tbuckley/cabot-search huggingface dataset:
Abstract 4134426: Targeting the TRIM29-PERK signaling axis for treating viral myocarditis
Authors: Wenting Lu, Junying Wang, Shangqing Li, Ellen Yin, Zhiqiang Zhang, Junji Xing
Journal: Circulation (2024)

Introduction: Viral myocarditis is an inflammatory disease of the myocardium that significantly contributes to sudden death in children and young adults. The COVID-19 pandemic underscores the critical need to understand the pathogenesis and develop effective treatment strategies for viral myocarditis. Methods: To investigate the role of the novel E3 ligase TRIM29 in viral myocarditis, we used wild-type and TRIM29 knockout mice infected with coxsackievirus B3 (CVB3) and encephalomyocarditis virus (EMCV), to induce the myocarditis. Additionally, wild-type mice infected with CVB3 were treated with the protein kinase RNA-like endoplasmic reticulum kinase (PERK) inhibitor GSK2656157 or a DMSO control to evaluate potential therapeutic interventions. Mice survival and heart function were monitored using transthoracic echocardiography, and hearts were harvested for histological and immunohistochemical analysis. Techniques including real-time PCR, western blotting, co-immunoprecipitation, enzyme-linked immunoassay, flow cytometry, over-expression, and knockdown were employed to elucidate the pathogenic mechanisms by which TRIM29 regulates the endoplasmic reticulum stress response after viral infection. Results: We found that TRIM29 was highly induced by cardiotropic viruses, including CVB3 and EMCV, and promoted PERK-mediated endoplasmic reticulum (ER) stress, apoptosis, and reactive oxygen species (ROS) responses, which restricted viral replication in cardiomyocytes in vitro . TRIM29 deficiency protected mice from viral myocarditis by enhancing cardiac antiviral functions and reducing PERK-mediated inflammation and immunosuppressive cells in vivo . Mechanistically, TRIM29 interacted with PERK to catalyze the SUMOylation of PERK, maintaining its stability and thereby promoting PERK-mediated signaling pathways. Furthermore, we demonstrated that the PERK inhibitor GSK2656157 mitigated viral myocarditis by disrupting the TRIM29-PERK interaction, which improved cardiac function, enhanced cardiac antiviral responses, and reduced inflammation and immunosuppressive cells in vivo . Conclusions: Our findings provide the first evidence that the TRIM29-PERK signaling axis can be targeted for the treatment of viral myocarditis. This suggests that targeting the TRIM29-PERK axis could effectively mitigate viral myocarditis and associated cardiovascular diseases.
Abstract 4132769: Carnosine Supplementation Improves Walking Ability of Peripheral Arterial Disease Patients
Authors: Shahid baba, Amit Dwivedi, Mamata Chaudhari, Benjamin Doelling, Manjuri Kulkarni, David Hoetker, Timothy O Toole, Leslie Haysley, Tatiana Krivokhizhina, Pawel Lorkiewicz, Daniel Riggs, Aruni Bhatnagar
Journal: Circulation (2024)

Introduction: Peripheral artery disease (PAD) is a significant cause of cardiovascular morbidity and mortality, characterized by atherosclerosis in the skeletal muscle. Currently no mechanism-based therapeutics are available for this diseased population. In the muscle, histidyl dipeptides, such as carnosine (ranging between 5-10 mM) possess the abilities to bind with toxic lipid peroxidation products, such as acrolein. Preclincial studies show carnosine is depleted in the ischemic leg, increasing intramuscular carnosine improves angiogenesis, and blood flow in the ischemic leg. In humans, carnosine levels are increased in the muscle with carnosine supplementation. However, little is known whether carnosine levels are affected in PAD patients and its effect on their walking ability. Hypothesis: Carnosine supplementation will improve walking ability of PAD patients. Methods: We recruited normal (males: n=48; females: n=52; age: 50 ±10 years) and PAD subjects (males: n=52; females: n=41; age: 67±8 years; ankle brachial index (ABI): 0.65±0.18 measured urinary histidyl dipeptides, histidyl dipeptide-aldehyde conjugates, and oxidative stress markers: N-Acetyl-S-(3-hydroxypropyl)-L-Cysteine (3-HPMA) and N-acetyl-S-(2-carboxyethyl)-L-cysteine (CEMA), both are acrolein metabolites. PAD subjects (n=7; n=5 females and n=2 males; ABI: 0.68±0.08, age: 63±8 years) were supplemented with carnosine 2 g/day for 3 months, measured distance covered in a six-minute walk test (6MWT), ABI, blood profile at baseline and after completion. Results: In PAD subjects urinary carnosine was decreased (normal: 20±29 vs PAD:11±14 nmoles/mg creatinine, p&lt;0.024), carnosine aldehdye conjugates were increased (carnosine propanal: 1.46±1.27 vs normal 0.56±1.08 nmoles/mg creatinine, p&lt;0.0001; and carnosine propanol: 4.66±2.80 vs normal 1.52±1.21 nmoles/mg creatinine, p&lt;0.0001). Oxidative stress markers were increased in the PAD subjects (CEMA: 341±210 vs normal: 119±86 ng/mg creatinine, p&lt;0.0004 and 3HPMA: 6.57±6.32 ng/mg protien vs normal: 5.49±5.28 ng/mg creatinine, p&lt;0.001). Following carnosine supplementation, blood profile was unchanged. Distance covered in 6MWT increased by 166±204 feet (before: 577±129 vs 743±152 feet after, p&lt;0.048) and there was an increasing trend in ABI (before: 0.68±0.08 vs 0.80±0.19; after, p&lt;0.18). Conclusion: Urinary carnosine could serve as a biomarker to evaluate PAD pathology and carnosine supplementation may improve walking ability of PAD patients.
Abstract 4134975: ROS-Traf6-Yap Promotes the Development of Cardiac Hypertrophy
Authors: Yuting Li, Xiaoxia Zhou
Journal: Circulation (2024)

