tbuckley/cabot-search huggingface dataset:
Abstract 19722: Cardiac Deletion of miRNA-17-92 Cluster Augments Acute Myocardial Ischemia-Reperfusion Injury
Authors: Mi Zhou, Lijuan Chen, Qiang Zhao, Yingjie Wang, Ming Jiang, Yaohua Pan, Muhammad Ashraf, Neal Weintraub, Jack Rubinstein, Yaoliang Tang
Journal: Circulation (2012)

Objective: MicroRNAs (miRNA) are small, endogenous, conserved, noncoding RNAs that down-regulate protein production by translational repression. The miR-17-92 cluster (encoding miR-17, -18a, -19a/b, -20a, and miR-92a) is highly expressed in stem cells and is up-regulated by ischemia, but little is known about the postnatal role of miR-17-92 in myocardial ischemia-reperfusion injury (I/R). Methods and Results: We established a transgenic mouse model with cardiac-specific deletion of miR-17-92 by crossing miR-17-92 flox/flox (F/F) mice with myh6-MerCreMer (MCM) via tamoxifen dependent Cre-loxP mediated DNA recombination. Two weeks after tamoxifen induced miRNA-17-92 inactivation, no significant differences in histology were observed between tamoxifen and corn oil treated animals despite downregulation of miR-17, -18a, -19a/b, -20a, and miR-92a in the heart. However, in response to 45min ischemia by LAD ligation followed by 24hrs reperfusion in vivo, cardiac miR-17-92 knockout resulted in increased I/R injury, and TTC and phthalocyanine blue staining revealed significantly larger infarct size as compared with control (63.6%±3.9%, n=10 vs. 41.0%±3.1%, n=7, P&lt;0.05). Consistent with increased infarct size, cardiac miR-17-92 inactivation led to increased cardiomyocyte apoptosis after I/R injury, as identified by TUNEL staining. Furthermore, PTEN levels were increased while Phospho-Akt levels were significantly decreased in miR-17-92 inactivated hearts. Conclusions: We conclude that cardiac deletion of miR-17-92 augments the ischemia-reperfusion injury by inhibiting survival signaling. .
Abstract 18985: K-Ras Activates Mammalian Hippo Signaling to Promote Ischemia/Reperfusion Injury in the Heart
Authors: Dominic P Del Re, Takahisa Matsuda, Peiyong Zhai, Junichi Sadoshima
Journal: Circulation (2012)

Acute myocardial ischemia and reperfusion (I/R) cause damage to the heart, thereby impairing its ability to function effectively. Therapies aimed at preventing I/R injury are limited and a better understanding of the mechanisms involved remains critical. In hearts of mice subjected to I/R we found differing kinetics of H- and K-Ras activation, and only K-Ras modification following oxidative stress was observed. Expression of active H-Ras12V caused increased phosphorylation of AKT (1.8±0.3-fold vs LacZ) and ERK1/2 (3.3±0.3-fold vs LacZ) and protected cardiomyocytes against apoptosis, whereas K-Ras12V activated mammalian sterile 20-like kinase 1 (Mst1)(2.1±0.1-fold vs LacZ), which led to myocyte death. Endogenous K-Ras, but not H-Ras, was detected at mitochondria and associated with Ras association domain family 1 isoform A (RASSF1A) in both cardiomyocytes and mouse hearts. Genetic disruption of RASSF1A prevented K-Ras-induced Mst1 activation and inhibited Mst1 translocation to mitochondria in response to oxidative stress. Mass spectrometry analysis revealed that active Mst1 phosphorylates Bcl-xL at Ser14, a previously unreported residue, in cardiomyocytes and mouse heart, and mediates Bcl-xL phosphorylation in response to I/R in vivo. Ser14 phosphorylation attenuated Bcl-xL-Bax binding and the phosphomimetic Bcl-xL S14D mutant showed a weakened protective capacity against apoptotic insult (cell viability; LacZ + H2O2 45±5%, XL WT + H2O2 76±4%, XL SD + H2O2 51±5%, p&lt;0.05). Following in vivo I/R, Kras+/- mice had significantly smaller myocardial infarct size vs WT mice (22±4% vs 39±2%, p&lt;0.05), while no significant difference in infarct size was observed in Hras+/- mice (37±3% vs 38±3%). Conversely, cardiac-specific K-Ras12V TG mice had increased Mst1 activation and significantly larger infarcts vs NTG mice (67±10% vs 36±2%, p&lt;0.05). This myocardial damage was rescued in bigenic mice expressing both K-Ras12V and Dn-Mst1 (41±7%, p&lt;0.05), implicating Mst1 as a critical mediator of K-Ras in vivo. Our work demonstrates a distinct role for K-Ras as an endogenous promoter of mammalian Hippo signaling, and identifies a novel mechanism involving phosphorylation of Bcl-xL by which Mst1 mediates cardiomyocyte apoptosis and I/R injury in the heart.
Abstract 19809: Intrinsic Right Ventricle Dysfunction is a Major Cause of Post LVAD Mortality
Authors: Lin Wang, Mark Zucker, Marc Cohen, Michael Amponsah, David Baran, Margarita Camacho, Chunguang Chen
Journal: Circulation (2012)

