tbuckley/cabot-search huggingface dataset:
Abstract 15420: Resolving a Controversy: Inhibition of Cardiac Ryanodine Receptors is the Principal Mechanism of Antiarrhythmic Action of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia
Authors: Dmytro O Kryshtal, Daniel J Blackwell, Christian L Egly, Abigail N Smith, Suzanne M Batiste, Jeffrey N Johnston, Derek R Laver, Bjorn C Knollmann
Journal: Circulation (2020)

Rationale: The class Ic antiarrhythmic drug flecainide prevents ventricular tachyarrhythmia in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease caused by hyperactive cardiac ryanodine receptor (RyR2) calcium (Ca) release. Although flecainide inhibits single RyR2 channels in vitro , reports have claimed that RyR2 inhibition by flecainide is not relevant for its mechanism of antiarrhythmic action and concluded that sodium channel block alone is responsible for flecainide’s efficacy in CPVT. Objective: To determine whether RyR2 block independently contributes to flecainide’s efficacy for suppressing spontaneous sarcoplasmic reticulum (SR) Ca release and for preventing ventricular tachycardia in vivo . Methods and Results: We synthesized N -methyl flecainide analogues (QX-FL and NM-FL) and showed that N -methylation reduces flecainide’s inhibitory potency on RyR2 channels but not on cardiac sodium channels. Antiarrhythmic efficacy was tested utilizing a calsequestrin knockout (Casq2-/-) CPVT mouse model. In membrane-permeabilized Casq2-/- cardiomyocytes — lacking intact sarcolemma and devoid of sodium channel contribution — flecainide, but not its analogues, suppressed RyR2-mediated Ca release at clinically relevant concentrations. In voltage-clamped, intact Casq2-/- cardiomyocytes pretreated with tetrodotoxin (TTX) to inhibit sodium channels and isolate the effect of flecainide on RyR2, flecainide significantly reduced the frequency of spontaneous SR Ca release, while QX-FL and NM-FL did not. In vivo , flecainide effectively suppressed catecholamine-induced ventricular tachyarrhythmias in Casq2-/- mice, whereas NM-FL did not, despite comparable sodium channel block. Conclusions: Flecainide remains an effective inhibitor of RyR2-mediated arrhythmogenic Ca release even when cardiac sodium channels are blocked. In mice with CPVT, sodium channel block alone was not enough to prevent arrhythmias. Hence, RyR2 inhibition by flecainide is critical for its mechanism of antiarrhythmic action.
Abstract 17246: Sensitivity and Specificity of Relative Sparing of Apical Longitudinal Strain for Detection of Systemic Light-Chain Amyloidosis versus Transthyretin Amyloidosis
Authors: Michael Jiang, Julia M Simkowski, Nadia El Hangouche, Jeesoo Lee, Milica Marion, Inga Vaitenas, James D Thomas
Journal: Circulation (2020)

Introduction: Relative apical sparing of longitudinal strain (RALS, the ratio of apical strain vs the rest of the heart) on echocardiography has been found to have high sensitivity and specificity for differentiating cardiac amyloidosis (CA) from other causes of left ventricular hypertrophy. Previous studies have shown no significant difference between amyloid subtypes, systemic light-chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) Hypothesis: There will be a significant difference in sensitivity and specificity of RALS to detect CA across amyloid subtypes. Methods: A cohort of patients with either AL or ATTR amyloid was identified, with a control cohort of patients with left ventricular hypertrophy (LVH) of other etiologies. Speckle tracking echocardiography was performed on EchoPAC (GE Medical Systems) software to obtain values of basal, mid, and apical longitudinal strain for each patient; relative apical strain was then calculated. Results: The TTR group (n=22) was older (66.4±7.9, 76.6±11.6, p=0.001) and more likely to be female (p=0.009) than the AL group (n=30), both groups had similar rates of hypertension, diabetes mellitus, and end stage renal disease. Echocardiographic markers of diastolic function were decreased in both groups; the AL group had decreased left ventricle end diastolic volume (60.9±25.5, 94.9±50.2, p=0.012) and mean wall thickness (1.4±0.3, 1.6±0.4 p=0.017). ROC analysis using a RALS cutoff of 2 to differentiate AL and ATTR from the LVH control group revealed similar specificity (AL 85%, ATTR 85%) and sensitivity (AL 40%, ATTR 50%). Difference in area-under-curve (AUC) was not significant (p=0.2) (figure). Conclusions: ATTR and AL amyloid have similar specificity, but ATTR has a trend towards improved sensitivity over AL for detection of CA using RALS with the previously validated threshold of 2. This might become significant with a larger sample, work that is currently on-going..
Abstract 14192: Breakfast Consumption is Associated With Weight Loss During an Intensive Lifestyle Intervention for Adults With Overweight/Obesity and Type 2 Diabetes: Results From the Look AHEAD Trial
Authors: Daisy Duan, Scott J Pilla, Jeanne M Clark, Nisa M Maruthur
Journal: Circulation (2020)