Introduction: Heart failure (HF) is caused by structural and functional abnormalities of the heart and is associated with high morbidity and mortality. Pathological myocardial hypertrophy accounts for a significant portion heart failure. The Yap protein was found to be responsive to mechanotransduction signals and can limit organ size by inducing cell cycle arrest during development. In the heart, pathological activation of Yap has been shown to drive cardiac hypertrophy, but regenerative activation of Yap can promote myocardial cell-cycle re-entry. However, how Yap is pathologically activated in the beating cardiomyocyte remains elusive. Hypothesis: ROS-Traf6 promotes the development of cardiac hypertrophy by activating Yap in a non-canonical fashion. Methods: Traf6 protein levels in heart failure patients biopsies as well as in various murine failing hearts were examined by immunofluorescence. Molecular interrogation of ROS-Traf6-Yap signaling axis was performed in primary neonatal rat cardiomyocytes (NRCM) and human induced pluripotent stem cell derived cardiomyocytes. Yap protein stability and activation by Traf6 was examined by immunoprecipitation, CHX induction, and point mutation. Myocardial specific Traf6 knockout and Yap mutant animals were used to evaluate Traf6-Yap signaling in vivo . Results: We found that Traf6 expression was significantly elevated in multiple heart failure models. Using the transverse aortic constriction (TAC)-induced cardiac hypertrophy model, pressure overload increased ROS levels which activated Traf6. Traf6 overexpression induced myocardial hypertrophy while knockdown blocked myocardial hypertrophy in Ang II treated NRCMs. Mechanistically, Traf6 binds to and ubiquitinates Yap-K234 – this promotes Yap protein stability and nuclear translocation evidenced by increase in phosphorylated Yap. Myocardial Traf6 deficiency prevents TAC-induced cardiac hypertrophy. Moreover, overexpression of Yap-K237 mutant did not restore TAC-induced cardiac hypertrophy in myocardial Yap deficient mice. Conclusions: Our results demonstrate that non-canonical Yap activation is responsible for pressure overload induced cardiac hypertrophy. Targeting of the newly identified ROS-Traf6-Yap signaling axis may provide a new approach to prevent pathogenic cardiac hypertrophy.
Abstract 4137594: Intrinsic Capacity Trajectories and Cardiovascular Disease Among Chinese Older Adults: A Population-Based Longitudinal Study
Authors: ZHITING GUO, Yuling Chen, Cheryl Dennison Himmelfarb, Binu Koirala, Jiaying Li, jingfen jin
Journal: Circulation (2024)