Background: Right ventricular (RV) dysfunction after left ventricular assistant device (LVAD) confers significant challenges for post-device managements and increases mortality. The purpose of this study was to test the hypothesis that intrinsic RV myocardial dysfunction measured by 2-D echocardiography speckle tracking imaging prior to LVAD implantation is the most common cause of post-LVAD failure. Methods: Thirty-nine patients who underwent Heartmate II LVAD placement from 2010 to 2011, and 10 age-matched controls were studied. Pre- and post-operative clinical, and echocardiographic data were prospectively collected for LVAD database. RV longitudinal myocardial velocity, strain, and strain rate were measured retrospectively using an off-line speckle-tracking analysis software. Results: Of the 39 LVAD recipients, 24 patients developed acute RV failure immediately post LVAD implantation, among which 13 patients recovered from RV dysfunction after LVAD adjustment and medical management, while 11 patients with intrinsic RV dysfunction as identified by significantly lower global RV peak myocardial velocity, strain, and strain rate prior to LVAD (p&lt;0.05), eventually required RVAD and/or death despite optimal medical therapy. Intrinsic RV myocardial dysfunction often cannot be completely improved by LVAD implantation alone and may be exaggerated by septal shifting caused by emptying or decompressing LV, thus, worsening severe or deteriorating RV dysfunction which eventually requires RVAD or leads to death. Eight of 11 patients including all 7 RVAD patients died within 6 months from LVAD implantation had a peak longitudinal systolic RV global strain of -3% or lower (absolute value). Twenty-four of 27 (88%) patients with the global RV strain higher than -3% (absolute value) survived without RVAD (p&lt;0.05). Conclusions: Poor intrinsic RV myocardial function is often worsened in LVAD patients and is a leading cause for a high LVAD mortality.
Abstract 19780: Mammalian Cardiac Renewal by Preexisting Cardiomyocytes
Authors: Samuel E Senyo, Matthew L Steinhauser, Christie L Pizzimenti, Vicky K Yang, Mei Wang, Lei Cai, Ting-Di Wu, Jean-Luc Guerquin-Kern, Claude P Lechene, Richard T Lee
Journal: Circulation (2012)

