tbuckley/cabot-search huggingface dataset:
Abstract 4143150: Long-term Effect of Screening for Coronary Artery Disease Using CT Angiography on Mortality and Cardiac Events in High-risk Patients with Diabetes: the FACTOR-64 Follow-up Study
Authors: Joseph Muhlestein, Heidi May, Stacey Knight, Viet Le, Tami Bair, Jeffrey Anderson, Kirk Knowlton
Journal: Circulation (2024)

Background: The FACTOR-64 study was a randomized controlled trial designed to assess whether routine screening for CAD by coronary computed tomography angiography (CCTA) in high-risk patients with diabetes followed by CCTA-directed therapy would reduce the risk of death and nonfatal coronary outcomes. Results at four years showed a lower revascularization rate (3.1% (14) vs. 8.9% (40), p&lt;0.005) among the control group. But there was also a non-significant trend toward a lower incidence of all-cause mortality and nonfatal MI (hazard ratio, 0.82 [95% CI, 0.49-1.32]; p=0.38). Whether screening CCTA might have a more significant effect on the outcomes of patients after longer follow-up is unknown. Methods: The FACTOR-64 study randomized 900 patients (age = 61.5 years, males = 52%, Type 2 DM = 88%, DM duration = 13 years) with type 1 or type 2 diabetes for at least 3 to 5 years without CAD symptoms to screening with CCTA (n = 452) or standard national guidelines-based optimal diabetes care (n = 448). Standard primary prevention medical therapy or aggressive secondary prevention therapy with invasive coronary angiography was recommended based on CCTA findings. Enrollment occurred between July 2007 and May 2013, and follow-up extended to May 2024. Results: The mean follow-up time was 12.7±3.2 (CCTA=12.8±3.1; control=12.6±3.3, p=0.47) years. During longer-term follow-up after the initial four years, essentially the same numbers of further revascularizations (20 vs. 21) occurred in the CCTA group vs. the control group, thus continuing a significantly higher rate of revascularization among those receiving CCTA (Table). However, the composite and individual outcomes of all-cause mortality and nonfatal MI did not differ between the CCTA and control groups. Conclusion: Among asymptomatic patients with type 1 or type 2 diabetes followed for over twelve years, the use of CCTA to screen for CAD did not significantly affect the rates of all-cause mortality or nonfatal MI. This was despite an overall significantly increased use of revascularization among those receiving CCTA. These definitive findings do not support CCTA screening in this population.
Abstract 4143088: Abnormal Calcium Regulation Leads to Pathological Cardiac Hypertrophy During Pregnancy in the GSNOR-Deficient Mouse Model of Preeclampsia
Authors: Raul Dulce, Wayne Balkan, Joshua Hare, Shathiyah Kulandavelu
Journal: Circulation (2024)

Introduction: Preeclampsia (PE), a leading cause of maternal mortality, is linked to cardiac hypertrophy and impaired relaxation, predisposing the mother to an increased risk of cardiovascular (CV) injury during pregnancy. Mice lacking S-nitrosoglutathione reductase (GSNOR –/– mice ) exhibit all the clinical features of PE. Calcium regulation plays an important role in cardiac relaxation and hypertrophy, but whether alterations in calcium handling contribute to the impairment in these PE mice is unknown. Hypothesis: Cardiac hypertrophy and impaired relaxation in pregnant GSNOR –/– mice may be due in part to altered Ca 2+ handling mechanisms. Methods: Pregnant control (WT [C57B6]) and GSNOR –/– mice were examined at non-pregnant (NP) and late pregnancy (17.5 dpc). Cardiomyocytes (CMs) were isolated (N=3-4 mice/group; n=8-24 CMs/heart) and assessed for intracellular Ca 2+ and sarcomere shortening using IonOptix. Ca 2+ decay and sarcomere relaxation rates were recorded. Ventricular tissue homogenates were assessed for Ca 2+ handling and sarcomere-associated protein expression and post-translational modifications by Western Blot. Results: At late pregnancy, the