tbuckley/cabot-search huggingface dataset:
Abstract 18480: Attenuation of Cardiac Autonomic Neuropathy and Left Ventricular Function by Inhibition of Matrix Metalloproteinase 2&amp;9 in Diabetic Rats
Authors: Lokesh K Bhatt, Veeranjaneyulu Addepalli
Journal: Circulation (2012)

Cardiovascular autonomic neuropathy (CAN) is a serious and common complication of diabetes. Along with other cardiovascular dysfunction CAN further worsen the performance of heart in diabetics. We hypothesized that MMP-2 and MMP-9 inhibition can attenuate cardiovascular autonomic neuropathy in diabetics. The present study was designed to investigate effect of MMP-2 and MMP-9 inhibition on cardiac autonomic neuropathy and left ventricular function in streptozotocin-induced (55 mg/kg i.p.) diabetic rats by analysis of heart rate variability (HRV) and left ventricular functions. Minocycline (50mg/kg) was used as a MMP-2 and MMP-9 inhibitor. Eight weeks after induction of diabetes, rats were administered Minocycline (50 mg/kg) over a four-week period. Gelatine zymography was performed to evaluate MMP-2 and MMP-9 levels in vagus nerve and heart. Diabetes resulted in reduction in heart rate (290±31 vs. 376±29 beat per min; P&lt;0.0001). This bradycardia was partly reversed with MMP-2 and MMP-9 inhibitor Minocycline (352 ± 42 beat per min; P&lt;0.05 vs. diabetic control). Both time- and frequency-domain parameters of HRV were significantly reduced in diabetic rats. Spectral power was reduced around 45% at high frequencies and about 65% at low frequencies in diabetic rats. This suggested a decrease of parasympathetic activity. Ratio of low/high frequency was also significantly decreased in diabetic rats suggesting decreased sympathetic tone. Standard deviation of heart rate in minocycline treated rats was significantly higher than in untreated diabetic rats (P&lt;0.05). Significant attenuation (P&lt;0.05) was also observed in power spectrum of treated animals. Treatment also significantly ameliorated left ventricular functions dp/dt max and dp/dt min compared to diabetic control. MMP-2 and MMP-9 levels were significantly decreased in minocycline treated group compared to diabetic control. In conclusion, inhibition of MMP-2 and MMP-9 by minocycline prevented development of cardiovascular autonomic neuropathy and ameliorated left ventricular function in streptozotocin-induced diabetes in rats.
Abstract 18462: Heparin Cofactor II Promotes Angiogenesis in Response to Ischemic Hindlimb via an AMPK-eNOS-dependent Manner
Authors: Yasumasa Ikeda, Ken-ichi Aihara, Sumiko Yoshida, Masataka Sata, Masashi Akaike, Toshio Matsumoto, Toshiaki Tamaki
Journal: Circulation (2012)

Background: Heparin cofactor II (HCII) generally exerts to suppress activated thrombin by binding to dermatan sulfate at injured vascular walls. We have revealed that protective actions of HCII against cardiovascular disease in both experimental and clinical studies. In the present study, we investigated to clarify HCII effect on angiogenesis. Methods and Results: Male heterozygous HCII deficient (HCII+/−) mice and male littermate wild-type (HCII+/+) mice at the age of 12-16 weeks were subjected to unilateral ischemic hindlimb surgery. The analysis of laser speckle blood flow showed that blood flow recovery in response to ischemia was insufficient in HCII+/− mice compared to HCII+/+ mice. Number of capillaries and arterioles, eNOS and AMPK phosphorylation in ischemic adductor muscles were reduced in HCII+/− mice. Blood flow recovery and capillary density, as well as phosphorylation levels of eNOS and AMPK in ischemic muscles of HCII+/− mice were almost restored by administration of human purified HCII (h-HCII) protein. In in vitro studies, h-HCII treatment augmented tube formation, cell proliferation and migration of human aortic endothelial cells (HAECs). h-HCII increased the phosphorylation levels of endothelial nitric oxide synthesis (eNOS) and AMP-activated protein kinase (AMPK) in HAECs. On the other hand, h-HCII-induced tube formation, cellular migration and proliferation and eNOS phosphorylation in HAECs were abolished by compound C, an AMPK inhibitor. Thrombin-induced reduction of eNOS phosphorylation and expression was also prevented by h-HCII asministration. Conclusion: HCII enhances cellular activity of endothelial cells and promotes angiogenesis in response to ischemic hindlimb via an AMPK-eNOS signaling pathway. HCII potentiates to be a new therapeutic target for treatment in patients with peripheral artery disease.
