tbuckley/cabot-search huggingface dataset:
Abstract 4135712: Mortality and Cardiovascular Complications Associated with Weight Loss Drugs among Breast Cancer Females Under Cardiotoxic Therapies: A Real-World Populational Study in the United States
Authors: Chuan LU, Ting-Wei Ernie Liao, Gin-Yi Lee, Yi-Jin Hsieh, Sheng-Yin Chen, Cheng-Chung Wei
Journal: Circulation (2024)

Background: Obesity is an adverse prognostic factor for breast cancer (BC). While liraglutide and semaglutide, derived from antidiabetic glucagon-like peptide-1 receptor agonists (GLP1RA), are established weight loss drugs known for their cardiovascular safety in the general obese population, their safety in BC patients undergoing cardiotoxic antineoplastic therapies remains less understood. Objective: To investigate the mortality and cardiovascular outcomes related to GLP1RA used for weight loss among the highly susceptible BC females. Methods: This retrospective cohort study was based on the TrinetX network, comprising real-time health records from over 60 US healthcare organizations. The study population included obese females (≥18 years old) who received at least three prescriptions of either exclusive GLP1RA (liraglutide or semaglutide) or non-GLP1RA weight loss drugs (phentermine, bupropion-naltrexone, orlistat) upon BC diagnosis between 01/01/2015 and 01/01/2022. The index date was the initiation of systemic anti-cancer treatment, including chemotherapy (anthracycline, taxane, or cyclophosphamide), and/or anti-HER2 agents (trastuzumab, pertuzumab, or lapatinib). We used 1:1 propensity score-matching (PSM) to balance demographics, BMI, comorbidities, concurrent medications for cardiovascular diseases and metabolic disorders, BC receptor status and prior treatment, and levels of serum cholesterol (LDL, HDL) and hemoglobin A1c. Cox regression models were applied to compute hazard ratios (HR) and 95% confidence intervals (CIs). Follow-up continued until 05/24/2024, or until adverse cardiovascular events or death occurred. Results: Among 380 PSM-balanced pairs, the GLP1RA group (mean age: 57.6±11) showed significantly lower risks of all-cause mortality (HR 0.593, 95% CI 0.457-0.77), acute heart failure (HR 0.496, 95% CI 0.286-0.859), angina pectoris (HR 0.566, 95% CI 0.343-0.936), and acute stroke (HR 0.661, 95% CI 0.46-0.951) than the non-GLP1RA group (mean age: 57.5±12). Otherwise, no significant difference was shown in acute myocardial infarction (HR 0.787, 95% CI 0.495-1.251), pulmonary hypertension (HR 0.777, 95% CI 0.55-1.099), or arrhythmias (HR 0.829, 95% CI 0.566-1.215). Conclusion: Compared to non-GLP1RA weight loss agents, GLP1RA offers better survival and cardiovascular protection for BC patients undergoing cardiotoxic therapies. Future studies are warranted to validate the safety of these weight loss drugs during the BC treatment continuum.
