tbuckley/cabot-search huggingface dataset:
Abstract 17305: Overexpression of Sodium Channel beta 4 Subunit is Responsible for Increase in Late Sodium Current in Mice with Mecp2 Deficiency
Authors: Shin Yoo, Mark McCauley, Jose Herrera, Tiannan Wang, Melissa Arvide, Jeffrey L Neul, Xander H Wehrens
Journal: Circulation (2011)

Introduction: The methyl-CpG-binding protein (MeCP2) is an epigenetic modifier of genetic expression and repression, and its dysfunction has been shown to cause Rett Syndrome, a progressive neurological disorder associated with sudden cardiac death. MeCP2 dysfunction has also been shown to be associated with QT interval in human patients, however the underlying mechanisms are unclear. We evaluated mice deficient in MeCP2 (KO) to determine whether there were differences in expression of genes commonly associated with long QT syndrome (LQTS). Hypothesis: MeCP2 dysfunction alters expression of plasma membrane ion channels or its interacting proteins, which are necessary for normal cardiomyocyte action potential. Methods and Results: qPCR was performed on wild type mice (WT) and KO heart lysates. Among 11 LQTS genes, SCN4B, one of beta subunits of the cardiac voltage gated sodium channel, was elevated 2.5 fold (n = 3, P = 0.04), while other 10 LQTS genes were not significantly altered. Western blot analysis on heart lysates showed increase of SCN4B protein in KO, consistent with immunostaining on isolated ventricular myocytes, which showed a qualitative increase of plasma membrane enhancement of SCN4B. Sodium current was recorded from a holding potential of -120 mV and activated to -20 mV. There was no change in peak sodium current, however, late sodium current was significantly increased in KO compared to WT (WT, -170.4 ± 29.2 pA, n = 5 vs. Rett, -590.0 ± 145.7 pA, n = 5; WT vs. Rett, p &lt; 0.01). and Phenytoin, a late sodium current blocking agent, reduced late sodium current near normal levels (Rett + Phenytoin, -183.8 ± 40.6 pA, n = 5; Rett vs. Rett + Phenytoin, p &lt; 0.05). Conclusion: Mice deficient in MeCP 2 have an increase in SCN4B expression, which may be associated with prolongation of QT interval. Phenytoin inhibits the late sodium current and may be an effective treatment for prevention of arrhythmias in patients with MeCP2 dysfunction.
Abstract 17332: Are Current Electrocardiographic Criteria For Detecting LVH Relevant in African Americans? Evidence From the Jackson Heart Study
Authors: Thomas C Fugate, Joseph Guido, Herman Taylor, Thomas Pearson
Journal: Circulation (2011)

Left Ventricular Hypertrophy (LVH) is a major risk factor for cardiac arrhythmias, heart failure, and sudden death. The current gold standard for detecting LVH is echocardiography, but individuals can be first screened using a resting electrocardiogram (ECG). The current algorithm for detecting LVH by ECG is derived from the nearly all-Caucasian Framingham Heart Study (FHS).The use of Framingham ECG criteria to predict LVH in African Americans (AA) has not been validated. We tested whether Framingham ECG criteria used to detect LVH performed as well in AA. The Jackson Heart Study is a population-based study of AA, consisting of 1941 men and 3360 women. Linear regression analysis of five different ECG LVH criteria proposed in FHS, correlated left ventricular mass (LVM) on M-mode echocardiogram with ECG voltage before and after adjusting for BMI and age. Limb and chest leads voltages in JHS men and women, in comparison to the FHS men and women, showed S wave leads in V3, V4, in men, and V2 and V3 in women have the strongest correlation to LVM (P value&lt; .0001). Among the limb leads, the JHS results were similar to the Framingham cohort, showing RI, SIII and RAVL most strongly associated with LVM in both sexes (P value&lt;.0001). Sensitivity was calculated for five ECG criteria before and after adjusting for BMI and age using the definition of LVH as 2SD above the height- adjusted, sex specific JHS mean (95% specificity). Two of the ECG criteria, RAVL+SV3 and (RAVL+SV3)x QRS duration, in both men and women, had significantly greater sensitivities before and after adjusting than their FHS counterparts. JHS data identified ECG criteria (RAVL+SV3)x QRS duration to have the greatest sensitivity in both sexes unadjusted and adjusted for BMI and age (males 28.3% unadjusted, 71.4% adjusted; females 29.4% unadjusted and 60.3% adjusted). The data suggest that current criteria used to define LVH in a Caucasian population, (RAVL+SV3)x QRS duration, is at least as sensitive at the same level of specificity in African American populations and perhaps more so. These data support the utility of current LVH criteria for use in LVH screening in African American men and women.
