tbuckley/cabot-search huggingface dataset:
Abstract 4138847: Home Blood Pressure Reductions With Zilebesiran In Patients With Mild-To-Moderate Hypertension Are Consistent With Ambulatory And Office Blood Pressure Reductions In The KARDIA-1 Study
Authors: Dion Zappe, Manish Saxena, Akshay Desai, Chinedu Nweke, Jan Basile, George Carr, Rajvir Chauhan, Tiffany Zee, Nitender Goyal, George Bakris
Journal: Circulation (2024)

Background: Zilebesiran is an investigational subcutaneous (SC) RNA interference therapeutic targeting hepatic angiotensinogen synthesis. In the Phase 2 KARDIA-1 study (NCT04936035), changes in blood pressure (BP) were assessed with different zilebesiran dosing regimens as monotherapy in patients with mild-to-moderate hypertension, and clinically significant reductions in ambulatory and office systolic BP (SBP) were observed throughout the 6-month treatment period. In this analysis, we report time-adjusted changes in SBP, a measure of weighted average BP over time, assessed by three modalities: ambulatory, office, and weekly home BP monitoring. Method: Adults with daytime mean ambulatory SBP of 135–160 mmHg were randomized equally to zilebesiran (150 mg, 300 mg, or 600 mg once every 6 months, or 300 mg once every 3 months [Q3M]) or placebo SC Q3M. Secondary and post hoc analyses included calculation of time-adjusted change in SBP from baseline through Month 3 and through Month 6 for ambulatory (24-hour mean and daytime), office, and home BP assessments. Rescue antihypertensive medication was permitted between Months 3 and 5. Results: KARDIA-1 included 377 patients (24.7% Black, 55.7% men, mean age 56.8 years). Time-adjusted least squares mean changes in SBP (mmHg) from baseline through Month 3 for different zilebesiran doses ranged from −5.5 to –9.0 for 24-hour mean ambulatory, −5.7 to –9.2 for daytime mean ambulatory, −9.1 to −10.9 for office, and −8.3 to −9.9 for home BP assessments, compared to −0.6 to 5.6 for placebo across the different modalities (Table). Time-adjusted reductions from baseline in SBP were sustained up to Month 6. Additional measures of BP control through Month 6, including percentage of time in target range, will be presented. Conclusion: Clinically significant time-adjusted reductions observed with self-assessed home BP following treatment with zilebesiran were consistent with ambulatory and office BP reductions, indicating that self-monitoring of BP control with zilebesiran is viable outside of the clinical visit setting. Weekly home BP measurements demonstrated consistent reductions in SBP, highlighting the potential of zilebesiran for providing sustained BP control.
Abstract 4138908: Sex-Specific Differences During Heart Failure Development In Double Transgenic Cyclin T1/Gq Alpha Subunit Mice
Authors: Alexander Benkner, Dominik Magers, Elke Hammer, Sabine Ameling, Kristin Wenzel, Uwe Volker, Stephanie Koenemann
Journal: Circulation (2024)

Background: In an aging population, heart failure (HF) remains a leading cause of mortality worldwide. This study utilized genetically modified mice to investigate cardiac hypertrophy and HF, exploring potential age and sex-related differences. The focus was on understanding proteomic changes, functional impairment, and cardiac remodeling to gain deeper insights into the molecular intricacies of HF. Experimental Approach: Double transgenic (DTG) male and female mice overexpressing both Cyclin T1 and Gαq under the control of the cardiac-specific α-myosin heavy chain promoter, show pathological myocardial cell growth and develop hypertrophy, eventually progressing to HF. Comparative analyses were conducted between DTG mice and respective wild-type (WT) littermates at the age of 5 and 9 weeks (n=4 per group, time point and sex). Heart function was evaluated via small animal echocardiography. Proteomes of the left ventricles (LV) of DTG and WT mice were analyzed by mass spectrometry and altered proteins categorized using Ingenuity Pathway Analysis. Results: DTG mice showed a decrease in heart function over time. Independent of sex, DTG mice exhibited a significant decrease in left ventricular ejection fraction (LVEF) after 9 weeks compared to WT (DTG vs. WT: LVEF: 38.4±10.2% vs. 63.3±4.3%; p&lt;0.001) and in relation to younger 5-week-old animals (DTG vs. WT: LVEF: 61.1±2.7% vs. 68.6±4%; p=0.16). Functional and morphological changes were clearly visible earlier in DTG males at 5 weeks compared to females. Also, LV proteomes showed differences between DTG and WT, and between sexes. The most and strongest changes in protein abundance (q&lt;0.05, FC≥|1.5|) were observed after 9 weeks in DTG compared to WT, and much stronger in females (overall: 450↑, 437↓; males: 312↑, 347↓; females: 464↑, 463↓). Regarding age and sex differences, effects were again more pronounced at a younger age in males (5 weeks; altered proteins: 761 in males, 572 in females). These differences became even more apparent from further enrichment analyses of significantly altered proteins categorized into functional pathways such as energy metabolism and CVD-related categories. Conclusion: Female mice tend to be more resistant to a down-regulation of mitochondrial oxidative capacity during pathological hypertrophy at earlier stages of disease progression. These sex differences emphasize the complexity of HF, pointing to the need of sex-specific considerations in therapeutic approaches.
Abstract 4139355: Improvement in Cardiorespiratory Fitness During Cardiac Rehabilitation: Effect of Smoking Status
Authors: Diann Gaalema, Patrick Savage, Sherrie Khadanga, Michael Desarno, Philip Ades
Journal: Circulation (2024)