Abstract 4135307: Integrating genomics and proteomics to identify causal proteins and biologic pathways for incident atrial fibrillation in chronic kidney disease
Authors: Adrian Petzl, Faye Norby, Yue Ren, Jianqiao Wang, Ruth Dubin, Hongzhe Li, Mark Segal, Lin Chen, Alvaro Alonso, Aditya Surapaneni, Joe Coresh, Morgan Grams, Harold Feldman, Nisha Bansal, Francis Marchlinski, Alan Go, Peter Ganz, Rajat Deo
Journal: Circulation (2024)

Introduction/ Background: Individuals with chronic kidney disease (CKD) are at an increased risk for developing atrial fibrillation (AF). Research Objective: By integrating genomics and proteomics, we sought to identify proteins and biologic pathways causally linked to the development of AF in the CKD population. Methods / Approach: We measured 4638 unique plasma proteins using SomaScan v.4.0 in participants (ppts) with CKD and no prior AF from 2 cohorts: Chronic Renal Insufficiency Cohort (CRIC, n=2654) and Atherosclerosis Risk in Communities Cohort (ARIC, n=1326). Associations of individual proteins with incident AF were analyzed using Cox regression after adjustment for demographics, comorbidities, and kidney function. Among proteins independently associated with incident AF in both cohorts, we tested for causality using two-sample Mendelian Randomization (MR). Previously published genome wide association studies (GWAS) were used to identify both protein quantitative loci (cis-pQTL) and summary statistics for incident AF. We then used Ingenuity Pathway Analysis to compare proteins and pathways associated with both incident AF and an increase in left atrial (LA) size across serial echocardiograms in CRIC. Results / Data: Over the 5-year analytic period, incident AF occurred in 150 ppts from CRIC and 140 ppts from ARIC. Eight proteins were independently associated with AF in both cohorts: NT-proBNP, SVEP1, TAGLN, TFF3, WAP4, MMP-12, CILP2 and NELL-1. Of these, 3 were significant in MR analysis (Figure 1): CILP2 and MMP-12 maintain structural integrity of the extracellular matrix in the heart and modulate the fibrotic response; NELL-1 is responsible for cell signaling in kidney disease and cardiovascular development. In addition, leading biologic pathways implicated in both development of AF and increase in LA size included systemic fibrosis (p=1.7x10 -4 for AF and 2.3 x10 -4 for LA); regulation of insulin-like growth factor (p=2.3 x10 -4 for AF and p=4.3 x10 -7 for LA) and extracellular matrix degradation (p=5.5 x10 -4 for AF and p=4.2 x10 -4 for LA). Conclusions: Trans-omics analyses identified 3 proteins causally associated with developing AF in the CKD population. Also, several pathways involved with cardiac remodeling and fibrosis are common to the development of AF and LA remodeling.
Abstract 4135443: A Phase 1, Single Ascending Dose Study to Evaluate ALN-TTRsc04, a Next-Generation RNA Interference Therapeutic, in Healthy Participants for Potential Treatment of Transthyretin Amyloidosis
Authors: Ali Murad, Maxwell Lasko, Prajakta Badri, Satyawan Jadhav, Katherine Boyle, Juanjuan Li, John Vest, Jorg Taubel
Journal: Circulation (2024)

Introduction: Transthyretin amyloidosis (ATTR) is a progressive, debilitating, fatal disease caused by deposition of misfolded toxic transthyretin (TTR) amyloid fibrils in multiple organs and tissues. Major ATTR manifestations include polyneuropathy and cardiomyopathy. Ongoing amyloid deposition drives rapid progression of ATTR, leading to morbidity and mortality. ALN-TTRsc04 is an investigational small interfering RNA that targets hepatic TTR mRNA to reduce circulating TTR protein levels. Hypothesis: ALN-TTRsc04 rapidly knocks down serum TTR and is well tolerated. Aims: Describe safety, pharmacokinetics, and pharmacodynamics of single ascending ALN-TTRsc04 doses. Methods: This ongoing, Phase 1, randomized, double-blind, placebo-controlled study (NCT05661916) enrolled healthy adults (18–65 yrs; 18.0–30 kg/m 2 ) sequentially included in 6 cohorts receiving subcutaneous single ascending doses of ALN-TTRsc04 (5, 25, 100, 300, 600, or 900 mg) or placebo (randomized 3:1). Urine and plasma concentrations were measured on Days 1–2 and 1–4, respectively; change from baseline (BL) in serum TTR and AEs will be assessed over 12 months. Results: Overall, 36 and 12 adults (of similar age/sex distribution) were randomized to 1 of the 6 ALN-TTRsc04 groups or placebo, respectively. ALN-TTRsc04 plasma concentrations declined below lower limit of quantification within 24–48 hrs; mean (SD) plasma half-life ranged from 4.5 (1.5) hrs (300 mg dose) to 7.6 (3.2) hrs (100 mg dose). ALN-TTRsc04 was minimally excreted by renal route (&lt;20%) after 24 hrs. Rapid and sustained knockdown in serum TTR occurred following all ALN-TTRsc04 doses ( Figure ). Mean (SD) serum TTR was 236.2 (47.4) µg/mL and 290.1 (73.3) µg/mL at BL and 22.2 (1.8) µg/mL and 289.0 (59.1) µg/mL at Day 15, for ALN-TTRsc04 300 mg and placebo, respectively. Mean percent knockdown at Day 15 was 90.3% vs 1.8%, respectively. Robust mean serum TTR knockdown of &gt;90% from BL was seen with ALN-TTRsc04 doses ≥300 mg at Day 29 and sustained until Day 90 (or Day 180 with 300 mg dose, 92.6% reduction). Majority of AEs across doses were mild; none were considered related to treatment. No injection-site reactions or safety signals, including liver-related signals, were identified. Conclusion: A single ALN-TTRsc04 dose led to a rapid and sustained knockdown in serum TTR; a reduction &gt;90% from BL was sustained until Day 180 with the 300 mg dose. All ALN-TTRsc04 doses have been well tolerated to date; data through 12 months will be assessed.
