bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17517: Genetics of Left Ventricular Noncompaction Cardiomyopathy
Authors: Haas Jan , Feng Zhu , Geier Christian , Pribe-Wolferts Regina , Frese Karen S , Kayvanpour Elham , Sedaghat-Hamedani Farbod , Peil Barbara , Lorenzo Bermejo Justo , Franke Jennifer , Keller Andreas , Liao Yuhua , Katus Hugo A , Meder Benjamin
Published: July 2021

Left ventricular noncompaction cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmias, thrombembolic events, and sudden cardiac death. To better understand the contribution of genetic factors to this disease, allowing a better diagnosis, counseling of affected families and estimation of prognosis, we have performed whole-exome deep-sequencing on a cohort of in 104 subjects (67 unrelated LVNC probands, 26 affected relatives form 15 families and 11 additional healthy relatives). By annotating the detected variants with mutation databases (HGMD), we were able to for the first time show an overlap between the distinct causes of LVNC and other genetic cardiomyopathies, as 8 mutations were previously reported to cause hypertrophic cardiomyopathy (HCM), 9 dilated cardiomyopathy (DCM) and 6 arrhythmogenic right ventricular cardiomyopathy (ARVC). Besides already known genetic causes, we identified a number of genes contributing to different pathways, so far not discussed to be of relevance for LVNC. From those, TTN truncating mutations were very frequent, affecting 17.9% of all index patients and one fifth of the familial cases. For two genes, which have already been linked to cardiac noncompaction in animal models, we are first to describe a relevant number of patients carrying mutations in these genes NCOR2 (frequency = 7.5%) and XIRP2 (4.5%). By performing segregation and linkage analyses, as well as in vivo studies, we provide for the first time evidence for a gene that was previously not known to cause a human disease, Compactin1. In conclusion, we show that LVNC has a substantial genetic component and suggest new candidate genes for a functional dissection of their contribution to cardiac development and as potential therapeutic target.
Abstract 17544: Reproducibility Between Online and Offline Analysis of Qualitative Optical Coherence Tomography Results After Stenting in non-ST Elevation Acute Coronary Syndromes
Authors: Meneveau Nicolas F , Ecarnot Fiona , Chopard Romain , Seronde Marie-France , Plastaras Philoktimon , Huang Jian-Feng , Belmadani Kamal , Schiele Francois
Published: July 2021

Introduction & Hypothesis:
We evaluated reproducibility between online and offline analysis of optical coherence tomography (OCT) results of angioplasty with stent implantation in non-ST elevation acute coronary syndromes (NSTEACS).

Methods:
In a prospective series of consecutive patients undergoing angioplasty of a single lesion responsible for NSTEACS (symptom onset <48 h) with use of OCT to optimise procedural result, we compared presence of thrombus or tissue protrusion, residual dissection, stent malapposition, stent under-expansion, complete coverage of the lesion and side branches by the stent, as assessed online by the operator, versus results of offline analysis by two independent observers. Stent underexpansion was defined as a ratio of in-stent minimal lumen area (MLA) to average reference MLA <80%. Other definitions were based on available consensus documents. Agreement was calculated using the Kappa coefficient with 95% confidence interval (CI).

Results:
31 procedures were analyzed. Mean age was 65.7±8 years; 24 (77%) were men. Lesions were situated on the left anterior descending (n=14), right coronary (n=10) or circumflex artery (n=7). Results are shown in the table.

Conclusion:
There is good agreement between online and offline analysis for stent malapposition, and coverage of the lesion and side branches by the stent. Conversely, presence of thrombus and/or tissue protrusion, and residual dissection is under-estimated during online evaluation.
Abstract 17570: Rescue of Dilated Cardiomyopathy in Nav1.5 Mutant Mice Defective in Calmodulin Binding by Inhibition of Late Na+ Current
Authors: Cho Hana , Aiba Takeshi , DiSilvestre Deborah , Halperin Victoria , Takimoto Eiki , Sekar Rajesh , Tung Leslie , Tomaselli Gordon F
Published: July 2021

Introduction:
Nav1.5, the main voltage-gated Na+ channel in the heart, has been shown to be involved in many cardiac diseases such as long QT syndrome, Brugada syndrome, and heart failure. Na+ channels are importantly regulated by Ca2+ calmodulin (CaM) mediated signaling: however, a fundamental understanding and physiological significance of CaM regulation of Na+ channel is incomplete. Here, we have created a transgenic mouse that harbors a mutated CaM binding motif (NaV1.5-IQ/AA), which is critical for Na+ channel regulation by Ca2+-CaM.

Methods:
Ventricle mass and function were analyzed with electrocardiogram, echocardiogram, and detailed invasive pressure-volume analysis. Additionally, single ventricular myocytes were obtained. Whole cell patch clamp was used to record membrane ionic currents, including sodium current, Ca2+ current, K+ currents and NCX current.

Results:
Homozygous mice are embryonic lethal and IQ/AA+/- mice exhibit a dramatic phenotype consisting of dilated cardiomyopathy (DCM) at 4-6 months of age with prolongation of QT. The Na+ current in IQ mice exhibits an enhanced slowly inactivating late component (INa,L) with concomitant up regulation of Na+/Ca2+ exchanger currents. Consistent with other models of DCM and heart failure, DCM in IQ/AA+/- mice was associated with a down regulation of transient outward K+ currents (Ito) and an increase in T-type Ca2+ currents. Chronic treatment with ranolazine designed to block INa,L prevented electrical remodeling of the hearts including an increase in INa,L and a down regulation of Ito. Consistent with the changes in INa,L and Ito, in ranolazine-fed IQ/AA+/- mice, the QT interval was decreased compared to vehicle (p<0.05). Further, the contractile dysfunction, cardiac hypertrophy, and myocardial fibrosis were attenuated in all ranolazine- fed animals, while ventricular dysfunction persisted in animals not fed drug (p<0.05).