Although recent studies have revealed that adult heart cells are generated after birth in mammals, the frequency and source of these new heart cells is unclear. Here we combined two different pulse-chase approaches--genetic fate-mapping and stable isotope labeling with Multi-isotope Imaging Mass Spectrometry (MIMS)--to determine the origin of cardiomyocytes in adult mice. MIMS allows quantitative imaging of stable isotope reporters in domains smaller than a micron cubed. The nuclear incorporation of a 15N stable isotope-enriched tracer here as 15N-thymidine is detectable with high precision by an increase in the 15N/14N ratio above natural abundance (0.37%) in a pattern resembling chromatin evident in cells having divided during a labeling period. We administered 15N-thymidine for 8 weeks to three age groups of C57BL6 mice starting at day-4 (neonate), at 10-weeks (young adult) and at 22-months (old adult) and extrapolated DNA synthesis yields a yearly rate of 5.5% in the young adult that declines further to 2.6% in advanced aged mice. Fig1a. To evaluate the origin of newly generated cardiomyocytes, we performed 15N-thymidine labeling of double-transgenic MerCreMer/ZEG mice, which we previously developed for genetic lineage mapping. Fig1b. After treatment with 4OH-tamoxifen, we show that DNA synthesis occurs at a low rate in predominantly pre-existing cardiomyocytes [77% expressed GFP, a frequency essentially identical to that of surrounding 15N- cardiomyocytes (15N, 77% vs 15N-, 84%; Fisher’s exact=n.s.)]. Fig1c. Cell cycle activity in cardiomyocytes led to polyploidy and multinucleation, and to new diploid, mononucleated cardiomyocytes [17% of total; predominantly GFP+ (83% vs 82%, p=n.s.)]. Fig1d. Our results support a low rate of cell division of cardiomyocytes as the origin of mammalian adult cardiogenesis and are inconsistent with a high rate of stem cell activity in the normal mammalian myocardium.
Abstract 19423: Co-Transplantation of iPS Cell-Derived Cardiomyocytes and Mesenchymal Stem Cells for the Regeneration of Infarcted Myocardium
Authors: Klaus Neef, Florian Drey, Vera Lenerz, Azra Fatima, Christof Stamm, Oliver J Liakopoulos, Thorsten Wahlers, Tomo Saric, Yeong-Hoon Choi
Journal: Circulation (2012)

Introduction: In this study the regenerative potential of co-transplantation of cardiomyocytes derived from induced pluripotent stem cells (iPS-CM) and mesenchymal stem cells (MSC) was assessed in a mouse model of myocardial infarction. Methods: After induction of myocardial infarction in CL57BL/6 mice, either iPS-CM expressing EGFP and luciferase, or magnetically labeled MSC, or a combination of both or saline were transplanted intramyocardially. Cell retention of iPS-CM by in vivo bioluminscent imaging (BLI), and magnetically labeled MSC by MRI was performed sequentially over four weeks. MRI was also used for the assessment of left ventricular ejection fraction (LVEF) at weekly intervals. Hearts explanted 1, 2 and 4 weeks after transplantation were analyzed histologically to locate and quantify transplanted cells, evaluate infarction size and structural integration of iPS-CM. Results: Transplanted cells were tracked over the course of four weeks by BLI for iPS-CM showing a 80% decrease in luminiscence intensity and no loss of signal for MSC by MRI. LVEF increased significantly in the iPS-CM/MSC (55.7±2.3%) compared to MSC (47.6±1.9%; p&lt;0.001) and sham (44.2±2.6%; p&lt;0.001) groups at 4 weeks after transplantation. Infarct size was significantly decreased in iPS-CM/MSC (2.1±0.8 mm2) compared to MSC (5.0±1.9 mm2; p&lt;0.02) and sham (8.4±3.4 mm2; p&lt;0.01). Immunohistochemical analyses for α-actinin and connexin 43 revealed functional integration and structural maturation of iPS-CM. Conclusion: The synergistic effects of co- transplanted iPS cell-derived cardiomyocytes and MSC resulted in functional integration and structural maturation of iPS-CM and, in turn, improved recovery of heart function after myocardial infarction. This novel approach opens a new perspective for the regenerative therapy of the heart.
Abstract 19086: Pulmonary Hypertension Accompanied by Changes in Left Ventricular Structure and Function in End Stage Renal Disease Patients on Maintenance Hemodialysis
Authors: Jon P Blaschke, Betty Skipper, Sandra L McClelland, Kathleen Fagan, Darlene Begay, Antonia A Harford, Philip G Zager, Veena Raizada
Journal: Circulation (2012)

