tbuckley/cabot-search huggingface dataset:
Abstract 12760: Association of Machine Learning-Derived Measures of Body Fat Distribution in &gt;40,000 Individuals With Cardiometabolic Diseases
Authors: Saaket Agrawal, Marcus D Klarqvist, Nathaniel Diamant, Patrick T Ellinor, Nehal N Mehta, Anthony Philippakis, Kenney Ng, Puneet Batra, Amit V Khera
Journal: Circulation (2021)

Background: Obesity is defined based on body-mass index (BMI), a proxy for overall adiposity. However, for any given BMI, individuals vary substantially in fat distribution. The clinical implications of this variability are not fully understood. Methods: We studied MRI imaging data of 40,032 UK Biobank participants. Using previously quantified visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) adipose tissue volume in up to 9,041 to train convolutional neural networks, we quantified these depots in the remainder of the participants. We derived new metrics for each adipose depot - fully independent of BMI - by quantifying deviation from values predicted by BMI (e.g. VAT adjusted for BMI, VATadjBMI) and determined associations with cardiometabolic diseases. Results: Machine learning models based on two-dimensional projection images enabled near-perfect estimation of VAT, ASAT, and GFAT, with r 2 in a holdout testing dataset &gt;0.97 for each. Using the newly derived measures of local adiposity - residualized based on BMI - we note marked heterogeneity in associations with cardiometabolic diseases. Taking presence of type 2 diabetes as an example, VATadjBMI was associated with significantly increased risk (odds ratio per standard deviation increase (OR/SD) 1.49; 95%CI: 1.43-1.55), while ASATadjBMI was largely neutral (OR/SD 1.08; 95%CI: 1.03-1.14) and GFATadjBMI conferred protection (OR/SD 0.75; 95%CI: 0.71-0.79). Similar patterns were observed for coronary artery disease. Conclusions: For any given BMI, measures of local adiposity have variable and divergent associations with cardiometabolic diseases.
Abstract 12769: Neutrophil <i>Peptidylarginine Deiminase 4</i> is Essential for Detrimental Age-Related Cardiac Remodeling in Mice
Authors: Stijn Van Bruggen, Kimberly Martinod, Thilo Witsch, Liesbeth Frederix, Paolo Carai, Jore Van wauwe
Journal: Circulation (2021)

During a period of chronic inflammation, such as in aging, neutrophils have a decreased threshold for activation. Neutrophils express peptidylarginine deiminase 4 ( PAD4 ), an enzyme which converts arginine residues to citrulline, resulting in chromatin decondensation and formation of neutrophil extracellular traps (NETs). These NETs have been shown to be prothrombotic and proinflammatory. However, their specific contribution to cardiac remodeling remains elusive. We hypothesized that during chronic inflammation, neutrophil PAD4, via NETs, promotes cardiac damage and resultant tissue fibrosis. We therefore generated neutrophil-specific PAD4 knockout mice (PAD4 fl/fl MRP8Cre + ), confirmed they have a NET defect, and assessed the effect of this deletion on cardiac tissue during natural aging. These mice, as well as PAD4 fl/fl (WT) littermate controls, were aged for two years, after which cardiac function, remodeling-related gene expression, and tissue remodeling were measured. Young and healthy (YH) controls (8-12 weeks old) were assessed in parallel. We saw that systolic function, via ejection fraction (EF), in old WT mice (53±10%, n = 24) was significantly decreased as compared to old PAD4 fl/fl MRP8Cre + (67±7%, n = 14, P = 0.002). Which in turn was not different from the YH group (67±6%, n = 11, P = 0.86). In addition, old WT mice had a deterioration in diastolic function (E/A) (1.21±0.17) as compared to old PAD4 fl/fl MRP8Cre + (1.38±0.21, P = 0.0326), while there was no difference with the YH group (1.50±0.23, P = 0.48). Histological examination revealed that collagen deposition in the heart tissue was negatively correlated to systolic function. Analysis of cardiac gene expression shows a significant downregulation of CCL12, CCN2, CCL3, Col1α3, and MMP13, and upregulation of Col3α1 and TIMP4 in old PAD4 fl/fl MRP8Cre + mice compared to old WT mice. In conclusion, lack of PAD4 in neutrophils results in healthy cardiac aging, due to the absence of increased collagen deposition in the heart muscle. This can be explained by reduced production of pro-inflammatory cytokines by the heart, resulting in less immune cell recruitment and activation, and a decrease in growth factor expression, inhibiting downstream fibroblast proliferation and collagen deposition.