Abstract 18483: Absence of Chemokine (c-x-c Motif) Ligand 10 Diminishes Perfusion Recovery After Local Arterial Occlusion in Mice
Authors: Pleunie van den Borne, René T Haverslag, Imo E Hoefer, Gerard Pasterkamp, Dominique P de Kleijn
Journal: Circulation (2012)

Background In arteriogenesis, pre-existing anastomoses undergo enlargement into functional collateral arteries that are able to restore blood flow in ischemic tissues. Chemokine (C-X-C motif) ligand 10 (CXCL10) is secreted after Toll-like Receptor activation and involved in chemo-attraction of monocytes and T cells. Previously, we have shown that TLR2 and 4 are involved in arteriogenesis. In this study, we investigated the role of CXCL10 in the process of arteriogenesis. Methods Unilateral femoral artery ligation was performed in wildtype (WT) and CXCL10-/- (KO) mice and perfusion recovery was measured over 7 days using Laser-Doppler analysis. Histology was performed in hind limb muscles for vessel number and influx of inflammatory cells. Chimerisation experiments were performed to assess the role of bone marrow-derived CXCL10. See table below for all animal numbers per experimental group. Data are shown as mean±SEM. Results At 4 and 7 days after operation, perfusion recovery was significantly lower in KO mice compared to WT (50%±13 vs 35%±5 at day 4; p=0.003, 92%±2 vs 76%±13 at day 7; p=0.005) as well as numbers of vessels in the hind limb muscle (α-SMA, 102±7 vs 67±5 at day 4, p&lt;0.001 and 88±9 vs 60±6 at day 7 p=0.02; CD-31, 102±7 vs 67±5 at day 4, p&lt;0.001 and 74±14 vs 109±18 at day 7, p=0.02). Local macrophage and T cell infiltration did not significantly differ between WT and KO. Compared to WT, chimeric mice (KO bone marrow in WT) showed significantly lower perfusion recovery (WT vs chimers: 50%±13 vs 44%±4 at day 4 p=0.046, and 92%±2 vs 61%±5 at day 7, p&lt;0.001). Compared to KO, chimeric mice (WT bone marrow in KO) showed significantly higher perfusion recovery, only at day 4 (KO vs chimers: 35%±5 vs 63%±4 at day 4, p&lt;0.001, and 76%±13 vs 74%±6 at day 7, p=0.24). Conclusions CXCL10 plays a critical role in arteriogenesis. Bone marrow-derived, as well as tissue derived CXCL10, plays a critical role in accelerating perfusion recovery after arterial occlusion in mice.
