tbuckley/cabot-search huggingface dataset:
Abstract 16605: Peripheral Blood-Derived Myeloid Subtypes Are Associated With Cardiac Allograft Vasculopathy
Authors: Luise Holzhauser, Allison Schroeder, Kathryn A Arnold, Teruhiko Imamura, Ann Nguyen, Ben Chung, Nikhil Narang, Daniel Rodgers, Valluvan Jeevanandam, Catherine Murks, Tiana Riley, JoDel Powers, Nitasha Sarswat, Sara Kalantari, Jayant Raikhelkar, Gabriel Sayer, Gene H Kim, Nir Uriel, Francis J Alenghat
Journal: Circulation (2018)

Introduction: The evidence for innate immunity’s role in cardiac allograft rejection does not necessarily extend to cardiac allograft vasculopathy (CAV), and predictors of CAV remain elusive. We hypothesize that circulating monocytes and their derived macrophage subtypes, as well as associated inflammatory and angiogenesis markers, correlate with CAV. Methods: 49 consecutive heart transplant recipients over 2 years post-transplant were enrolled. Peripheral blood mononuclear cells were isolated, with monocytes stained and measured by flow cytometry for classical (CD14 ++ /CD16 - ), intermediate (CD14 ++ /CD16 + ), and nonclassical (CD14 lo /CD16 ++ ) subtypes. Monocytes were cultured into macrophages, driven by M-CSF, and assayed for polarization markers CD86 and CD206. Serum concentrations of multiple factors including IL8, IL6, TNFα, angiopoietin-2, and VEGF-A were measured by immunoassay. CAV was assessed by angiogram and intravascular ultrasound (IVUS). Results: 22 patients had no significant CAV (Stanford class I-II) while 27 had significant CAV by angiogram or IVUS (class III-IV). Other than time since transplant (77±13 vs 135±12 months), baseline characteristics of the two groups were similar. There were no differences between monocyte subgroups in isolation, but when combined with derived macrophage polarization, patients with CAV tended toward lower M2 (CD206 + ) macrophage production (0.18±0.04%) than those without CAV (0.35±0.11%). The CAV monocyte/macrophage profile was distinct from that of a reference native CAD population. IL8 was higher late post-transplant (&gt;7.5 years) compared to early post-transplant (1.8±0.3 vs 1.0±0.1 pg/ml). There was also higher expression of angiopoietin-2 with time after transplant and with CAV. Conclusions: The reduced ability of CAV patients to generate regulatory M2 macrophages and their higher circulating IL8 and angiopoietin-2, both linked to inflammatory macrophage signatures, support a model in which pro-inflammatory myeloid phenotypes are connected to development of CAV, and notably, these circulating monocyte and macrophage subtypes differ from those of native CAD. These cell-based and paired circulating markers could be useful to differentiate high vs. low CAV risk phenotypes.
Abstract 16836: Incidence and In-Hospital Outcomes of Post-Operative Venous Thromboembolism in Patients Undergoing Coronary Artery Bypass Surgery - a National Analysis
Authors: Muhammad S Panhwar, Ankur Kalra, Tanush Gupta, Sahil Khera, Mahazarin Ginwalla
Journal: Circulation (2018)

Introduction: Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is rare after coronary artery bypass grafting (CABG). Given the low incidence of VTE, post-operative anticoagulation in these patients is controversial. Given the low rate of VTE, prior studies on this topic may not have been adequately powered to detect adverse outcomes. We sought to investigate the post-operative incidence and outcomes of VTE in CABG patients using a large national in-patient database. Methods: We utilized the 2013-2014 National Inpatient Sample to identify all patients over 18 years of age who underwent