCE in hiPSC-CMs. In addition, the hiPSC-CMs exhibit a property of spontaneous rhythmic beating. After SR Ca 2+ depletion, spontaneous Ca 2+ waves reappeared via refilling from the extracellular Ca 2+ source, suggesting the involvement of SOCE in the generation of spontaneous Ca 2+ waves. This idea was confirmed by the application of TRPC blockers, including gadolinium, SKF-96265 and Pyr3, all of which showed mild to potent inhibitory effects on the spontaneous Ca 2+ waves. In conclusion, we demonstrated the existence of SOCE in hiPSC-CMs. SOCE mediated by TRPC channels, especially the TRPC6, may act as an important mechanism of controlling Ca 2+ handling and arrhythmogenesis in the developing human heart.
Abstract 19379: Failure of Regenerative Cell-Based Therapy to Stimulate Coronary Collateral Growth in a Rat Model of Metabolic Syndrome
Authors: Suzanna Logan, William M Chilian, Vahagn A Ohanyan, Kelly Stevanov, Molly Enrick, Christopher L Kolz, Liya Yin
Journal: Circulation (2012)

Nearly 30-40% of patients with coronary disease show little or no coronary collateral growth and have a poorer prognosis than those with well-developed collaterals. Stem cell therapies hold promise for stimulating vascular growth in the heart, but most results to date have been modest. Perhaps stem cell survival and differentiation are compromised by the oxidative environment occurring in cardiovascular disease. To test this, we determined if cell-based regenerative therapies stimulate coronary collateral growth in a rat model characterized by oxidative stress and poor coronary collateralization. Previously we found that induced vascular progenitor cells (iVPCs) were the best cell type (compared to MSCs and iPS cells) to stimulate coronary collateral growth in lean (LN) rats (10-day repetitive ischemia [RI] protocol). Using the RI protocol, iVPCs were implanted intramuscularly in the heart of Zucker Obese Fatty (ZOF) rats. Coronary collateral flow was significantly increased by iVPCs in LN but not in ZOF (Figure 1), suggesting that under oxidative stress, iVPCs fail to induce coronary collateral growth. To understand why iVPCs did not stimulate collateral growth in ZOF rats, we mimicked conditions of oxidative stress and mitochondrial DNA damage in ZOF rats (previously observed in our lab) by treating the cells with H 2 O 2 (100 µM or 800 µM) for 2 hrs followed by 100 µM 4-Nitroquinoline 1-oxide for 1 hr. These stressors decreased viability of iVPCs by 19.8% and 62.7% (high and low H 2 O 2 ; p&lt;0.05; MTT assay) and decreased the expression of stemness lineage markers for SSEA1, CD133, and c-kit by 79%, 84% and 67%, respectively (real-time PCR). These data indicate that oxidative stress in ZOF rats compromises cell survival and stemness of the implanted iVPCs, limiting their regenerative potential. Our results suggest that consideration of adjunctive therapies to improve cell survival and regenerative capacity is important in cell-based therapies for vascular disease.
Abstract 19664: Clinical Characteristics and Cardiac Magnetic Resonance for the Patients Received Repeating Alcohol Septal Ablation in Refractory Hypertrophic Obstructive Cardiomyopathy
Authors: Mitsunobu Kitamura, Morimasa Takayama, Junya Matsuda, Syunichi Nakamura, Gen Takagi, Hitoshi Takano, Kuniya Asai, Kyoichi Mizuno
Journal: Circulation (2012)

Backgound : Alcohol septal ablation (ASA) is an alternative option to surgical myectomy, however, there are problems regarding the residual gradient and repeating septal reduction. Therefore, we investigated the patients’ characteristics needed repeating ASA with geometric analysis by cardiac magnetic resonance (CMR). Method: We performed 174 ASA from 1998 to 2012, and there were 28 cases (Group R) needed repeating procedures because of recurrent drug-refractory symptoms due to intraventricular obstruction. We investigated the procedural details and the CMR findings to pursue the predictive factor of unsatisfied ASA result, in comparison with 36 patients (Group S) with successful procedures, in which the symptom improved to NYHA class I and there was no repeating ASA until 5 years from the first procedure. Results: The time interval of both ASA procedures in group R was 584±496 days, and 16 patients (57%) received 2nd procedure within 1 years. In group R, the patients were younger (55±16 in group R and 65±13 years-old in group S, p=0.006), and similar to gender (Female 25 and 18), baseline pressure gradient (PG) (81±51 and 82±38 mmHg), ethanol dosage (2.2±1.0 and 2.2±0.9ml) than group S. Notably, the PG after ASA in group R was significantly higher (35±34 and 16±18mmHg, p=0.011), moreover the peak CPK was significantly lower (804±388 and 1206±533U/l, p=0.001). From CMR findings, the left ventricular mass, the left atrial diameter, the geometry of the left ventricle and late gadolinium enhancement were similar in both groups. Conclusion: Younger patients, high PG after ASA and low peak CPK were likely to need repeating procedure. Therefore, sufficient ablation for culplit septal myocardium was desirable.
Abstract 19695: Platelet TSC1 is an Important Mediator of Arterial Thrombosis
Authors: Yong-Joo Ahn, Hyung-Hwan Kim
Journal: Circulation (2012)