Background: Breakfast skipping is linked to obesity and related cardiometabolic outcomes in observational studies, but the association between breakfast eating and weight loss is not well-established. We examined if weight loss outcomes in Look AHEAD were related to breakfast consumption frequency (BCF). Methods: We included a subset of participants (n=3862) from the public access dataset of Look AHEAD, an RCT that compared intensive lifestyle intervention (ILI) to diabetes support and education (DSE) control in adults with overweight/obesity and type 2 diabetes. A self-reported questionnaire collected BCF over a 7-day week annually. This value (0-7) was averaged across 4 years of the intervention to calculate an average BCF. We used robust multivariable linear regression analysis to estimate the association between % weight change and 4-year average BCF controlling for baseline sociodemographics, BMI, and diabetes-related variables. In separate models, we adjusted for self-reported caloric intake (n=880) and self-reported physical activity level (n=735) among those with data. Results: 4-year average BCF was similar in DSE (n=1914) and ILI (n=1948) arms, with a median of 7 days (IQR 6-7) for both arms (p=0.11). Each 1 day increase in average BCF was associated with an additional 0.43% weight loss in the ILI arm (p=0.002) but not in the DSE arm (β-coefficient 0.04% weight loss; p=0.73; p-interaction for arm x BCF=0.01). This association in the ILI arm remained significant after adjustment for daily caloric intake (p=0.04) but not after adjustment for physical activity (p=0.16). Conclusions: Breakfast consumption was associated with greater weight loss in subjects who received ILI, which was attenuated after adjustment for caloric intake and physical activity. To optimize weight loss interventions, the relationship between breakfast consumption and other weight loss behaviors should be further explored.
Abstract 17184: An Increase in the Respiratory Effort Immediately Intensifies the Hemodynamic Congestion; a Mechanism for Progressive Cardiac Decompensation
Authors: Noa Markovitch, Shmuel Rispler, Yair Feld, Amir Solomonica, Sergey Yalonetsky, ARIEL ROGUIN, Arthur Kerner, Amir Landesberg
Journal: Circulation (2020)

Introduction: An increase in the pulmonary wedge pressure (PCWP) is associated with an increase in the respiratory effort and the sensation of dyspnea. Hypothesis: We investigated the inverse cause and effect relationship, whether an increase in the respiratory effort can by itself aggravate the hemodynamic congestion. Methods: We scrutinized the cardiopulmonary interactions by simultaneously measuring hemodynamic and respiratory indices in heart failure (HF) patients undergoing right heart catheterization. The immediate effects of the respiratory effort on the hemodynamic indices were analyzed by asking the patients to perform short events of apnea and intentional vigorous breathing. The cardiac waves are superimposed on the respiratory waves in the PCWP. To quantify the respiratory effort, the PCWP was decomposed into cardiac and respiratory waves. The respiratory effort (PRESP) was defined as the peak to peak swing in the respiratory wave that modulated the PCWP. Results: HF patients (n=38) exhibited a high PRESP of 9.0±3.2 mmHg, ~3.5-fold higher than the reported normal respiratory effort. The end-expiratory PCWP rose with PRESP, by 0.83±0.06 mmHg for every 1 mmHg of PRESP (p&lt;0.01). The pulmonary artery pressure (PAP) rose with PRESP by 1.40±0.09 mmHg for every 1 mmHg of PRESP. The changes in the respiratory effort had immediate effect on PCWP, within a single breathing-cycle (t =1.67±0.40 s) in all patients. Interestingly, similar changes in the PCWP with PRESP were obtained in all the patients, independently of the HF etiology. Conclusions: An increase in the respiratory effort is not just a result of cardiac decompensation. The respiratory effort has immediate detrimental effects on the PCWP, PAP and the workloads of the heart. The results highlight the existence of a cardiopulmonary vicious cycle the can lead to progressive decompensation, where the respiratory effort plays a pivotal role.
Abstract 13921: Targeting Receptor-Interacting Protein 140 to Modulate Energy Metabolism in the Failing Heart
Authors: Tsunehisa Yamamoto, Elizabeth Pruzinsky, Kirill Batmanov, Daniel P Kelly
Journal: Circulation (2020)

