tbuckley/cabot-search huggingface dataset:
Abstract 16984: Oral Delivery of Angiotensin Converting Enzyme 2 and Angiotensin-(1-7) Bioencapsulated in Lettuce Cells Attenuates Experimental Pulmonary Hypertension (PH)
Authors: Tim Lahm, Bakhtiyor Yakubov, Venkata Mangu, Jiyoung Park, Henry Daniell
Journal: Circulation (2018)

Introduction: The renin-angiotensin system (RAS) plays a key role in the development of PH. Angiotensin converting enzyme 2 (ACE2) and its product, angiotensin-(1-7) [Ang-(1-7)] are RAS inhibitors, and their administration attenuates PH development in animal models. However, oral delivery systems for repetitive delivery of ACE2/Ang-(1-7) are not available, thus limiting their clinical applicability. Bioencapsulation of protein drugs within plant cells and their fusion with the transmucosal carrier CTB facilitates oral delivery of biopharmaceuticals. Hypothesis: Orally delivered, CTB-fused ACE2/Ang-(1-7) bioencapsulated in lettuce cells increases plasma Ang-(1-7) levels and attenuates experimental PH. Methods: CTB-ACE2 and CTB-Ang-(1-7) were expressed in lettuce chloroplasts. Proper folding, quantification and assembly of CTB-ACE2/Ang-(1-7) pentamers in lyophilized plant cells were confirmed by immunoblots or GM1 ganglioside receptor ELISA. PH was induced by monocrotaline (MCT) in male Sprague Dawley rats. Rats were gavaged with plant cells (5x/week for 4 weeks) expressing 250 μg, 500 μg or 750 μg of CTB-ACE2 and 400 μg, 800 μg or 1200 μg of CTB-Ang-(1-7). A control group of MCT rats received plant cells without ACE2 or Ang-(1-7). Ang-(1-7) in plasma was measured by ELISA. Functional/structural PH endpoints were assessed by echocardiography, right heart catheterization, Fulton index and analysis of pulmonary artery (PA) remodeling. Expression of PH-relevant genes was evaluated by real-time RT-PCR. p&lt;0.05 by one-way ANOVA was considered significant. Results: Oral administration of CTB-ACE2 and CTB-Ang-(1-7) resulted in dose-dependent accumulation of Ang-(1-7) in plasma (p&lt;0.05 vs control) and attenuation of PH development, evidenced by 30-50% decreases in right ventricular (RV) hypertrophy, RV systolic pressure, total pulmonary resistance and PA remodeling (p&lt;0.05 vs control). Cardiac index increased in a dose-dependent manner (p&lt;0.05 vs control). Bioencapsulated ACE2/Ang-(1-7) dose-dependently attenuated PH-induced alterations in mRNA expression of Ang-(1-7) receptor MAS and angiotensin II receptor AGTRI as well as IL-1β and TGF-β1 (p&lt;0.05 vs control). Conclusions: Orally delivered CTB-ACE2/CTB-Ang-(1-7) bioencapsulated in plant cells dose-dependently increased Ang-(1-7) in the circulatory system, attenuated experimental PH and abrogated PH-induced gene alterations. Chloroplast-derived CTB-ACE2/CTB-Ang-(1-7) may be a novel oral treatment strategy for PH.
Abstract 16593: Deficiency of Myocardial miR-17-92 Cluster Exacerbates Ischemic Injury and Abrogates Rapamycin-Induced Protection in Diabetic Mice
Authors: Arun Samidurai, Sean K Roh, Fadi N Salloum, Rakesh C Kukreja, Anindita Das
Journal: Circulation (2018)