Background: Patients who smoke have high-risk cardiovascular profiles. However, it is less well-known whether smoking interferes with gains made during cardiac rehabilitation (CR), such as improvements in cardiorespiratory fitness (VO 2peak ). Hypothesis: Current smoking impedes improvement in VO 2peak during CR. Aims: To determine if smoking status was independently associated with improvement in directly measured VO 2peak . Methods: Data were obtained from a prospectively collected clinical database at the University of Vermont Medical Center. Individuals were included if data was available on entry and exit VO 2peak (measured during a symptom-limited treadmill test) and self-reported smoking status (current, former, or never). Data were extracted on sex, age, body mass index, comorbidity score (severity of exercise-limiting comorbidities) and number of CR sessions completed. Analyses of variance and linear regressions were used to test for associations between the aforementioned variables and change in VO 2peak . Variables with significant associations were entered into multivariable general linear models predicting change in VO 2peak . Results: 2390 patients (111 current, 1114 former and 1165 never smokers) were included. Current smokers differed significantly from former/never smokers, being younger (58.3±10.8 vs. 65.4±10.2 and 64.2±11.2), having higher comorbidity scores (0.8±1.4 vs. 0.6±1.2 and 0.5±1.0), and attending fewer CR sessions (25.3±11.1 vs. 29.5±9.2 and 29.1±9.6). All variables examined were significantly associated with change in VO 2peak except for number of CR sessions attended and remained significantly associated with change in VO 2peak in the multivariable models. Estimated mean improvement (controlling for other variables) in VO 2peak was [mean(SE)]: 1.6(0.3), 2.8(0.1), and 3.2(0.1) mLO 2 *kg-1*min-1 in current, former, and never smokers, respectively. Percent improvement in VO 2peak also varied across groups [11.6(2.1), 16.8(0.7), and 18.2(0.7)%]. In both models, improvement in the current smoking group was significantly less than the other two groups (ps&lt;.05 for all comparisons). Conclusion: Smoking status at CR entry was significantly, independently associated with improvement in VO 2peak during CR.
Abstract 4138199: Examining the regulating mechanism of the HIF-FOXM1 axis in promoting adult pig cardiomyocyte proliferation
Authors: Yuji Nakada, THANH NGUYEN, Yalin Wu, Gregory Walcott, Daniel Garry, Hesham Sadek, Jianyi Zhang
Journal: Circulation (2024)