CMs of GSNOR –/– mothers were significantly wider and systolic and diastolic Ca 2+ levels were elevated as compared to WT. At 17.5 dpc, expression of Ca 2+ handling proteins, RyR2, L-TCC and NCX1 were increased, and phosphorylation of RyR2 and L-TCC were increased in the GSNOR –/– mothers as compared to WT. The Ca 2+ decay rate improved in CMs from pregnant versus NP WT CMs but not in GSNOR –/– CMs. PLB phosphorylation at Thr-17 was augmented in pregnant WT hearts, while phosphorylation at Ser-16 was reduced in pregnant GSNOR –/– . Sarcomere relaxation parameters and sarcomere resting length were improved in CMs from pregnant WT mice but were impaired in pregnant versus NP GSNOR –/– mice in association with increased expression of MyBPC in pregnant GSNOR –/– . Conclusion: The PE-related cardiac hypertrophy and impaired relaxation at late pregnancy in GSNOR –/– mice were associated with elevated cytosolic Ca 2+ levels, altered expression and post-translational modifications of Ca 2+ handling and sarcomeric proteins, which may predispose these mice to higher CV injury during pregnancy
Abstract 4143101: Cardiotoxicity of Anthracycline and Pembrolizumab Compared to Anthracycline Alone in Management of Triple-Negative Breast Cancer: A Retrospective Cohort Study
Authors: Nolan Holley, Gary Monroe, Micheal Gallagher, Syed Ahmad, Sonya Inderbitzin-Fischer, Michelle Hartzell, Pranathi Tella, Izza Batool, Jordan Hill, Sobha Kurian, Brijesh Patel
Journal: Circulation (2024)

Introduction: In a major paradigm shift of management of high-risk early-stage triple negative breast cancer (TNBC), the KEYNOTE-522 trial showed evidence to suggest that the addition of the immune checkpoint inhibitor (ICI) pembrolizumab to current standard-of-care chemotherapy leads to greater clinical efficacy than that of chemotherapy alone. However, the addition of an ICI carries with it the risk of immunotherapy-related cardiotoxicities. This raises concern for additive risks for cardiotoxicity for patients with high-risk early-stage TNBC receiving both anthracycline and ICI. Hypothesis: Management of high-risk early-stage TNBC with a treatment regimen consisting of anthracycline and ICI will have no increase in cardiotoxicity when compared to those receiving anthracycline alone. Aims: The purpose of this study is to identify if the combination of anthracycline and ICI in the management of high-risk early-stage TNBC is associated with greater cardiotoxicity than that of those on anthracycline alone. Methods: Patients with TNBC were identified within the electronic health record system at our institution. Cohorts were created based on management strategy: anthracycline with ICI and anthracycline without ICI. Patient demographics, comorbidities, functional status, medications, cardiac imaging, management, and outcomes were analyzed retrospectively. Cohorts were then compared for analysis of time to adverse cardiac event. An alpha value of 0.05 was used to determine statistical significance. Results: A total of 385 patients with TNBC were included in the study, with 312 receiving anthracycline without ICI and 73 receiving anthracycline with ICI. Baseline characteristics between the two cohorts were well balanced with no significant differences in prevalence of comorbidities. There were no significant differences in incidence of general cardiac events, heart failure, acute coronary syndrome, cardiac arrhythmias, and pericardial effusion between these two cohorts following each respective treatment regimen. Furthermore, there was no significant difference in time to cardiac events between the two groups. Conclusion: There appears to be no significant differences in cardiac events between patients with TNBC on anthracycline with ICI and those on anthracycline without ICI. Given no significant differences in cardiotoxicity, these findings further favor use of an ICI in management of high-risk early-stage TNBC and serve to reduce clinician hesitancy.