Abstract 4135311: Cryptogenic stroke associated with a double interatrial septum treated with surgical closure
Authors: Michelle Nabi, Jeannine Jeha, jennifer walker, Vaikom Mahadevan, Ujjwal Rastogi
Journal: Circulation (2024)

Introduction: A double atrium septum is a rare congenital anomaly characterized by a double-walled atrial septum with persistent interatrial space. This could be an asymptomatic presentation but also serve as a nidus of thromboembolic complications. We hereby present a case of a 57-year-old female with a cryptogenic stroke found to have a patent foramen ovale and double atrial septum. Case Description: A 57 year-old-female with a past medical history of hypertension presented with acute complaints of word-finding difficulty, left-sided neck pain and lightheadedness after a head strike while swimming. She was found to have a right-sided cerebellar stroke. A carotid artery ultrasound showed no evidence of atherosclerotic disease. Her lipid profile was normal. A transthoracic echocardiogram showed a patent foramen ovale with a positive bubble study revealing a large right to left shunt with Valsalva. A transesophageal echocardiogram confirmed a patent foramen ovale with an incidental finding of a double atrial septum with extreme redundancy of septal issue. The patient had a surgical closure of the interatrial septum and resection of the accessory interatrial septum tissue. She developed chronic post-sternotomy pain and subsequently had sternal wire removal. Discussion: A double atrial septum is a rare congenital anomaly seen as two parallel interatrial septa accompanied by a distinct echo-lucent midline space that expands during systole and contracts during diastole. It can happen embryologically by either the abnormal development of the septum secundum, resorption failure of the superior portion of the septum primum, or the persistence of the left venous valve of the sinus venosus. Typically, individuals with double atrial septum are asymptomatic, but they may encounter cardioembolic events due to the potential thrombi formation in the interatrial space. Communication between the septa increases the likelihood of such events. Unlike atrial fibrillation/flutter, there are currently no established criteria for initiating anticoagulation therapy for double atrial septum, primarily due to its rarity. Some options include antiplatelet agents, oral anticoagulation therapy, and percutaneous or surgical PFO closure. Surgical closure provides a permanent closure of the defect, thereby preventing future paradoxical emboli without the potential risks associated with long-term anticoagulation.