Background: WHO defined intrinsic capacity (IC), a composite of physical and mental capacities, is a marker of healthy aging. Monitoring IC trajectories in older adults may guide preventative strategies and delay negative health outcomes. With the rapidly increasing proportion of older adults and the high prevalence of cardiovascular disease (CVD) in China, this study aimed to identify IC trajectories over time and determine whether IC trajectories can predict CVD outcomes. Hypothesis: The IC trajectory among Chinese older adults is heterogeneous; the decline of IC will be associated with increased CVD. Methods: The study used data from five waves (2011 to 2020) of the China Health and Retirement Longitudinal Study (CHARLS). A total of 3,336 adults aged 60 years or older without CVD during the baseline survey in 2011 (T1), who completed the follow-ups in 2013 (T2) and 2015 (T3) were included to determine IC trajectory. IC was assessed through five domains (locomotion, sensory, vitality, cognition, and psychology) using the WHO framework. The CVD outcomes were determined by self-reported diagnoses of heart disease or stroke in the 2020 (T5) wave. A group-based trajectory model (GBTM) was used to identify IC trajectory, and logistic regression was employed to explore the association between IC trajectory groups and CVD outcomes adjusting for covariates. Results: Three IC trajectory groups were identified (Fig 1): high IC-stable group (13.40%), medium IC-stable group (56.12%), and low IC-decline group (30.48%). By the 2020 follow-up, 1204 participants (36.1%) reported CVD diagnosis. Adjusted for sociodemographic, lifestyle factors (smoking, drinking), and cardiovascular metabolic factors (hypertension, diabetes, dyslipidemia), compared to the high IC-stable group, the low IC-decline group had 63.7% higher odds of CVD (OR=1.637, 95%CI=1.268-2.114), and medium IC-stable group had 7.1% higher odds of CVD (OR=1.071, 95%CI=0.851-1.349). Conclusion: IC trajectory among Chinese older adults is heterogeneous, and IC declines predict higher odds of CVD onset. Regular monitoring of IC and tailored intervention to improve IC may facilitate CVD prevention.
Abstract 4137925: Long-term Outcome of Initial Thoracic Endovascular Repair or Medical Therapy in Acute Uncomplicated Type B Aortic Dissection: Real-world Data from a Nationwide Claims-Database in Japan.
Authors: Yuki Kimura, Hiroshi Ohtsu, Naohiro Yonemoto, Nobuyoshi Azuma, Kazuhiro Sase
Journal: Circulation (2024)

Introduction: Thoracic endovascular aortic repair (TEVAR) has emerged as a promising treatment option for patients with type B aortic dissection (TBAD). However, there is a lack of evidence regarding the long-term morbidity of initial TEVAR compared to optimal medical therapy (OMT) in acute uncomplicated TBAD (uTBAD). Objective: To evaluate real-world data(RWD) on the long-term outcome of Japanese patients with acute uTBAD using a nationwide claims database. Methods: This retrospective cohort study utilizes JMDC, a nationwide claims database under Japan's universal healthcare system. We included patients who were initially hospitalized with a diagnosis of acute TBAD. We defined acute uTBAD by excluding those who died within one month, suffered aortic rupture, traumatic thoracic aortic injury, underwent open-chest surgery, experienced stroke or paralysis, or had less than six months of history in the JMDC. Patients who underwent TEVAR within three months of the index hospitalization (TEVAR group) were compared with those who received optimal medical therapy (OMT group). Propensity score (PS) matching was performed based on age, sex, and year of hospitalization. Using the Kaplan-Meier method, we calculated the cumulative rate of all-cause mortality and aorta-related events. Results: Of 18,445 patients diagnosed with aortic disease between January 2005 and December 2020, 641 were included in the study (OMT group: n=580, TEVAR group: n=61). After PS-matching, demographics of the groups (OMT_PSM: n=183 vs. TEVAR_PSM: n=61) were female (12.6% vs. 13.1%), median age (54 years [IQR, 48-60] vs. 54 years [IQR, 50-61]) and follow-up time (18 months [8-32] vs. 19 months [9-32]), respectively. Kaplan-Meier curves for the aortic-related events (Figure1, 2) are shown as long-term outcomes. Conclusions: This study successfully demonstrated that the estimated 5-year aortic-related event rate in acute uTBAD patients undergoing OMT is approximately 20%, demonstrating the relevance of the RWD source. However, the number of death events in the TEVAR and OMT groups was not sufficient to provide statistical power. Therefore, further studies are warranted to evaluate the long-term prognosis of initial TEVAR for uTBAD.
Abstract 4134962: Association between Chronotype and Psychological Health in South Korean Adolescents
Authors: Jinhee Seo, Sung-Il Cho, Sung-Ho Won
Journal: Circulation (2024)