Conclusions:
The data suggest that loss of CaM-mediated regulation of Na+ channel induces dilated cardiomyopathy by enhancing late Na+ current. Taken together, our data demonstrate a dynamic interplay for Ca2+ and Na+ signaling via the CaM binding motif of Na+ channels and highlight the critical importance of late Na+ currents to myopathy and arrhythmia.
Abstract 17590: Long Term Results of Septal Defect Occlusion Using the Transcatheter Patch
Authors: Sideris Eleftherios , Toumanides Savvas , Macuil Benjamin , Zanjani Keyhan , Moulopoulos Spyridon D
Published: July 2021

Introduction:
The Transcatherer Patch (TP) is a bioabsorbale device used in the occlusion of septal defects including atrial septal defects(ASDs) and ventricular septal defects(VSDs) the last 15 years. Acute results have been described as effective occlusions with rare small residual shunts and occasional instability of the immediately release patch on the septum.

Hypothesis:
Long term results of successful implantations were critically examined to determine effectiveness of occlusion and the extent of septal reconstruction.

Method:
The records of 200 successfully implanted devices (149 ASDs, 51 VSDs) were analyzed. ASDs were of secundum type with the exception of five that were ostium primum and sinus venosus types. All VSDs were peri-membranous except for four malalignment (Fallot Tetralogy) and one muscular defect. Defect size varied from 13 to 35mm for ASDs and 4-16mm for VSDs. The TP was deployed in three versions including, temporary double balloon support (48hrs), temporary double balloon support with surgical adhesive (45min - 2hrs), and extended single balloon support with immediate release.

Results:
Long term results were free from deaths or serious complications including perforation, erosion, heart block, thrombus, and arrhythmia. All occlusions were effective with occasional persistence of trivial residual shunts. The septum was normalized and the patch was undetectable by echocardiography 1-2yrs after implantation. Normalization of the septum required a longer period of time with the immediate release patch.

Conclusions:
Long term results of the TP in septal defect occlusion were excellent. Serious complications seen with metallic devices did not occur. The TP offers a promising alternative in septal defect occlusion although further improvements must be made to eliminate rare acute problems and residual shunts. A double balloon immediately released patch could be a solution.

B
Abstract 17597: Endogenous Del-1 is a Negative Regulator of Ischemia-induced Angiogenesis by Interacting With the Leukocytic LFA-1 Integrin
Authors: Cremer Sebastian , Klotzsche-von Ameln Anne , Orlandi Alessia , Korovina Irina , Gercken Bettina , Zeiher Andreas M , Dimmeler Stefanie , Chavakis Triantafyllos , Chavakis Emmanouil
Published: July 2021

Developmental endothelial locus-1 (Del-1) is an endothelial cell-derived secreted protein circulating in blood and associated with the cell surface and the extracellular matrix. As we previously demonstrated, Del-1 restricts leukocyte recruitment by inhibiting the β2-integrin, LFA-1. Leukocytes and progenitor cells (PC) may contribute to angiogenesis. The role of endogenous Del-1 in angiogenesis is elusive. We found, that physiological angiogenesis of the developing retina was not affected in the Del-1-/- mice compared to the wildtype (WT) mice. Surprisingly, Del-1-/- mice displayed a significantly increased angiogenic response compared to WT mice after induction of hind limb ischemia (144 ± 6 % increase of capillary density) and retinal ischemia (retinopathy of prematurity model) suggesting that endogenous Del-1 is an inhibitor of ischemia-induced neovascularization. Silencing of Del-1 with siRNA did not affect the angiogenic sprouting of endothelial cell (EC) spheroids, indicating that Del-1 blocks angiogenesis in a non-endothelial cell autonomous pathway. Soluble Del-1 blocked the adhesion of inflammatory cells on EC monolayers. In line with these results, ischemic muscles and ischemic retinae from Del-1-/- mice displayed an enhanced infiltration with inflammatory cells compared to the WT mice. Since Del-1 blocks inflammatory cell homing by inhibiting the leukocytic LFA-1-integrin, we addressed the role of the Del-1/LFA-1-integrin interaction on the inhibitory function of endogenous Del-1 on angiogenesis. Indeed, Del-1/LFA-1-double deficiency reversed the pro-angiogenic phenotype of the Del-1-/- mice to the level of WT mice in the model of hind limb ischemia. Thus, the inhibitory role of Del-1 on neovascularization is mediated by the interaction of Del-1 with the LFA-1-integrin. Moreover, Del-1-deficiency led to an increased homing of intravenously injected murine fluorescence-labeled WT Lin- BM PC in ischemic muscles in comparison to WT mice after the induction of hind limb ischemia. Taken together, Del-1 acts as a negative regulator of ischemia-induced angiogenesis by interacting with the LFA-1-integrin expressed in hematopoietic cells, thereby inhibiting the homing of hematopoietic cells to ischemic tissues.
Abstract 17636: Health Status Outcomes in Patients With Radial Access for PCI
Authors: Baklanov Dmitri , Tang Fengming , Jones Philip , Ting Henry , Curtis Jeptha , Spertus John
Published: July 2021

Background:
While concerns about the safety and procedural success of radial, as opposed to femoral, access for PCI have largely been abated, the association of radial access with patients’ health status recovery has not been explored. To address this gap in knowledge, we compared the symptoms, physical function and quality of life 1 year after PCI in patients treated with radial, as compared with femoral, access.

Methods:
This is a 10-center study of PCI, in whom 48 of 139 (35%) interventionalists used both radial and femoral approaches between 2009-2010. A total 2628 patients without prior CABG were interviewed and followed for one year. The previously validated Seattle Angina Questionnaire (SAQ) was used to assess disease-specific health status and the EQ-5D was used to quantify generic quality of life. Clinical characteristics and health status outcomes were compared between 296 radial and 2332 femoral PCI procedures.