Background: Chronic treatment with rapamycin (RAPA, an mTOR inhibitor) improves cardiac function in type 2 diabetic (T2D) mice through attenuation of oxidative stress and alteration of antioxidants and contractile protein expression. The miR-17-92 cluster is indispensable for the cardiac development; its deletion leads to neonatal lethality due to severe anomalies of the cardiovascular system. Following microRNA array analysis, we identified that miR-17 and miR-20a were significantly up-regulated in diabetic hearts with RAPA treatment. We therefore investigated their role in RAPA-induced protection in diabetic mice following ischemia/reperfusion (I/R) injury. Methods and Results: Adult male db/db T2D mice were treated daily with RAPA (0.25 mg/kg, i.p.) for 28 days. RAPA significantly reduced myocardial infarct size following global I (30 min) and R (60 min) in Langendorff mode ( Fig. A ). Real-time PCR showed that miR-17 and -20a, part of miR-17-92 cluster, were induced in hearts from RAPA-treated db/db mice ( Fig.B ). To further elucidate their role in RAPA-induced protection in diabetes, wild type (WT:MCM:NTG:miR-17-92 flox/flox ) and cardiac-specific miR-17-92-deficient (miR-17-92-def:MCM:TG:miR-17-92 flox/flox ) mice were fed with high-fat-diet (HFD) for 16 weeks. HFD-fed mice exhibited impaired glucose tolerance ( Fig. C ). Treatment with RAPA improved blood glucose level, cardiac function and reduced infarct size following I/R in diabetic WT mice, which were abolished in diabetic tamoxifen-inducible miR-17-92-deficient mice ( Fig. D, E, F ). In addition, miR-17-92-deficient mice had larger infarct size after I/R compared to WT controls (Fig F) . Conclusion: Cardiac miR-17-92 plays a critical role in RAPA-induced protection against I/R injury in diabetic mice. Future studies are required to identify downstream targets of miR-17-92 responsible for cardioprotection.
Abstract 13856: Hydrogen Sulfide Donor, SG1002, Preserves Left Ventricular Global Function and Contractile Reserve in a Mouse Model of Doxorubicin Cardiotoxicity
Authors: Adolfo G Mauro, Katherine Hunter, Taylor I Schultz, Donatas Kraskauskas, Stefano Toldo, Fadi N Salloum
Journal: Circulation (2021)

Background: Despite being one of the most widely used chemotherapeutic agents, Doxorubicin [DOX] is limited by its dose-dependent side effects, including cardiotoxicity and heart failure (HF). Reactive oxygen species, inflammation, mitochondrial dysfunction, and dysregulated autophagy have been proposed as potential mediators of cardiotoxicity. Hydrogen sulfide (H 2 S) has been shown to promote mitochondrial stability and reduce inflammation in the setting of myocardial infarction. Hypothesis: To determine if the orally active, slow-releasing H 2 S-compound SG1002 attenuates DOX-induced cardiotoxicity. Methods: Following baseline echocardiography, male C57BL mice (12 weeks old) were treated with DOX (5 doses of 5mg/kg, ip; once a week) over 5 weeks. One week before the first DOX treatment, mice were placed onSG1002-enriched chow to achieve a dosage of 40 mg/kg/day for the duration of the study. The control group received normal chow. Mice were followed up to 5 weeks after the last DOX treatment. Left ventricular (LV) function was assessed via echocardiography, including LV global longitudinal strain [GLS]. Contractile reserve was measured as a percent increase in LV ejection fraction (LVEF) following isoproterenol challenge (10ng/mouse). Results: The cumulative dose of 25mg/kg of DOX led to impaired cardiac contractile reserve in control mice, which was preserved in SG1002-fed mice (Fig.A). Despite no changes observed in LVEF throughout the study, LV GLS detected early signs of cardiac dyssynchrony following the DOX regimen (Fig.B). SG1002 treatment prevented the early decline in cardiac function following chemotherapy. Conclusion: Our results indicate that LV GLS and cardiac contractile reserve are able to detect early changes in LV contractility due to cardiotoxicity following DOX treatment, which can be prevented with SG1002. This further highlights the importance of early screening with advanced imaging to identify signs of cardiotoxicity.
Abstract 11902: Evaluating Right Ventricular Pacing Burden Leading to Pacing Induced Cardiomyopathy
Authors: pranav mahajan, Surya Aedma, Jemin Jose, Sanjivani Sathe, Anant Naik, Anuj Garg, Abraham G Kocheril
Journal: Circulation (2021)

Introduction: Pacing induced cardiomyopathy (PICM) is defined as a drop in left ventricular ejection fraction (LVEF) due to high amount of right ventricular (RV) pacing. Although PICM occurs with chronic, and occasionally, acute high burden RV pacing, the minimum burden of RV pacing inducing PICM is not widely established. Hypothesis: Based on multiple cases at our hospital, we hypothesize that &gt;40% RV pacing would induce PICM. Methods: A single center retrospective analysis was done on patients undergoing permanent pacemaker (PPM) placement between January 2019 and April 2020 at our hospital. Data for 88 patients was collected and analyzed using paired student’s t test, comparing mean LVEF in the two groups. Results: Out of 88 patients, 6 patients with cardiac ischemia and 9 patients with biventricular PPM were excluded. 40 out of the remaining 73 (54.8%) patients had &gt;40% RV pacing, out of which 36 patients had pre-PPM and post-PPM implantation echocardiograms and were included in the final analysis. 33 patients (45.2%) had &lt;40% RV pacing, out of which 30 patients had pre-PPM and post-PPM implantation echocardiograms and were included in the final analysis. Median duration of pacing at the time of analysis was 418 days. There was a statistically significant decrease in LVEF in patients with &gt;40% RV pacing [pre-PPM LVEF= 55.4861%, post-PPM LVEF= 51.5972%, mean difference between post-PPM and pre-PPM LVEF= -3.8889% (p=0.032)], but not in patients with &lt;40% pacing [pre-PPM LVEF= 57.1167%, post-PPM LVEF= 57.4833%, mean difference= 0.3666% (p=0.810)] (Image 1; ns: not significant). Conclusion: Our findings showed a statistically significant decrease in LVEF for patients with &gt;40% RV pacing, but not for patients with &lt;40% RV pacing, suggesting that 40% RV pacing is the likely threshold for producing LV systolic dysfunction and cardiomyopathy. Although this difference is statistically significant, clinical significance of this difference varies case-by-case.
Abstract 13940: Whole Mount Confocal Microscopy of Mouse Aortic Valve Leaflet Innervation
Authors: Daniel Chaparro, Joshua Hutcheson
Journal: Circulation (2021)