CABG without concomitant valvular procedures (isolated CABG) and had VTE during the hospital stay. We then compared clinically relevant outcomes in patients with and without VTE. Results: Of 59,391,030 patients, we identified 401,075 (0.7%) hospitalizations with CABG listed as the primary or secondary procedure. We excluded 69,125 hospitalizations with concomitant valvular procedures, resulting in 331,950 procedures for isolated CABG. Of these, 4,205 (1.3%) had VTE. Patients with VTE were more likely to be older (mean 67.2 vs 65.2 years, p&lt;0.0001), female (30.4% vs 25.2%, p&lt;0.0001), have coagulopathy (32.0% vs 17.8%, p&lt;0.0001), and prior VTE (4.5% vs 1.8%, p&lt;0.0001). Patients with VTE also had higher hospital costs (median $74,639 vs $40,702, p&lt;0.0001) and longer length of stay (median 16 vs 8 days, p&lt;0.0001). In multivariate regression analysis adjusting for baseline patient characteristics, patients with VTE had higher odds of inpatient mortality (adjusted odds ratio(aOR) 2.10 [95% confidence interval: 1.53-2.90]; p&lt;0.0001), acute kidney injury (aOR 2.50 [2.12-3.05]; p&lt;0.0001), dialysis (aOR 1.81 [1.17-2.81]; p = 0.008), acute respiratory failure (aOR 2.98 [2.55-3.49]; p&lt;0.0001), and stroke (aOR 2.78 [2.00-3.87]; p&lt;0.0001). Discussion: Our analysis of over 330,000 CABG procedures suggests that while post-operative VTE after CABG is rare, it is a strong independent predictor of adverse in-patient outcomes. Clinicians taking care of such patients should consider prophylactic mechanical or pharmacologic measures to prevent VTE when safe to do so.
Abstract 16747: High Incidence of Congenital Heart Defects in a Dominant Mouse Forward Genetic Screen Using Fetal Echocardiography
Authors: Tuantuan Tan, Michael Wang, Caleb W Radomile, Sebastian Elliot Ho, Devine William, Xiaoqin Liu, Reinholdt Laura, Yijen Wu, Lauren Elizabeth Meyer, Cecilia W Lo
Journal: Circulation (2018)

Introduction: Congenital heart disease (CHD) is largely sporadic and suggested to be largely mediated by non-Mendelian or complex genetics. We previously showed the efficacy of mouse mutagenesis in recovering recessive mutations causing CHD. Here we hypothesize the complex genetics of human CHD can be modeled in mice using a sensitized mutagenesis screen for dominant mutations causing CHD. Methods: C57BL/6J mice were mutagenized using ethylnirosourea, then mated with C57BL/6J mice to generate G1 males that were further mated to females harboring heterozygous “driver” mutation ( Kif7, Anks6, Sap130 ) that can cause CHD when in homozygosity. The G2 fetuses generated by each G1 male were considered a pedigree and were ultrasound scanned (US) at E13.5-19.5 using a 40 MHz transducer with the Vevo2100 ultrasound system. Results: We US scanned 17,750 fetuses from 487 G1 pedigrees, yielding 123 fetuses with CHD from 90 G1 lines (Table 1A). Interestingly, the overall incidence of CHD (0.69%) is similar to that observed in the previous recessive mutagenesis screen (0.76%) (Table 1A). Surprisingly, no laterality mutants were recovered compared to the 2.2% recovered in the recessive screen (Table 1A). Regardless of the driver mutations, similar spectrum of CHD was observed (Table 1B). Besides VSD, the predominant CHD phenotype observed was double outlet right ventricle and overriding aorta (Fig.1) and atrioventricular septal defect (Table 1B). Conclusion: We showed the feasibility of using mice to model dominant mutations causing CHD. The incidence of CHD observed in the dominant screen was similar to that of the recessive screen, indicating the genetics of CHD in mice and human are similar.