Results:
Radial access was used in 11.2% of patients. No demographic (age, gender, race) or clinical factors (e.g. BMI, smoking, diabetes, hypertension, renal disease or prior cardiac history) were associated with radial use, except for an increased use among those with PAD (10.5% radial vs. 6.8% femoral, p=0.022) but reduced use among those with prior PCI (38.3% vs. 32.1%, p=0.037). There was no difference in health status outcomes based on SAQ angina frequency and quality of life, or the EQ-5D at baseline, 6 months or one year (table).

Conclusion:
In this multi-center observational registry, there was no association of radial access with long-term health status outcomes. These data suggest that there are no offsetting concerns about patients’ long-term health status benefits to counterbalance the peri-procedural safety benefits of a radial approach.
Abstract 17652: Application of Pediatric and Adult Lipid Treatment Guidelines to U.S. Adolescents Transitioning to Young Adulthood
Authors: Gooding Holly C , Rodday Angie M , Wong John B , Lloyd-Jones Donald , Gillman Matthew W , Leslie Laurel K , de Ferranti Sarah D
Published: July 2021

Introduction:
Current pediatric and adult lipid treatment guidelines differ in their approach to pharmacologic treatment of cholesterol in adolescents and young adults. We hypothesized that a greater proportion of young people ages 17-21 would meet criteria for statin treatment under the pediatric guidelines compared to adult guidelines, but that overall eligibility for statin treatment would be low in this age group.

Methods:
We applied treatment algorithms from the 2011 NHLBI Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents and the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults to participants in the 1999-2011 National Health and Nutrition Examination Surveys who were 17-21 years of age and had an LDL level measured (n=2,652). We extrapolated the results to a population of 11.2 million individuals ages 17-21 years living in the US.

Results:
Almost 2% of participants (n=50, 1.9%) qualified for statin treatment under the pediatric guidelines, but only 0.7% (n=18) met treatment criteria under the adult guidelines. Participants who met pediatric criteria had lower mean LDL levels but were more likely to have other cardiovascular risk factors, including hypertension, smoking, and obesity (Table 1). Despite the relatively low percentage of participants reaching LDL treatment thresholds under either guideline, 258,816 U.S. young people would be eligible for statin treatment under the pediatric guidelines and 84,651 would be eligible for treatment under the adult guidelines.

Conclusions:
Providers who care for adolescents transitioning to adulthood are faced with incongruent lipid guidelines. Application of pediatric guidelines, which use a life course approach and consider additional cardiovascular risk factors beyond age, may result in statin treatment for more young people.
Abstract 17661: Optical Coherence Tomography Identifies Artifactual Thin-cap Fibroatheromas: A Histologic Study
Authors: Phipps Jennifer E , Vela Deborah , Hoyt Taylor , Buja L. Maximilian , Milner Thomas E , Feldman Marc D
Published: July 2021

Introduction:
Current methods to identify thin-cap fibroatheroma (TCFA) with optical coherence tomography (OCT) are qualitative. While two mechanisms for the appearance of false TCFA have been identified and include macrophages that cause superficial shadowing and tangential light dropout, we report three new mechanisms for the appearance of false TCFAs in OCT images.

Methods:
13 coronary arteries from 8 human cadaver hearts (6 male, 2 female, aged 63 ± 12 years) were imaged with OCT. OCT TCFAs were identified independently by three expert OCT readers and defined by a bright homogenous fibrous cap overlying a diffusely shadowed signal-poor region. Analysis was performed to confirm the identification of TCFA or to identify the histologic origin of the OCT TCFA appearance. Arc length of the signal-poor region of each OCT TCFA was also measured.

Results:
38 OCT TCFA were identified, of which only 5 were verified with histology. Measurements of arc length and thickness of the cap are summarized in the table. Of the 33 false TCFA, three morphologic plaque types were identified: thick-cap fibroatheroma (TkFA; N=18), pathologic intimal thickening (PIT; N=10), and fibrocalcific (FC; N=5). New mechanisms for the signal-poor regions that appeared as lipid cores included loose connective tissue (N=7), neovasculature (N=3), and proteoglycans (N=4). Superficial shadowing of macrophages caused the appearance of TCFA in 5 cases. In the 18 TkFA cases, OCT underestimated the thickness of the fibrous cap (45.2 ± 4.0 μm by OCT compared to 197.5 ± 18.8 μm by histology).

Conclusion:
Using an arc length of greater than 90 degrees will aid in differentiating true from false TCFA. Additionally, due to incomplete light penetration, TkFA can be mistaken for TCFA. These results demonstrate that caution should be used when diagnosing vulnerable plaque with OCT.
Abstract 17672: Interaction of Global Coronary Vasomotor Dysfunction and Early Revascularization on Adverse Cardiovascular Outcomes
Authors: Taqueti Viviany R , Hachamovitch Rory , Murthy Venkatesh , Naya Masanao , Foster Courtney , Hainer Jon , Dorbala Sharmila , Blankstein Ron , Di Carli Marcelo F
Published: July 2021

Background:
Coronary vasomotor dysfunction identifies patients at risk for cardiac death. We sought to determine the association between global coronary flow reserve (CFR, an integrated measure of coronary vasomotor function) and adverse cardiovascular events, in patients referred for coronary angiography with or without subsequent revascularization.

