tbuckley/cabot-search huggingface dataset:
Abstract 19641: Kv 4.3 Expression Improves Cardiac Function in Heart Failure Mice
Authors: Arnaud Guilbert, Jun Cheng, Yanggan Wang
Journal: Circulation (2012)

Background: It is known that CaMKII inhibition improves contractility in failing ventricle. However, we reported that drug and genetic CaMKII inhibition deteriorates diastolic function. We recently uncovered a mechanism that I to channel Kv 4.3 inhibits CaMKII activation by directly binding to the CaM binding sites. Unfortunately, this endogenous CaMKII inhibitor is down-regulated in heart failure (HF). Objective: We have tested whether Kv4.3 expression in HF ventricular myocytes can improve contractility without impairment of diastolic function. Methods: HF was induced in mice by severe aortic thoracic banding (sTAB). Kv4.3 was transfected in HF mouse left ventricle (LV) by myocardium Ad-Kv4.3 injection in the week two after sTAB. Heart function was assessed by echocardiography at the day before (day 0) and day 7 after adenovirus injection, respectively, while sarcoplasmic reticulum (SR) Ca 2+ leak, Ca 2+ transient and sarcomere shortening and relaxation were recorded in HF ventricular myocytes with Kv4.3 transfection. Results: HF was produced in one week after sTAB and heart function then remains stable from the post-sTAB week 2 to 5. Compared to the HF mice transfected with Ad-β-gal (control), LV myocytes transfected with Ad-Kv 4.3 showed a reduction of overall CaMKII activity by 10 ± 0.5 % with a reduction of CaMKII-dependent phosphorylation of PLB-Thr17 (13 ± 1.3 %) and RyR-2815 (10 ± 1.2 %), indicating only the localized CaMKII inhibition in the SR microdomain, consistent with the membrane distribution of Kv4.3. Kv4.3 transfection in HF mice produced a significant increase in systolic function (increased EF) and improvement of diastolic function (reduced E/E’). LV myocytes transfected with Kv4.3 showed a significant reduction of SR Ca 2+ leak, an increase in Ca 2+ transient and sarcomere shortening. Importantly, unlike drug inhibition, Kv4.3 transfected HF myocytes showed unchanged sarcomere relaxation, FDAR, and myofilament sensitivity to Ca 2+ . This is associated with an unchanged CaMKII-dependent troponin-I phosphorylation. Conclusion: Our results suggest that Kv4.3 expression (restoration) in failing ventricle can improve contractility without deterioration of relaxation, likely via inhibition of the compartmentalized CaMKII.
Abstract 19352: Obstructive Sleep Apnea Impairs the Time Delay of the Baroreflex Control and the Oscilattory Pattern of the Sympathetic Activity in Patients with Metabolic Syndrome
Authors: Edgar Toschi-Dias, Ivani C Trombetta, Valdo J Dias da Silva, Cristiane Maki-Nunes, Felipe X Cepeda, Maria Janieire N Alves, Luciano F Drager, Geraldo Lorenzi-Filho, Carlos E Negrão, Maria Urbana P Rondon
Journal: Circulation (2012)

Background: Incidence and oscillatory pattern of muscle sympathetic nerve activity (MSNA) depends on the magnitude (sensitivity) and time delay of the arterial baroreflex. In metabolic syndrome (MetS), the obstructive sleep apnea (OSA) exacerbates the MSNA and baroreflex control of heart rate. Unknown is the impact of MetS and OSA on oscillatory pattern of MSNA and time delay of the baroreflex control of MSNA in MetS patients. We tested the hypotheses that: 1) MetS would impair these autonomic functions; 2) OSA would impair even further these autonomic functions. Methods and Results: Thirty-nine never-treated MetS patients (ATP III) were allocated in two groups according to the presence of OSA (MetS+OSA, n=17 and MetS-OSA, n=22). Twelve aged-paired healthy subjects were enrolled in the study as control group (C). OSA (apnea-hypopnea index&gt;15 events/hour) was determined during a polysomnography. We recorded MSNA (microneurography), blood pressure (beat-to-beat basis) and HR (ECG), during 10 min. Oscillatory patterns of MSNA, HR and systolic arterial pressure were