Introduction: Within the aortic valve leaflets (AVLs) reside a heterogeneous cell population holistically referred to as valve interstitial cells (VICs). These cells maintain the highly organized trilaminar extracellular matrix (ECM) structure in the AVL and are involved in the pathological progression of aortic valve disease (AVD). Various cell types have been reported in the AVL, including an understudied subpopulation of neurons. Since the mid-2000s, little has been done to report the possible role these neurons have in tissue homeostasis. Typically, imbedded sections of tissue chosen from specific areas of the valves are used to visualize immunoreactivity of these proteins. These sections usually come from the belly region or annular sections of the valve and seldom depict the entire leaflet anatomy. Hypothesis: Whole mount immunofluorescence microscopy allows us to map the 3D localization of these neuroendocrine markers throughout the entire aortic valve. Methods: Here, we gathered high resolution confocal microscopy images in whole mount mouse aortic valve tissues of various neuroendocrine markers such as tyrosine hydroxylase, protein gene product 9.5, and calcitonin gene related peptide. Results: We note that neuroendocrine markers mainly localize near the free edge on the ventricular surface of AVL tissue. We do not see the long dendritic neurons seen in the mitral and tricuspid valves, instead these markers are present in cells of varying morphologies throughout. Conclusions: The data gathered in this study aids our future efforts in determining mechanosensitive neural regulation of aortic valve leaflet mechanics and ECM remodeling. Future experiments will assess neuromodulation of valve rigidity under mechanical strain.
Abstract 13962: Understanding Hospital-Acquired Venous Thromboembolisms in Pediatric Cardiology Patients
Authors: Nancy Song, Yessica Martinez Mulet, Andrea Banuet Gonzalez, Ling Loh, Andrew Shin, Lane Donnelly, David Scheinker
Journal: Circulation (2021)

Objective: This study set out to determine risk factors for hospital-acquired venous thromboembolisms (VTEs) in pediatric cardiology patients in the setting of the 2016 Solutions for Patient Safety prevention guidelines. Methods: This retrospective cohort study considered all hospitalized patients discharged between 1/1/2019 and 12/31/2020, inclusive, in an university-affiliated children’s hospital. Demographic data for all patients, including service, presence of central venous catheters, administered intravenous medications, and initial Braden QD scores were included. Hospital-acquired VTEs as defined by the National Healthcare Safety Network were included. Standard descriptive statistics were utilized. Univariate analyses were conducted using the appropriate test as appropriate based on data distribution. Regularized regression using elastic net was performed to ascertain significant risk factors with p&lt;0.05. Results: Over the study period, 28,409 patients were included. Contemporary guidelines for VTE prevention in pediatric patients only include patients greater than 12 years of age and only prevent VTEs not related to central venous catheters. However, of the 143 hospital-acquired VTEs within the study period, 67.8% occurred in patients younger than 12 years of age and 66.0% were related to a central venous catheter. The majority (54.5%) of hospital-acquired VTEs occurred in patients on the cardiology service. In a subsequent multivariable regression analysis performed on pediatric cardiology patients, risk factors for hospital-acquired VTEs included having two or more central lines simultaneously (OR 4.46, p=0.03) and treatment with IV antidiuretics (OR 3.08, p=0.04). Total Braden QD score and Braden QD subscores were not associated with hospital-acquired VTEs. (OR 1.02, p=0.99 and OR 1.37, p=0.53, respectively). Conclusion: We found that the current prevention guidelines for hospital-acquired VTEs are not applicable to the majority of pediatric cardiology patients who develop hospital-acquired VTEs. A better understanding of risk factors for hospital-acquired VTEs is needed to inform future interventions.
Abstract 16816: 1-Year Outcomes From the Low Risk Transcatheter Aortic Valve Replacement (LRT) Study
Authors: Ron Waksman, Toby Rogers, Federico Asch, Paul Gordon, John Goncalves, Robert Levitt, Puja Parikh, David Butzel, Nicholas Hanna, Rebecca Torguson, Hector Garcia-Garcia, Paul Corso
Journal: Circulation (2018)