Abstract 17278: The Cardiac Channel Molecular Autopsy for Structurally Normal Heart Sudden Unexplained Death
Authors: David J Tester, Argelia Medeiros-Domingo, Melissa L Will, Michael J Ackerman
Journal: Circulation (2011)

Background: Potentially lethal syndromes such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) may account for a significant number of autopsy-negative sudden unexplained deaths (SUD). Here, the spectrum and prevalence of putative LQTS-/CPVT-causative mutations in autopsy- negative SUD was determined following a cardiac channel molecular autopsy. Methods: From September 1998 to October 2010, 173 cases of SUD (106 males, 18 ± 13 years, 89% white) were referred by Medical Examiners/Coroners for a cardiac channel molecular autopsy. Using PCR, DHPLC, and DNA sequencing, a comprehensive mutational analysis of the LQTS-susceptibility genes ( KCNQ1 , KCNH2 , SCN5A, KCNE1, and KCNE2 ) and a targeted analysis of the CPVT1-associated gene ( RYR2 ) was conducted. Results: Overall, 45 putative pathogenic mutations (20 RYR2 , 11 KCNQ1 , 6 KCNH2 , 6 SCN5A , and 2 KCNE2 , absent in 400 - 700 controls, were identified in 45 (26%) autopsy negative SUD cases. The yield was greatest for those with an exercise-induced death (16/46, 35%) or a positive personal/family history of a syncope (13/25, 52%), or sudden death (9/20, 45%). Females had a higher yield (26/67, 39%) than males (19/106, 18%, p &lt; 0.005) especially if the SUD was during adolescence (12/25, 48% females vs. 9/50, 18% males). Females were more likely to have LQTS-associated mutations (65%) while males were more likely to have CPVT1-associated mutations (58%). Among SUD victims with exercise-induced death, the yield was much higher among the 1 - 10 year olds compared to the 11 -20 year olds (females, 71% vs 14%, p&lt;0.05; males, 60% vs 15%, p = 0.07). However for those with death during a period of sleep, the 11 - 20 year olds had a much higher yield than the 1-10 year old group (females, 75% vs 0%, p&lt;0.01; males 18% vs 6%). Conclusions: Over one-fourth of autopsy-negative SUD may stem from LQTS and CPVT. A cardiac channel molecular autopsy should be considered as a standard part of the evaluation of autopsy-negative SUD especially among children with exercise-induced SUD, adolescent females, and those with a positive personal/family history of cardiac events. A two-tiered approach starting with the LQTS-susceptibility genes in females and the CPVT-susceptibility genes in males may be prudent.