Background: Contractile tissue that is lost to myocardial infarction (MI) in adult mammalian hearts cannot be regenerated, because cardiomyocytes (CMs) undergo cell-cycle arrest within a few days after birth; however, when apical resection (AR) surgery was performed in neonatal pigs on postnatal day (P) 1 (AR P1 ), followed by MI induction on P28 (MI P28 ), the animals completely recovered, and the regenerative process was driven primarily by CM proliferation. Furthermore, analysis of single-nucleus RNA sequencing (snRNAseq) data collected from the hearts of animals studied in our pig AR P1 MI P28 model and in a mouse MI model indicated that FOXM1 expression was upregulated in clusters of CMs that were co-enriched for markers of proliferation, cytokinesis, mitosis, and DNA synthesis. FOXM1 also reactivated cell-cycle progression in CMs differentiated from human-induced pluripotent stem cells (hiPSC-CMs) after the cells had lost their intrinsic cell-cycle activity, and FOXM1 promotes proliferation in cancer cells, where its expression is regulated by HIF signaling. However, the mechanisms that regulate FOXM1-induced cell-cycle reactivation in CMs are not well studied. Hypothesis: The HIF signaling pathway regulates FOXM1 expression in the cycling CMs of AR P1 MI P28 pig hearts. Approach: The expression of FOXM1, four HIF proteins (HIF1A, ARNT, EPAS1, and ARNT2), and markers for reactive oxygen species (ROS) and DNA damage were compared in CMs from regenerating and nonregenerating hearts (i.e., pigs that underwent AR P1 MI P28 or MI P28 alone, respectively) via snRNAseq analysis and immunohistochemistry. Results: Both FOXM1 and EPAS1 were upregulated in AR P1 MI P28 CMs, and these increases were accompanied by significant declines in ROS production and DNA damage, both of which are known downstream effects of HIF pathway activation. Furthermore, the results from Eukaryotic Promoter Database indicated that EPAS1 directly binds the FOXM1 promoter in CMs. Conclusion: Reactivation of the CM cell cycle in AR P1 MI P28 hearts was at least partially induced via the HIF-mediated upregulation of FOXM1 expression, which also protected CMs from ROS and DNA damage.
Abstract 4139367: A major uremic toxin indoxyl sulfate impairs macrophage efferocytosis and accelerates atherogenesis: a potential mechanism for cardiovascular risk in chronic kidney disease
Authors: Prabhash Jha, Adrien Lupieri, Abhijeet Sonawane, Thanh-Dat Le, Dakota Becker-Greene, Sarvesh Chelvanambi, Mandy Turner, Yuto Nakamura, Livia Passos, Taku Kasai, Amelie Vromman, Rachel Holden, Peter Libby, Ira Tabas, Sasha Singh, Elena Aikawa, Masanori Aikawa
Journal: Circulation (2024)

Background: Chronic kidney disease (CKD) is a global burden with high unmet medical needs. Despite the availability of potent drugs such as statins, CKD patients have accelerated atherogenesis and succumb to vascular complications. Underlying mechanisms, however, remain unclear. Elevated levels of a major uremic toxin, indoxyl sulfate (IS), is an independent cardiovascular risk factor in CKD patients. Using a multi-layer systems approach followed by in vitro and in vivo experiments, we investigated the mechanisms by which IS accelerates atherogenesis. Methods&amp;Results: Gene expression meta-analysis of microarray datasets of patients with atherosclerosis or CKD (CKD n=102; atherosclerosis n=136) implicated efferocytosis as a shared mechanism between two diseases (Fig. A and B). Impaired efferocytosis contributes to the development of high-risk atherosclerotic plaques. In vitro validation using live cell imaging demonstrated that clinically relevant concentration of IS (1mmol/L) suppressed efferocytosis of human primary macrophages (n=6 PBMC donors) (Fig. C). In in vivo experiments, daily IS administration (100 mg/kg/day, i.p.) for 4 weeks in hyperlipidemic Ldlr-/- mice caused expansion of %-necrotic core area (n=10/group, Fig. D), typical features of high-risk plaques. Multi-omic integration of global proteomics and transcriptomics of IS-treated human primary macrophages and Ldlr-/- mice atherosclerotic plaque further enriched efferocytosis-related signals and identified reduced growth arrest specific protein 6 (GAS6), a tethering molecule between macrophages and dying cells, as a potential key mediator. IS treatment decreased the expression levels of GAS6 in both human primary macrophages (n=14, Fig. E) and Ldlr-/- mice atherosclerotic plaque (n=6, Fig. F). Moreover, in vivo gain-of-function studies in macrophage-selective Gas6 knock-in mice demonstrated that Gas6 restored IS-induced defective efferocytosis in peritoneal macrophages (Fig. G and H). Conclusions: IS suppresses GAS6, impairs human macrophage efferocytosis, and accelerates experimental atherogenesis. Our findings provide molecular bases for the future development of new therapies for cardiovascular complications in CKD patients.
Abstract 4139413: Free Testosterone is Associated with Lower Microvascular Function in Men with Prostate Cancer
Authors: Abigayle Simon, Jacob Looney, Marsha Blackburn, REVA CRANDALL, jeffrey thomas, McKay Mullen, Avirup Guha, Martha Terris, Zachary Klaassen, Neal Weintraub, Ryan Harris
Journal: Circulation (2024)