Introduction: Transcatheter aortic valve replacement (TAVR) is now standard of care for patients with symptomatic severe aortic stenosis who are extreme, high or intermediate risk for surgical aortic valve replacement (SAVR). However, safety and effectiveness of TAVR in low risk patients remains untested. Hypothesis: To test the safety and effectiveness of TAVR in low risk patients. Methods: The Low Risk TAVR (LRT) trial was the first FDA-approved Investigational Device Exemption (IDE) trial to enroll in the United States (US). This investigator-led trial was a prospective, multicenter, unblinded, non-randomized, feasibility study at 11 centers in the US. Subjects determined to be low risk by the enrolling center multidisciplinary Heart Team and by an independent Case Review Committee underwent TAVR using a commercially available balloon-expandable or self-expandable TAVR device. All imaging studies were analyzed by an independent Core Lab and endpoints were adjudicated by an independent Clinical Events Committee using Valve Academic Research Consortium (VARC 2) definitions. Results: A total of 200 subjects with symptomatic severe aortic stenosis were enrolled. Interim short-term results have been reported previously. Mean age was 74.6±5.7 years, and mean Society of Thoracic Surgeons (STS) score was 1.9±0.5%. There was no mortality or disabling stroke at 30 days. The permanent pacemaker implantation rate was 4.8% at 30 days. No patients had ≥moderate paravalvular leak at 30 days. We will present 6-month and 1-year clinical outcomes and echocardiographic findings at the American Heart Association 2018 Scientific Sessions. Conclusions: LRT was the first FDA-approved prospective multicenter clinical trial of TAVR in low risk patients in the US. Interim short-term results demonstrated excellent safety and effectiveness at 30-days. We will present the 6-month and 1-year clinical outcomes and echocardiographic findings at the American Heart Association 2018 Scientific Sessions.
Abstract 16905: Relationship Between Cardiac Magnetic Resonance Derived Regional Systolic Strain and Myocardial Tissue Characteristics in Children With Duchenne Muscular Dystrophy
Authors: Ganesh Kumar Gnanappa, Jennifer Conway, Joseph Pagano, Chentel Cunningham, Kumaradevan Punithakumar, Michelle Noga, Edythe Tham
Journal: Circulation (2018)

Background: Duchenne Muscular dystrophy (DMD) is an X linked disorder associated with deterioration in cardiac function. Identification of subclinical abnormalities using cardiac magnetic resonance (CMR) may provide an earlier marker to trigger therapy. We aimed to correlate regional left ventricle (LV) myocardial native T1 and extracellular volume (ECV) with regional strain in children with DMD. Methods: Fourteen boys with DMD (median 14 years, range 9-18) underwent CMR to measure segmental native T1 and ECV at the basal and mid-ventricular level. Native T1 and ECV were measured from the MOLLI sequence using cvi42 software. Circumferential (CS) and longitudinal (LS) strain values were assessed in the corresponding cine images using an in-house developed, semi-automated deformation technique. Associations of T1 and ECV with strain were examined using Pearson correlation coefficient. Results: The majority had LVEF &gt;50% (79%). Median global basal CS (-20.5%) and mid-cavity CS (-18.9%) were normal, but the global LS was reduced (-15.2%). Regions with LGE and CS abnormalities were similar (inferior and inferolateral) but differed from regions with increased T1 &amp; ECV (inferoseptal, anteroseptal) and LS abnormalities (inferoseptal and anteroseptal). CS and LS abnormalities were noted more in mid-cavity than basal segments. There were strong correlations between lower CS and higher native T1 in four segments, and correlations with higher ECV in all segments (Table 1). LS showed no correlations with either native T1 or ECV. Conclusions: Native T1 and ECV abnormalities were noted in segments not associated with positive LGE. The relationship between native T1, ECV and CS suggest that regional diffuse fibrosis is associated with subclinical systolic dysfunction and is detectable on CMR prior to global abnormalities. These findings may provide evidence for early medical therapy aimed at delaying cardiac dysfunction in DMD.
Abstract 16845: Functional Regulation of Native Coronary Kv1 Channels by Pyridine Nucleotides
Authors: Marc M Dwenger, Zachary B Wohl, Aruni Bhatnagar, Matthew A Nystoriak
Journal: Circulation (2018)