Methods and Results:
Consecutive patients (n=329) without prior coronary artery bypass surgery (CABG), heart failure, or left ventricular (LV) systolic dysfunction referred for invasive coronary angiography after stress testing with myocardial perfusion positron emission tomography (PET) were followed (median 3.1 years) for cardiovascular death and heart failure admission. Extent and severity of coronary angiographic stenosis was estimated using the CAD prognostic index (CADPI) and CFR measured noninvasively by PET. A subset of patients (n=193) underwent early revascularization, defined as CABG and/or percutaneous coronary intervention (PCI) within 90 days after PET. After adjusting for clinical risk score, LV ejection fraction, LV ischemia, CADPI, and time-dependent early revascularization with CABG and/or PCI, CFR remained independently associated with events (hazard ratio for unit decrease in CFR, 2.02; 95% CI 1.20-3.40, p=0.008). In adjusted analysis, there was a significant interaction (p=0.04) between CFR and early revascularization by CABG, such that patients with impaired CFR who underwent CABG (n=39), but not PCI (n=154), experienced event rates comparable to those with preserved CFR, independently of revascularization.

Conclusions:
CFR associated with adverse cardiovascular outcomes independently of angiographic severity, and modified the effect of early revascularization. Diffuse atherosclerosis and microvascular dysfunction may contribute to the pathophysiology of cardiovascular death and heart failure, and impact upon the outcomes of revascularization.
Abstract 17713: A Three year Retrospective Analysis of Adverse Cardiac Outcomes in Heart Failure Patients Using Cocaine on Beta-blockers
Authors: Akpa Bimaje , Nwazue Victor , Bhoggireddy Varija , Okafor Henry
Published: July 2021

Background:
It is an established fact that beta-blockers (BB) improve survival in patients with HFrEF. However cocaine abusers with HFrEF are currently excluded from this life-saving treatment due to concerns with a theoretical risk of unopposed alpha adrenergic receptor-mediated coronary vasospasms and possible myocardial infarctions (MI). Our study seeks to compare heart failure (HF) outcomes in patients on beta blockers with surreptitious cocaine abuse to those not receiving beta blockers.

Methods:
From our HF registry, we retrospectively identified 132 patients admitted to the hospital for CHF with related complaints like chest pain or shortness of breath between 2006 and 2008 and cocaine positive drug test. We reviewed the concomitant use of BB in relation to the primary composite end points: MI, total ER visits, HF related admissions 2006-2008, ejection fraction (EF), mean BNP and all- cause mortality. Characteristics of patients with and without BB use were compared using chi-square for categorical and t-test for continuous variables. Considering the variance in baseline characteristics between patients, we also adjusted for co-founding factors like age, sex, Body mass index (BMI) and race before evaluating the independent relationship between BB use and the composite primary endpoints listed above.

Results:
BB were used in 60 patients (45%), no distinction was made between selective BBs or nonselective BBs. The analysis of our cohort data showed no significant difference in the number of MI (p - 0.819), ER visits (p - 0.627), HF- related admissions (p-0.382), mean BNP (p-0.480), EF (p-0.273) in HF patients using cocaine on BB vs those not on BB. Findings were similar after adjusting for cofounding variables - race, sex, BMI and race (OR for having an MI with BB use was 1.185[95% CI 0.277-5.069]).

Conclusions:
BB treatment of HFrEF with concomitant cocaine abuse may be safer than previously suggested. Prospectively randomized trials will be needed to clarify the safety of beta blockers in cocaine abusing HFrEF patients.

Limitations:
Our study was limited by the absence of distinction between selective and nonselective BB as alpha-blocking BBs like carvedilol have been proposed as safe since they can moderate the theoretical alpha mediated effects of cocaine.
Abstract 17767: A MiR-31-dependent Loss of Dystrophin & Nnos in the Human Atria Plays a Key Role in Atrial Fibrillation-induced Electrical Remodelling
Authors: Reilly Svetlana , Liu Xing , Carnicer Ricardo , Rajakumar Timothy , Sayeed Rana , Krasopoulos George , Verheule Sander , Fulga Tudor , Schotten Ulrich , Casadei Barbara
Published: July 2021

Background:
Management of atrial fibrillation (AF) remains a challenge. AF remodels the atrial electrical properties, thereby increasing resistance to treatment. Although remodeling has long been a target for therapeutic intervention in AF, the mechanisms driving this phenomenon are incompletely understood.

Methods & Results:
Using atrial samples from 351 patients (73 AF), and 67 goats (34 AF), we show that atrial-specific upregulation of miR31 causes dystrophin (DYS) translational repression and accelerates mRNA degradation of neuronal nitric oxide synthase (nNOS) leading to a profound reduction in NO availability. Six prediction algorithms and reporter assays established DYS and nNOS as miR-31 targets. In atrial myocytes from patients with AF (hAFm), both DYS and nNOS bind to miR-31 within the RNA induced silencing complex (RISC). In actinomycin D-treated myocytes from patients in sinus rhythm (hSRm), miR31 accelerated nNOS (but not DYS) mRNA decay. mRNA of nNOS (but not DYS) & protein content of nNOS, DYS & DYS associated proteins were significantly reduced in hAFm. Inhibition of miR31 in hAFm restored both DYS & nNOS protein. Protection of the nNOS miR31 binding site with a target site blocker (TSB) restored nNOS mRNA and protein (but not DYS), whereas, DYS-TSB increased both DYS and nNOS protein (but not mRNA), in keeping with an effect of DYS restoration on nNOS protein stability. Indeed, K48-linked polyubiquitination of nNOS was increased in hAFm & prevented by proteasome inhibition with MG132.

NOS:
inhibition (SMTC, 100 nmol) or transfection with a miR31 mimic was employed to evaluate the impact of these findings on atrial electrical properties. Both interventions shortened action potential duration (APD90) and abolished rate-dependency of the APD90 in hSRm but not in hAFm. By contrast, miR31 inhibition restored APD & APD rate-dependency in hAFm (both reversed by SMTC) but had no effect on hSRm. In mice (n=126), nNOS gene deletion or inhibition shortened atrial APD90 & lead to a 2-fold increase in AF inducibility in response to atrial burst pacing.