Abstract 4143069: Serum Glucocorticoid Regulated Kinase 1 (SGK-1) Inhibitor Reduced Hypertension in a Salt-Sensitive Hypertension Model of Heart Failure with Preserved Ejection Fraction
Authors: Sabindra Pradhananga, Olga Shilova, Dinesh Srinivasan, Peter Senese, Michael Gralinski, Melissa Zammit, Philip Sager, Saumya Das
Journal: Circulation (2024)

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is a complex clinical syndrome marked by multiple cardiac and extracardiac pathophysiological alterations. Despite accounting for 50% of HF diagnoses, treatment options for HFpEF remain limited. Serum and glucocorticoid regulated kinase 1 (SGK1), a PI3-kinase-dependent kinase, is demonstrated to play a role in HF and atrial fibrillation. Hypothesis: Based on the role of SGK1 in renal sodium homeostasis, inflammation, and fibrosis, we hypothesized that SGK1 inhibition would prevent the progression of HFpEF. This hypothesis was tested by assessing the efficacy of a novel and potent SGK1 inhibitor, SGK1-I, in a rat model of HFpEF. Methods: Forty Dahl salt sensitive (Dahl SS) rats were fed low salt diet (LSD, 0.3% NaCl) or high salt diet (HSD, 8% NaCl) for a total of 12 weeks. After 6 weeks, rats were treated with vehicle or SGK1-I (10 or 25 mg/kg/day) via oral gavage for an additional 6 weeks. Intracardiac hemodynamics and cardiac structure and function were assayed using pressure volume loop and echocardiography respectively. BP and cardiac structure data from 4-6 animals/group are discussed. Results: Dahl SS rats fed with HSD exhibited increased systolic arterial pressure (SAP; LSD: 85±9.8, HSD: 132±29.4 mmHg, p =0.01) and diastolic arterial blood pressure (DAP; LSD: 152±12.5, HSD: 202.8±27.0 mmHg, p = 0.03); SGK1-I reduced the HFD SAP (10 mg/kg/day: 190±37 mmHg, p=0.13 and 25 mg/kg/day: 164±5 mmHg, p=0.93) and DAP (10 mg/kg/day: 122±29 mmHg, p=0.07 and 25 mg/kg/day: 99±6 mmHg, p=0.84) in a dose dependent manner to the LSD levels. The high dose of SGK1-I also reduced HSD-induced alteration in left ventricular (LV) morphology, including posterior wall thickness (HSD: 2.38±0.32 mm, SGK1-I: 2.21±0.24 mm, p&lt; 0.05) and improved ratio of LV+septum mass to tibia length (HSD: 26.53±0.00 mg/mm, SGK1-I: 25.18±0.00 mg/mm, p&lt;0.05). The dose dependent reduction of left ventricle pressure development and maximal pressure in HSD rats administered with SGK1-I suggests protection is due to alleviation of hypertension induced pressure overload in the heart. Conclusion: Data analyzed to date suggest SGK1-I administration reduces elevations in blood pressure and subsequent alteration in LV morphology in Dahl SS rats fed with HSD. These data support the need for additional preclinical studies to explore the use of SGK1 inhibition as a promising target for the treatment of HFpEF associated with hypertension.