Introduction: Pulmonary hypertension (PH) is increasingly recognized in patients with end stage renal disease (ESRD) on hemodialysis (HD). The causes of PH include features characteristic of ESRD and HD including the hemodynamic effects of an AV fistula and left heart disease. Although LV abnormalities occur frequently in ESRD patients, the association of such abnormalities with PH has been rarely studied. Hypothesis: PH in patients on chronic HD is associated with LV structural and functional abnormalities, including LV diastolic dysfunction (LVDF). Methods: Ninety- four patients (age range, 23-77 years; females, 45) underwent Doppler echocardiography 10-12 hours after HD. PH was considered present when the pulmonary artery systolic pressure (PAP) was ≥ 40 mmHg. LV measurements included thickness of the interventricular septum (IVS) and posterior wall (PW); LV mass; LV size calculated from the LV internal dimensions at the end of diastole and systole (LVIDd and LVIDs); and LV systolic function from ejection fraction (EF). LVDF was assessed from mitral diastolic velocity waves: deceleration time (DT) of the early wave (E) and the ratio (E/A) of E and the late velocity (A). Results: Sixty- seven patients (71%) had PH whereas 27 patients (29%) had normal PAP (&lt;40 mmHg). Systolic and diastolic blood pressures (155 ± 29 vs. 148 ± 25 mm Hg, p =0.3; and 82 ± 15 vs. 84 ± 13 mm Hg, p = 0.38) were similar in patients with PH and those with a normal PAP (NPAP). LVIDd (5.21 ± 0.88 vs. 4.87 ± 0.84 cm, p= 0.05); LVIDs (3.45 ± 0.96 vs. 3.07± 0.76 cm, p= 0.05); IVS and PW thicknesses (1.03 ± 0.15 vs. 1.09 ± 0.19 cm, p = 0.19; and 1.07 ± 0.16 vs. 1.12 ± 0.17 cm, p = 0.25); and LV mass, (123 ± 38 vs. 113 ± 3 g/m 2 , p= 0.12) were all similar in PH vs. NPAP patients. The LVEF was lower in PH than in NPAP patients (46.4 ± 17.6 vs. 62.4 ± 14.4%, p &lt; 0.001). Both groups exhibited DTs of &gt; 200 ms (215 ± 47 vs. 257 ± 52 ms, p = 0.006), with no significant between-group difference in the E/A ratio (E/A 1.48 ±0.74 vs. 1.15 ±0.44, p=0.06). Conclusions: We observed a surprisingly high prevalence of PH among patients on HD. PH was associated with a moderate depression in LV systolic function in the absence of clear changes in LVDF. Further studies are warranted to clarify the role of LVDF in the pathogenesis of PH in HD patients.
Abstract 9003: Evolution of the Arterial Structure and Function from Infancy to Adolescence is related to Anthropometric and Blood Pressure Changes
Authors: Taisto Sarkola, Cedric Manlhiot, Cameron Slorach, Timothy J. Bradley, Wei Hui, Luc Mertens, Andrew Redington, Edgar Jaeggi
Journal: Circulation (2012)

Objective: To develop a normative dataset and to study the relationship between arterial structure, different anthropometric measures, blood pressure and arterial function during healthy childhood using very-high resolution ultrasound (25-55 MHz). Methods and Results: In 135 healthy children between 0 and 18 years we assessed the structure of the carotid arteries, larger peripheral arteries, aorta and left ventricle with ultrasound. Arterial stiffness was assessed by pulse wave velocity (PWV) and endothelial function by brachial flow-mediated dilatation (FMD). Reference curves adjusted for age and body surface area of arterial lumen diameters (LD), intima-media (IMT) and adventitia (AT) thickness were developed. Arterial walls thicken during childhood predominantly due to a progressive increase in IMT. There were significant associations between LD (R 2 range: 0.20-0.88 for different arteries; p&lt;0.001), IMT (R 2 range: 0.47-0.85; p&lt;0.001), left ventricular mass (LV mass; R 2 = 0.90; p&lt;0.001) and AT (R 2 range: 0.15-0.22; p&lt;0.001) with gender, age, body surface and systolic blood pressure. Arterial wall stress was associated with LD (R 2 range 0.52-0.83; p&lt;0.001) and IMT (R 2 range 0.53-0.88; p&lt;0.001). Limited relations were found between arterial wall layer thickness, stiffness and endothelial function. Conclusion: In healthy children the evolution of the arterial structure is mainly related to anthropometrics and blood pressure.
Abstract 8256: Timing of Perioperative Methylprednisolone and Outcome in Infants Undergoing Heart Surgery
Authors: Sara K Pasquali, Jeffrey P Jacobs, Xia He, Marshall L Jacobs, Sean M O'Brien, Matthew Hall, Robert D Jaquiss, Karl F Welke, Eric D Peterson, Samir S Shah, J. W Gaynor, Jennifer S Li
Journal: Circulation (2011)