Abstract 18482: cAMP-mediated Cardiac Myocyte-fibroblast Crosstalk
Authors: Yassine Sassi, Jeffery Truong, Andrea Ahles, Stefan Engelhardt
Journal: Circulation (2012)

Cyclic adenosine monophosphate (cAMP) serves as an intracellular second messenger to transduce the effects of the stimulation of Gs-coupled receptors. Recent studies indicated that cAMP can be extruded by the multidrug resistance associated-protein 4 (MRP4) from many cell types including cardiac myocytes (CM). The present study investigated whether the cAMP extruded from CM acts as a signalling molecule. We employed a fluorescence resonance energy transfer (FRET)-based sensor (Epac2-cAMPs) to directly assay for the formation of cAMP in CM and fibroblasts (CF). We found cAMP to be extruded from neonatal and adult CM upon β-adrenergic receptor (βAR) stimulation (1µM isoproterenol, ISO), an effect that was largely sensitive to MRP inhibition. Extracellular cAMP blocked the βAR-mediated increase in intracellular cAMP in CM. This negative feedback was reversed by a non-specific adenosine receptor antagonist (DPSPX) and an A1 adenosine receptor specific antagonist (DPCPX) but not by an A2 adenosine receptor specific antagonist (ZM-241385) (FRET ratio: 12.6±0.6 after ISO treatment vs. 4.5±0.8 after ISO+ecto-cAMP, 12.6±1.3 after ISO+ecto-cAMP+DPSPX, p&lt;0.001). In contrast, application of extracellular cAMP onto CF induced an increase in intracellular cAMP levels while A2 adenosine receptor specific antagonist blocked this effect (FRET ratio: 8.1±1.1 after ecto-cAMP treatment vs 0.07±0.3 after ecto-cAMP+ZM, p&lt;0.001). To determine if extracellular cAMP released from CM is sufficient to stimulate cAMP formation in CF, we stimulated CF isolated from β1β2-AR-deficient mice with conditioned medium (coM) from ISO or control-treated CM. Exposure of βAR-deficient CF to coM from ISO-treated CMs yielded a significant increase in intracellular cAMP compared to control-coM. DPSPX again markedly attenuated the elevation of cAMP in response to ISO-coM (FRET ratio: control-coM: 3.1±0.6, ISO-coM: 7±1.2, ISO-coM+DPSPX: 2.2±1.3, p&lt;0.05). In conclusion, this study provides evidence that βAR stimulation of CM induces an inside-out signaling through secreted cAMP. cAMP is exported from CM, metabolized to adenosine and in an autocrine and paracrine manner stimulates adenosine receptors on CM (A1 receptors) and CF (A2a,2b receptors).
Abstract 18481: Genetic Polymorphisms Associated with Response to Intraoperative Heparin Anticoagulation and Thrombosis Risk in Pediatric Patients Undergoing Cardiac Surgery
Authors: Cedric Manlhiot, Seema Mital, Colleen E Gruenwald, Leonardo R Brandao, Ashok K Manickaraj, Christopher A Caldarone, Jennifer L Russell, VB Sivarajan, Steven M Schwartz, Helen M Holtby, Brian W McCrindle
Journal: Circulation (2012)

Introduction: Thrombosis is an important and widespread post-operative complication of pediatric cardiac surgery. Prophylaxis intraoperative anticoagulation in this context is obtained by using heparin which requires a bond with antithrombin to achieve anticoagulant effect. We sought to identify SNPs associated with blood antithrombin levels, response to heparin and post-operative thrombosis risk in pediatric patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Methods: A total of 625 cardiac operations with CPB in 383 patients were reviewed. Ninety-six SNPs on 53 genes in the coagulation/fibrinolysis pathways were assayed using the the Illumina GoldenGate custom SNP panel. Genotyping was successful for &gt;99% of SNPs. Regression models adjusted for repeated measures and bootstrap resampling (1,000 samples) were used to offset multiple comparisons bias; SNPs with very low minor allele frequencies were excluded. Results: Average preoperative antithrombin activity was 89±18% (normal 100%, adjusted for age and oxygen saturation) and average response to heparin was 1.0±0.3U/ml/100U/kg (blood heparin concentration achieved per 100U/kg of heparin). Post-operative thrombosis was observed after 86 operations (14%) (within 30 days of surgery, risk-adjusted according to a previously published model of post-operative thrombosis risk). SNPs associated with higher antithrombin levels, lower heparin response and higher postoperative thrombosis are listed in the Table. Conclusions: Polymorphisms in genes in the coagulation and fibrinolytic systems activity were associated with antithrombin levels, response to heparin and risk of post-operative thrombosis. The association of individual SNPs at the laboratory and clinical levels suggest a mechanism for upstream alteration in the coagulation system that is correlated with undesirable clinical outcome and could be the target for genetically tailored clinical interventions.