Abstract 4143104: Atherosclerotic features of plaque instability are transmitted via gut microbial transplantation
Authors: Riccardo Nieri, Eleonora Foglio, Flavio De Maio, Anna Severino, Luca Masucci, Alessia D Aiello, Maria Chiara Grimaldi, Jacopo Gervasoni, Daniele Santoni, Daniela Pedicino, Matteo Russo, Giovanna Liuzzo, Federica Limana
Journal: Circulation (2024)

Background: Gut microbiota have been suggested as a causative agent of atherosclerosis mainly by converting dietary and endogenous molecules into active metabolites like the trimethylamine N-oxide (TMAO). Nevertheless, the relationship between gut microbiota and plaque features has not been well documented. In this study, we tested the hypothesis that gut microbial transplantation can transmit atherosclerotic plaque characteristics. Methods and Results: In a fecal microbiota transplantation mouse model, the colonization of gut microbiota from patients with acute coronary syndrome (ACS, n=9), chronic coronary syndrome (CCS, n=11) and control subjects (CTRL, n=8) was evaluated and plaque features of stability were assessed. Transplantation was performed into ApoE KO mice fed a diet containing 1% choline or a standard diet. Initially, resident intestinal microbes were suppressed using antibiotics, followed by the administration of fecal oral gavages from human donors over a period of 12 weeks. Firstly, a significant positive correlation was detected between TMAO serum levels assessed by UPLC-MS/MS system and atherosclerotic lesion formation measured by Oil Red O staining of aortic root cross-sections; however, no correlations were identified with plaque instability. Plaque composition was analyzed using necrotic core area and fibrous cap thickness as primary readouts of plaque vulnerability. Interestingly, microbiota from ACS patients significantly decreased plaque stability as showed by increased necrotic core and fibrous cap thinning. Further, it decreased α-SMA + cell population and increased MMP2 staining, indicating intraplaque metalloprotease activity. Gut microbiota composition was evaluated using 16S rRNA sequencing of ApoE KO mice fecal samples. In ACS transplanted mice, 14 bacterial genera were positively associated with larger necrotic core and 6 bacterial genera with MMP2. In CCS transplanted mice, 6 bacterial genera showed negative correlations with necrotic core size and 2 bacterial genera positively correlated with α-SMA + cells. Conclusions: In conclusion, we identified bacteria significantly associated with the vulnerable plaque phenotype, which provides potential insights to modulate atherosclerotic plaque composition by influencing the gut microbiota.
Abstract 4143119: National Inpatient Mortality Trend of Mitral Valve Transcatheter Edge-to-Edge Repair in Patients With End-Stage Renal Disease on Dialysis
Authors: Zaid Abood, Suhail Allaqaband, Patrycja Galazka, Kirsten Tunink, Balamrit Sokhal, Mohamed Hommeida, Tanvir Bajwa, M. Fuad Jan
Journal: Circulation (2024)

Background: Mitral valve transcatheter edge-to-edge repair (M-TEER) is performed for high-risk patients with severe mitral regurgitation and multiple comorbidities. End-stage renal disease (ESRD) is one poor prognostic factor in M-TEER. However, real-life, large-scale data on inpatient mortality in ESRD patients undergoing M-TEER are lacking. Methods: The National Inpatient Sample from Jan 2015 to Dec 2020 was used to identify the study cohort using the International Classification of Diseases, 9th&amp;10 th Revisions, Clinical Modificatio n. The primary outcome was overall in-hospital mortality for patients with and without ESRD undergoing M-TEER. The secondary outcome was inpatient mortality trends in these groups. Univariate and multivariate logistic regressions (adjustment for age, race, Elixhauser comorbidity index score) were used. Results: We evaluated 44,845 patients who underwent M-TEER, of whom 2135 (4.7%) had ESRD on dialysis. The ESRD group was younger than the non-ESRD group (69.9 vs 76.4 years, P&lt;.001), with a similar percentage of females (41.9% vs 45.4%, P=.151). Total procedure number increased significantly from 3184 to 11680 during the study period (Fig 1A). Overall mortality was significantly higher in ESRD patients (11.7% vs 1.5%, P&lt;.001). Adjusted mortality in the ESRD group increased from 2.2% in 2015 to 12.9% in 2020 (P=.025), whereas the mortality rate remained relatively stable in non-ESRD patients (2.1% to 1.5%, P=.150) (Fig 1B). The ESRD group was associated with a higher incidence of immediate postoperative complications, which may have contributed to higher mortality (Table). Conclusion: Patients with ESRD on dialysis undergoing M-TEER had significantly higher mortality rates than non-ESRD patients. Despite younger age, mortality for ESRD patients rose substantially; it remained relatively stable for non-ESRD patients. These findings highlight the elevated risk and need for tailored management strategies for ESRD patients undergoing M-TEER.