Background: Chronotype influences general health, with late chronotypes often linked to psychological problems. However, longitudinal studies on this topic are limited. This study assessed the association between chronotype and adolescent mental health, focusing on depression and somatic symptoms through cross-sectional and longitudinal analyses. Methods: This longitudinal study used data from the Korean Children and Youth Panel Survey (KCYPS), targeting middle school students aged 13. Participants were assessed annually over four years (2018-2021). Chronotype was determined by analyzing sleep onset and wake times. Depression and somatic symptoms were evaluated using preexisting questionnaires like the SCL-90. Multilevel linear regression analyses were conducted both concurrently and prospectively, with gender stratification. Covariates included sleep quality, physical activity, smartphone usage, breakfast and friendship. Results: The study included 1,882 students who completed all follow-ups. Students with a late chronotype, short sleep duration, and low sleep quality reported more mental health symptoms. Late chronotype was associated with higher levels of depression (β=0.062, p&lt;.001) and somatic symptoms (β=0.056, p=.018) within the same year, and predicted somatic symptoms one year later (β=0.055, p=.019). For males, insufficient sleep worsened the effects of late chronotype on depression one year later (β=0.100, p=.042), and late chronotype predicted somatic symptoms one year later (β=0.072, p=.024). In females, late chronotype was associated with depression (β=0.061, p=.025) and somatic symptoms (β=0.075, p=.005) within the same year but did not predict future symptoms. Conclusions: Late chronotype negatively impacted depression and somatic symptoms and predicted future somatic symptoms. In females, late chronotype was related only to current mental health issues, whereas in males, it predicted future mental health problems, especially when combined with insufficient sleep. These findings highlight the impact of chronotype on adolescent mental health and suggest that its negative effects can be moderated by factors like sleep duration.
Abstract 4134379: Mediterranean-Style Diet and Adverse Pregnancy Outcomes by Race and Overweight or Obesity Status in the Boston Birth Cohort
Authors: Linh Tran, Xiumei Hong, Theresa Boyer, Xiaobin Wang, Anum Minhas
Journal: Circulation (2024)

Introduction: Mediterranean-style diet (MSD) is associated with a lower risk of cardiovascular and metabolic diseases. However, the association of MSD during pregnancy with adverse pregnancy outcomes (APOs) among different racial and ethnic groups and overweight or obesity (OWO) status remains unclear. Question: We examined if MSD during pregnancy is protective for developing any APO and individual APOs in a large cohort of racially and ethnically diverse, urban, low-income women. Methods: Among 8,511 patients in the Boston Birth Cohort (mean age 28.2±6.5 yrs), 47% were non-Hispanic Blacks and 28% were Hispanics. Among 4,343 (51%) with pre-pregnancy OWO status, 25% Black and 12% Hispanic women developed any APO (Figure 1). Individual Mediterranean-style diet score (MDS) was based on maternal diet intake during pregnancy via food frequency questionnaire interviews at 24-72 hours postpartum. Results: Increase in the MDS by one standard deviation was inversely associated with any APO (aOR, 0.86 [95% CI, 0.82–0.90]), preeclampsia or eclampsia or HELLP (aOR, 0.89 [95% CI, 0.82–0.97]), gestational diabetes (aOR, 0.88 [95% CI, 0.81–0.95]), preterm birth (aOR, 0.90 [95% CI, 0.86–0.95]), and low birth weight (aOR, 0.87 [95% CI, 0.83–0.92]) (Table 1). In the subgroup analysis, higher adherence to MSD was associated with lower odds of developing, preeclampsia or eclampsia or HELLP, low birth weight, and preterm birth in Black women with or without OWO. The benefit of MDS was also observed for gestational diabetes in Hispanic women with OWO (Figure 2). Conclusion: Greater adherence to MSD during pregnancy is associated with a lower risk of composite APOs, with benefits varying across types of APOs, racial/ethnic groups, and OWO status.
Abstract 4134449: Increasing Histidyl dipeptides in Skeletal Muscle Preserves Muscle Mass and Function During Heart Failure.
Authors: Mamata Chaudhari, Benjamin Doelling, David Hoetker, Yibing Nong, Kenneth Brittian, Aruni Bhatnagar, Shahid baba
Journal: Circulation (2024)