Background: Prior studies suggested peri-operative corticosteroids may reduce the post-bypass inflammatory response after congenital heart surgery, particularly regimens involving 2 doses (most often 1 dose given the night before surgery, and 1 in the operating room). More recent studies have called this into question, including a trial of methylprednisolone (MP) showing no benefit of 2 doses vs. 1 in infants. Lack of a placebo group and power to assess mortality or risks of treatment (infection) have limited prior analyses. In the present study we evaluated outcomes across MP regimens vs. no steroids in a large cohort. Methods: Clinical data from the Society of Thoracic Surgeons Database were linked to medication data from the Pediatric Health Information Systems Database for 25 participating centers. All infants (≤30d) undergoing heart surgery from 2004-2008 were included. Multivariable analysis adjusting for patient and center characteristics, surgical risk category, and within center clustering was used to evaluate the association of MP regimen with outcome. Results: A total of 3180 infants were included: 22% received MP on both the day before and day of surgery, 12% on the day before surgery, 28% on the day of surgery, and 38% did not receive any peri-operative steroids. In multivariable analysis (Table), there was no significant mortality or length of stay benefit associated with any MP regimen (vs. no steroids), and no difference in infection (sepsis, mediastinitis, wound infection). In subgroup analysis by surgical risk group there was a significant association of MP with infection consistent across all regimens (overall OR 2.6, 95% CI 1.3-5.2) in the lower surgical risk group. Conclusions: This multicenter observational analysis did not find any benefit associated with MP in infants undergoing heart surgery and suggested increased infection in certain subgroups. These data reinforce the need for a large randomized trial in this population.
Abstract 9089: Impact of Semiautomated Border Tracking on the Analysis Time and the Accuracy of Right Ventricular Volume Measurements Using DICOM Gradient Cine MR Datasets
Authors: Muhammad Ashraf, Meihua Zhu, Cole Streiff, David J Sahn
Journal: Circulation (2012)

Background: Right ventricular (RV) volume measurements on MR images require significant time for tracing multiple short axis planes and is subject to errors due to through plane motion of tricuspid plane, which limits routine clinical application. We tested a new 3D method of RV volume estimation using semiautomated border tracking to reduce both errors and analysis time. Methods: We studied 20 latex RV shaped models of different sizes (25-225ml). Each RV model was driven by a calibrated pulsatile pump at 3-5 different stroke volumes (SV, 20-80ml). Motion of the RV model was scanned for gradient cine stacks in multiple short axis, sagittal and coronal planes with a 3T Siemens MR Scanner. Image data was analyzed on an offline RV analysis program embedded in Research Arena VA® (TomTec). Each cine loop was analyzed with manual tracing employing automated border tracking. Datasets were then analyzed for RV volume after manual editing of borders at each short axis level. Results: Semiautomated tracking used 3-5 minutes rather than the manual 30-45 minutes. Both methods overestimated ESV and underestimated SV but showed a positive linear correlation (r = 0.80 &amp; 0.87 for ESV and 0.85 &amp; 0.89 for SV respectively) compared to reference values, and good interobserver variability (r = 0.92 &amp; 0.77 respectively). Bland-Altman analysis showed slightly lower bias for manual editing (3.45±0.80) compared to automated tracking (5.25±1.45) but all data points were within 95% confidence intervals. Conclusions: The new RVMR program is a user friendly semiautomated program that may be used for clinical assessment of RV volumes.
Abstract 327: Efficacy of Lower Limb Compression in the Management of Vasovagal Syncope: A Randomized Crossover Study
Authors: Juarez Barbisan, Rafael Queiroz dos Santos, Bruna H Suzigan, Lucas Souza, Patricia Santánna, Luis Smidt, Vitor Pedrozo, Cristina Gazeta, Isabella Dossin
Journal: Circulation (2012)

