tbuckley/cabot-search huggingface dataset:
Abstract 4139706: A Systematic Review and Network Meta-Analysis of Metastatic Castrate-Resistant Prostate Cancer Therapy Cardiotoxicity Given Metastatic Hormone-Sensitive Prostate Cancer Treatment History
Authors: Moez Aziz, Donald Molony, Dominique Monlezun, Noel Higgason, Oliver Brunckhorst, Jerry Roland, Christopher Owen, Alexander Samuel Iacobucci, Jacob Galan, Justin Swaby, Brett Deng, Taylor Hartshorne, Shubh Desai, Allan Zhang, Daniel Xiao, Darren Sanchez, Jared Imber, Jeffrey Song, Alexis Rivas, Maya Guhan, Shreyas Ranganath, Jerril Jacob, Ali Ziaolhagh, Abdelrahman Ali, Syed Yusuf, Steven Canfield, Cezar Iliescu
Journal: Circulation (2024)

Background and Aim: For metastatic castrate-resistant prostate cancer (mCRPC), the European Association of Urology recommends multiple therapies as first-line. However, these recommendations do not account for additional cardiotoxicity of the therapies for prior stages of the disease, such as the metastatic hormone-sensitive prostate cancer (mHSPC) stage. We seek to adjudicate the cardiotoxicities of first-line mCRPC therapies assuming history of mHSPC treatment based on the five International Cardio-Oncology Society (IC-OS) cardiotoxicity domains: heart failure, myocarditis, vascular toxicity, hypertension, and arrhythmias. Methods: Ovid Medline, Elsevier Embase, and the Cochrane Library were searched for randomized clinical trials (RCTs) of mCRPC and mHSPC patients from inception until January 2024. Studies reporting at least one first-line therapy and effect size of at least one cardiotoxicity domain were included. Network meta-analyses with indirect treatment comparison with multivariate multi-level analysis were performed for each cardiotoxicity domain to estimate relative risk (RR) with 95% confidence intervals (CI) for mCRPC and mHSPC therapies. A Bayesian model was then constructed using the mHSPC network as a prior for informing the RRs and 95% CIs of mCRPC first-line therapies. Results: Network meta-analyses of mHSPC treatment cardiotoxicity, mCRPC treatment cardiotoxicity assuming no treatment history, and mCRPC treatment cardiotoxicity assuming prior mHSPC treatment are provided in Images 1-2. We did not find any studies assessing myocarditis. For patients with mHSPC treatment history, olaparib (OLA) plus androgen deprivation therapy (ADT) plus abiraterone with prednisone (AA+P) decreased hypertensive risk relative to ADT+AA+P (RR 0.20, 95% CI 0.16-0.26). Conclusion: OLA may offer a protective antihypertensive effect when superimposed on ADT+AA+P for mCRPC treatment after prior androgen deprivation from mHSPC therapy.
Abstract 4139747: Inhibition of Acetyl -CoA Carboxylase 2 (ACC2) enhances fatty acid oxidation and improves cardiac function and survival in a severe model of heart failure
Authors: Mai Usui, Yu Tsurekawa, Tatsuya Ikehara, Atsuyuki Shimazaki, Archana Vijayakumar, Robert Myers, G. Mani Subramanian, Eisuke Murakami
Journal: Circulation (2024)