Abstract 12594: GRK2 is a Novel Regulator of Cardiac Mitochondrial Bioenergetics
Authors: Kimberly Ferrero, Jessica M Pfleger, Kurt Chuprun, Erhe Gao, Walter J Koch
Journal: Circulation (2021)

Introduction: The GPCR kinase GRK2 is highly expressed the heart; during cardiac injury or heart failure (HF) levels and activity of GRK2 increase. While GRKs are canonically studied upstream of β-adrenergic desensitization, GRK2 has a large non-GPCR interactome and novel, noncanonical functions. We have discovered that in the heart, GRK2 translocates to mitochondria ( mtGRK2 ) following injury and negatively affects cellular metabolism and substrate utilization. Thus, we have sought to identify the mechanism(s) by which GRK2 regulates mitochondrial function. Hypothesis: mtGRK2 phosphorylates proteins involved in mitochondrial bioenergetics, which may explain the altered metabolic phenotype seen following cardiac injury or HF. Methods: Stress-induced mitochondrial translocation of GRK2 was validated in rat ventricular myocytes, murine cardiac tissue and a cardiac-derived cell line. The mtGRK2 interactome was then via protein immunoprecipitation followed by liquid chromatography-mass spectroscopy (LCMS) analysis. Proteomics analysis identified mtGRK2 interacting proteins which were involved in mitochondrial dysfunction. Results: Complexes I, II, IV and V of the electron transport chain (ETC) were identified as mtGRK2 interacting partners. Several mtGRK2 interactions were increased following stress, particularly those with Complex V. We further established that mtGRK2 phosphorylates some of the subunits of Complex V, particularly the ATP synthase barrel which is critical for ATP production. Specific amino acid residues on these subunits have been identified using PTM-LCMS and are currently being validated in a murine myocardial infarction model. Additionally, alterations in either the levels or activity of GRK2 appear to alter the enzymatic activity of Complex V in vitro , thus regulating ATP production in cardiomyocytes. Conclusions: The phosphorylation of the ATP synthesis machinery by mtGRK2 may be regulating some of the phenotypic effects of injured or failing hearts such as reduced substrate utilization. Research is ongoing to further elucidate the novel role of mtGRK2 in regulating bioenergetics and cell death, uncovering a novel, treatable target for rescuing cardiac function in patients with injured or failing hearts.