Abstract 18536: Camkii-δ Splice Variants Exert Differential Effects on Heart Failure Development and Myocardial Ischemia / Reperfusion Injury
Authors: B. Daan Westenbrink, Charlie B Gray, Sunny Xiang, Shika Mishra, Jan Shilling, Hemal Patel, Joan H. Brown
Journal: Circulation (2012)

Background: Ca2+/calmodulin-dependent kinase II-δ (CaMKII-δ) has been implicated in heart failure development and ischemia / reperfusion injury. It has been suggested that the most abundant cardiac isoforms, CaMKII-δb and CaMKII-δc, serve distinct and opposing roles on cardiomyocyte survival. We therefore evaluated their effects on heart failure development and myocardial ischemia reperfusion injury. Methods: Mice with cardiac specific overexpression of the CaMKII-δb or CaMKII-δC, were crossbred with CaMKIIδ knockout (δ-KO) mice to generate mice that exclusively express CaMKII-δb (δb/KO) or CaMKII-δc (δc/KO). Cardiac mRNA profiling, longitudinal cardiac function, survival and the cardiac response to ischemia reperfusion injury were compared. Results: Overexpression of CaMKII-δb and CaMKII-δc in the heart resulted in markedly different mRNA expression profile, with less than 10% overlapping genes. Loss of CaMKII-δb resulted in a more severe heart failure phenotype in δc/KO mice, as evidenced by accelerated development of left ventricular dysfunction and a marked reduction in survival compared to conventional CaMKII-δC transgenic mice. In contrast δb/KO mice only developed mild cardiac hypertrophy after 4 months. When challenged by ex vivo ischemia/reperfusion (I/R), δb/KO mice displayed a 75% reduction in infarct size, significantly greater than the reduction observed in KO mice lacking both splice variants. Conversely infarct formation was markedly increased in δc/KO mice (figure). These findings were recapitulated in functional recovery and LDH release. Studies with adult ventricular myocytes indicated that CaMKII-δb and δc have opposing roles in the response to oxidative stress. Conclusion: CaMKII-delta splice variants play distinct and opposing roles in heart failure and ischemia / reperfusion injury. These opposing effects may need to be considered when developing CaMKII modulating drugs for clinical application application. .
Abstract 18528: Knocking out of E2F4 Aggravates Cardiac Function During Pressure Overload
Authors: Takanubo Yamamoto, Peiyong Zhai, Junichi Sadoshima
Journal: Circulation (2012)

Background: The E2F family constitutes a family of transcription factors involved in the cell cycle. E2F4 is considered to be a repressive E2F due to its lacking the N-terminal domain characteristic of the activating E2Fs, including E2F1, E2F2, and E2F3a. The activating E2Fs are known not only as cell cycle regulators but also as pro-apoptotic factors. Cardiac specific ablation of Rb, a negative regulator of the activating E2Fs, enhances cardiac hypertrophy and failure in response to transverse aortic constriction (TAC). Currently, however, the function of the repressive E2Fs in cardiac hypertrophy and failure is unknown. Methods: To evaluate the role of E2F4 in regulating cardiac hypertrophy and function during pressure overload (PO), E2F4 knockout (E2F4-/-) and wild type (WT) mice were subjected to TAC for 4 weeks. Results: In the sham operation group, there was no significant difference in left ventricular (LV) weight/ tibial length (TL) or ejection fraction (EF) between E2F4-/- and WT (LV weight/ TL: E2F4-/-= 5.5±0.2 mg, WT= 5.7±0.3 mg/mm, n.s.; EF: E2F4-/-= 70.3±3.3%, WT= 71.6±2.9%, n.s.; n=5-8). In the TAC group (4 weeks), there was no significant difference in LV weight/ TL between E2F4-/- and WT (E2F4-/-= 8.6±1.1, WT= 8.9±0.6 mg/mm, n.s.; n=4-7), whereas the EF was significantly lower in E2F4-/- than in WT (E2F4-/-= 48.0±2.9%, WT= 64.6±3.4%, p&lt;0.01; n=4-7). In histological analyses, although the cell size of cardiomyocytes in E2F4-/- was not different from that in WT (E2F4-/-= 690±13 μ m 2 , WT= 637±64 μ m 2 , n.s.; n-3-4), fibrosis and the number of TdT-mediated dUTP nick-end labeling (TUNEL) positive cells were significantly greater in E2F4-/- than in WT (fibrosis: E2F4-/-= 5.2±1.3%, WT= 0.8±0.6%, p&lt;0.05; TUNEL: E2F4-/-= 0.50±0.06%, WT= 0.07±0.03%, p&lt;0.01; n=3-4). RT-PCR showed that mRNA expression of E2F1 and its target genes that are involved in apoptosis were increased in E2F4-/- compared to in WT (E2F1: 2.5-fold, p&lt;0.05; caspase-8: 2.6-fold, p&lt;0.05), indicating upregulation of the pro-apoptotic mechanism in E2F4-/-. Conclusions: These results suggest that E2F4 plays an essential role in maintaining cardiac function during pressure overload by negatively regulating the pro-apoptotic mechanisms and suppressing cardiac fibrosis.