Conclusions:
These findings identify atrial-specific upregulation of miR31 in human AF as a key mechanism causing atrial loss of dystrophin and nNOS, which, in turn, lead to the electrical phenotype begetting AF.
Abstract 17784: The Genesips Project: an NHLBI-Sponsored induced Pluripotent Stem Cell (iPSC) Resource for the Study of Cardiovascular Diseases
Authors: Carcamo-Orive Ivan , Cundiff Paige , Lancero Hope , Shahbazi Mohammad , Abbasi Fahim , Abraham Sheena , Reaven Gerald , Whalen Sean , D’Souza Sunita , Pandey Gaurav , Patel Achchhe , Schadt Eric , Lemischka Ihor , Knowles Joshua , Quertermous Thomas
Published: July 2021

The study of complex cardiovascular disease (CVD) has been hampered by the lack of appropriate human cellular model systems. In response, the NHBLI sponsored the NextGen Consortium, which encompasses 9 independent efforts spanning the portfolio of NHLBI related phenotypes. The goals of the consortium include: 1. To develop and improve methods for large-scale production and characterization of induced pluripotent stem cell (iPSC) models for CVD; 2. To create a resource of iPSC lines from a large number of phenotypically and genotypically characterized individuals.

Our GENESiPS project is focused on insulin resistance (IR), a condition that affects 25-33% of the US population with serious health consequences including risk of type II diabetes and CVD. Although much is known about the physiological changes occurring during IR, little is known about the molecular pathways that drive the appearance of IR. Certain mature cell types as adipocytes, endothelial cells and skeletal muscle cells have been associated with the origin, maintenance and progression of IR. IPSCs offer an unprecedented opportunity of modeling human disease in vitro. We have created iPSC lines on insulin resistant and insulin sensitive patient groups with prior GWAS genotyping. Differentiation of these iPSCs to relevant cell types is providing the opportunity to correlate insulin sensitivity and high-density genetic variation data with specific cell-based profiling. We will validate our in vitro model and study the molecular pathways that define IR and its relationship to endothelial dysfunction.

Relevant to the larger scientific community the establishment of iPSC lines on over 150 individuals (3 to 6 clones per patient) that reflect the range of insulin resistance in the general population. The iPSC lines were created from erythroblasts using the non-integrative Sendai virus system, passaged to allow clearance of Sendai virus and growth in feeder free conditions. The lines have been extensively characterized for markers of pluripotency (Tra1-60), sample identity and genomic integrity. Through the NextGen consortium, these lines, as well as phenotypic and genome-wide genotyping data will be available to qualified investigators.
Abstract 17791: Yield of Different Approaches for Screening for Cardiovascular Disease in Asymptomatic Diabetics
Authors: Churchill Timothy W , Rassi Carlos H , Fernandes Tavares Carlos A , Fahel Mateus G , Rassi Fabricia P , Uchida Augusto H , Wajchenberg Bernardo L , Lerario Antonio C , Hulten Edward , Bittencourt Marcio S , Blankstein Ron
Published: July 2021

Introduction:
While diabetes has long been considered a coronary heart disease equivalent, there is increasing evidence to suggest that not all individuals with diabetes have cardiovascular disease, and it is unclear how best to risk stratify this population. We sought to compare the yield of testing for pre-clinical atherosclerosis with various approaches.

Methods:
A group of 98 asymptomatic subjects with type 2 diabetes mellitus (T2DM) without known coronary artery disease (CAD) were enrolled in a prospective study and underwent carotid ultrasound, exercise treadmill testing (ETT), coronary artery calcium (CAC) scoring, and coronary computed tomography angiography (CTA). CTA was used as the reference standard for CAD.

Results:
Of 98 subjects (average age 55±6, 64% female, 22 on insulin, mean A1c 7.3%), 43 (44%) had coronary plaque detectable on CTA, and 38 (39%) had CAC score > 0. By CTA, 16 (16%) had coronary stenosis ≥ 50%, including 3 subjects with CAC=0. Subjects with coronary plaque had greater prevalence of carotid plaque (58% vs. 38%, p=0.01) and greater carotid intima media thickness (0.80±0.20 mm vs. 0.70±0.11mm, p=0.02). However, 18 of the 55 subjects (33%) with normal CTA had carotid plaque. Eight subjects had a positive ETT, of whom 5 had ≥ 50% coronary stenosis and 2 had <50% stenosis, but there was no difference in METS achieved between subjects with and without plaque (8.2 vs. 8.7, p=0.19). Test characteristics of different imaging modalities for prediction of coronary plaque are shown in Figure 1.

Conclusion:
Among asymptomatic subjects with T2DM, a majority (56%) had no CAD by CTA. CAC was the most accurate screening modality for detection of CAD while ETT and carotid ultrasound had a limited sensitivity. Interestingly, 33% of subjects with normal CTA had carotid plaque. Further studies are needed to better characterize stroke risk in such patients and whether there is a role for screening for carotid plaque in diabetics without CAC or with normal CTA.
Abstract 17797: Noninvasive Optical Imaging of Response to On-Demand Antioxidant Therapy in a Model of Peripheral Arterial Disease
Authors: Poole Kristin M , Nelson Christopher E , Martin John R , McCormack Devin R , Joshi Rucha V , Skala Melissa C , Duvall Craig L
Published: July 2021