Abstract 4135708: Obesity and the risk of cardiac death in coronary artery disease
Authors: Lauri Holmstrom, Maria Hannula, Mikko Tulppo, Ida Hookana, Juha Perkiomaki, Heikki Huikuri, Juhani Junttila
Journal: Circulation (2024)

Background: The prevalence of obesity is increasing worldwide reaching epidemic proportions. Obesity increases the risk of coronary artery disease (CAD), but there is little prospective evidence about the effect of obesity on the risk of cardiac death in CAD patients. Aim: We aimed to investigate the effect of obesity and the risk of cardiac death in a prospective cohort of CAD patients. Methods: We have prospectively enrolled 1,946 patients with CAD (mean age 66.9±8.6, 68% male), with a mean follow-up of 8.7±2.2 years. BMI was measured at baseline and was categorized into 4 groups: 1) BMI 18.5-24.9 kg/m 2 (normal weight, reference group), 2) BMI 25-29.9 kg/m 2 (overweight), 3) BMI 30-34.9 kg/m 2 (class 1 obesity), and 4) BMI &gt;35 kg/m 2 (class 2 obesity). The primary endpoint was cardiac death and secondary endpoints were sudden cardiac death/arrest (SCD/SCA), non-sudden cardiac death, non-cardiac death, and heart failure (HF) hospitalization. Statistical analysis was performed with Cox regression and was adjusted for age, sex, type 2 diabetes, CCS class, kidney function (eGFR), systolic and diastolic blood pressure, LDL, smoking, SYNTAX score, and left ventricle ejection fraction. Results: The prevalence of BMI 18.5-24.9 kg/m 2 was 18.5% (n=359), BMI 25-29.9 kg/m 2 was 47.8% (n=929), BMI 30-34.9 kg/m 2 was 24.0% (n=466), and BMI&gt;35 kg/m 2 was 9.7% (n=189). During the follow-up, cardiac death occurred in 156 subjects, SCD/SCA in 75 subjects, non-sudden cardiac death in 81 subjects, and non-cardiac death in 197 subjects. BMI &gt;35 kg/m 2 was associated with an increased trend of cardiac death (adjusted HR 1.92, 95% CI 0.92-4.01; p=0.08) and an increased risk of non-sudden cardiac death (adjusted HR 4.11, 95% CI 1.58-10.68; p=0.004) and HF hospitalization (adjusted HR 2.83, 95% CI 1.06-7-54; p=0.04), but not with SCD/SCA (adjusted HR 0.79, 95% CI 0.24-2.56; p=0.69) or noncardiac death (adjusted HR 0.85, 95% CI 0.43-1.69; p=0.64). The risk of cardiac death or secondary endpoints was not increased in patients with overweight or class 1 obesity. Conclusions: Class 2 obesity was associated with an increased risk of non-sudden cardiac death and heart failure hospitalization among CAD patients. Obesity may have adverse long-term effects on cardiac function and prognosis among CAD patients, supporting the benefit of optimal weight control therapy.
Abstract 4135352: Neighborhood-level Determinants and Disparities in Incident Type 2 Diabetes in a Population-Based Cohort, 2015–2020
Authors: Ben Varghese, Karen Fischer, Ruchi Gupta, Michelle Mielke, Adrian Vella, Alanna Chamberlain, Jennifer St Sauver, Kent Bailey, Sagar Dugani
Journal: Circulation (2024)

Introduction: Living in an area with high Area Deprivation Index (ADI) is linked to worse cardiovascular disease (CVD) outcomes. However, the association of ADI with type 2 diabetes (T2D), a major CVD risk factor, is incompletely described. This knowledge may guide primary CVD prevention. Method: Rochester Epidemiology Project is a medical record linkage system of persons in southeast Minnesota and southwest Wisconsin. We identified 253,890 persons (aged 4–98 yrs on July 1, 2015) in 9 counties with &gt;90% population coverage. ADI scores, from 2015 home addresses, were grouped into quartiles of low (Q1) to high (Q4) deprivation. We excluded persons with type 1 diabetes (T1D) or history of T2D and identified new T2D cases (2015-2020) using ICD codes, HbA1c and medications. We examined the association between ADI quartile and risk of incident T2D using Cox regression with persons right censored at death, T2D, T1D or last visit. Models were adjusted for age and gender, and reported adjusted hazard ratios (aHR [95% confidence interval]). Results: Age, gender, and race statistically differed across ADI quartiles (Table). Age × ADI interaction was significant ( P &lt;.001). T2D incidence ranged from 6.3 (Q1) to 9.0 (Q4) per 1000 person-years ( P &lt;.001). Women vs. men/non-binary persons (combined due to limited non-binary persons) had 30% lower risk of incident T2D (aHR 0.70 [0.67–0.72]). Risk of incident T2D was higher in persons from higher ADI areas. At median age of 48.6 yrs, the risk was 30% higher in Q2 (aHR 1.3 [1.22–1.38]), 38% higher in Q3 (aHR 1.38 [1.30–1.47]) and 53% higher in Q4 (aHR 1.53 [1.43–1.62]) vs. Q1. Higher ADI was associated with higher incident T2D in younger persons, with risk attenuation with increasing age (Figure). Conclusion: In this population cohort, persons, particularly of younger age, living in more deprived areas had a higher risk of incident T2D. ADI may help identify areas for targeted T2D screening, with implications for CVD screening and prevention.