Abstract 18475: Association of Plasma Omega-3 to Omega-6 Polyunsaturated Fatty Acid Ratio with Apical Ballooning Syndrome (Tako-Tsubo cardiomyopathy -TTC)
Authors: Youichi Katoh, Sho Nagamine, Takeshi Wada, Hiroyuki Isogai, Hiroshige Yuu, Dai Ozaki, Ryota Shimai, Miki Yamase, Kenji Yaginuma, Ken Yokoyama, Tetsuya Oigawa, Toshihisa Enjyoji, Yuji Nakazato
Journal: Circulation (2012)

Background: Eicosapentaenoic acid (EPA) of the omega-3 polyunsaturated fatty acids (ω-3 PUFA) family plays important roles in the prevention of cardiovascular disease (CVD), while arachidonic acid (AA) of the ω-6 PUFA family promotes inflammatory and prothrombotic influences. Tako-Tsubo cardiomyopathy (TTC, also reffered as apical balloning syndrome) is a heart syndrome associated with transient myocardial contractile dysfunction. Decreased endothelial function in response to acute mental stress has been reported in patients with a prior episode of TTC. However, the pathogenesis of TTC remains unclear and the relationship between TTC and EPA/AA ratio has not been elucidated. Methods and Results: This study consisted of 10 consecutive patients with clinically diagnosed TTC. The aim of this study was to investigate the association between the plasma EPA/AA ratio and the early stage of clinically diagnosed TTC. To examine the plasma fatty acid level, blood samples were obtained from control, old myocardial infarction, and clinically diagnosed TTC patients. A clinically diagnosed TTC patients revealed a lower plasma EPA/AA ratio [Control patients, 0.58 (n=18) vs Old myocardial infarction patients, 0.38 (n=22) vs TTC patients, 0.15 (n=10), p=0.011]. High-sensitivity CRP levels and a low plasma EPA/AA ratio could independently predict the prevalence of TTC on multivariate logistic regression analysis [odds ratio 1.83 (95%CI 1.03-3.25), p=0.036 and odds ratio 2.05 (95%CI 1.12-3.92), p=0.02)]. Conclusion: In patients with TTC, a low plasma EPA/AA ratio was significantly associated with the early stage of clinically diagnosed TTC. The findings implicate lower EPA/AA ratio and the following endothelial dysfunction as a potential mechanism involved in the pathogenesis of this unique cardiomyopathy.