Abstract 4142045: Costs and Healthcare Resource Utilization in Transthyretin Amyloid Cardiomyopathy Exceeds That of Non-amyloid Heart Failure
Authors: Justin Grodin, Ahmad Masri, Richard Wright, Jean-Francois Tamby, Heather Falvey, Liana Hennum, Chaitanya Badwe, Melissa Allison, Rakesh Ramesh, Shradha Sanghi, Sandesh Dev, Jose Nativi-Nicolau
Journal: Circulation (2024)

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, fatal condition characterized by worsening heart failure (HF), exercise intolerance, cardiac arrhythmias, aortic stenosis, and orthopedic manifestations. Recent analyses have shown ATTR-CM presents a significant burden to the healthcare system, but data on healthcare resource utilization (HCRU) comparing ATTR-CM to non-ATTR HF in the US are lacking. Aim: To compare HCRU and costs in patients (pts) with ATTR-CM to that of pts with non-ATTR HF using medical and pharmacy claims. Methods: Using the Optum Clinformatics Data Mart (Jan 2016-Sep 2023), pts with ATTR-CM were identified based on presence of HF and/or cardiomyopathy (CM) occurring within 2 years of first amyloidosis diagnosis (excluding light-chain amyloidosis) and followed for at least 12 months after first HF/CM diagnosis. ATTR-CM pts were matched 1:1 to non-ATTR HF pts using propensity score matching. After index diagnosis, both groups were assessed for HCRU, including inpatient acute cardiovascular (CV) hospitalizations (CVH), length of stay, and cost. Hospitalizations were considered CV if a pt received a CV diagnosis during the hospitalization period. Results: There were 4581 pts with ATTR-CM (mean [±SD] age: 76 [9.13] years; 56.2% male) who met inclusion criteria and were matched to 4581 non-ATTR HF pts (mean [±SD] age: 76 [8.86] years; 56.0% male) for comparison (Table). ATTR-CM pts had a higher trend of CVH and a higher number of total CVHs and mean hospitalizations per pt compared to non-ATTR HF pts (p&lt;0.001). The mean cost per hospitalization (p=0.00463) and mean cost per annual hospitalizations per pt (p&lt;0.001) were higher for ATTR-CM compared to non-ATTR HF. ATTR-CM pts were also hospitalized for more mean days annually for CV-related reasons compared to non-ATTR HF pts (p&lt;0.001). On average, pts with ATTR-CM spent 2.3 days more than matched non-ATTR HF pts in the hospital each year. Conclusion: Compared to non-ATTR HF, ATTR-CM is associated with a greater burden on the healthcare system as evaluated by hospitalization rate, costs per hospitalization, annual hospitalization costs, and days hospitalized annually.
Abstract 4142129: The Role of Neutrophil to Lymphocyte Ratio and Right Ventricular Dysfunction in Indonesian Patients with COVID-19
Authors: Raksheeth Agarwal, Hary Muliawan, Raka Nugraha, Gatut Priyonugroho, Siti Hertine, Sony Hilal Wicaksono, Prima Almazini, Dian Zamroni
Journal: Circulation (2024)

Background: The clinical impact of neutrophil to lymphocyte ratio (NLR) and right ventricular (RV) dysfunction on clinical outcomes in COVID-19 have not been studied in the often-underrepresented Indonesian population. Aim: To investigate the role of NLR and RV dysfunction in Indonesian patients hospitalized for COVID-19. Methods: A retrospective cohort study was conducted at a COVID-19 referral hospital in Indonesia. We included all adult patients hospitalized with COVID-19 between April 2020 – April 2021 who had transthoracic echocardiography (TTE) during admission. Clinical data were extracted from electronic medical records. TTE variables were defined according to the American Society of Echocardiography criteria. All statistical analyses were conducted using the SPSS software. This study was approved by the IRB at Universitas Indonesia (#2022-01-135). Results: A total of 488 patients were included – 29 with and 459 without RV dysfunction. The mean age of the population was 54.8 (SD ± 13.5), and 42% were females. Receiver operating curve analysis and Youden’s J statistics were used to determine the optimal NLR cut-off (Figure 1). An NLR &gt; 4.79 was considered elevated, and had a sensitivity of 70.6% and a specificity of 80.6% in predicting severe - critical COVID-19. A high NLR (OR: 3.38, P = 0.02) and LV systolic dysfunction (OR: 9.76, P &lt; 0.01) were independently associated with RV dysfunction. In multivariate cox regression analysis, older age (HR: 1.02, P = 0.01), obesity (HR: 1.85, P &lt; 0.01), chronic kidney disease (HR: 1.69, P = 0.01), high NLR (HR: 2.75, P &lt; 0.01), and RV dysfunction (HR: 2.07, P = 0.02) increased the risk of 30-day mortality. Conclusions: In Indonesian patients hospitalized with COVID-19, A high NLR is predictive of severe – critical COVID-19 and is associated with RV dysfunction. A high NLR at admission and RV dysfunction independently increase the risk of 30-day mortality in hospitalized Indonesian adults with COVID-19.