Abstract 13701: Short Term Outcomes of Takotsubo Cardiomyopathy in Patients With Right Ventricular Dysfunction in the US Veteran Affairs Healthcare System
Authors: Bilal Alqam, Fuad Habash, Zaid Gheith, SRIKANTH VALLURUPALLI, Waddah Maskoun
Journal: Circulation (2021)

Introduction: Takotsubo cardiomyopathy is characterized by significant transient left ventricular dysfunction that is not due to obstructive coronary artery disease, but concurrent right ventricular (RV) dysfunction has been described previously. The aim of our study was to investigate the rates and outcomes of patients diagnosed with Takotsubo cardiomyopathy with RV dysfunction in the Veteran Affairs (VA) system. Methods: We performed a retrospective study using chart review for patients diagnosed with Takotsubo cardiomyopathy between 2005 and 2018 in the VA national database. We included patients who met the Mayo Clinic diagnostic criteria for Takotsubo cardiomyopathy. We collected data for demographics, clinical course, and outcomes. Results: 276 patients (70% males) were included. Median age was 64 years, 18.5% were known to have coronary artery disease, 34.8% had Diabetes and 58.1% had hypertension. 96.3% of patients had apical variant of Takotsubo cardiomyopathy. Biventricular dysfunction was identified in 14.1% of patients; of those 71.8% were identified as new RV dysfunction in which 92.3% were apical. There was no significant difference in the in-hospital mortality rates between patients with new biventricular dysfunction compared to patients with normal RV function or old RV dysfunction (10.7% vs 8.1%, p = 0.63). There was also no significant difference in 30-day mortality rates between patients with new biventricular dysfunction compared to patients with normal RV function or old RV dysfunction (4.2% vs 1.8%, p = 0.45). Similar findings were observed when patients with previous RV dysfunction were excluded. On follow up echocardiogram 96.3% of patients who survived had full recovery of their RV function. Conclusions: In patients diagnosed with Takotsubo cardiomyopathy with new RV dysfunction, there was no significant difference in mortality rates in the hospital or at 30-day follow up.
Abstract 16953: Prospective Negative Microvolt T-Wave Alternans Testing is a Marker for Lower Risk of Cardiovascular Death and Appropriate Shock Therapy
Authors: Yitschak Biton, Jayson R Baman, Moussa Mansour, E K Heist, Jeremy N Ruskin, Ottorino Costantini, Ludmila Danilowicz-Szymanowicz, Jorge A Salerno-Uriarte, Fabrizio Caravati, Robert Pedretti, Giulio Molon, Leonardo Calo, Takanori Ikeda, Demet Erciyes, Massimo Zecchin, Maurizio Piancastelli, Philippe Maury, Daniele Marangoni, Faisal Merchant, Antonis Armoundas
Journal: Circulation (2018)

Introduction: Microvolt T-wave alternans (MTWA) refers to a pattern of beat-to-beat oscillations in T-wave morphology. Hypothesis: We hypothesized that patients with negative MTWA testing were at decreased risk for cardiovascular death and appropriate shock therapy. Methods: We studied 913 patients from a prospective international registry from Europe, Asia and USA (9 centers total). All recruited patients qualified for primary prevention of sudden cardiac death with ICD or CRT-D. Beta-blockers were discontinued prior to MTWA testing. We used best-subsets analysis of our study population to identify predictors of all-cause mortality. Ten clinical and demographic variables were included in the analysis. We then used these predictors to evaluate the predictive capacity of MTWA in a multivariate model. Results: The mean follow-up was 4.0 ± 3.0 years, mean age was 69.5 ± 12.5 years, 84% were male, and 63% had ischemic cardiomyopathy. 52% and 11% of patients received ICD and CRT-D, respectively. LVEF &lt;25% (HR 2.17, p&lt;0.001), NYHA class&gt;II (HR 1.75, p=0.01) and use of diuretics (HR 2.64, p&lt;0.001) were significantly associated with all-cause mortality in a multivariate model. Using this multivariate model, a negative MTWA outcome was not associated with all-cause mortality (HR 0.95, p=0.80), however a negative MTWA outcome was associated with the risk of cardiovascular death (HR 0.40, p=0.01) and the combined endpoint of cardiovascular death and ICD-rendered shock therapy (HR 0.28, p&lt;0.001). This was consistent in both ischemic and nonischemic cardiomyopathy (p value for interaction=0.999). Conclusions: These findings suggest that non-negative MTWA testing is indicative of an underlying arrhythmogenic substrate, manifested as cardiovascular death and appropriate shock therapy. MTWA testing can provide further information for patient selection for ICD placement. Figure 1 . Kaplan-Meier Curve demonstrating the time-dependent endpoint of cardiovascular death. The follow-up time displayed on this graph is measured in days.