Introduction: Vasovagal syncope (VS) is the most prevalent cause of transient loss of consciousness among the population. The treatment consists of lifestyle modifications and the use of a pacemaker in some subgroups of patients. The purpose of this study is to evaluate the effect of measures to compress the lower limbs in patients with recurrent episodes of VS submitted to the Tilt Test (TT). Methods and Results: Twenty patients, average age 30.5 years (15-75), 13 (65%) female, with a clinical diagnosis of VS and previous TT with a positive result and who had at least one episode of syncope during the last year were included in this placebo-controlled randomized cross-over study. The patients underwent two consecutive TT, at a one-hour interval, with and without compression by pneumatic compression boots with 40 mmHg at the heels and 30 mmHg for the legs. The blood pressure (BP) and heart rate (HR) of these patients were monitored continuously. The outcome assessor was blinded. The results of the TT were positive in 13 (65%) of the patients in the control groups and in 2 (10%) of the patients with compression (p&lt;0.0001). Throughout the tests, the systolic BP measures were not different among the groups. On the other hand, the HR measures showed a difference only in the tilted position at two minutes, of 73±16 bpm in the control group and of 69±16 bpm (p=0.047) in the compression group. Conclusion: Compression of the lower limbs is very effective to render the TT negative in patients with a diagnosis of VS.
Abstract 19208: Higher Cornell Product and QTc on Exercise Stress Testing are Correlated with Lower Cardiac MRI T1 Times in Hypertrophic Cardiomyopathy
Authors: Sudip Saha, Celia Corona-Villalobos, Stefan Zimmerman, Radwa Noureldin, Ihab Kamel, David Bluemke, Theodore Abraham, M. Roselle Abraham
Journal: Circulation (2012)

Hypertrophic cardiomyopathy (HCM) is characterized by ventricular hypertrophy, myocyte disarray and interstitial fibrosis which result in arrhythmias, sudden death and heart failure. Studies have shown that the resting EKG can be used to predict abnormalities on contrast enhanced cardiac MRIs. However, studies correlating changes seen in the EKG during exercise and measurements on MRIs in the HCM population have not been studied. The exercise state is clinically relevant for patients with HCM and exercise stress testing is an economical tool that is often abnormal in HCM patients. We assessed the hypothesis that during the exercise state changes in various EKG parameters such as the Cornell product, for example, would correlate with lower T1 times on contrast enhanced MRIs. One hundred and sixty three patients (67% male) were evaluated fulfilling standard HCM criteria and clinical history was obtained. EKGs from Bruce protocol treadmill stress testing were independently analyzed for heart rate, QRS duration, LVH criteria including Sokolow-Lyon and Cornell product, ST changes, T wave inversions, and strain pattern. Contrast enhanced MRIs were performed and T1 mapping was analyzed independently. As shown in Table 1, compared to the rest state, peak exercise EKGs showed higher Cornell product, QTc, QRS duration, greater presence of strain pattern, and non-specific ST depressions and T wave inversions (p &lt; 0.001 in all groups). The Cornell product (r = -0.71 for rest, r = -0.86 for exercise state) and QTc (r = -0.62 for rest, r = -0.74 for exercise) were correlated with lower T1 times. In conclusion, the novel findings of this study are that abnormalities in parameters such as the Cornell product or QTc correlate with lower T1 times on MRI, especially in the exercise state. Lower T1 times are associated with greater fibrosis and abnormalities in repolarization or conduction (as seen in EKGs during the exercise state) could indicate a subpopulation of HCM patients at greater risk.