The nuclear receptors, peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs), and their co-regulator PPARγ coactivator-1α (PGC-1α), control postnatal cardiac mitochondrial biogenesis and energy metabolism. During the development of heart failure (HF), the activity of PGC-1/PPAR/ERR is reduced resulting in diminished capacity for fatty acid oxidation (FAO) and ATP production potentially contributing to an “energy-starved” state that contributes to progression of HF. Receptor-Interacting protein 140 (RIP140) serves as a co-repressor of PGC-1/PPAR/ERR in skeletal muscle and adipose tissue. We hypothesized that RIP140 represses cardiac energy metabolism in the normal and failing heart. Accordingly, we targeted Nrip1 (encoding RIP140) using a muscle creatinine kinase (MCK)-driven Cre recombinase to generate striated muscle-specific RIP140 knockout (msRIP140 KO) mice. msRIP140 KO mice appeared normal at baseline with no difference in survival or cardiac systolic function compared to littermate controls. RNA-sequence analysis demonstrated that the expression of genes involved in a wide array of mitochondrial energy metabolic pathways including FAO, tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and branched-chain amino acid (BCAA) degradation pathways were upregulated in msRIP140 KO ventricles, and in msRIP140 KO skeletal muscle. msRIP140 KO mice exhibited significantly less cardiac hypertrophy and diastolic dysfunction in response to chronic pressure overload. Next, cardiac-specific (cs) RIP140 KO mice were generated and subjected to transverse aortic constriction/apical myocardial infarction surgery (TAC/MI), an established HF model. csRIP140 KO mice exhibited less cardiac remodeling and systolic dysfunction compared to littermate controls, along with less downregulation of metabolic genes and induction of cardiac stress ( Nppa and Nppb ) and fibrosis response markers ( Tgfb2 and Col3a1 ). We conclude that RIP140 serves as a global co-repressor of cardiac energy metabolic genes in the adult heart and that modulation of RIP140 activity could prove to be a novel therapeutic approach for HF.
Abstract 14197: C14a Mutation Abolishes Mg53-Aggravated Glucose Metabolic Dysfunction and Exerts a Dominant Therapeutic Target for Ischemia and Reperfusion (i/r) Injury in Diabetic Heart
Authors: Han Feng, Hao Shen, Matthew J Robeson, Hongkun Wu, Gengjia Chen, Shuo Zhang, Fengxiang Lv, Xinli Hu, Yan Zhang, Ruiping Xiao
Journal: Circulation (2020)