Heart failure (HF) is characterized by disordered energy metabolism including impaired mitochondrial oxidation and altered energy substrate preference. In triglyceride (TG) deposit cardiomyovasculopathy (TGCV; ORPHA code 565612), a rare form of HF characterized by impaired fatty acid oxidation (FAO), massive TG accumulation occurs in cardiac muscle and vasculature due to deficiency of adipose triglyceride lipase (ATGL). Since acetyl-CoA carboxylase 2 (ACC2) regulates fatty acid transport into mitochondria for oxidation, we hypothesized that genetic deletion or pharmacologic inhibition of ACC2 may improve cardiac function in the Atgl knockout (KO) mouse model of TGCV. Relative to Atgl KO mice, Atgl/Acc2 double KO mice had reduced cardiac TG accumulation and fibrosis, and significant improvements in cardiac function by echocardiography, locomotor activity, and survival (log-rank p &lt;0.0001). These findings were recapitulated by treatment of Atgl KO mice with TLC-3595, a highly selective, systemic, small molecule ACC2 inhibitor in development for type 2 diabetes ( Figure ). After a single dose of TLC-3595 to Atgl KO mice, dose-dependent reductions in cardiac malonyl-CoA levels and TG content were observed. Further, in a detailed time-course echocardiographic analysis, Atgl KO mice had reduced left ventricular ejection fraction and evidence of cardiac remodeling which was ameliorated by TLC-3595 treatment. Metabolomic profiling of cardiac tissue revealed ACC2-specific changes, including reduced malonyl-CoA and increased acylcarnitines, consistent with increased FAO with TLC-3595 treatment. Moreover, levels of TCA cycle metabolites and acetylcarnitine were reduced in Atgl KO mice but increased with ACC2 deletion or TLC-3595. In summary, ACC2 deletion or pharmacologic inhibition restored cardiac energy metabolism towards increased FAO in Atgl KO mice, resulting in improved cardiac function and survival. These findings support the therapeutic targeting of ACC2, including with the selective small molecule ACC2 inhibitor TLC-3595, for the treatment of patients with HF associated with FAO deficiency.
Abstract 4139791: A short version of HFD/L-NAME mouse model enabling time-effective proof of concept studies to evaluate drugs targeting the cardiometabolic and mild hypertension associated HFpEF phenotype.
Authors: Rana Assaly, Caroline Dubroca, Aurelie Waget, Kevin Perrier, Thierry SULPICE
Journal: Circulation (2024)

Intro: Drug Development for Heart failure with Preserved Ejection Fraction (HFpEF) is a major challenge facing cardiovascular research due to its complex pathophysiology and existence of comorbidities, leading to recognize distinct HFpEF phenogroups. Animal model development should consider this heterogeneity and each model capturing features of specific phenogroups. Hypothesis: We established a 2-hit model consistent with one of the leading phenogroups, the cardiometabolic and mild hypertension associated HFpEF, by combining a high fat diet to trigger obesity/metabolic syndrome and L-NAME to induce mild hypertension (HFD/L-NAME). We evaluated the presence of HFpEF hallmark and corroborated our data with literature. Empagliflozin (EMPA), the clinical benchmark, was used to confirm the relevance of the model. Methods: To induce obesity/metabolic syndrome, mild and HFpEF, C57BL6N mice were fed HFD (60% Kcal from fat) and water with L-NAME (0.5g/l) for 8 weeks. Control mice (Ctrl) were fed normal chow and water. At 5weeks, mice were randomized based on E/A ratio and ejection fraction and were treated QD for 3weeks with vehicle or EMPA (10mg/kg). Then, treadmill exercise tolerance test was performed, cardiac geometry, systolic and diastolic function were evaluated by echocardiography and heart and lungs were harvested. Longitudinal blood pressure was evaluated by tail cuff. Results: Compared with Ctrl, HFD/L-NAME mice showed cardiac remodeling, preserved systolic function and moderate diastolic dysfunction characterized by inverted or pseudonormal profiles and higher filling pressure (E/A=1.2±0.04 E’/A’=1.1±0.02 E/E’=16.4±0.6 in HFD/L-NAME vs E/A=1.4 ± 0.02 E’/A’=1.3±0.01 E/E’=14.4±0.4 in Ctrl). HFD/L-NAME mice showed altered exercise capacity (p&lt;0.05 for running distance and time vs. Ctrl). Cardiac hypertrophy was confirmed by increased heart weight (p&lt;0.01 vs. Ctrl). Consistent with elevated filling pressure, lung weight was increased in HFD/L-NAME mice (p&lt;0.01 vs. Ctrl), indicative of pulmonary congestion. Mean blood pressure was consistently increased in HFD/L-NAME mice (p&lt;0.05 vs. Ctrl). EMPA had positive outcome on cardiac remodeling in terms of left ventricle hypertrophy and enlargement (p&lt;0.05 vs. Ctrl) and alleviated diastolic dysfunction. Conclusion: The 8-week HFD diet/L-NAME captures several aspects of patients suffering from moderate HFpEF associated to obesity/metabolic syndrome and mild hypertension allowing cost and time effective POC studies.
Abstract 4139547: Price and Affordability of Guideline-Directed Medical Therapy for Heart Failure in Venezuela
Authors: Karim Gebran, Diana De Oliveira Gomes, Maria Bacci, Gabriela Lombardo Pascareli
Journal: Circulation (2024)