Introduction: Recent studies indicate that vasodilation and enhanced blood flow to the heart following increases in myocardial O 2 demand are mediated by voltage-gated Kv1 channels in coronary smooth muscle cells (CVSM). Periods of high O 2 demand alter the intracellular pyridine nucleotide (PN) redox (e.g., elevated NADH:NAD + ), which, in heterologous systems, differentially modulates the gating properties of Kv1 channels by binding to intracellular Kvβ subunits. Hypothesis: Elevated levels of reduced PNs increase Kv1 channel activity in CVSM via the Kvβ complex. Methods: We performed patch clamp electrophysiology on CVSM freshly isolated from the left anterior descending coronary arteries (1 st and 2 nd order) of wild type and Kvβ2-null (Kvβ2 -/- ) mice. In the conventional whole cell configuration, we measured outward K + current density and the voltage-dependence of activation and inactivation (V 0.5, act, V 0.5,inact , respectively) in the absence and presence of extracellular lactate or pyruvate (10 mM), which alter intracellular PN levels. In inside-out membrane patches, we measured the open probability (nPo) of single K + -permeable channels that are sensitive to the Kv1 channel inhibitors 4-aminopyridine (4-AP; 1 mM) and psora-4 (500 nM), in the absence and presence of NADH (1 mM). Results: Treatment of wild type CVSM with lactate to elevate [NADH] I significantly increased whole cell Kv current density and shifted V 0.5, act to more negative membrane potentials (n=4, P&lt;0.05). This response was effectively reversed upon increasing [NAD + ] i by treatment with pyruvate. Recordings performed in the inside-out configuration revealed K + currents that were sensitive to inhibition by psora-4 and 4-AP and had a unitary conductance of 70.2 ± 2.4 pS. Perfusion with a bath solution that contained 1 mM NADH lead to a significant increase (~2-fold) in the nPo of 4-AP-sensitive channels (n=25-30 cells, P&lt;0.05). However, this effect was largely attenuated in membrane patches from Kvβ2 -/- CVSM. Conclusions: Native Kv1 channels in CVSM are functionally regulated by the intracellular NADH:NAD + ratio via their auxiliary Kvβ subunit complex.
Abstract 17003: Impact of Ex-Vivo Lung Perfusion on T Regulatory Cells and Monocytes in Bronchoalveolar Lavage and Peripheral Blood
Authors: Lourdes I Chacon, Gabriel T Loor, Daoud T Daoud, Ahmed T Alnajar, Luiz C Sampaio, Doris A Taylor
Journal: Circulation (2018)

Background: Availability of donor lungs suitable for transplant falls short of current demand and results in long waiting times. More than 80% of donor lungs are potentially injured and therefore not considered suitable for transplantation. Ex-Vivo Lung Perfusion (EVLP) offers the opportunity to objectively assess and recondition organs unsuitable for immediate transplant. However, the biological mechanisms of EVLP are not well understood. The objective of this study was to investigate the Bronchoalveolar Lavage (BAL) and peripheral blood (PB) inflammatory cell profile in patients who had EVLP. We hypothesized that EVLP is related to a differential expression of monocytes in BAL and PB as compared to patients who did not receive EVLP. Methods: BAL was collected and analyzed via flow cytometry at baseline (before transplant) and 6 h after transplant. PB was collected and analyzed at baseline, 6 h, 24 h, 48 h, and 72 h after transplant from consented participants (EVLP and non-EVLP, n=5 each). Statistical difference between groups were determined using t-test and nonparametric tests. A p-value &lt;0.05 was considered significant. Results: In the donor lung prior to transplant, classical monocytes (CD14+CD16-) were significantly higher in BAL at baseline (77.48±4.64 vs. 32.30±23.12, p=0.04) in the EVLP group when compared to non-EVLP group. In the recipients at 6 h after transplant, the EVLP group had a significant increase in T regulatory cells (Treg) (CD4+CD25+CD127dim) in BAL (4.08±1.2 vs. 18.00±6.61, p=0.05) and classical monocytes (CD14+CD16-) in PB (66.2 vs. 90.8, p=0.04) when compared to baseline. Additionally, the EVLP group had significantly higher M2 monocytes (CD14+CD80-CD163+) (86.97±7.21 vs. 62.85±3.15, p=0.03) in PB at 6 h after transplant when compared to non-EVLP group. Conclusion: EVLP causes a significant change in monocytes, their subpopulations and regulatory T cells in the donor and recipient.