evaluated by autoregressive spectral analysis. The baroreflex control of MSNA (gain and time delay), were evaluated by bivariate autoregressive analysis. Patients with MetS+OSA had increased high frequency band of MSNA (HF MSNA , 60±3 vs. 49±2 and 37±2 n.u., P&lt;0.001) and decreased low frequency band of MSNA (LF MSNA , 40±3 vs. 51±2 and 63±2 nu, P&lt;0.001) compared to MetS-OSA and C. The gain of the baroreflex control of MSNA was lower in MetS+OSA compared MetS-OSA and C (13±1 vs. 30±3 and 43±3 a.u./mmHg, P&lt;0.001). The time delay of the baroreflex control of MSNA was augmented in MetS+OSA compared to MetS-OSA and C (6±0.3 vs. 4±0.3 and 3±0.2 s, P&lt;0.001). MetS-OSA patients showed increased HF MSNA (P&lt;0.001) and decreased LF MSNA (P&lt;0.001) compared with C. And, the gain of the baroreflex control of MSNA was lower in MetS-OSA than in C groups (P&lt;0.001). Conclusions: MetS reduces the oscillatory pattern of MSNA and the gain of the baroreflex control of MSNA. OSA exacerbates these dysfunctions and further increases the time delay of the baroreflex control of MSNA in these patients. These central autonomic dysregulation of sympathetic modulation may have important clinical implications in patients with MetS+OSA.
Abstract 9070: Secretoneurin is Produced in the Ischemic Border Zone of Animals with Myocardial Infarction and Heart Failure, Attenuates Ischemic Injury, and is Associated with the Progression of Heart Failure in Patients
Authors: Helge Røsjø, Mats Stridsberg, Geir Florholmen, Kåre-Olav Stensløkken, Anett H Ottesen, Ivar Sjaastad, Cathrine Husberg, Mai Britt Dahl, Arne D Høiseth, Erik Øie, William E Louch, Torbjørn Omland, Geir Christensen
Journal: Circulation (2011)

Background: Secretoneurin (SN) is a peptide belonging to the granin protein family. As two other granin proteins, chromogranin A and B, are increased in cardiac tissue in heart failure (HF), we hypothesized that SN could play a role in cardiovascular pathophysiology. Methods: Production and functional aspects of SN were assessed in experimental models and circulating levels measured in two cohorts of HF patients. Results: Pro-SN mRNA levels were 11.5 fold increased in viable left ventricular (LV) tissue of mice subjected to coronary artery ligation and with echocardiographical confirmed HF. Protein levels were also increased in the LV of HF animals vs. sham-operated animals, including in the ischemic border zone where we observed increased processing from pro-SN to shorter SN fragments (&gt;100% increase, p=0.001). Immunohistochemistry localized myocardial SN production to cardiomyocytes. We did not observe increased SN production in other organs than the LV. Perfusing isolated cardiomyocytes with SN rapidly induced Stat3 and Erk1/2 phosphorylation, protected from hydrogen peroxide-induced cardiomyocyte apoptosis in vitro , and reduced ischemia-reperfusion injury by 30% (p&lt;0.05) in the isolated perfused rat heart. Circulating levels of SN were increased in patients with stable and acute HF compared to control subjects and increased in proportion to HF severity as evaluated by NYHA functional class (p=0.04 for trend). In 68 patients hospitalized for acute HF, admission SN levels provided excellent discrimination for all-cause mortality (n=17) during a median follow-up of 373 days: Hazard ratio [per 0.05 nmol/L increase of SN] 2.34 (95% CI 1.63-3.38), p&lt;0.001. Adjustment for established clinical risk factors including comorbidities, renal function, and LV ejection fraction in multivariate analysis did not attenuate the association between SN levels and mortality: HR 2.43 (95% CI 1.63-3.61), p&lt;0.001. Conclusion: SN production is increased in viable cardiomyocytes adjacent to the infarcted area in animals with myocardial infarction and HF, which could be beneficial as SN protects from myocardial ischemia. Based on our results, SN could represent a protective feedback response that is activated in proportion to the severity of HF.