Abstract 12406: Mitral Valve Prolapse: Immune Response as a New Player
Authors: constance delwarde, Pascal Aumond, claire toquet, Melissa Sizorn, Benjamin Lauzier, Joëlle VEZIERS, Stephanie Blandin, Amir H Kayvanjoo, Elvira Mass, Severine Remy, Ignacio Anegon, Jean-Jacques Schott, Thierry Le Tourneau, Jean Merot, Romain Capoulade
Journal: Circulation (2021)

Introduction: Mitral Valve Prolapse (MVP) is observed in 3% of the population. The pathophysiological mechanisms leading to MVP remain elusive and the only therapeutic option is to perform valve surgery. We previously identified FLNA as the first gene causing MVP and generated a unique knock-in (KI) rat model for the FLNA-P637Q mutation. Hypothesis: We assessed the hypothesis that MVP pathophysiology is multifactorial. Methods: 5 WT and 10 KI rats were morphologically, functionally and histologically evaluated at 3, 6 and 13 weeks based on 2D echocardiography, 3D micro computed tomography (μCT) and histology. Mitral valve (MV) RNA-sequencing was performed and metaclusters (MC) have been identified. Immunofluorescence and cytometry experiments on MV were used. Results: Echocardiographic and μCT imaging confirmed the presence of MV prolapse, elongated anterior leaflet (+12 to +14% for all time points p&lt;0.01) and increased MV volume (+20 to +58% for all time points p&lt;0.05) in KI rats vs WT. Histological analyses revealed a myxomatous remodelling in KI MV. 6 MC were identified by RNA-seq: chemotaxis, epithelial and immune cell migration, extracellular matrix, stress molecular pathways, endothelial to mesenchymal transition and oxidative stress (all GO-terms p&lt;1x10-5). A higher proportion of CD45 + leukocytes (20% vs 14%, p=0.002), as well as a trend for CD206 + “resident macrophages” (28% vs 16%, p=0.09), and CD34 + stem cell progenitors (8% vs 15%, p=0.10) were observed in KI compared to WT rats. CD45 + and CD206 + cells were located in the medial third and atrial border of the MV leaflet in WT rats, and more diffusely observed in KI. Conclusions: Our results establish the KI FLNA-P637Q rat as a model of myxomatous MVP, a complex and multifactorial disease. Among others, we have characterized an increase of distinct immune cells in MVP. The course of cell recruitment, the cell-specific activity, and causality with the other MC need to be further studied.
Abstract 12445: Association Between Leptin and Left Ventricular Diastolic Dysfunction in Patients With Type 2 Diabetes
Authors: Meizhen Wu, Qing-wen Ren, Yi Kei Tse, Si-Yeung Yu, Li Hang Long, Hung Fat Tse, Kai Hang Yiu
Journal: Circulation (2021)

Background: Type 2 diabetes (T2DM) is associated with left ventricular (LV) hypertrophy, diastolic dysfunction, and elevated circulating leptin levels. However, the relationship of leptin with LV hypertrophy and diastolic dysfunction is unclear in patients with T2DM. Methods: A total of 176 T2DM patients (mean age 60±10 years; women, 46.6%) without cardiovascular diseases (CVD) were recruited. Circulating leptin levels were measured and detailed transthoracic echocardiography was performed to all patients. Multivariable linear regression analyses were applied to assess the associations between circulating leptin levels and echocardiography parameters. Results: Patients were divided into four groups based on their circulating leptin level. Higher sex-specific leptin quartiles were associated with worsening of diastolic function, reflected as lower septal e’, lateral e’, and elevated average E/e’ (all P &lt; 0.05). However, Leptin was not associated with LV mass index. Multivariable linear regression, after adjustments for age, sex, body mass index, hypertension, and creatinine level, showed that leptin in the highest quartile was independently associated with worsening of average E/e′ (β = 1.26, P &lt; 0.05). Conclusion: Circulating leptin level was associated with LV diastolic dysfunction in diabetic patients without CVD.