Abstract 17217: Impaired Coupling of Myocardial Blood Flow to Cardiac Work Leads to Cardiac Dysfunction
Authors: Vahagn A Ohanyan, Liya Yin, Yuh F Pung, Molly Enrick, Tatevik A Hakobyan, Christopher L Kolz, Suzanna Logan, Ian Bratz, William M Chilian
Journal: Circulation (2011)

The heart is highly dependent on a continuous supply of oxygen from the coronary circulation to meet its metabolic requirements. There are many mechanisms that contribute to the regulation of coronary blood flow, including redox and oxygen sensing voltage-gated potassium channels. These channels are expressed in coronary smooth muscle cells and appear to couple cardiac work to myocardial blood flow; specifically, we found reduced levels of flow per unit of cardiac work in mice null for the redox sensing Kv1.5 channel (Kv1.5 -/- ) compared to wild types (WT). Accordingly, we hypothesized that Kv1.5 -/- mice, with impaired coronary metabolic dilation, would gradually develop cardiac pump dysfunction due to inadequate perfusion which would lead to microareas of hypoxia, then to apoptosis, to diffuse fibrosis and finally cardiac dysfunction. Methods: Kv1.5 -/- male mice (n=8) and WT (n=6) were used for this study. For cardiac function measurements, transthoracic echocardiography was performed under sevoflurane anesthesia at 4, 8 and 12 months. After echocardiography, animals recovered and measurements were repeated at 8 and 12 months of age. As shown in the diagram, at 4 months of age, %EF is 13% lower in Kv 1.5 -/- mice compared to WT animals (P&lt;0.05). In Kv 1.5 -/- mice at 8 and 12 months, %EF was 20% and 23% lower, respectively, compared to WT animals (P&lt;0.05). Although the E/A ratio, a measure of diastolic function, did not show a significant decline in the Kv1.5 -/- mice compared to WT, there was a trend towards diastolic dysfunction. Hypoxyprobe staining (to label protein adducts produced by severe hypoxia) revealed microareas of hypoxia in hearts from the Kv1.5 -/- mice, but no such areas in WT. Also, Kv1.5 -/- mice show much more collagen deposition in the myocardium than WT. Based on these data, we conclude that alteration in the coupling of myocardial blood flow to cardiac work can lead to cardiac systolic and diastolic dysfunction
Abstract 17267: Enhanced Engraftment and Therapeutic Benefit of Human Cardiosphere-Derived Cells Delivered in an <i>In Situ</i> Polymerizable Hydrogel
Authors: Ke Cheng, Agnieszka Blusztajin, Deliang Shen, Rachel R Smith, Raj Makkar, Eduardo Marbán, Linda Marbán
Journal: Circulation (2011)

Background: The vast majority of cells delivered into the heart by conventional means are lost within the first 24 hours. Cardiosphere-derived cells (CDCs) face the same fate, suggesting that novel methods are needed to enhance retention. Methods and Results: We tested a cell-hydrogel delivery strategy. CDCs were grown from adult human cardiac biopsy specimens (n=7). In situ polymerizable hydrogels made of hyaluronan and porcine gelatin (HyStem-C™, Glycosan Biosciences) were formulated as a liquid at room temperature so as to gel within 20 minutes at 37°C. We verified that such a formulation could be passed through human injection catheters with full cell product recovery and viability. In vitro , average CDC viability in HyStem-C assayed using WST-8 was 87±9% after 72 hrs in culture, and remained high after one week (84±19%). Trans-membrane migration assays showed the migration capacity of CDCs was not compromised in the HyStem-C. Myocardial infarction was created in SCID mice and CDCs were injected intramyocardially in the infarct border zone. 24 hours after injection, real time PCR revealed a small fraction (5.8±2.2%, n=4) of CDCs delivered in conventional vehicle (PBS) engrafted. In contrast, engraftment of CDCs delivered in HyStem-C was increased by nearly an order of magnitude (35.0±25.2%, n=5, p&lt;0.05). The superior engraftment persisted for at least 3 weeks (n=3; 1.2±0.4% vs. 5.9±0.5%, p&lt;0.05). Cardiac echos (n=7-8 per group), analyzed in a blinded manner, revealed comparable LVEFs two hours post-MI, indicating similar ischemic injury among groups. At 3 weeks, LVEF deteriorated in the control (PBS only) group (-9.4±4.4%). In contrast, HyStem-C alone or CDC alone preserved LVEF (+0.5±8.6% and +5.8±5.3%, respectively), while HyStem-C + CDC resulted in a sizable boost in LVEF (+16.6±4.3%). Three weeks after treatment, the highest cardiac function was seen in the HyStem-C + CDC group (p&lt;0.05 vs others). Quantitative morphometry revealed the greatest attenuation of LV remodeling in the HyStem-C + CDC group, with smallest infarct size and thickest infarct walls (n=4; p&lt;0.05). Conclusions: A CDC/hydrogel formulation suitable for catheter-based intramyocardial injection exhibits superior engraftment and functional benefits relative to naked CDCs.