Abstract 18448: Partial Blockade of Inwardly Rectifying K <sup>+</sup> Current Enhances Electrotonic Interactions and Destabilizes Spiral Wave Reentry
Authors: Yasunori Kushiyama, Haruo Honjo, Ryoko Niwa, Hiroki Takanari, Masatoshi Yamazaki, Yoshio Takemoto, Ichiro Sakuma, Itsuo Kodama, Kaichiro Kamiya
Journal: Circulation (2012)

Introduction: Spiral wave (SW) reentry is a principal mechanism for the maintenance of tachyarrhythmias, such as ventricular tachycardia/fibrillation (VT/VF). We have recently reported that partial blockade of the inward rectifier K + current (I K1 ) destabilizes the rotation center of SWs without enhancement of wavefront-tail interaction in the arm, in favor of their termination (ESC 2012), but underling mechanisms remain to be clarified. We hypothesized that alteration in electrotonic influence due to decreased membrane conductance plays a role in destabilization of the SW rotation center. Methods: A 2-dimensional ventricular muscle layer was prepared in Langendorff-perfused rabbit hearts, and optical action potential signals were recorded from the epicardial surface of the left ventricle. The dynamics of SW reentry were analyzed during VT induced by modified cross-field stimulation. The space constant ( λ ) was estimated by a decay of electrotonic depolarization induced by injection of subthreshold cathodal current. Results: Partial blockade of I K1 by 50 µM Ba 2+ significantly increased theλ: e.g., the value in a direction across the fiber orientation (λ T ) increased from 0.82±0.19 mm in control to 1.27±0.33 mm after 50 µM Ba 2+ (n=5, P&lt;0.05, Figure A). SW reentry under control condition rotated around a short line of block (FBL, 4.2±1.4 mm, n=12). In contrast, SW reentry induced after 50 µM Ba 2+ was destabilized: the FBL was significantly prolonged (11.7±3.2 mm, n=12, P&lt;0.05) and, in 6/12 hearts, showed a prominent change in its shape with a cycle of a few rotations, resulting from intermittent conduction block near the rotation center (Figure B). Conclusions: These results suggest that partial I K1 blockade enhances electrotonic interactions, which could contribute to destabilization of SW reentry.
Abstract 18488: The Impact of Mechanical Circulatory Support Type for Bridge-to-Transplantation on Post-transplant Prognosis: An Analysis of the United Network for Organ Sharing (UNOS)
Authors: Shuichi Kitada, P. Christian Schulze, Jonathan A Yang, Hiroo Takayama, Yoshifumi Naka, Donna M Mancini, Tomoko S Kato
Journal: Circulation (2012)

Purpose Mechanical circulatory support through left ventricular assist devices (LVAD) and extracorporeal membrane oxygenators (ECMO) is a reliable and useful support for bridge-to-transplantation (BTT) therapy. The purpose of this study was to investigate the impact of mechanical circulatory support on post-transplant prognosis and its changes during recent years. Methods The United Network for Organ Sharing (UNOS) database was used to identify adults patients (≥18 yrs) undergoing orthotopic heart transplantation (OHT) from 1987 to 2010. The cohort was separated into 5 groups according to the era of OHT: before '91, '92 to '96, '97 to '01, '02 to '06, and after '07. We compared two-year post-OHT survival of patients initially supported by an LVAD only and those with biventricular mechanical circulatory support at the time of OHT. Patients who required the additional use of ECMO during LVAD support and those with urgent assist device placement for right and left ventricule were considered as biventricular support group. Results A total of 17257 patients underwent OHT under mechanical circulatory support. Post-transplant mortality of patients with biventricular support was worse compared to patients with LVAD support alone after 1997 (Biventricular vs. LVAD alone, ’97-‘01, 56.3 vs. 77.0%, p=0.014; ’02-’06, 58.6% vs. 83.7%, p&lt;0.001; ’07- 60.9% vs. 87.7%, p&lt;0.001, respectively). Comparison among 5 groups by time period showed that post-transplant mortality of patients with LVAD support showed significant improvement after 1997. The mortality of patients with biventricular support, however, showed no improvement over time (Figure). Conclusion Post-transplant mortality in patients with LVAD BTT support improved significantly during the recent era of OHT. Patients undergoing biventricular support prior to OHT, especially those with hemodynamic instability requiring urgent ECMO placement on top of LVAD support remain to have poor outcome in any era of OHT.