Abstract 4135476: The Cardiomyocyte Hypertrophy Inhibitor RFN-409, Identified by High Throughput Screening Assay, Suppresses Pressure Overload-induced Systolic Dysfunction in Mice by Suppressing p38 Activity
Authors: Yudai Irokawa, Takahiro Katagiri, Risa Maeda, Satoshi Shimizu, Masafumi Funamoto, Toshihide Hamabe, Yoichi Sunagawa, Yuto Kawase, Ryuya Naruta, Yasufumi Katanasaka, Koji Hasegawa, Tatsuya Morimoto
Journal: Circulation (2024)

Purpose: When the heart is exposed to stresses such as myocardial infarction or hypertension, it undergoes compensatory hypertrophy in response. However, continuation of the stress causes this compensatory mechanism to fail, and eventually systolic dysfunction or decompensated heart failure occur. As the hypertrophy of individual cardiomyocytes has been observed in this process, controlling cardiomyocyte hypertrophy is a potential target the prevention and treatment of heart failure. In this study, we constructed a high throughput screening (HTS) assay using cardiomyocyte hypertrophy as an index parameter. Compounds that inhibit cardiomyocyte hypertrophy were selected from our low molecular compound library. Methods and Results: In the primary screening, cultured rat primary cardiomyocytes were treated with each compound at a final concentration of 1 µM and then stimulated with 30 µM phenylephrine (PE) for 48 hours. These cells were subjected to fluorescent immunostaining with α-actinin, and cardiomyocyte area was measured using an ArrayScan™ system. The hypertrophy inhibition rate (%) of each compound was calculated as [(PE(+) - compound) / (PE(+) - PE(-))] × 100. The compounds with a hypertrophy inhibition rate greater than 50% and less than 150% were selected as hit compounds. In the secondary screening, these hit compounds were evaluated based on the dose-dependency of cardiomyocyte hypertrophy inhibition and the inhibition of the mRNA levels of the cardiac hypertrophy response genes ANF and BNP using real-time PCR. From the 269 low molecular-weight compounds in the original compound library, eight were selected through the primary and secondary screenings. Among them, we focused on Reference Number 409 (RFN-409). Western blotting indicated that RFN-409 inhibited PE-induced p38 activation. Next, we investigated the effect of RFN-409 on heart failure. Eight-week-old male C57 BL/6J mice were subjected to transverse aortic constriction (TAC) surgery and then randomly assigned to intraperitoneal treatment with RFN-409 (3, 10 mg/kg) or vehicle for eight weeks. RFN-409 at 10 mg/kg significantly prevented TAC-induced increase in left ventricular posterior wall thickness and decrease in left ventricular fractional shortening. Discussion: RFN-409 suppressed TAC-induced development of heart failure, at least partially by inhibiting p38 activity. These findings suggest that RFN-409 may be an effective agent for heart failure therapy.