Abstract 12426: Influence of Body Mass Index in Donor Recipient Size Mismatch in Pediatric Heart Transplantation
Authors: Laura Lowrey, Jaimin Trivedi, Karthik Ramakrishnan, Pranav Sinha, Shri Deshpande
Journal: Circulation (2021)

Introduction: Body weight has been the traditional metric for matching donor and recipient size for pediatric heart transplantation (pHT). However, the impact of such mismatch is not well established. We hypothesized that mismatch in compound measures such as body mass index (BMI) or body surface area (BSA) rather than weight, may impact outcomes of pHT and therefore should be used for donor-recipient size matching. Methods: Analysis of the United Network for Organ Sharing database limited to pHT recipients was performed. Donor and recipient mismatch tertiles were created for weight, BMI, and BSA ratios. Differences in recipient characteristics between each tertile were studied using univariate analysis. Multivariable analysis was used to assess the impact of each mismatch on one-year survival. Kaplan Meier analysis was used to assess overall survival. Results: A total of 4,465 pHT patients were available and included in the analysis of which 43% had congenital heart disease (CHD). Overall, those with low donor-recipient ratio for BMI were more likely to be younger recipients, less likely to be Caucasian and be on ECMO (all p&lt;0.01). In both CHD and non-CHD cohorts, multivariable regression analysis showed that use of ECMO (CHD OR 3.97; non-CHD OR 3.24), presence of liver dysfunction (CHD OR 1.10; non-CHD OR 1.11), and low donor to recipient BMI ratio (compared to normal) (CHD OR 1.70; non-CHD OR 2.28) were the only predictors of one-year mortality (all p &lt;0.001). Low BMI ratio was also associated with worse long-term survival in non-CHD groups, but not in the CHD cohort. This finding probably reflects inferior overall outcomes in the CHD cohort. Weight and BSA ratio did not predict one year or long-term survival. Conclusions: Traditional matching practice using weight may be inadequate and use of BMI matching may provide improved donor-recipient matching. Use of low BMI donors compared to recipients may predict poor early and long-term survival and therefore should be avoided in pediatric heart transplantation. Further refinement of matching may be needed in specific recipient populations.
Abstract 12451: Monocytes Enhance Inflammatory Responses to Soluble Matrilin-2 in Human Aortic Valve Interstitial Cells via the Interaction of β <sub>2</sub> -integrin With ICAM-1
Authors: Zichao Luo, Erlinda The, Peijian Zhang, Qingzhou Yao, Yufeng Zhai, Lihua Ao, Qingchun Zeng, David Fullerton, Xianzhong Meng
Journal: Circulation (2021)

Calcific aortic valve disease (CAVD) is a slow progressive disease. Chronic inflammation plays a crucial role in CAVD progression. Monocyte infiltration and macrophage accumulation are found in calcified aortic valves. Soluble extracellular matrix proteins can act as damage-associated molecular patterns to induce the pathobiology associated with CAVD in aortic valve interstitial cells (AVICs). While human AVICs exhibit inflammatory response to soluble matrilin-2, the impact of monocytes on this response is unknown. We hypothesized that monocytes enhance AVIC inflammatory response to soluble matrilin-2 by a mechanism involving cell-cell interaction. Methods and Results: Human AVICs isolated from normal aortic valves were cultured alone or cocultured with monocytes in the absence or presence of recombinant matrilin-2 (1, 2 or 4 μg/ml). AVIC expression of ICAM-1 and IL-6 following an exposure to any dose of matrilin-2 was markedly enhanced by the presence of monocytes although matrilin-2 in the tested dose range had no effect on monocyte production of ICAM-1 or IL-6. Monocytes adhered to AVICs following matrilin-2 stimulation. Interestingly, matrilin-2 up-regulated the expression of β 2 -integrin in monocytes and ICAM-1 in AVICs. Neutralization of β 2 -integrin or ICAM-1 in coculture with specific antibody reduced the number of monocytes adhering to AVICs and suppressed the expression of ICAM-1 and IL-6 . Conversely, addition of β 2 -integrin CD18 enhanced the expression of ICAM-1 and IL-6 in AVICs exposed to matrilin-2. Further, stimulation of coculture with matrilin-2 induced greater YAP and NF-κB phosphorylation compared to AVIC monoculture. Inhibition of either YAP or NF-κB markedly suppressed the inflammatory response to matrilin-2 in coculture. Conclusions: Monocyte β 2 -integrin interacts with AVIC ICAM-1 to augment AVIC inflammatory response to soluble matrilin-2 through enhancing the activation of YAP and NF-κB signaling pathways. Infiltrated monocytes may promote valvular inflammation through cell-cell interaction with AVICs to enhance their sensitivity to damage - associated molecular patterns.