Abstract 4143125: Definition of cardiomyocyte generation in infants with heart disease
Authors: Anita Bargaje, NIYATIE AMMANAMANCHI, Jessie Yester, Hairu Zhou, Jocelyn Mich-Basso, Christelle Guillermier, Matthew Steinhauser, Yunbin Guan, Kathryn Little, Dawn Thomas, Shannon Janzef, Jacqueline Weinberg, Jennifer Johnson, Thomas Joseph Seery, Bryan Funari, Tyler Harris, Gaurav Arora, Kirsten Rose-Felker, Matthew Zinn, SUSAN MILLER, Shawn West, Brian Feingold, Victor Morell, MELITA VIEGAS, Luciana da Silva, Mario Castro Medina, Mara Sullivan, Mousumi Moulik, Miguel Reyes-Mugica, Honghai Liu, Bernhard Kuhn
Journal: Circulation (2024)

Introduction: Cell cycle entry and division of differentiated heart muscle cells (cardiomyocytes, CMs) is the evolutionarily conserved mechanism of heart development and regeneration. Quantification of CM proliferation in humans is a critical step towards developing new regenerative therapies for heart failure. To provide definitive evidence for CM proliferation and to characterize the generated phenotypes in humans, we implemented a new research approach using 15 N-thymidine administration to mark cells in S-phase. Tetralogy of Fallot (ToF) is the most common cyanotic congenital heart disease and heart failure is the most common indication for heart transplantation. We selected these patient populations because they undergo heart surgery or transplantation, which provide myocardial samples for research. Research Goal: To define CM generation in human infants. Methods: We administered 15 N-thymidine on five consecutive days in infants who subsequently underwent heart surgery or heart transplantation. The retention of 15 N was visualized by analyzing heart muscle sections with Multi-isotope Imaging Mass Spectrometry (MIMS). Tissue sections adjacent to the MIMS sections were stained with the DNA-dye, Hoechst, to identify and quantify formation of post-mitotic phenotypes, i.e., CMs with polyploid nuclei and multinucleated CMs. Quantitative results presented as mean ± SEM. Results: Infants of 2 months of age and younger at label administration generated 3.9 ± 1.3% new cardiomyocytes (n = 5) and infants between the ages of &gt;2 to 4 months at label administration generated 2.9 ± 1.0% new cardiomyocytes (n = 6). Infants 4 months of age and older generated 0.1 ± 0.1% new cardiomyocytes (n = 3). In ToF (n = 9 infants), 36.0 ± 10.5% of generated cardiomyocytes were mononucleated with polyploid nuclei. Available results from four infants showed formation of binucleated CMs, with the majority having polyploid nuclei. Conclusions: Infants with ToF or heart failure showed a decrease in CM generation with increasing postnatal age. Infants with heart disease generated a high proportion of multinucleated CMs and CMs with polyploid nuclei, indicating increased formation of postmitotic CMs. In conclusion, this study provides definitive evidence for the generation of CMs in infants with heart disease, identifies formation of postmitotic CMs as targetable cellular mechanism, and defines the age window in which therapies to direct CM generation could be effective.