Introduction: Heart failure (HF) is a global health burden, with disproportionately higher mortality rates in low and low-middle income countries (LIC/LMIC). Despite advances in guideline-directed medical therapy (GDMT), its accessibility and affordability remain major challenges, particularly in developing countries such as Venezuela. Methods: This study aimed to assess the price and affordability of GDMT for HF in Venezuela. Prices of GDMT medications were obtained from leading pharmacies across the nation, and salary data retrieved from Observatorio Venezolano de Finanzas (OVF). Prices were adjusted to represent a standardized 30-day supply at GDMT target dosages. Affordability was assessed by comparing medication costs to monthly salaries across different employment categories. Results: The study revealed substantial barriers to accessing GDMT in Venezuela, with prices of certain medications representing a significant percentage of monthly salaries. The cost of Angiotensin Receptor-Neprilysin Inhibitors (ARNI) alone consumes nearly 80% of the income for individuals in managing positions, rendering it almost inaccessible. Moreover, those earning minimum wages would struggle to afford any type of GDMT combination. (Table 1) Discussion: These findings underscore the economic disparities in accessing GDMT for HF in Venezuela, reflecting broader challenges in LIC/LMICs. Comparison with similar studies in other countries highlights the global issue of medication affordability and availability. Addressing these barriers is crucial to improving HF outcomes and reducing disparities in healthcare access. Furthermore, there is a pressing need for comprehensive epidemiological data and national registries to inform policy decisions and optimize HF management strategies in Venezuela. Conclusion: The study highlights the critical need for interventions to address the cost-related barriers to GDMT access for HF patients in Venezuela. Efforts to improve affordability and availability of essential medications are essential to ensure equitable access to life-saving therapies and reduce the burden of HF in developing countries.
Abstract 4139677: A rare case of ventriculobronchial fistula caused by an epicardial defibrillator patch
Authors: Sai Vikram Alampoondi Venkataramanan, John Windle
Journal: Circulation (2024)

Background: Epicardial patch defibrillators (EPDs) were commonly implanted in the 1990s for secondary prevention of sudden cardiac death. Despite being largely obsolete, some EPDs remain in patients and can cause late complications. This case highlights such a scenario. Case: A 75-year-old female with a history of cardiac arrest 30 years ago presented with shortness of breath and left leg swelling. She had idiopathic ventricular fibrillation in 1992, treated with an EPD (Picture 1A), later replaced by a transvenous ICD. She was diagnosed with left femoral deep venous thrombosis and bilateral pulmonary embolism and started on therapeutic anticoagulation. She experienced massive hemoptysis, leading to respiratory and cardiac arrest, but was resuscitated. A CT angiogram showed no active bleeding but noted the EPD was close to the lower lobe of the left lung. Upper gastrointestinal endoscopy showed no active bleeding. Bronchoscopy revealed clots in the left lower lobe. Despite empiric bronchial artery embolization, hemoptysis persisted. A repeat bronchoscopy showed reaccumulation of clots. A repeat CT angiogram indicated contrast extension into the ventricular myocardium near the EPD but no lung spillage suggestive of pseudoaneurysm (Picture 1B). She was transferred to our institution for further evaluation. A coronary angiogram revealed normal arteries, while a left ventriculogram revealed contrast extravasation through the lateral wall (Picture 1C). An urgent surgery revealed two EPDs: anterior and lateral. The lateral EPD had eroded into the ventricle, creating a ventriculo bronchial fistula (Picture 1D). The lateral EPD was removed (Picture 1E); the anterior EPD was left in place (Picture 1F). The ventricular defect was debrided and repaired. Postoperative recovery was successful, with no further hemoptysis, and the patient was discharged to a rehabilitation facility. Discussion: EPDs are no longer used due to high failure rates and complications like scar formation and constrictive pericarditis. However, patients with EPDs from the 1990s may present with delayed complications. Accurate diagnosis using multimodality imaging and early management is crucial to reduce morbidity and mortality.
Abstract 4139567: Relationship between Cardiac Implantable Electronic Devices and Tricuspid Regurgitation in the General Population
Authors: Hilary Bowman, Janet Tang, Anna-Sophie Thein, Thomas Dewland, Gregory Marcus
Journal: Circulation (2024)