Abstract 19457: Succesfull Heart Transplantation after Twelve Hours of Cold Ischemic Storage in the Novel Organ Preservation Solution, Custodiol-N
Authors: Gábor SzabÓ, Tamás Radovits, Gábor Veres, Bastian Schmack, Alexander Weymann, Sevil Korkmaz, Matthias Karck, Ferenc Horkay, Béla Merkely, Istvan Hartyanszky
Journal: Circulation (2012)

Objective: We currently developed a novel HTK based solution Custodiol-N which includes iron chelators to reduce oxidative injury and amino acids, in particular L-arginine, to improve endothelial function. We investigated the effects of Custodiol-N, on ischemia/reperfusion injury in a canine orthotopic heart transplant model. Methods: After 4, 8, and 12 hours of ischemic preservation, 36 orthotopic heart transplantations were performed. The hearts were preserved with either HTK (Custudiol, control) or Custodiol-N solution. The slope of the left ventricular pressure-volume relationships (Ees) was calculated before explantation and after 120 minutes of reperfusion. Coronary blood flow (CBF), endothelium-dependent vasodilatation to acetylcholine (ACH) and endothelium-independent vasodilatation to sodium nitroprusside (SNP) were also determined. Results: Custodiol-N led to significantly better recovery of Ees (91±5 vs. 49±8%, p&lt;0.05). CBF was significantly higher in the Custodiol-N group (53±5 vs. 27±4, ml/min, p&lt;0.05). While the vasodilatatory response to SNP was similar in both groups, ACH resulted in a significantly higher increase in CBF in the Custodiol-N group (72±8% vs. 29±7%, p&lt;0.05). While none of the control animals could wean from cardiopulmonary bypass after 8 and 12 hours of ischemic preservation, all the animals could successfully weaned both after 8 and 12 hours in the Custodiol-N group. The recovery of Ees was 88±6% and 92±8%, respectively which did not differ significantly from baseline values. Conclusions: The novel organ preservation solution, Custodiol-N, reduces myocardial and endothelial reperfusion injury after orthotopic heart transplantation and successfully extends the safe hypothermic ischemic cardiac preservation times up to 12 hours.
Abstract 19694: <i>Etv2-</i> Regulated Micrornas are Essential for Endothelial Development
Authors: Bhairab N Singh
Journal: Circulation (2012)

Precise regulation of the fate of endothelial precursors is critical for vascular development. Currently, no known microRNAs have been shown to have a functional role in the specification of the endothelial progenitor cell fate during early embryogenesis. To decipher the requirement of miRNAs during endothelial and vascular development, we disrupted Dicer in a tissue-specific manner, utilizing the Etv2 -Cre transgenic mouse model that we engineered to ablate microRNA biogenesis in endothelial progenitors. Using this strategy, we determined that miRNA biogenesis is essential for vasculogenesis as Etv2-Cre:Dicer F/F embryos are lethal by E11.5-12.5. Histological analysis reveals that the Dicer conditional knockout embryos have severe vascular defects and hemorrhage compared to the wildtype littermates. We have previously reported enrichment of a Pdgfr-α + cell population in the Etv2 mutant embryos, however the mechanism is unclear. In the present study, we have identified miR-27a and miR-130a as Etv2 downstream target genes. Using transcriptional assays, we observed that Etv2 transactivated both miR-27a and miR-130a in a dose-dependent manner. Further, we have identified and mapped the miR-27a and miR130a binding sites on the Pdgfr- α 3’-UTR. Our transcriptional assays indicate that miR-27a and miR-130a attenuate the expression of Pdgfr- α. Collectively, these findings identify novel microRNA-mediated mechanisms that govern lineage decisions of mesodermal progenitors and ultimately impact cardiovascular development.