Abstract 16848: Over 25 Years of Experience With the Ross Procedure in Children: A Single-Centre Experience
Authors: Elisabeth Martin, Charles Laurin, Frédéric Jacques, Christine Houde, Jean-Marc Côté, Philippe Chetaille, Christian Drolet, Laurence Vaujois, Dimitri Kalavrouziotis, Siamak Mohammadi, Jean Perron
Journal: Circulation (2018)

Introduction: Aortic valve replacement in children and infants poses an important clinical challenge. The Ross procedure offers advantages such as growth potential and low thrombogenicity. Concerns regarding pulmonary autograft and homograft longevity as well as subsequent reoperations are well recognized. We reviewed our experience with the Ross procedure with the aim of defining survival rate and freedom from reintervention. Methods: This is a single-center retrospective cohort including 63 consecutive children who underwent the Ross procedure. The first Ross procedure was performed in 1990. Complete postoperative clinical and echocardiographic evaluation was obtained. Long-term survival was assessed using Kaplan-Meier estimator. Results: There were 51 males (81%) and mean age at surgery was 10.1 (+/- 5.8) years. Isolated aortic stenosis was the most common diagnosis and found in 28 (44.4%) patients. Median follow-up duration was 20.5 years and ranged up to 26.9 years. There was one (1.6%) hospital death. Survival at 5, 15 and 25 years was 96.6%, 94.4% and 94.4%, respectively. Freedom from autograft-related reintervention was 98.1%, 88.9% and 66.8% at 5, 15 and 25 years, respectively. Twelve patients underwent reoperations on the autograft and there was no post-operative death. Among these patients, 7 (58.3%) patients underwent valve-sparing autograft reoperation. Reintervention on the pulmonary homograft was performed on 29 (46.0%) patients. Freedom from homograft-related reintervention was 93.2%, 58.2% and 29.8% at 5, 15 and 25 years, respectively. Conclusions: The Ross procedure in children is associated with excellent long-term outcomes. Ross-related reinterventions are more than twice as common on the pulmonary homograft than autograft.
Abstract 16886: Caspase-4/11 Mediates Intima Formation by Increasing Inflammation and Smooth Muscle Cell Migration and Proliferation
Authors: Ze Yu, Guofu Zhu, Dongyang Jiang, Hao Liu, Linlin Fan, Xiankai Li, Dekui Zhang, Yawei Xu, Junbo Ge, Hong Luo, Jinjiang Pang
Journal: Circulation (2018)

Introduction: Intima formation after vessel injury occurs via vascular smooth muscle cell(VSMC) proliferation, migration, dedifferentiation and inflammatory response. Recently, it was demonstrated that caspase-4 (Casp4, human)/caspase11(Casp11, mouse) increases the synthesis and release of inflammatory factors in macrophages, indicating a potential role of Casp4/Casp11 in intima formation. However, to date, the biological role of Casp4/Casp11 in vivo has not been investigated. Therefore, we hypothesize that Casp4/Casp11 deficiency will inhibit intima formation. Method and Results: We measured Casp4 expression and location by immunohistochemistry (IHC) staining in human coronary artery intima lesions from coronary artery disease patients. Surprisingly, we found Casp4 expression was remarkably increased in smooth muscle cells (SMC) and macrophages. We observed similar phenomena of Casp11 expression and location in intima of complete carotid ligation mouse model. These findings imply an important role of Casp4/11 in SMC function. Thus, we performed complete carotid ligation on Casp11 wild type (WT) and knockout (KO) mice.Morphometric analysis demonstrated that Casp11 depletion robustly attenuated intima area and intima/media ratio (I/M) compared with WT mice . Inflammation was quantified by CD45 IHC staining . SMC proliferation was detected by PCNA staining and there was a marked decrease of PCNA positive SMCs. In vitro, Casp4 expression was time- and dose-dependently increased by platelet-derived growth factor(PDGF), angiotensin II(AngII) and TNF-α in human coronary artery SMCs(HCASMCs). Depletion of Casp4 by siRNA decreased expression of cytokines, e.g. IL-1α, IL-1β, IL-6, as well as protein expression of adhesion factors (VCAM-1, ICAM-1, MCP-1) induced by PDGF, AngII or TNF-α. Moreover, HCASMC proliferation stimulated by PDGF was measured by EdU cell proliferation assay and was inhibited by 65% after knockdown of Casp4. Wound scratch assay demonstrated impaired HCASMC migration in Casp4 depleted cells. However, Casp4 has no effects on HCASMCs dedifferentiation. Mechanistically, Casp4 knockdown significantly inhibited NF-κB signaling. Conclusions: Casp4/11 promotes intima formation by increasing SMC proliferation, migration and inflammation through NF κB signaling. Specific inhibition of the Casp4/11 will provide novel therapeutic strategy for vascular remodeling related diseases.