Peripheral arterial disease is often modeled by surgical induction of hind limb ischemia (HLI) in mice to study collateral vessel development. However, there is a need for methodologies that provide intravital, multifunctional, quantitative data on ischemic recovery for robust evaluation of new therapeutics. Here, we apply hyperspectral imaging and optical coherence tomography (OCT) to longitudinally assess hemoglobin oxygen saturation (SaO
2
) and vessel morphology in response to a novel therapy. Injectable microspheres loaded with curcumin were synthesized from reactive oxygen species (ROS)-responsive poly(propylene) sulfide (PPS) to provide “on demand”, local release of the antioxidant drug curcumin to reduce tissue-damaging oxidative stress in a mouse model of diabetic HLI. Curcumin-PPS microspheres significantly reduced intracellular ROS in LPS-activated RAW 264.7 macrophages and rescued viability of 3T3 fibroblasts treated with cytotoxic levels of H
2
O
2
in vitro
. HLI was induced in FVB mice with streptozotocin-induced diabetes, and curcumin-PPS or blank-PPS microspheres were injected into the ischemic limb. Curcumin-PPS significantly improved recovery of SaO
2
in the ischemic footpad relative to blank-PPS and vehicle (saline) groups over a one week time course evaluated with hyperspectral imaging (n≥8/group, p<0.05). Vessel structure in the gastrocnemius was imaged noninvasively with OCT at day 7 (Figure), revealing trends toward increased vessel area density and vessel length fraction in the curcumin-PPS group (n=5/group). The vessel diameter distribution was also extracted from OCT data. Our collective data indicate that sustained, on demand curcumin delivery has significant therapeutic promise for improving ischemic tissue recovery. Also, the hyperspectral and OCT imaging methods showcased provide quantitative, noninvasive monitoring of vasculature and can accelerate screening of novel therapies.
Abstract 17802: Ips Cells -derived Cardiac Progenitors Induce Dramatic Cardiac Regeneration and Improve Function by Cxcr4 Signaling Pathway in Infarcted Myocardium
Authors: Pasha Zeshan , Saeed Romana , Ashraf Muhammad
Published: July 2021

Background:
The participation of endogenous cardiac stem/progenitor cells is limited in restoring cardiac structure and function in the ischemic myocardium which is further aggravated by poor survival and propagation of transplanted stem cells of different origin in the infarcted heart. The goal of this study was to explore the survival and engraftability of newly discovered induced pluripotent stem cells (IPS) in the myocardium following infarction (MI).

Methods and Results:
Integration free iPS were generated from myoblasts and characterized. Cardiac progenitors (CPs) were created by treatment with a small molecule. CPs proliferation was assessed by BrdU labeling; Differentiation by both RT-PCR and immunofluorescent staining for cardiac markers Nkx2.5, actinin, and -MHC. Gene expression profiling was performed using Affymetrix array. In vivo studies were carried out by injecting CPs or nontreated IPS (3x105), into mouse model of permanent LAD. Echocardiography, histological parameters, TUNEL assay and capillary vessel density were measured 6 weeks post transplantation. Treatment of IPS with a small molecule upregulated Nkx2.5 and maintained up to 4 weeks (p<0.01 vs nontreated IPS). Expression of actinin and -MHC was also detectable at 3 weeks. Increased proliferative activity (p<0.01) evaluated by cell proliferation and Brdu assay was observed. Significant CPs survival and reduced apoptosis were noticed in the small molecule treated iPSC compared to nontreated and/or saline group. Enhanced ejection fraction and fractional shortening (p< 0.05) was observed 6 weeks post transplantation. Interestingly there was 2-3 fold upregulation of chemokines including CCL7, CXCR2, CXCR5. miR Microarray analysis showed upregulation of cardiac specific mir-133,762. Western blot analysis showed increased phospho-Akt levels as compared to nontreated IPSC (p<0.01). Survival and differentiation properties of CPs were abolished by concomitant treatment of IPS with CXR4 blocker (p<0.05).

Conclusion:
This study provides a novel strategy for generating CPs and their enhanced survival, engraftment and differentiation with the treatment of cardiogenic small molecule post transplantation in the infarcted myocardium through CXCR4 signaling pathway.
Abstract 17809: In Vivo High Resolution Isotropic 3D MRI of Coronary Atherosclerosis in Hypertensive Hypercholesterolemic Minipigs
Authors: Al-Mashhadi Rozh H , Hansen Esben S , Bloch Lars ø , Al-Mashhadi Ahmed H , Ringgaard Steffen , Botnar René M , Kim Won Y , Bentzon Jacob F
Published: July 2021

Introduction:
Accurate non-invasive visualization and quantification of coronary atherosclerosis may greatly facilitate clinical research and practice, but the lack of suitable human-sized atherosclerosis models with progressive coronary lesions has hampered development and validation of reliable imaging techniques.

Methods:
D374Y-PCSK9 transgenic minipigs with (n=7) or without (n=8) hypertension, induced by suprarenal aortic banding, were placed on a cholesterol-rich diet for 16 months. Wildtype minipigs (n=4) on normal diet served as disease-free controls. A T1-weighted inversion recovery fast gradient echo magnetic resonance imaging (MRI) sequence was used to acquire 1x1x1mm images of the coronary arteries. MRI scans were conducted following injection of a gadolinium labeled elastin specific contrast agent (LMI1174). Pigs were subsequently euthanized and the coronary arteries were processed for pathological analysis. LMI1174 was provided by Lantheus Medical Imaging under a material transfer agreement

Results:
Hypertension significantly augmented coronary fibroatheromas by more than 5-fold compared to normotensive transgenic pigs. No signal enhancement was observed in lesion-free coronaries of wildtype pigs. In hypertensive pigs, there was a strong correlation between plaque area measured by MRI and plaque area measured postmortem r2=0.84, p=0.02 (Fig 1).

Conclusions:
Hypertensive transgenic minipigs with accelerated coronary atherosclerosis provide a useful model for coronary imaging. Using this model we were able to develop a high-resolution isotropic LMI1174-enhanced scanning technique that accurately depicts coronary atherosclerotic lesion size and distribution.