Background : Arterial thrombosis is responsible for peripheral vascular disease, myocardial infarction, and stroke. Mammalian target of rapamycin (mTOR) inhibition promotes arterial thrombosis. To determine the contributions of platelet specific Tuberous sclerosis 1 (TSC1) deficiency to arterial thrombosis, we generated PF4Cre-TSC1 flox/+ mice. Because the effect of mTOR activation on thrombus formation in vivo has not yet been studied, we hypothesize that mTORC1 signaling pathway in platelets may play an important role in arterial thrombosis. Methods and Results : To determine the role of platelet TSC1 in arterial thrombosis, we generated a mouse strain with platelet-specific TSC1 deficiency (PF4Cre-TSC1 flox/+ ) using conditional TSC1 flox/flox mice and platelet-specific PF4-Cre mice. PF4Cre-TSC1 flox/+ mice did not show any obvious phenotypic abnormalities. Arterial thrombus formation was investigated using in vivo ferric chloride induced thrombosis model. Ferric Chloride (5% FeCl 3 ) induced thrombotic occlusion. Compared to PF4-Cre mice, PF4Cre-TSC1 flox/+ mice exhibited elongated thrombotic occlusion time by 21.7%. Platelet specific TSC1 deficiency promotes arterial thrombosis via activation of mTOR and S6, a downstream target of mTORC1. Conclusion : These finding indicate that platelet specific TSC1 deficiency promotes arterial thrombosis in vivo . These results suggest that activation of mTORC1 may have therapeutic benefits in arterial thrombosis.
Abstract 19282: NAT10 Mutaion Causes Ciliary Aplisia and Congenital Heart Disease Associated with Heterotaxy
Authors: You Li, Hisato Yagi, Ezenwa O Onuoha, Gregory Pazour, Linda Leatherbury, Michael Tsang, Cecilia Lo
Journal: Circulation (2012)

Introduction: We recently showed patients with CHD associated with heterotaxy can exhibit respiratory ciliary dysfunction (CD) similar to that of patients with primary ciliary dyskinesia (PCD) - a ciliopathy with airway mucociliary clearance defects. Exome sequencing analysis revealed known PCD causing mutation and rare coding variants in known PCD genes were enriched in heterotaxy patients with CD, suggesting a common etiology for heterotaxy and motile cilia dysfunction. Further interrogation for novel variants in non-PCD genes have uncovered one patient with a homozygous mutation in the acetyltransferase NAT10 . In this study, we investigated the hypothesis that NAT10 may play an essential role in ciliogenesis and is required for left-right patterning. Methods and Results: Exome sequencing was carried out in heterotaxy patients with ciliary dysfunction. Coding variants were filtered against dbSNP and 1000 genome databases. Novel homozygous coding variant in NAT10 (M638V) was identified in one heterotaxy patient with ciliary aplasia. This mutation is in a highly conserved residue of the HAT domain and is predicted to be deleterious. As NAT10 is known to acetylate tubulin, a key structural component of cilia, this seems likely to be disease causing. Using human hertRPE cells, we showed shRNA knockdown of NAT10 resulted in the inhibition of primary cilia formation. We further did NAT10 shRNA knockdown in ciliated human airway epithelial cells and showed complete repression of ciliogenesis. In contrast, reciliating airway epithelial cells treated with control shRNA formed normal motile cilia. Further analysis of zebrafish embryos after Nat10 morpholino injections showed laterality defects consistent with heterotaxy, confirming a requirement for NAT10 in left-right patterning. Conclusion: We identified a novel homozygous NAT10 mutation in heterotaxy patient with ciliary aplasia. We showed NAT10 is required for both formation of nonmotile primary cilia and motile cilia in the airway. Studies in zebrafish embryos further suggest NAT10 is required for motile cilia function regulating left-right patterning. Together these findings support the conclusion that NAT10 mutation can cause heterotaxy and ciliary aplasia phenotypes.
Abstract 8889: Isovolumic Acceleration Correlates with Single Ventricle Pre or Post Fontan Ventricular End Diastolic Pressure, Not E/e′
Authors: Nee Scze Khoo, Jeffrey F Smallhorn, Sachie Kaneko, Shelby Kutty, Lisa Hornberger, James Coe, Edythe B Tham
Journal: Circulation (2011)