Introduction: Case series suggest that cardiac implantable electronic devices (CIEDs) with right ventricular leads may tether the tricuspid valve, leading to clinically relevant tricuspid regurgitation (TR). However, the impact of these devices on tricuspid disease in the general population has not been investigated. Methods: Using California’s Department of Health Care Access and Information databases, a longitudinal Cox proportional-hazards analysis of adults who received care in an emergency department, hospital, or outpatient surgery facility from 1 January 2005 to 31 December 2020 was performed. Patients with prevalent TR, rheumatic or congenital heart disease, and endocarditis were excluded. Outcomes were (1) the development of TR and (2) tricuspid intervention. Results: Of 16,893,314 participants contributing 56,095,327 person years, there were 11,234 instances of TR. In the unadjusted analyses, CIED implantation was associated with a 13-fold higher risk of incident TR. After adjusting for age, sex, race and ethnicity, income, heart failure, atrial fibrillation, hypertension, pulmonary hypertension, coronary artery disease, chronic kidney disease, hyperlipidemia, diabetes mellitus, chronic obstructive pulmonary disease, asthma, obstructive sleep apnea, alcohol use, cocaine use, methamphetamine use, opiate use, and tobacco use, patients with a CIED exhibited a 15% higher risk of TR ( Figure 1 ). Heart failure, pulmonary hypertension, hypertension, and atrial fibrillation each exhibited larger magnitudes of risk for TR than having a CIED. In the same population, 74 tricuspid valve interventions were identified. While a CIED was associated with a subsequent tricuspid intervention with HR 19.43 (p&lt;0.0001) in the unadjusted model, this lost statistical significance after adjusting for the same covariates listed above (HR 1.3, p=0.34). Conclusions: Patients with a CIED experienced a higher risk of TR, although the magnitude of the hazard was smaller than other cardiovascular risk factors. While the point estimate favored a higher risk of requiring tricuspid interventions among those with CIEDs, statistical significance was lost after multivariable adjustment, likely due to a small number of outcomes.
Abstract 4139537: An Emerging Epidemic: Obesity Related High Output Heart Failure
Authors: Pooja Singh, Admasu Wondmagegn, Phillip Lam
Journal: Circulation (2024)

Introduction: High output heart failure (HOHF) can be attributed to a wide array of diseases such as severe anemia, hyperthyroidism, arteriovenous fistulas, cirrhosis, chronic lung disease, and morbid obesity. Amongst the causes, obesity is the most common, accounting for 31% of those diagnosed with HOHF; however, there is limited data regarding this topic despite the increasing prevalence of obesity worldwide. We recount a unique case of HOHF in a young woman. Case Description: A 22-year-old woman with a history of class 3 obesity (body mass index 60.1 kg/m2) presented with shortness of breath for 3 weeks and new bilateral lower extremity edema. She was found to have newly reduced left ventricular function of 10-15% with severe dilation of the left ventricle and global hypokinesis. Her cardiac catheterization showed insignificant coronary artery disease. However, hemodynamics showed elevated filling pressures, a cardiac index of 4.6 L/min/m2 and output of 11.9 L/min, both measured by thermodilution; establishing a diagnosis of high output heart failure. The patient’s right ventricular biopsy returned and showed chronic cardiomyopathy, demonstrated by hypertrophied myocytes. Other etiologies of HOHF were ruled out with further workup, including arteriovenous shunting, thyroid disease, liver disease, and pulmonary pathologies. The etiology of her HOHF was ultimately attributed to severe obesity. After diuresis, the patient was discharged on guideline directed medical therapy, which included sacubitril-valsartan, metoprolol succinate, spironolactone, and empagliflozin. She was set to follow up with advanced heart failure and bariatric surgery. Conclusion: HOHF is due to unmet demands by the body, by increased oxygen consumption or by decrease systemic vascular resistance. The pathophysiology for HOHF due to obesity is not entirely understood, however there are several working hypotheses. The pathophysiology stems from obesity causing increased leptin, neprilysin, and decreased adiponectin; increased vasoactive adipokines increasing increased vasodilation; insulin resistance causing cardiac remodeling seen as impaired diastology with low ejection fractions. Treatment of HOHF due to morbid obesity is with bariatric surgery and lifestyle changes. However, given the role of active adipokines in this disease, future studies can aim to investigate intervening at this level to prevent severe consequences, as seen in our patient.
Abstract 4139730: Impact of Telemedicine on Access to Care for New Patients at an Academic Cardiovascular Center: An Analysis of Distance and Time to Visit
Authors: Sean Tsung, Yan Bo Zeng, Vijaya Parameswaran, Fatima Rodriguez, Yue Hu, David Scheinker, Neil Kalwani
Journal: Circulation (2024)