Abstract 16870: Dickkopf-Related Protein 1, a Wingless-Regulatory Molecule, Identifies Maladaptive Left Ventricular Remodeling in Aortic Stenosis
Authors: Kanjit Leungsuwan, Abdullah Shahid, Julie Tirrell, Harish R Rammohan, Melissa Scribani, Paul Jenkins, Deborah Hyink, Paul Klotman, Randolph Hutter, Daniel Katz
Journal: Circulation (2018)

Introduction: Aortic stenosis (AS) may lead to left ventricular (LV) dysfunction with inadequate LV remodeling or may result in excessive LV hypertrophy. We hypothesized that circulatory Dickkopf-related protein 1 (DKK-1) as experimental regulator of myocardial repair could identify patients with a maladaptive LV response to AS. Maladaptive response may be defined by inadequate remodeling resulting in LV dysfunction or excessive hypertrophy. Methods: There were 53 adult patients demonstrated to have AS by echocardiogram or cardiac MRI completed between Jan 1st, 2016 and Dec 31st, 2017. Study patients were compared with 239 patients without AS. Patient and imaging data were collected. DKK-1 level was measured using Human DKK-1 quantikine ELISA kit. Values of DKK-1 were skewed, so non-parametric tests were used to determine the associations between DKK-1 and LV and AS parameters in echocardiography and cardiac MRI. Spearman’s Rank Order Correlation, Wilcoxon Rank Sum Test, and analysis of variance (ANOVA) were used to assess associations. Results: Among the 53 patients with AS, 29 (54.7%) were mild, 6 (11.3%) were moderate, and 18 (34%) were severe as per standard imaging criteria. In the study group, 32 (60.4%) were male, 21 (39.6%) were female, with a mean age of 72.2 years (range 47-90). In patients with AS, the median DKK-1 was 427.57 pg/mL, mean LV ejection fraction was 48.07%, mean LV mass was 147.5 g, and mean LV mass index was 69.1 g/m 2 . There was a statistically significant inverse correlation between DKK-1 and LV ejection fraction (correlation coefficient -0.28, p&lt;0.05) only in patients with AS. There was an inverse trend of a correlation between DKK-1 and LV mass and mass index (correlation coefficient -0.3 and -0.23, respectively). There was no association between the severity of AS (aortic valve area, maximum velocity, or mean pressure gradient) and the level of DKK-1. Conclusions: In conclusion, DKK-1 might be a predictor of a maladaptive response in AS patients. In patients with elevated DKK-1 level, there is an associated diminished myocardial repair and LV dysfunction. In patients with low DKK-1 level there is a trend towards the development of accentuated LV hypertrophy. Our findings support further prospective clinical investigations of DKK-1 and other Wnt-regulatory molecules in patients with AS in the future.