Figure 1:
A) Digitally unfolded and color coded MRI of the LAD (left) and corresponding sudan IV stained segment opened and viewed en face (right). B) Cross-sectional MRI of another LAD and corresponding histological sections showing fibroatheromas.
Abstract 17878: Calmodulin Mutation (CALM-F90L) Associated With Familial Idiopathic Ventricular Fibrillation Disrupts L-type Ca Channel Inactivation and Activates Sarcoplasmic Reticulum Ca Release in Ventricular Myocytes
Authors: Kryshtal Dmytro , Hwang Hyun S , Johnson Christopher , Chazin Walter , George Alfred L , Knollmann Bjorn
Published: July 2021

Introduction:
The F90L mutation in calmodulin (CaM) has been associated with a familial form of autosomal-dominant idiopathic ventricular fibrillation (IVF) with features of exercise-induced QT prolongation, but the underlying arrhythmia mechanism is unknown. We previously found that CaM mutations that cause sudden death due to catecholaminergic polymorphic ventricular tachycardia (CPVT) activate ryanodine receptor (RyR2) Ca release channels; whereas CaM mutations associated with long QT syndrome (LQTS) have no effects on RyR2 channels but prolong the cardiac action potential by impairing L-type Ca current inactivation.

Objective:
To determine the effect of F90L mutant CaM on Ca binding affinity, L-type Ca currents and Ca handling and compare them to CaM mutants associated with CPVT (CPVT-CaM) and LQTS (LQTS-CaM).

Methods and Results:
We prepared recombinant wild-type (WT) and mutant CaM proteins associated with CPVT (N54I), LQTS (D96V, D130G, F142L) and IVF (F90L). Similar to LQTS CaMs, the F90L IVF mutation drastically reduced Ca binding affinity of CaM C-lobe (7-fold reduction compared to WT-CaM), whereas CPVT N54I has no effect. In voltage-clamped mouse ventricular myocytes dialyzed either with WT or mutant CaM, IVF-CaM F90L significantly impaired L-type Ca channel inactivation, similar to the effect of LQTS-CaMs, whereas CPVT-CaM had no effect (Fig. A, **p<0.01 vs WT). Next, mutant CaMs effects on sarcoplasmic reticulum Ca release were tested in permeabilized ventricular myocytes. At physiological free CaM [100 nM] and Ca [120 nM], IVF-CaM F90L increased spontaneous Ca wave activity analogous to CPVT-CaM N54I, but of significantly smaller effect size (Fig. B). In contrast, LQTS-CaMs had either no effect or reduced Ca waves (Fig. B).

Conclusion:
The F90L CaM mutation shares characteristics with both CPVT and LQTS CaMs, which may help explain clinical features of modest exercise-induced QT prolongation and sudden arrhythmic death in patient carriers.
Abstract 17881: Overcoming the Tyranny of Distance- an Analysis of Out-Reach Visits to Optimise Secondary Prevention of Cardiovascular Disease in High Risk Individuals Living in Central Australia
Authors: Tuttle Camilla , Carrington Melinda , Stewart Simon , Brown Alex ,   on behalf of the CAHPS Trial Investigators
Published: July 2021

Introduction:
Compared to the non-Indigenous of the population, Aboriginal Australians have a life expectancy that is 15-20 years less. Inequitable access to healthcare services (particularly in remote areas) contributes to this phenomenon.

Objectives:
We examined the logistical challenges of providing outreach visits, as part of an outreach, secondary prevention program in Central Australia for CVD.

Methods:
Prospective data from the Central Australia Heart Protection Study (n=200), a pragmatic, single-center, randomized study of a nurse-led, family-based, secondary prevention program designed to reduce major cardiac events, were analyzed. Clinical and logistic data were used to examine the characteristics of outreach visits for 50 consecutive subjects initially randomized to the study intervention.

Results:
Most subjects had presented with an acute coronary syndrome (44/50 [88%]) and 31 (62%) self-identified as Indigenous. Despite a similar gender profile (55% versus 58% Indigenous and non-Indigenous women), Indigenous subjects had a greater risk factor and co-morbid profile, with significantly more diabetes (77% vs. 26% p = 0.0002), hypertension (81% vs. 53% p = 0.04) and renal failure (52% vs. 21% p = 0.03). The community of origin of Indigenous subjects was 230 ± 208 km from the central hospital compared to 61 ± 150 km for the rest (p = 0.004). There was no difference in the number of subjects who missed initial baseline and ad hoc visits attended by the health care team according to ethnicity. However, perhaps reflecting their greater mobility, Indigenous subjects missed a significantly higher number of scheduled visits at 6 months (1.39 ± 2.14 vs. 0.16 ± 0.50 visits; p = 0.02). Finally, multivariate analyses (including all baseline profiling data) suggested that distance from Alice Springs did not influence completion of outreach visits.

Conclusions:
These data are invaluable to understanding and improving the cost dynamics and impact of secondary prevention for Indigenous adults living with heart disease remote from specialist health services.
Abstract 17883: Racial and Insurance disparities in Paroxysmal Supraventricular Tachycardia Ablation
Authors: Patel Nileshkumar J , Patel Achint , Patel Neil , Solanki Shantanu , Deshmukh Abhishek , Dhaduk Grishma , Manvar Sohilkumar , Arora Shilpkumar , Patel Nilay , Badheka Apurva O , Kowalski Marcin , Paydak Hakan , Viles Gonzalez Juan F , Myerburg Robert J , Mitrani Raul D
Published: July 2021

Objective:
To identify racial and/or health insurance disparities in the population undergoing ablation for paroxysmal supraventricular tachycardia(PSVT).

Method:
We identified adult patients (pts) admitted with principle diagnosis of PSVT by ICD 9 code 427.0 who had catheter ablation (ICD 9 code - 37.34), using the Nationwide Inpatient Sample (2000-2011). We stratified patients by race (White, Black, Hispanic, and other minority racial groups)and insurance status, and a hierarchical mixed effect multivariate model was created to identify independent predictors of PSVT ablation.