Abstract 17451: Dense Genotyping of Candidate Gene Loci Identifies Variants Associated with Oxidized Ldl Serum Levels
Authors: Mahir Karakas, Jens Baumert, Barbara Thorand, Christa Meisinger, Wolfgang Rottbauer, Thomas Illig, Wolfgang Koenig
Journal: Circulation (2011)

Background: Oxidized low-density lipoprotein (oxLDL) as a marker of oxidative stress has been proposed to play an important role in the development of atherosclerosis. OxLDL consists of a number of heterogeneously modified particles, including apoB, phospholipids, LDL-cholesterol, and unsaturated fatty acids. Serum levels of oxLDL are known to be heritable, but the degree of heritability has not been established yet. Methods: We used a high-density genotyping array containing single-nucleotide polymorphisms (SNPs) from oxLDL candidate genes selected on known biology of oxLDL metabolism, mouse genetic studies, and human genetic association studies. SNP selection was based on tagging SNPs and included low-frequency nonsynonymous SNPs. 1,332 men and women from a randomly drawn subsample of the baseline examination of the MONICA/KORA Augsburg Cohort Study, conducted between 1984 and 1995, with measurements of oxLDL (Mercodia assay) and genotyping by the 50K IBC Chip comprised the study population. Linear regression analysis with adjustment for age, sex and survey was applied to assess the associations between gene variants and oxLDL levels. Statistical significance was defined as 5.0e-6 accounting for multiple testing. Results: Eight SNPs showed a statistically significant association with ox-LDL and were located at chromosome 2 in the APOB gene with rs676210 having the strongest association (p value = 4.13e-12). All eight SNPs had minor allele frequencies above 20% showing a substantial gene variation. Conclusions: In summary, we identified variants in the APOB gene that are associated with levels of oxLDL in the general population. These findings may not only enhance our understanding of oxidative pathways and lipid metabolism and function, but may also pave the way for novel research avenues.
Abstract 17230: BMP9 Regulates Endothelin-1 Gene Transcription in Cooperation With TGF-β Signaling
Authors: Jana Bagarova, Samuel D Paskin-Flerlage, Carol S Lai, Kenneth D Bloch, Paul B Yu
Journal: Circulation (2011)

Pulmonary arterial hypertension (PAH) is characterized by abnormal pulmonary vasoreactivity and pulmonary angiopathy, leading to progressively increased pulmonary resistance, right heart failure and high mortality. The mechanisms of PAH have not been fully elucidated, although dysregulated bone morphogenetic protein (BMP) signaling due to loss-of-function mutations in the gene encoding the BMP type II receptor (BMPRII) are implicated in heritable PAH. It has been recently reported that BMP9, a BMPRII ligand, regulates transcription of the potent vasoconstrictor and smooth muscle mitogen endothelin-1 (ET-1), an important mediator of PAH. BMP9 functions as a circulating vascular quiescence factor that promotes endothelial survival while inhibiting angiogenesis. We hypothesized that altered BMP signaling in pulmonary vascular endothelium may affect the regulation of ET-1 and thereby contribute to the pathophysiology of PAH. We found that stimulation of cultured human and murine lung microvascular endothelial cells with BMP9 activates both canonical BMP and TGF-β pathways via their respective effector molecules, SMAD1/5/8 and SMAD2/3. BMP9-induced transcription of ET-1 appeared to require coordinated activation of both BMP and TGF-β signaling pathways, based on the finding that ET-1 gene transcription was inhibited by selective small molecule inhibitors of BMP or TGF-β receptor kinases, by recombinant BMP receptor ectodomains, or by siRNA-mediated suppression of BMP or TGF-β type I receptor expression. In addition, functional analysis of the human ET-1 gene promoter revealed the presence of distinct cis -regulatory elements involved in BMP9- versus TGF-β-mediated activation of ET-1 gene transcription. Mutational inactivation of a novel BMP-responsive regulatory element, as well as known TGF-β-responsive elements, abolished ET-1 gene promoter activity in response to BMP9, underscoring further the cooperative nature of BMP and TGF-β signaling in ET-1 regulation. These results suggest that perturbation of BMP signaling may alter the regulation of ET-1 in the endothelium, impact endothelial and vascular homeostasis, and thus contribute to the pathogenesis of PAH.