Introduction: Telemedicine allows patients to attend visits from a distance and has been linked to reduced clinic wait times. However, little is known about its impact on catchment area and scheduling efficiency for new patients. We assessed the association of new patient visit (NPV) modality with patient–clinic distance and time to visit (wait time from day of scheduling to day of visit) across patient demographics and pandemic phases. Methods: We extracted visit data at an academic cardiovascular center in Northern California from Jan 2017 to Nov 2023. We used linear models with fixed effects for clinician and patient characteristics to assess the association of NPV modality with distance and time to visit. Results: There were 8,104 and 3,566 NPVs in the mid-pandemic (Jan 2021–Mar 2022) and post-pandemic (Apr 2023 onwards) periods respectively, conducted by 141 clinicians. The proportion of visits conducted by telemedicine decreased from 58% to 40% from the mid- to post-pandemic periods. During the mid-pandemic period, NPVs conducted by telemedicine were more likely to fall outside the center’s pre-pandemic catchment area (100-mile radius) with an adjusted odds ratio of 1.06 (95% CI 1.03, 1.09). This effect did not change significantly post-pandemic, nor did it vary by sex, race, ethnicity, or public insurance status in either period. Time to visit for telemedicine NPVs was 8 days shorter (95% CI 2, 14) during the mid-pandemic period, and 20 days shorter post-pandemic (95% CI 10, 29). During the post-pandemic period, those with Medicaid waited 28 fewer days (95% CI 16, 41) and those with Medicare waited 16 fewer days (95% CI 6, 25) when the modality was telemedicine, whereas those with private insurance saw a smaller reduction of 12 days (95% CI 3, 21). Conclusions: At this academic cardiovascular center, new patients seen via telemedicine were more likely to reside outside the center’s traditional catchment area and had shorter times to new cardiology visits. These effects persisted throughout and beyond the pandemic. Strategic implementation of telemedicine may allow cardiovascular practices to broaden their reach to new patients.
Abstract 4139743: Alfa-tubulin detyrosination causes mitochondrial dysfunction through suppression of Parkin-mediated mitophagy linking to heart failure with preserved ejection fraction
Authors: Shunsuke Miura, Toranosuke Sekine, Ryo Ogawara, Shohei Ichimura, Tetsuro Yokokawa, Tomofumi Misaka, Masayoshi Oikawa, Atsushi Kobayashi, Takayoshi Yamaki, Kazuhiko Nakazato, Takafumi Ishida, Yasuchika Takeishi
Journal: Circulation (2024)

Background: Alfa-tubulin detyrosination is one of the post-translational modifications of tubulin c-terminal tail, observed in failing cardiomyocytes. Tubulin is known to regulate mitochondrial function, however, the effects of detyrosinated α-tubulin on mitochondrial function remains unrevealed. Methods and Results: We tested the effects of α-tubulin detyrosination on mitochondrial function with tubulin tyrosine ligase knocked out (TTL KO) H9C2 and Vasohibin 1 overexpressed (VASH1 OE) H9C2 cells, which had high amounts of detyrosinated α-tubulin. Alfa-tubulin detyrosination reduced mitochondrial respiration and mitochondrial membrane potential. Moreover, we found mitophagy, evaluated with Mito-Keima fluorescence and LC3 lipidation, were suppressed in TTL KO and VASH1 OE cells. Mitochondria in detyrosinated α-tubulin increasing cells contained less ubiquitinated proteins, suggesting that α-tubulin detyrosination might inhibit Parkin-mediated mitophagy. Next, we overexpressed VASH1 in the mouse heart with AAV9 to validate the effects of detyrosinated α-tubulin on cardiac function. Cardiomyocyte-restricted overexpression of VASH1 led to heart failure with preserved ejection fraction (HFpEF) evidenced by prolonged isovolumic relaxation time and increased mitral E/E' ratio. Cardiac VASH1 OE mice also displayed a reduction in running distance during exercise exhaustion test. The VASH1 OE heart showed suppressed LC3 lipidation, suggesting decreased mitophagy. Conclusion: We demonstrated α-tubulin detyrosination reduces mitochondrial function through the inhibition of mitophagy, leading to HFpEF progression. Our study elucidates that α-tubulin detyrosination may act as a potential target for the novel therapy for HFpEF patients.