Introduction: MG53, essential for cardiac ischemic protection, negatively regulates insulin receptor (IR) to trigger globular metabolic dysfunction, which makes up a big obstacle for its clinical use. In vitro evidence shows that C14A site of MG53 might be a promising target both to abolish MG53 regulation on IR and to keep as much protective function. However, in vivo effect on C14A mutation of MG53 is urgent to be explored. Results: Here, we found C14A knock-in mice exerted relieved insulin resistance, blood glucose, and metabolic phenotype in high fat diet-induced pre-diabetic model. C14A mutation did NOT lessen the protective effect of MG53 by either intracellular knock-in or extracellular addition of mutant protein against ischemia/reperfusion(I/R) injury in db/+ mice. Consistent with our previous study, we found that administration of MG53 on diabetic mice showed aggravated blood glucose, insulin resistance, and unstable cardiac function to induce a higher risk under I/R attack. C14A mutation reduced the affinity between IR ECD and MG53 to block recombinant human (rh) MG53-WT-triggered acute hyperglycemia, increased heart infarct area and death rate on db/db mice during I/R injury. Post-conditioning of rhMG53-C14A stabilized intra-operative blood glucose and showed stronger anti-I/R ability than MG53-WT protein on db/db mice. Conclusions: C14A mutation is a potential target for MG53 treatment on diabetic heart. This potential therapeutic approach for the treatment of patients within type 2 diabetes provides a strategy of gene engineering optimizing well-known target to draw on advantages and avoid pitfalls.
Abstract 14231: Balancing Exercise Risk With Cardiovascular Health in Pediatric Hypertrophic Cardiomyopathy
Authors: Frances Sobierajski, Melissa Bird, Samantha Anthony, Sarah Pol, Kate Storey, Tara Pidborochynski, Diana Balmer-Minnes, Alyssa Power, Aamir Jeewa, Jennifer Conway
Journal: Circulation (2020)

Introduction: Physical activity is vital to long-term cardiovascular health. However, patients with hypertrophic cardiomyopathy (HCM) are often advised to avoid strenuous physical activity due to the risk of sudden cardiac death. Objective: Given activity restrictions and recommendations for patients with HCM, our objective was to explore children and parents’ perceptions of a heart healthy lifestyle. Methods: Children with HCM and their parents were purposefully recruited at two Canadian sites for participation in a photovoice project. Participants (children and parents) were given a camera and asked to take pictures of everyday heart healthy or unhealthy choices. Photos were discussed during one-on-one qualitative interviews with children and parents separately to understand the photos meaning and significance. Inductive descriptive thematic analysis was used. Results: Thirteen child/parent pairs participated. Children (median 15.9 yrs old (range: 13.6-17.7), median BMI 28.5kg/m 2 (range: 17.8-36.7)) were mostly male (62%). Parents were all female. Most children were activity restricted (n=12). Participants took photos to represent being physically active, the majority being non-competitive activities. Specifically, they emphasized the importance of regular activity to support physical, emotional and heart health. While physical activity was identified as a healthy choice, participants learned from the cardiologist that certain activities were too risky to participate in. Despite these restrictions, children engaged in other types of activity and were supported by their parents and cardiologist. Two categories (self-limiting and finding the right sport) explained strategies children used to engage in physical activity in heart healthy ways. One child stated, “I think it got easier [over the years] because now I know my limits, and I know what I can and can’t do”. Conclusions: Children with HCM and their parents want to be physically active and sought guidance from the cardiologist. These data demonstrated how children with HCM used self-awareness to make heart healthy decisions about physical activity. This study supports the need for patient-centered, individualized physical activity counselling for patients with HCM.
Driving Hierarchical Collagen Fiber Formation for Functional Tendon, Ligament, and Meniscus Replacement
Authors: Jennifer L. Puetzer, Tianchi Ma, Ignacio Sallent, Amy Gelmi, Molly M. Stevens
Journal: Biomaterials (2020)

Hierarchical collagen fibers are the primary source of strength in musculoskeletal tendons, ligaments, and menisci. It has remained a challenge to develop these large fibers in engineered replacements or in vivo after injury. The objective of this study was to investigate the ability of restrained cell-seeded high density collagen gels to drive hierarchical fiber formation for multiple musculoskeletal tissues. We found boundary conditions applied to high density collagen gels were capable of driving tenocytes, ligament fibroblasts, and meniscal fibrochondrocytes to develop native-sized hierarchical collagen fibers 20–40 μm in diameter. The fibers organize similar to bovine juvenile collagen with native fibril banding patterns and hierarchical fiber bundles 50–350 μm in diameter by 6 weeks. Mirroring fiber organization, tensile properties of restrained samples improved significantly with time, reaching ~1 MPa. Additionally, tendon, ligament, and meniscal cells produced significantly different sized fibers, different degrees of crimp, and different GAG concentrations, which corresponded with respective juvenile tissue. To our knowledge, these are some of the largest, most organized fibers produced to date in vitro. Further, cells produced tissue specific hierarchical fibers, suggesting this system is a promising tool to better understand cellular regulation of fiber formation to better stimulate it in vivo after injury.
Abstract 15935: Socioeconomic Disparities in Urgent versus Elective Transcatheter Mitral Valve Repair: Insights From the National Inpatient Sample
Authors: Alexander M Spring, Michael A Catalano, Bruce J Rutkin, Alan R Hartman, Pey-Jen Yu
Journal: Circulation (2020)