Abstract 17373: MicroRNA-155 Over-expression Inhibits Angiogenesis Of Lin <sup>-</sup> /cd34 <sup>+</sup> Cells From Human CAD Patients and HUVECs
Authors: Jennipher N Adi, Nikhil C Adi, Keith A Webster
Journal: Circulation (2011)

Introduction: In the cellular hypothesis of atherosclerosis, bone marrow (BM) derived EPCs contribute to vascular repair and regeneration, and defects in number and/or function of EPCs may contribute to the progression of atherosclerosis and coronary artery disease (CAD). Autologous stem cell therapy for CAD requires functionally competent EPCs. Micro-RNAs (miRs) have been implicated in the regulation of angiogenesis; miR-155 is activated by inflammatory cytokines. Hypothesis: Dysregulated expression of miR-155 in response to an inflammatory environment within the BM of CAD patients causes functional defects in BM-derived EPCs that promote CAD progression and impairment of autologous stem cell therapy. Objective: To quantify the level of miR-155 in EPCs from CAD patients and functionally characterize the effects of miR 155 over-expression on the angiogenic potential of Lin - /CD34 + cells and HUVECs. Methods: BM was collected from 5 CAD, 4 non-CAD patients and healthy volunteers; Lin - /CD34 + cells were isolated and subjected to microarray and micro-RNA profiling. HUVECs were transfected with pre and anti-miRs of miR-155. HUVEC tube formation, proliferation and cell death were quantified. Protein and RNA were quantified by western blot and RT-PCR. Results: Microarray and RT-PCR confirmed &gt;5-fold up regulation of miR-155 in Lin - /CD34 + cells of CAD patients compared with non-CAD (p&lt;0.05). MiR-155 knockdown in HUVECs increased HIF1alpha and CCND1 protein as measured by western blot (p&lt;0.05). MiR-155 over-expression using precursor molecules significantly inhibited tube formation and cell proliferation of HUVECs (both p&lt;0.01). LDH assay revealed an increase in cell death of HUVECs transfected with pre-miR-155 (p&lt;0.05). The results are consistent with other studies showing that miR-155 regulates multiple biological processes including cell differentiation, survival, and cell migration and extrapolate this to suppression of angiogenesis. Conclusion: The expression of miR-155 is markedly increased in CD34+/Lin- EPCs from patients with CAD. miR-155 over expression represses angiogenesis and may drive disease progression. Neutralization of miR-155 over-expression in EPCs is predicted to improve autologous stem cell therapy for CAD.