Abstract 16698: Variation in Systolic Blood Pressure Among Low-Socioeconomic Urban Dwellers is Associated With Travel Distance by Mode of Transportation
Authors: Rhys Chua, Marynia Kolak, Stephanie A Besser, Elizabeth L Tung, Emeka Anyanwu, James K Liao, Corey E Tabit
Journal: Circulation (2018)

Introduction: Hypertension affects one third of American adults and is especially common among low-socioeconomic urban dwellers. Studies suggest that poor access to a pharmacy is associated with elevated blood pressure (BP). Residents on the South Side of Chicago typically travel locally using three common modes of transportation - walking, riding the city bus, or driving - based on the distance of the trip. Based on previous literature, walking is preferred for distances less than 3 km, taking the city bus is preferred for distances 3-10 km, and driving is preferred if possible for distances greater than 10 km. Because distances from home to the pharmacy at thresholds between each mode of transportation (i.e. a long walk vs. a short bus ride) could cause logistical uncertainty for patients, we hypothesized that blood pressure is higher for patients living at threshold distances from the pharmacy they typically use. Methods: Medical records of adult South Side residents who received care at the University of Chicago’s outpatient clinics from 2012 through 2017 were reviewed. Blood pressure (BP) measurements for each patient were averaged and each patient’s home and pharmacy addresses were geocoded. We calculated the walking and driving distance from each patient’s home to his or her pharmacy. The relationship between BP and travel distance was compared using Spearman rank correlation and Fisher’s exact test. Results: 47,084 patients were included in the study. Mean systolic BP was significantly lower for patients living ≤1 km from their pharmacy than for patients living farther (p&lt;0.0001). Mean systolic BP was highest at common distance thresholds for changing mode of transportation among urban dwellers (2-3 km and 10-20 km, Figure). Diastolic BP was not associated with distance from home to pharmacy. Conclusions: Among South Side Chicagoans, systolic BP is lowest for patients living ≤1 km from their pharmacy and highest at distance thresholds for walking, riding the city bus, or driving. Interventions to improve BP control among urban dwellers may benefit from targeting patients who live at threshold distances from their pharmacy.
Abstract 13952: A Novel Genetic Mini-Pig Model of Cardiac Myosin-Binding Protein C (MYBPC3) Dysfunction: Evidence for Altered Sarcomere Structure and Systolic/Diastolic Functional Reserve <i>in vivo</i>
Authors: Carlos L del Rio, Weikang Ma, David Ryba, Henry Gong, Marcus Henze, Sampath K Gollapudi, Robert Anderson, Suman Nag, Christopher Rogers, Thomas Irving
Journal: Circulation (2021)

Introduction: Mutations in MYPBC3, the gene encoding cardiac Myosin-Binding Protein C (cMyBP-C), a regulatory sarcomeric protein, are known to play a pathogenic role in hypertrophic cardiomyopathy (HCM). However, the molecular bases for this pathophysiology remain poorly understood. Here, a novel large-animal MYPBC3-mutant model was developed and characterized to determine the association between myofilament abnormalities induced by cMyBP-C dysfunction and the resulting in vivo phenotype. Methods: A missense (early stop) E330X MYPBC3 mutation was introduced in Yucatan mini-pigs. Young heterozygous mutants (C3) and age-matched wildtype (WT) herd-mates were studied. In vivo imaging (MRI) and invasive hemodynamics were performed along with ex vivo measurements of tension dynamics, sarcomere structure (x-ray diffraction), and ATP turnover rates, including the population of myosin heads in the super-relaxed state (SRX) in LV fibers/tissues. Load-independent systolic and diastolic function (via LV pressure-volume relationships), and β-adrenergic receptor (β-AR) cardiac reserve (dobutamine 5 ug/kg/min IV) were assessed in vivo. Results: Relaxed C3 fibers showed reduced ordering of the myosin heads around the thick filament and a sensitizing shift of myosin-heads towards actin. However, C3 pigs showed normal Ca2+ sensitivity ex vivo with mildly decreased systolic function at rest in vivo (LVEF: 49 ± 1 vs. 56 ± 2%; vmax: 31 ± 1 vs. 38 ± 5 1/s; Ees: 8.5 ± 1.0 vs. 10.2 ± 1.5 mmHg/mL; all P &lt; 0.05 vs. CTRL). Upon β-AR stimulation, C3 pigs became hypercontractile (Ees: 18.0 ± 3.1 vs. 14.3 ± 2.8 mmHg/mL in CTRL, P &lt;0.05) showing markedly increased (P&lt;0.05) end-diastolic stiffness (Eed: 1.7 ± 0.4 vs. 1.3 ± 0.3 mmHg/mL in CTRL) and pressures; C3 fibers showed SRX dysregulation dependent on the phosphorylation state. Conclusions: MYPBC3 mutant mini-pigs showed a complex phenotype, characterized by myofilament abnormalities ex vivo and β-AR dependent hypercontractility and diastolic dysfunction in vivo . Taken together, these data generated in a translationally-relevant novel large-animal model further support the role of cMyBP-C as a key regulator of contraction and relaxation, but also can provide insights into the pathophysiology of HCM.