Abstract 17001: Nebulette Knock-Out in Mice Leads to Dilated Cardiomyopathy
Authors: Subat Turdi, Ryan D Sullivan, Jeffrey A Towbin
Journal: Circulation (2018)

Introduction: Cardiomyopathy is a serious heart condition that can lead to heart failure. Nebulette is a cardiac-specific Z-disk protein which plays a crucial role in mechanosensing and force generation in the heart. Previous studies have shown that nebulette mutations are associated with various cardiomyopathies including hypertrophic, left ventricular noncompaction and dilated cardiomyopathy. However, the molecular mechanisms by which nebulette affects the cardiac structure and function are not well-understood. Hypothesis: In this study, we tested whether decrease in nebulette causes cardiac remodeling, dysfunction and dilated cardiomyopathy in vivo. Methods: We generated a novel nebulette knockout (KO, excision of exon 3) mice using the Cre/loxP technique. Mice were characterized prior to being subjected to serial echocardiography and electrocardiogram (ECG) at 6 weeks, 3 months, 6 months and one year of age. A separate cohort of mice were used for histopathological and molecular studies. Results: KO mice were born following Mendelian laws. Western blot and qPCR data revealed significant decrease in nebulette expression in KO mouse hearts compared to heterozygous (Het) and WT mice. Confocal microscopy further elicited diminished nebulette expression and perturbed distribution in myocardial sections as well as isolated cardiomyocytes from KO mice. Echocardiography showed a deterioration of cardiac function in KO mice starting from 6 weeks of age to one year of age, which were characterized by reduced fractional shortening and MV E/A, increased LV diastolic dimension as compared with age-matched WT mice. KO mice showed tachycardia and lower QRS voltage at one year of age compared to WT and Het mice. KO hearts revealed increased fibrosis, sarcomere disorganization, enlarged t-tubules and less apparent M-lines. Western blot demonstrated reduced cardiac TnT and increased TnI levels in the KO mice whereas desmin, actin and cardiac ankyrin repeat protein (CARP) remained comparable between the genotypes. Conclusions: Taken together, these data provide evidence for the critical role of nebulette in maintaining cardiac structure and function. Further data that provides mechanistic insight will be presented.
Abstract 16962: The Genetic Basis of Hypercholesterolemia in a Community-Based Cohort
Authors: Merin Jose, David C Kochan, Iftikhar J Kullo
Journal: Circulation (2018)

Introduction: Prior reports of the genetic etiology of hypercholesterolemia are affected by referral bias, inclusion of individuals with secondary hypercholesterolemia and variability in identifying pathogenic variants. We sought to assess the prevalence of monogenic and polygenic etiologies in a community based cohort of adults with primary hypercholesterolemia (LDL-C ≥155 mg/dL after excluding secondary causes). Methods: We identified 1719 individuals aged 18-70 years with primary hypercholesterolemia from SE Minnesota. The Dutch Lipid Clinic Network (DLCN) score was ascertained by an electronic health record (EHR) based algorithm followed by manual review. Familial hypercholesterolemia (FH) was considered present with a DLCN score ≥6 whereas a DLCN score of 3-5 was considered possible FH. Participants underwent sequencing of FH genes ( LDLR, APOB, PCSK9 ) and genotyping of 12 SNPs known to be associated with LDL-C. Rare (frequency &lt;0.1%) and putatively functional variants were identified and pathogenicity was assigned based on the ACMG guidelines using relevant database, literature and EHR review. A polygenic score (PGS) for LDL-C (derived from 12 SNPs) &gt;90 th percentile was considered an indicator of polygenic etiology. Results: A pathogenic/likely pathogenic variant (16 in LDLR , 1in APOB and 2 in PCSK9 ) was present in 24 (1.3%) individuals, a PGS &gt;90 th percentile was present in 265 (15.4%) and 4 (0.2%) had both a monogenic and polygenic etiology. The overall prevalence of an identifiable genetic etiology was 17%. Based on clinical criteria the overall prevalence of FH (DLCN ≥6) was 7.0% (6.1% probable and 0.9% definite) and that of possible FH was 30.0%. In the possible, probable and definite FH categories, a monogenic etiology was present in 2.4%, 9.5% and 26.7% and a polygenic etiology in 19.1%, 21.0% and 13.3% respectively. 52.0% of those with a monogenic etiology and 9.7% of those with a polygenic etiology met the DLCN criteria for FH. Conclusions: This study provides for the first time estimates of monogenic and polygenic etiology of hypercholesterolemia in adults from the community, excluding cases of secondary hypercholesterolemia and using standardized methods of variant annotation.