Abstract 17197: Closure of Multiple Atrial Septal Defects with the Helex Device
Authors: Smita Mehta, James A Hill, Athar M Qureshi, Larry A Latson, Lourdes R Prieto
Journal: Circulation (2011)

Background: The performance of the Helex Septal Occluder (HSO) for closure of fenestrated atrial septum/multiple ASDs (mASDs) has not been evaluated. We sought to review our experience with closure of mASDs with the HSO. Methods: We identified 48 patients with mASDs who underwent percutaneous closure between 6/2001 and 5/2011. Number and size of ASDs, number of implanted HSOs, residual shunt, and complications were recorded. Results: Of 48 patients, 27 had defect closure with ≥ 1 HSO. Indication for closure was RV enlargement (RVE) in 24 (89%) and cryptogenic neurologic event in 3 (11%). Median age was 9.1 (1.9-66.2) years, median weight 30.7 (12.2-99.5) kg. Six patients (22%) weighed &lt; 20 kg. Median number of ASDs was 2 (2-≥5). Median stop-flow diameter in 25/27 patients was 12 (6-24) mm. Two patients had multiple small defects that were not sized. One HSO was implanted in 21 patients (78%), and 2 HSOs in 6 patients (22%). Procedural complications included device embolization in 2 patients, and both were retrieved percutaneously with successful deployment of another HSO. Residual shunt immediately post-closure was absent in 5/27 (19%), trivial in 15/27 (55%), small in 6/27 (22%), and moderate in 1/27 (4%). The median length of follow-up was 2 (0-9) years. Residual shunt at last follow-up was absent in 13/27 (48%), trivial in 8/27 (30%), small in 5/27 (18%), and moderate in 1/27 (4%). No complication occurred during follow-up. Of the 24 patients with RVE before closure, 2 are recent without follow-up and 1 is lost to follow-up. RV size normalized in 20/21 (95%) patients. No patient with a prior neurological event had a recurrence. The patient with moderate residual shunt and RVE had 1 HSO, and placement of a second HSO is planned. Conclusions: We conclude that closure of mASDs with 1 or more HSOs is effective with a low complication rate. The complication observed, embolization, did not significantly affect outcome in this series, as percutaneous retrieval was successful. In addition, the low profile of the HSO may facilitate safe implantation of multiple devices in smaller patients.
Abstract 17237: The Underlying Necrotic Core is a Determinant of Occlusive Thrombosis
Authors: Masataka Nakano, Fumiyuki Otsuka, Saami K Yazdani, Robert Kutys, Naima Carter-Monroe, Elena R Ladich, Aloke V Finn, Frank D Kolodgie, Jagat Narula, Renu Virmani
Journal: Circulation (2011)

Background: It is well known that plaque rupture is not always associated acute coronary syndrome and in fact 10% of asymptomatic individuals dying of other causes have plaque rupture. To identify the underlying mechanisms of high risk plaque that leads to occlusive thrombosis, we examined coronary plaques from our registry of sudden coronary death victims. Methods and Results: From our sudden coronary death registry, 102 plaque ruptures (PR) were identified in proximal and middle segments of coronary trees; distal lesions were excluded. Histomorphometric area measurements included EEL, IEL, lumen, necrotic core (NC), calcification, and macrophage positivity (CD68) at the cross-section of rupture site. In addition, thinnest portion of fibrous cap adjacent to rupture site was measured. The lesions with PR were categorized into 2 groups: occlusive (&gt;75% luminal thrombus) or non-occlusive (&lt;75% luminal thrombus). PRs with occlusive thrombosis was associated with larger IEL area, larger NC, thicker fibrous cap as compared to those with non-occlusive thrombosis while EEL, lumen, calcification, and macrophage area were similar in both groups (Table). Multivariate regression analysis revealed that total NC volume is the best predictor of occlusive thrombus with an odds ratio of 1.15 (p=0.019), followed by cap thickness (odds: 1.04, p=0.024). ROC analysis of NC demonstrated the threshold of 2.89 mm 2 with sensitivity 0.61 and specificity 0.67 (AUC 0.67). Conclusion: These data suggest that strategies directed at detection of precise necrotic core area are necessary to assess high risk coronary plaques.