Abstract 4135465: Efficacy of SGLT-2 inhibitors combined with percutaneous coronary intervention on clinical and echocardiographic parameters in patients with acute myocardial infarction: A systematic review and meta-analysis
Authors: Shurjeel Qazi, Muhammad Ammar Samad, Huzaifa Ansari, Eman Mahboob, Abdul Hannan Siddiqui, Sana Qazii, Adeel Ahmad, Asad Rahman, Mushood Ahmed, Raheel Ahmed, mahboob alam
Journal: Circulation (2024)

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown benefits in improving cardiovascular outcomes in heart failure (HF) patients and may mitigate symptom progression in myocardial infarction (MI). However, their efficacy in acute MI patients undergoing percutaneous coronary intervention (PCI) is unclear. This study aims to evaluate whether SGLT2i combined with PCI improves clinical and echocardiographic outcomes. Methods: A comprehensive search of electronic databases, PubMed, Cochrane Central and SCOPUS was conducted from inception till May 2024. The study was conducted adhering to the PRISMA guidelines. The clinical benefit of PCI plus SGLT2i was assessed through risk reduction of acute kidney injury (AKI), CV death (CVD), hospitalization due to HF (hHF), all-cause mortality (ACM), and revascularization. Echocardiographic outcomes assessed were change in left ventricular ejection fraction (LVEF) and LV end-diastolic volume (LVEDV). Results were presented as risk ratios (RR) along with their 95% CI for dichotomous data while weighted mean difference (WMD) were reported for continuous outcomes. The data was aggregated using a random effects model. Results: Our analysis included eleven records comprising 6,411 participants. The results indicated that PCI plus SGLT2i significantly reduced the risk of AKI (RR: 0.66, 95% CI: [0.52, 0.83], p&lt;0.01) and ACM (RR: 0.54, 95% CI: [0.4, 0.7], p&lt;0.01) compared to PCI alone. However, the reduction in risk for CVD was not statistically significant (RR: 0.56, 95% CI: [0.2, 1.1], p=0.09), as was the case for hHF (RR: 0.65, 95% CI: [0.3, 1], p=0.07). Additionally, there was no significant difference in the risk of revascularization between the two groups (RR: 2.9, 95% CI: [0.62, 14.39], p=0.17). PCI plus SGLT2i was also significantly associated with an increase in LVEF (WMD: 2.73, 95% CI: [1.09, 4.36], p&lt;0.01) and decrease in LVEDV (WMD: -8.0, 95% CI: [-13.17, -2.90], p&lt;0.02). Conclusion: Our study demonstrates that SGLT2i administration in MI patients undergoing PCI leads to improved renal and mortality outcomes, along with enhanced cardiac function. These benefits are hypothesized to result from kidney-mediated natriuretic effects, improved blood flow regulation, reduced endothelial dysfunction, and decreased arterial stiffness, which optimize cardiac function. We recommend future studies with larger sample sizes and longer follow-ups to assess the long-term benefits of SGLT2i combined with PCI.
Abstract 4135335: A randomized trial of expedited intra-arrest transfer versus more extended on-scene resuscitation for refractory out of hospital cardiac arrest: the EVIDENCE Study
Authors: Mark Dennis, Brian Burns, Ian Marschner, Anthony Keech
Journal: Circulation (2024)

Background: Refractory out-of-hospital cardiac arrest (OHCA) has poor outcomes. The benefit of expedited intra-arrest transport with ongoing resuscitation versus more extended on-scene resuscitation for refractory OHCA is not clear. Methods: In this Phase III, multi-center (15 hospitals), randomized, controlled trial conducted in Sydney, Australia, we assigned patients with refractory out-of-hospital cardiac arrest to receive either expedited intra-arrest transport, with mechanical cardiopulmonary resuscitation, to a cardiac catherization-capable hospital for coronary angiography and, where available, extracorporeal membrane oxygenation (ECMO) cardiopulmonary resuscitation (ECPR) or more extended on-scene conventional CPR (advanced cardiac life support). Eligible patients were between 18 and 70 years of age, had received bystander CPR, initial rhythm VT/VF/PEA, and did not have a return of spontaneous circulation after 15 minutes of CPR, or three rounds of resuscitation. The primary outcome was survival with a favorable neurologic outcome, defined as a Cerebral Performance Category score of 1 or 2 at hospital discharge. Analyses were performed on an intention-to-treat basis. Results: One hundred and ninety-seven (197) eligible patients were randomized (median age, 57.0 years; 77 [81%] men), 149 VT/VF (76%). Ninety-five were assigned to receive expedited transfer and 102 to receive conventional CPR. Ten patients in the expedited arms and 6 patients in the conventional arm received ECPR at hospital. At hospital discharge, 15 patients (14.7%) in the expedited transfer group (median on scene time 26 mins) were alive with a favorable neurologic outcome, as compared with 15 patients (15.8%) (median on-scene time 36 minutes). This treatment difference was small and statistically insignificant (risk difference -1.1% [95% CI: -12.2% to 10.0%]), adjusted relative risk 0.95 [p=0.87, 95% CI: 0.50 to 1.8]. Conclusions: Among patients with refractory out-of-hospital cardiac arrest, expedited intra-arrest transport did not significantly improve survival with neurologically favorable outcome at discharge compared with more extended on-scene resuscitation. However, clinically relevant differences could still be consistent with our results.