Abstract 19347: The Mouse Mast Cell Protease 4 is Involved in the Generation of Endothelin-1 in vitro and in vivo
Authors: Martin Houde, Julie Labonté, Louisane Desbiens, Marc Jamain, Gunnar Pejler, Michael Gurish, Shinji Takai, Pedro D'Orléans-Juste
Journal: Circulation (2012)

The serine protease chymase converts intravenously (iv)- administered big-endothelin-1 to endothelin-1 (ET-1) in the mouse in vivo. The mouse mast cell protease 4 (mMCP-4) is among eight chymase-like murine isoforms and is involved in the generation of angiotensin-II (Ang-II) from its precursor Ang-I. It remains to be determined which chymase isoform is involved in the endothelin-converting enzyme -independent production of ET-1. In the present study, the contribution of mMCP-4 was determined in the conversion of exogenous Big-ET-1 in vitro and in vivo as well as in the tissue production of endogenous ET-1. In vitro analyses were performed from cardiac left ventricle, aorta, kidneys and lungs homogenates derived from wild type (WT) and mMCP-4 KO mice. The pressor response in anaesthetized mice to Big-ET-1, but not ET-1 (1-31) or ET-1 was significantly reduced in mMCP-4 KO mice compared to their WT congeners. Furthermore, a selective chymase inhibitor, TY-51469, significantly reduced the pressor response to Big-ET-1 in WT but not mMCP-4 KO mice. Radio-telemetry analysis in free-moving, conscious mice revealed no differences in basal blood pressure between WT and mMCP-4 KO mice. TY-51469 also inhibited the in vitro hydrolysis a chymotrypsin-sensitive fluorogenic peptide in soluble fractions derived from WT but not mMCP-4 KO tissues. HPLC-MALDI-MS analysis revealed that supernatants from WT but not mMCP-4 KO mice could yield ET-1 (1-31) from Big-ET-1 in vitro, and that this conversion is blocked by TY-51469 in WT samples. The in vivo conversion of iv-administered Big-ET-1 to plasmatic ET-1 (1-31) and ET-1 was also reduced in mMCP-4 KO mice compared to their WT congeners. Finally, tissue levels of immunoreactive ET-1 were reduced by 40% in lung homogenates from mMCP-4 KO mice when compared to those from WT congeners. We conclude that mMCP-4 is the predominantly involved chymase isoform in the production of endogenous ET-1 in the mouse model.