Abstract 16753: Efficacy &amp; Efficiency of Genome Editing With CRISPR/Cas9 in a Humanized Knock-In Mouse Model of PLN <sup>R14del</sup>
Authors: Francesca Stillitano, Nour Raad, Lu Zhang, Anthony Fargnoli, Dongtak Jeong, Delaine Ceholski, Erik Kohlbrenner, Jaydev Dave, Chenleng Cai, Fadi Akar, Roger J Hajjar
Journal: Circulation (2018)

Introduction: A mutation in the Phospholamban (PLN) gene, a calcium regulating protein, the Arg14 deletion (R14del), has been identified in patients with atypical Arrhythmogenic Cardiomyopathy (ACM). Carriers of this mutation are at high risk for malignant ventricular arrhythmias and ventricular dilation. Objective: To evaluate the efficiency and efficacy of genome editing by using CRISPR/Cas9 and a cardiotropic Adeno-Associated Vector (AAV) in a knock-in mouse model expressing the human coding sequence of mutant PLN (hPLN R14del ). Methods: We generated wild-type (WT), heterozygous (Het) and double mutant (Mut) humanized mice. We designed a CRISPR-Cas9/gRNA construct which cut around the site encoding R14Del-PLN gene. To check for CRISPR-Cas9 efficiency we used droplet digital (ddPCR) Genome Edit Detection assay that consist of primer pair to amplify the sequence that includes the mutation, and a FAM-labeled probe designed to bind the mutant allele. Heterozygous mice were injected with 2x10 12 vg of AAV9.CRISPR/Cas9/gRNA for inactivation of the R14del allele. Cardiac function and heart morphology were assessed by Magnetic Resonance Imaging (MRI), echocardiography and H&amp;E staining. Ventricular tachycardia (VT) threshold was defined as the pacing frequency (f Pacing ) required for induction of sustained VT in ex vivo set-up. Results: Echocardiography and histology showed no significant changes in cardiac function and structure in the R14del Het &amp; Mut mice. Eight weeks after AAV injection the hearts were harvested and analyzed for indel frequencies at on-target site in the genome. ddPCR analysis showed an efficiency of ~13% inactivation of the R14del mutation in AAV9/CRISPR-Cas9 injected mice compared to controls. Seventy-five percent of Het hearts exhibited adrenergic mediated VT (f Pacing = 19.6±4.7Hz) vs. only 30% of their WT counterparts (25.8±1.4Hz, p&lt;0.05). VT susceptibility in Het hearts was significantly suppressed by AAV-mediated CRISPR/Cas9 delivery targeting the mutant allele. Conclusions: Our results demonstrate that mouse model harboring the human R14del mutation does not result in gross cardiac morphological changes. Silencing this mutation by CRISPR/Cas9 AAV based gene therapy reversed the VT susceptibility in the Het mice.