Background: Estimation of diastolic function in single ventricle (SV) hearts with varied ventricular loading from staged palliative surgery is particularly challenging. To define the best non-invasive correlate of diastolic function in SV, we studied the relationship between echocardiography function parameters, and invasively measured end diastolic pressure (EDP) of the dominant ventricle in SV patients. Methods and Results: Thirty SV patients, mean age 41±11 months, with cardiac catheterization pre (n=20) or post Fontan (n=10), had their most closely associated echocardiogram (median 3.5, 0.6 to 9.9 months), assessed using conventional and color tissue Doppler imaging (TDI) parameters for systolic and diastolic function. Echocardiogram parameters and catheter-derived data were explored for linear correlations with p&lt;0.05 being significant. The EDP and mean pulmonary artery (PAP) pressures were 6.5±3.5 and 9.6±3.4 mmHg respectively. No significant correlation was found between echocardiography diastolic parameters, early and late peak inflow velocities (E, A and E/A), TDI annular velocities (e′, a′ and E/e′), pulmonary venous Doppler spectra, isovolumic relaxation time, atrial size and function, and invasively measured EDP or PAP. Systolic parameters, ventricular annular excursion, TDI (s′ and Tei index), ventricular size and function, had no significant correlation with EDP or PAP. Only isovolumic acceleration (IVA), a mostly load independent non-invasive measure of myocardial contractility, held a highly significant negative correlation with EDP (Figure). Conclusions: Decreased IVA, a marker of reduced myocardial contractility, has the best non-invasive correlate with invasively measured EDP in SV. In contrast E/e′ and other parameters of diastolic function do not. Current echocardiographic diastolic parameters established in adults with heart failure may not be useful in SV.
Abstract 19296: In-Stent Neoatherosclerosis: Are First Generation Drug Eluting Stents Different Than Bare Metal Stents? An Optical Coherence Tomography Study
Authors: Antonios Karanasos, Karen Witberg, Jurgen Ligthart, Robert-Jan van Geuns, Joost Daemen, Nico Bruining, Gijs van Soest, Felix Zijlstra, Konstantinos Toutouzas, Evelyn Regar
Journal: Circulation (2012)

Purpose: In-stent neoatherosclerosis has been recognised in pathologic specimens of bare metal stents (BMS), and recently in first generation drug eluting stents (1st-DES) as well. However, in vivo data are scarce. By optical coherence tomography (OCT), we investigated the incidence and morphological characteristics of neoatherosclerosis (NA) very late after BMS or 1st-DES implantation. Methods: From 1/1/2007 to 31/1/2012, 52 patients from two institutions underwent &gt;24 months follow-up OCT assessment of a BMS or a 1st-DES (13 BMS - 39 1st-DES). NA was characterized using criteria for native atherosclerosis. Results: Differences between BMS and 1st-DES are presented in the table. BMS had longer follow-up interval but no differences in clinical presentation at follow-up. No significant differences were evident in the incidence of NA, neointimal rupture, lipid content, neovascularization or macrophage infiltration between BMS and 1st-DES. There was however a trend for lower fibrous cap thickness (FCT) and for higher calcification in BMS (FCT: 51±31μ m vs. 92±59μ m, p=0.057; calcifications: 46.2% vs. 15.4%, p=0.051). 1st-DES with neoatherosclerosis had longer interval from implantation compared to 1st-DES with homogeneous coverage [Median 71 months (range 25-130) vs. 57 months (24-68), p&lt;0.05], but there was no difference for BMS with or without neoatherosclerosis [Median 125 months (range 90-201) vs. 168 months (132-168), p=0.54]. Conclusions: The incidence and morphological characteristics of NA are similar between 1st-DES and BMS of more prolonged follow-up. Our findings suggest a time-dependent pattern in the incidence of NA in 1st-DES with 2-11 years follow-up.
Abstract 8655: Caveolin-1-dependent Inhibition of Transforming Growth Factor-β Pathway Alters Inflammation Post Myocardial Infarction
Authors: Harshita Bhatnagar, Lisa Ji, Merry L Lindsey, Claude J Le Saux
Journal: Circulation (2011)