Abstract 19638: Watchman Left Atrial Appendage Closure in Atrial Fibrillation Patients with Contraindication to Oral Anticoagulation: The ‰ASA Plavix Registry” (ASAP)
Authors: Vivek Reddy, Peter Neuzil, Marc Miller, Gerard Schuler, Sven Möbius-Winkler, Jens Wiebe, Nina Wunderlich, Peter Sick, Horst Sievert
Journal: Circulation (2012)

Background: AF patients at the highest risk for embolic stroke also experience the greatest risk of hemorrhagic complications of anticoagulant use. The PROTECT AF trial revealed that LAA closure using the Watchman device was non-inferior to Warfarin for preventing stroke in AF pts with CHADS 2 ≥ 1. However, these pts were treated with Warfarin post-implant until a TEE demonstrated LAA closure at 6 wks. Due to the pressing need for strategies that can prevent stroke in pts with contraindications to Warfarin, we performed a prospective study of Watchman implantation in Warfarin-contraindicated pts. Methods: Prospective registry of pts with non-valvular AF, a CHADS 2 score ≥1, and a contraindication to Warfarin use. The Watchman device was implanted in standard fashion. Post-implant, patients were discharged on 6 mo of clopidogrel and life-long aspirin. Follow-up TEE was performed at 3/12 months. Results: At 4 centers, 150 pts were enrolled. The mean age was 72.5 ± 7.4 yrs. The prevalence of stroke risk factors was: CHF in 29%, HTN in 95%, Age ≥ 75 in 43%, DM in 32%, and stroke/TIA in 41%. The mean CHADS 2 score was 2.8 ± 1.2. The reason for Warfarin contraindication was: hemorrhagic tendencies (26%), blood dyscrasias (7%), bleeding tendencies (67%), unsupervised pts with senility/high fall risk (4%), and other (5%). Watchman implantation was successful in 95% (142/150). At 14.2 ± 8.7 mo of follow-up, there were 4 strokes (3 ischemic) and 6 instances of device-related thrombus by TEE. The observed rate of ischemic stroke 1.7% represents 77% fewer events from that expected in pts with a similar CHADS2 score treated with aspirin alone (7.3%; Figure). Data from additional follow-up (to a total of &gt;250 pt-yrs) will be available. Conclusion: Watchman implantation without a Warfarin transition is safe and effective in AF pts with contraindications to even short-term oral anticoagulation
Abstract 19310: High Frequency QRS Analysis has Incremental Diagnostic Accuracy Over ST-Segment Analysis Alone for Ischemia Identification in Patients Referred for Exercise Myocardial Perfusion Imaging
Authors: Margarita Perez, Valerie Izarnotegui, Denny Watson, Michael Sobczak, George Beller, Jamieson Bourque
Journal: Circulation (2012)

Introduction: Myocardial perfusion imaging (MPI) to identify ischemia is expensive, but existing electrocardiographic techniques have poor sensitivity. A novel method of high-frequency QRS analysis (HF-QRS) may improve ischemia detection. We sought to compare HF-QRS to standard ST-segment analysis for the identification of any and significant (≥10%) left ventricular (LV) ischemia by exercise SPECT MPI. Methods: We analyzed 292 consecutive patients. HF-QRS was determined within a bandwidth of 150 -250 Hz. A 50% relative reduction and ≥1 µV drop in the HF-QRS signal in ≥3 leads and ≥1mm ST-depression were the criteria for positivity for HF-QRS and ST-analysis, respectively. Quantitative, gated-SPECT MPI was performed according to standard protocols. Sensitivities and specificities and incremental diagnostic accuracy were assessed using chi-square and logistic regression analyses. Results: The mean cohort age was 59.6 years and 64.7 were male. Twenty nine percent had known coronary artery disease. LV ischemia was present in 54 patients (18.4%) and significant (≥10%) LV ischemia in 17 (5.8%). ST-analysis and HF-QRS analyses were positive in 42 (14.4%) and 70 (23.9%) respectively. As shown in the figure, ST-analysis had poor sensitivity for any ischemia that improved but remained low for ≥10% LV ischemia. HF-QRS had substantially higher sensitivities for both any and ≥10% LV ischemia. The 84.9% specificity of HF-QRS analysis for any ischemia was similar to the 86.6% specificity of ST-analysis. ST depression failed to add incremental diagnostic information to clinical risk factors (p=0.519), while HF-QRS increased the model Χ2 from 39.3 to 54.2 (p&lt;0.001). Conclusions: High-frequency QRS analysis substantially improves the detection of any and significant ischemia over ST-segment analysis alone in patients undergoing exercise stress. This novel method has the potential to decrease the high rate of MPI for CAD risk stratification.