Results:
64,564(20.2%) patients underwent ablation out of 319,579 patients admitted for PSVT during the period of 2000-2011. In absolute numbers, the majority of ablations were performed in Whites (58.7%) and patients with Medicare (56.3%) or private insurance (30.1%). After adjusting for confounding factors, the odds of having ablation were lower in Black pts (compare to White), and Medicare, Medicaid, and Uninsured pts (compare to private insurance) (see table). Other predictors of lower rate of ablations were: older age and female patients while odds of receiving ablation were higher for elective admissions and in teaching hospitals (p<0.001 for all comparisons).

Conclusion:
In a population of pts admitted for PSVT, those without private insurance and Black pts were less like to be treated with catheter ablation; and, this disparity persisted from 2000-2011. Since catheter ablation for PSVT is generally considered a curative procedure, future studies are needed to identify the factors that lead to these disparities of care.
Abstract 17939: Lack of the Alpha-11 Integrin in the Heart is Associated With Progressive Diastolic Dysfunction, Myofibrillar Disarray and Impaired Cardiomyocyte Growth
Authors: Civitarese Robert A , Talior-Volodarsky Ilana , Mitchell Melissa , Desjardins Jean-François , Kabir Golam , Gullberg Donald , McCulloch Christopher A , Connelly Kim A
Published: July 2021

BACKGROUND:
Integrins, transmembrane receptors, play crucial roles in diverse cellular and developmental processes due to critical interactions with the extracellular matrix (ECM). During fetal development and towards adulthood, heart growth and function is suggested to depend on forming and remodeling the ECM and its connection to the myocyte. Currently however, the role of integrins in cardiovascular development (CVD) is poorly defined. Thus, we hypothesized that the α11 integrin (α11), which is expressed by fibroblasts and binds preferentially to type I collagen fibers, plays a vital role in CVD.

METHODS:
α11 KO and wildtype littermate mice (both n = 8) were examined at 4 weeks and 8 weeks of age. Animals underwent function assessments, including echocardiography and invasive pressure volume (PV) loop analysis, and structural examination via histological and electron microscopy (EM) analysis.

RESULTS:
At 4 weeks, heart weight (HW) and HW indexed to tibial length were decreased in α11 KO mice (P < 0.05), which were normalized at 8 weeks. Echocardiography revealed reduced end-diastolic area (EDA) at 4 weeks (P < 0.05). Despite normalization of EDA at 8 weeks, PV loop revealed impaired diastolic function as evidence by increased EDP, prolonged Tau and steeper EDPVR (all P < 0.05). No differences in HR or systolic parameters were evident.

α11 KO mice also demonstrated structural changes. WGA staining revealed evidence of myofibrillar disarray. Connexin 43 and desmin staining showed increased Z-disk and intermediate filament clustering, respectively. LV myocyte size was also reduced (P < 0.05). Similarly, EM analysis showed reduced cardiomyocyte thickness and distance between end plates (both P < 0.05).

CONCLUSION:
Loss of α11 resulted in progressively worsening diastolic function that was associated with myofibrillar disarray and impaired cardiomyocyte growth. These findings suggest that α11 is required for the development of normal heart structure and function.
Abstract 17955: Thereapeutic Angiogenesis Induced by Human Trx-1 Gene in Mice Hind Limb Ischemia Model: Preclinical Study for Treatment of Peripheral Artery Disease
Authors: Thirunavukkarasu Mahesh , Shaikh Inam A , Selvaraju Vaithinathan , Palesty J.Alexandar , Maulik Nilanjana
Published: July 2021

Introduction:
Peripheral artery disease affects 12-20% Americans over the age of 60. Thioredoxin-1 (Trx-1) is a class of small redox proteins. We have demonstrated earlier that Trx-1 reduces oxidative stress resulting in less inflammation and increased angiogenesis in cardiac muscle via heme oxygenase-1 (HO-1) and VEGF after myocardial infarction. In the current study, we evaluate the effect of Trx-1 on post-ischemic hindlimb recovery.

Methods:
Peripheral artery disease was mimicked using a hindlimb ischemia (HLI) model. Wild type (WT) and Trx-1 transgenic (Trx-1Tg/+) mice (8-12 weeks old) were subjected to femoral artery ligation. Following surgery, mice were observed for 5 weeks. Serial laser doppler images were obtained, and perfusion ratios between the ischemic and non-ischemic limbs were calculated at set time intervals. The perfusion ratios were compared between WT and Trx-1Tg/+ groups. Immunohistochemical analysis of the skeletal muscle was performed to quantify the extent of fibrosis, capillary and arteriolar density 35 days after surgery. In addition, another set of experiments was designed with Ad.Trx-1 gene therapy after femoral artery ligation to study the molecular mechanism of neovascularization with Trx-1.

Results:
The recovery of hind limb perfusion was significantly increased in Trx-1Tg/+ mice at day 7 (0.19 ± 0.03 vs. 0.36 ± 0.07 (n=12-9), day-21 (0.37 ± 0.05 vs. 0.62 ± 0.03 (n=12-9), and day 28 (0.40 ± 0.04 vs. 0.79 ± 0.04 (n=10-9); p<0.05). Capillary density [1265 ± 87.8 vs. 762.4 ± 86.6 counts/mm2 ; (n=5); p<0.05] and arteriolar density [36.2 ± 2.96 vs. 22± 1.33 counts/mm2 ; (n=5); p<0.05] staining showed significant increase in Trx-1Tg/+ mice as compared to WT mice. Picrosirrus Red and immunofluorescence staining showed decreased fibrosis [8.3 ± 0.46 vs. 22.2 ± 1.04 (n=5); p<0.0001] and increased HO-1 expression respectively in Trx-1Tg/+ mice group as compared to WT mice, respectively. Trx-1 gene therapy study also revealed by Western blot analysis, increased Trx-1 (4.2 fold) and HO-1 (8.2 fold) expression in Ad.Trx-1-HLI as compared to Ad.LacZ-HLI.

Conclusions:
Our results suggest that Trx-1 is a potential therapeutic agent to increase blood perfusion and angiogenesis for the treatment of critical limb ischemia patients.