Myocardial Infarction (MI) leads to inflammatory events characterized by influx of neutrophils and macrophages, altering the local cytokine milieu. TGF-β is implicated as one of the key cytokines in this process. Caveolin-1 (Cav-1), the main structural protein of caveolae, negatively modulates TGF-β signaling by regulating TGF-β receptor turnover and downstream signaling. Thus, we hypothesized that Cav-1 will modulate TGF-β anti-inflammatory responses post-MI. Two-month old wild-type (WT) C57BL/6 and the Cav-1 null mice were subjected to left anterior descending artery ligation, a subset of which were treated with TGF-β neutralizing antibodies, 24 hours post-MI. Hearts were harvested 3 days post-injury. H &amp; E staining showed massive cell infiltration in WT mice post-MI in all groups. Neutrophil and macrophage counts paralleled this observation. Interestingly, in the Cav-1 null mice, a marked reduction in the infiltrating neutrophil and macrophage numbers was observed after anti-TGF-β treatment. Real-time PCR results further confirmed the regulatory effects of Cav-1 in the inflammatory responses. Thirty-five percent of the regulated inflammatory genes were TGF-β dependent (such as chemokine genes Ccl24 and Ccr9; cytokine genes IL-17b and Spp1 and cytokine receptor gene IL1r2). Out of them, 60% were Cav-1-dependent. For example, Ccl24, Ccr9 and IL1r2 were Cav-1 dependent whereas Spp-1 was regulated independently of Cav-1. Ccl24 expression was increased 20-fold in Cav-1 null mice post-MI compared to WT mice. This increase was further enhanced after anti-TGF-β antibody treatment. Similar results were obtained for Ccr9 and IL1r2 expressions. Spp-1 expression was upregulated by 600-fold post-MI in WT and by 400-fold in Cav-1 null mice. After anti-TGF-β antibody treatment, Spp-1 expression returned to baseline in both strains. Thus, we demonstrate for the first time that in addition to TGF-β, Cav-1 plays a significant role in the inflammatory events post-MI; and regulating TGF-β and/or Cav-1 modulates these events. It would be interesting to study if Cav-1 has a role to play in the chemotaxis of the immune cells to the site of injury and in conjunction with TGF-β, affect the secretion of cytokines and chemokines by these cells, altering post-MI events.
Abstract 19513: Action Potential Prolongation and Heart Failure in an Inducible Mouse Model of Timothy Syndrome 2
Authors: Glenna C Bett, Stanley Fernandez, Albert Nayeri, Agniezka Lis, James Fallavollita, Randall L Rasmusson
Journal: Circulation (2012)

Introduction: Timothy syndrome (TS) is caused by a de novo gain of function missense glycine to arginine mutation (G406R) in both the 8 and 8a human splice variants of the Cav1.2 channel (TS1 and TS2 respectively). Hypothesis: TS mice will exhibit prolongation of the action potential and will develop heart failure due to calcium overload. Methods: Normal expression of the TS2 as a knock in defect is lethal to mice, but the defect is tolerated when suppressed though transcriptional interference by the NEO promoter (TS2-NEO mouse). By crossing TS2-NEO with a mouse carrying a cardiac-specific tamoxifen-inducible CRE we removed the transcriptional suppression and up-regulated expression of mutant channels. We extracted mRNA from cardiac left ventricle and probed with PCR primers to exons 7 and 9. Individual PCR products were incorporated into plasmid DNA and individual clones were isolated. Only 1 in 56 TS2-NEO colonies expressed mutant channels in heart demonstrating that the NEO cassette suppressed mutant isoforms. With tamoxifen, the ratio of mutant to non-mutant exons increased from 1:34 to 29:72 demonstrating a robust upregulation of the mutant TS2 channel. We performed electrophysiology, EKG analysis, and echocardiography. Results: TS2 mice showed a significant increase in QT duration before (33.1±1.8 ms) and after (74.0±5.5 ms) tamoxifen-activation of the mutant (n=5, p&lt;0.01). Echocardiography demonstrated a decrease in ejection fraction from 95±2 to 53±6% (n=9) in activated TS2 mice, indicative of development of heart failure, compared to with 95±1 to 89±7% (n=12) for controls (P&lt;0.0001). At the single myocyte level, action potentials were markedly prolonged, and both fast and slow components of inactivation of the calcium current were slowed. Fast inactivation in TS2 mice was 18.8±2.9ms (n=18) vs. 12.5±1.4 in controls (n=21,p&lt;0.05), and slow inactivation in TS was 98.2±4.4ms vs. 77.6±1.7 ms in controls (p&lt;0.0001). Conclusion: TS2 mice have QT prolongation, decreased ejection fraction, and altered calcium channel behavior. Calcium overload through the TS2 mutation can cause a rapid development of heart failure. This emphasizes the critical role of the L-type calcium channel inactivation in the physiology of repolarization and heart disease.