Background: In heart failure patients muscle wasting is a serious comorbidity. Oxidative stress and inflammatory cytokines, which cause muscle wasting, are increased in the skeletal muscle of heart failure patients. Oxidative stress leads to oxidation of lipids, generating toxic lipid peroxidation products, such as acrolein, which activates TNFa. Whether lipid peroxidation products accumulate in muscle and their removal from muscle influences muscle atrophy during heart failure has not been studied. In the muscle there are histidyl dipeptides, such as carnosine, ranging between 5-10 mM, synthesized via enzyme carnosine synthase (CARNS) that bind lipid peroxidation products. We examined whether intramuscular histidyl dipeptides influences heart failure-induced muscle wasting. Hypothesis: Histidyl dipeptides, alleviates intramuscular inflammation, preserves muscle mass and function during heart failure. Methods: Wild type (WT) and muscle-specific CARNS transgenic (Tg) mice were subjected to sham and transverse aortic constriction (TAC) surgeries. Cardiac function, muscle strength, atrophic and inflammatory markers, aldehyde modified protein, CARNS, and histidyl dipeptides were measured after 12 weeks. Results: In heart failure mice, weight of gastrocnemius (sham: 18.64 ± 1.73 vs TAC: 14.10 ± 0.90 mg, p=0.005), soleus (sham: 6.06 ± 0.82 vs TAC: 4.14 ± 0.70 mg, p=0.001), and tibialis anterior (sham:10.76 ± 1.62 vs TAC: 6.22 ± 1.83 mg, p=0.003), were decreased. Muscle strength was diminished (sham: 2.81 ± 0.36 vs TAC: 1.52 ± 0.27 N, p=0.004). Atrophic marker, atrogin1, aldehyde protein adducts and TNF-a were increased in the gastrocnemius muscle of TAC mice (~2-3-fold vs sham, p&lt;0.05). CARNS expression and carnosine was decreased in different muscles of TAC mice (gastrocnemius; sham: 43.38 ± 20.46 vs TAC: 24.48 ± 6.49 nmoles/mg protein, p=0.03; soleus; sham: 22.04 ± 11.36 vs TAC: 11.02 ± 4.69 nmoles/mg protein, p=0.03; and tibialis; sham: 27.9 ± 11.70 vs TAC: 15.50 ± 3.48 nmoles/mg protein, p=0.01). Gastrocnemius muscle weight (WT TAC: 14.38 ± 1.08 vs Tg TAC: 17.30 ± 1.32 mg, p=0.004) and muscle strength (WT TAC: 3.06 ± 0.32 vs Tg TAC: 3.98 ± 0.41 N) were preserved, atrogin and TNFa expressions were decreased in gastrocnemius muscle of Tg TAC mice (~2-3-fold, p=0.04). Conclusion: Increasing intramuscular histidyl dipeptides alleviates muscle inflammation, preserves muscle mass, and function during heart failure.
Abstract 4134947: Explainable Machine Learning to Predict Heart Failure Outcomes Using Exercise and Clinical Data
Authors: Varsha Karanam, Matthew Magoon, Neha Arunkumar, Andrew Pattock, Todd Dardas, Patrick Boyle, Yonatan Buber, David Leone
Journal: Circulation (2024)

Background: Heart failure (HF) hospitalizations are associated with disease burden and cardiovascular mortality. International guidelines highlight cardiopulmonary testing (CPET) for risk stratification and prognosis in HF. Identifying individuals at risk could direct interventions to prevent admissions. This study uses explainable machine learning (XML) tools to identify CPET and clinical variables predictive of HF hospitalizations. Hypothesis: XML analysis of CPET parameters and clinical factors can yield accurate, patient-specific prediction of HF admission within one year. Methods: A retrospective single center review of 178 CPETs in patients referred for HF was completed. Clinical data within one year of CPET trained a boosted machine learning model (XGBoost). SHAP (Shapley Additive Explanations) explainability analysis emphasized key features for model predictions. Results: 44 (24.7%) patients with CPET were admitted for HF within one year. The model predicted this outcome with an area under the receiver operating characteristic curve (AUC) of 0.772. SHAP analysis (Figure 1) selected factors for decision making: pulmonary artery systolic pressure (PASP) via cardiac catheterization or echocardiogram; oxygen consumption at the ventilatory threshold (VO 2 at VT); O 2 pulse at rest; ventilatory efficiency (VE/VCO 2 slope); minute ventilation per oxygen consumption at maximal exercise (VE/VO 2 max) during CPET; left ventricle end diastolic volume by echocardiogram; and sodium-glucose cotransporter-2 inhibitor usage. Peak VO2, predicted VO2, predicted O2 pulse, and VE/VCO2 slope were significant, consistent with past studies (Table 1). Conclusion: Our XML analysis emphasizes PASP (partially related to high left ventricular filling pressures) and VO 2 (at ventilatory threshold) as predictive for HF hospitalization within one year of CPET testing. Studies to prospectively evaluate these highlighted factors are needed to continue exploring predictive capabilities to tailor interventions.