Objective: Cardiac interventions performed urgently are known to be associated with poor outcomes compared to electively performed procedures. Transcatheter edge-to-edge mitral valve repair (TMVr) has developed as a reasonable alternative to mitral valve surgery in certain patient populations. We aimed to leverage a national database to identify predictors of urgent versus elective TMVr, as well as the association between urgency and outcomes. Methods: The National Inpatient Sample (NIS) was queried to identify weighted hospital discharge records of patients who underwent TMVr from 2016 - 2017. Hospitalizations are identified within the database as elective versus non-elective. Univariate and multivariable analyses were performed to identify patient characteristics associated with urgent procedures. In-hospital outcomes were assessed. Results: There were 10,195 cases of TMVr in this cohort, 24.2% of which were performed urgently. In multivariable analysis, Hispanic race, Medicaid insurance, and low income were associated with increased likelihood of urgent hospital admission and TMVr. Additionally, small hospital size and Northeast region were associated with increased likelihood of urgent admission and procedure. Older patients were more likely to undergo elective procedures (Table 1). Urgent TMVr was associated with increased mortality (4.5% vs. 1.6%, p &lt; .001), prolonged length of stay (6.0 vs. 2.0, p &lt; .001), and increased cost ($267,292 vs. $167,889, p &lt; .001). Conclusion: Socioeconomic disparities exist in the utilization of TMVr as an urgent versus elective procedure, suggesting differences in access to surveillance and preventive care. Urgent TMVr is associated with increased morbidity and mortality, prolonged length of stay, and increased hospital costs. Priority should be placed on mitigating such disparities to improve outcomes.
THU0028 Different variants of tnf-alpha mrna transcripts are expressed in rats with collagen-induced arthritis
Authors: MF Seidel, MP Junier, H Vetter
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Tumour necrosis factor alpha (TNF-a) is found in both, autoimmune and normal conditions and may therefore not mediate inflammation by overexpression alone. Upregulation of polymorph TNF-a peptides caused by single base pair (bp) exchanges in mRNA transcripts might modify inflammatory events in arthritis. <h3>Objectives</h3> We wished to examine variants of TNF-a transcripts expressed in collagen-induced arthritis (CIA) as a classical model of autoimmune diseases. <h3>Methods</h3> Severe osteodestructive CIA was induced in male Dark Agouti rats, the nature of arthritis was confirmed by radiology. Total articular RNA from diseased animals was used for cDNA synthesis. PCR was performed for the 705 bp TNF-a propeptide and the amplified bands were cloned in E. coli. Two clones were sequenced and the results compared to the NIH gene bank. To confirm polymorph expressions ribonuclease protection assays (RPA) were performed with RNA from normal spleen tissue and joints from healthy and arthritic animals. <h3>Results</h3> Radiology showed severe osteodestruction in CIA animals. Two clones with a complete open reading frame for the 705 bp TNF-a propeptide transcript were obtained by RT-PCR. Single base pair mismatches were found at position 365 and 568 leading to amino acid exchanges of proline versus leucine and lysine versus glutamic acid, respectively. Based on the NIH database four previously published rat TNF-a sequences showed up to twelve single base pair mismatches. In RPA analyses we found protected bands at 705 bp size in all conditions. In addition, smaller bands indicated the presence of transcripts with several single base pair mismatches. Some fragments were not observed in healthy control joints. <h3>Conclusion</h3> The two novel TNF-a transcripts described here are expressed in arthritic and control animals displaying a nonspecific polymorphism. The additional presence of smaller bands in the RPA suggest the coexpression of similar transcripts which may in part correspond to previously reported sequences. The absence of some fragments in healthy control joints is indirect evidence for differentially upregulated TNF-a peptide variants in arthritis.