Abstract 19381: Imatinib Mesylate Modifies Induced Pathological Hypertrophy by Altering Myocyte Calcium
Authors: Larry Barr, Haji Kubo, Hui Gao, Catherine Makarewich, Remus Berretta, Thomas Force, Steven R Houser
Journal: Circulation (2012)

Background — Imatinib mesylate (IM) is a small molecule inhibitor of the fusion protein Bcr-Abl, which causes chronic myelogenous leukemia. There is some concern that IM can induce cardiac dysfunction in cancer patients. A previous study showed that chronic treatment of adult mice with IM for 3-4 weeks leads to deterioration in contractile function and LV mass decrease. We investigated the effects of IM on neonatal rat ventricular myocytes (NRVMs). The hypothesis is that calcium regulatory mechanisms are altered to induce pathological hypertrophy. Methods and Results — NRVMs were treated with a clinical dosage (2 µM) of IM. Western analysis showed a significant increase in phospholamban phosphorylation at T-17, signifying activation of CaMKII. The rate of decay of the systolic Ca 2+ transient was increased, consistent with an increase in rate of Ca 2+ resequestration into the SR. Coulter counter analysis was used to determine cell size and showed that average NRVM volume increased significantly (Con-102 pl; IM-133 pl. p&lt;0.05). Myocyte surface area also increased with IM treatment (Con-6277 μm 2 ; imatinib-10259 μm 2 p&lt;0.05). Western analysis showed significant increases in ANP abundance, a pathological hypertrophy marker, after IM administration. NRVMs were infected with AdNFATc3-GFP and NFAT nuclear translocation was analyzed as nuclear/cytoplasmic GFP. Nuclear translocation was significantly increased with IM treatment. The calcineurin inhibitor FK506 inhibited IM induced NFAT nuclear translocation (Con-0.8162 ± 0.032; imatinib-2.233 ± 0.13; imatinib+FK506-0.6277 ± 0.037. p&lt;0.05). Conclusions — These data show that clinical doses of IM activate pathological hypertrophy signaling pathways by enhancing SR function. This could be a mechanism for adverse cardiac effects of IM.
Abstract 19461: Endogenous Protein Kinase Inhibitor Peptide (pki) Regulates β-Adrenergic Responses of the Heart
Authors: Ying Li, Xioaying Zhang, Xiajie Ai, Christopher Szeto, Xiongwen Chen
Journal: Circulation (2012)

Introduction: Protein kinase inhibitor peptide (PKI) isoforms are endogenous inhibitors of PKA and existing in the heart. The physiological relevance of PKI has not been studied. Aims: We will determine the role of PKIα (one of the major PKI isoforms in the heart) in β-adrenergic regulation of the heart with PKIα knockout (KO) versus c57bl/6 control (CTR) mice. Methods: In vivo cardiac function was evaluated by conventional echocardiography (ECHO) in PKIα KO mice. In vivo cardiac β-adrenergic response was determined by intra-LV hemodynamic measurements in response to different doses of isoproterenol (10-16g/g BW∼10-5g/g BW). Isolated ventricular myocytes were used to determine cellular responses to β-adrenergic agonist, isoproterenol (ISO, 1nM, 10nM and 100nM). Western blotting was used to determine phosphorylation levels of PKA-targets in the heart. Results: (1) The loss of PKI did not change basal cardiac morphology, function and life span of mice; (2) ISO (2μ g/g BW) enhanced cardiac function more in KO mice than in CTR mice when evaluated by ECHO and intra-LV hemodynamic measurements; (3) The loss of PKIα sensitizes the heart in response to ISO (Log[EC50] shifted from -9.2 to -10.8) and the maximum dp/dt increases more (by 25%) in KO mice than in CTR mcie; (4) PKIa KO myocytes were more sensitive to ISO in that 10nM ISO increased myocyte contraction and Ca2+ transient amplitudes more in KO myocytes; (5). At the ISO concentration of 10-9M, ISO increased more phosphorylation of the Ser16 site (PKA site) on phospholamban. Conclusion: PKI plays an important role in regulating cardiac β-adrenergic responses by antagonizing PKA.