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in men with prostate cancer (PC), and vascular function and arterial stiffness can predict CVD. High circulating free testosterone has been associated with increased arterial stiffness in PC, and higher circulating free testosterone early in prostate cancer diagnosis is associated with more aggressive disease. However, the role of circulating free testosterone and its influence on microvascular function in men with PC has yet to be elucidated. Thus, the present study sought to investigate the relationship between free testosterone and a comprehensive assessment of vascular health over time in men with PC. METHODS: Thirty-two men (Age: 67±1 years; BMI: 28.2±1.1 kg/m 2 ) with PC participated in this study. Fasting blood samples were collected to assess both total and free testosterone. The flow-mediated dilation (FMD) test was used to assess conduit vessel function and microvascular function was assessed using local thermal heating (LTH). Arterial stiffness was assessed using augmentation index (AIx75). Blood samples and assessments of vascular health were conducted at baseline and every 3 months thereafter. Data are reported as mean±SEM. RESULTS: Free testosterone decreased ( p =0.079) from baseline (5.0±0.5 pg/mL) to 3 months (4.6±1.1 pg/mL) and remained lower at 6 months (4.4±0.7 pg/mL), and 9 months (4.7±0.8 pg/mL). In addition, total testosterone was similar ( p &gt;0.05) from baseline (318±38 ng/dL) throughout the study. Free testosterone at baseline was inversely correlated with the change in LTH at 3 months ( r =-0.601; p =0.030), 6 months ( r =-0.638; p =0.035), and 9 months ( r =-0.671; p =0.048). There was a positive correlation between free testosterone at baseline and the change in AIx75 from baseline to 3 months ( r =0.668; p =0.013). No relationships between free testosterone and FMD over time were identified, nor were any relationships observed between total testosterone and indices of vascular health. DISCUSSION: Findings from this study demonstrate that a higher circulating free testosterone at baseline is associated with increased microvascular dysfunction and arterial stiffness over time. Future studies are needed to elucidate the precise mechanistic role of free testosterone on microvascular function in prostate cancer and whether therapeutic approaches can be used to mitigate the negative cardiovascular effects associated with lower concentrations of androgens.
Abstract 4139419: US National Trends in left atrial appendage occlusion volume and open payments to operators
Authors: Alexander Kolomaya, Brian Zenger, Ravi Ranjan, Thomas Bunch, Benjamin Steinberg
Journal: Circulation (2024)

Background: Left atrial appendage occlusion (LAAO) was first performed among Medicare beneficiaries in 2017 and has grown rapidly in popularity. Payments from device manufacturers to physicians have been shown to correlate with other procedures, which are now publicly available. We report trends of LAAO in Medicare patients, and the relationship between procedure volume and manufacturer payment. Methods: We linked Medicare procedural data with Open Payments data via NPI number and identified physicians performing ≥ 1 LAAO between 2017 and 2021. Baseline physician information, including sex, operating location, and specialty, was extracted from CMS registries. Payment data were highly skewed, and winsorized at the 95 th percentile and compared to procedural volume. Results: The number of LAAO procedures increased from 6069 procedures in 2017 to 29083 in 2021 and 15.695 to 79.994 per 100,000 beneficiaries nationally. Across states, the median rate of implants 46.151 (IQR 33.765 – 62.271) per 100,000 beneficiaries, with Nebraska having the highest rate at 255.269 per 100,000 beneficiaries (Figure 1). The number of operators implanting LAAO devices increased from 286 (97.6% male) to 1003 (96.6% male). Roughly 49% of operators are licensed as electrophysiologists and 47% as interventional cardiologists. Total payments to physicians varied widely (median $ 3179.12, IQR 1703.16 – 9000.42) with &gt;99% of operators receiving compensation from the LAAO device company; there is no clear relationship between compensation from the manufacturer and LAAO volume (r 2 =0.132) ( Figure 2 ). Conclusions: LAAO has seen dramatic growth in volume of procedures and operators nationally, with substantial regional variation. While almost all LAAO operators received compensation from the primary LAAO device company, there is no correlation between payment amount and procedural volume.
Abstract 4139340: Atherosclerotic Plaque Progresses Over Time in Healthy Individuals Without MACE, Risk Factors, or Interventions
Authors: Jairo Aldana, April Kinninger, Srikanth Krishnan, Keishi Ichikawa, Matthew Budoff, Ronald Karlsberg
Journal: Circulation (2024)

Introduction: Studies on the natural history of coronary artery disease have traditionally evaluated the progression of the disease in the presence of MACE, risk factors or risk modifying interventions including pharmacological and non-pharmacological treatment. It is not known how atherosclerotic plaque progresses over the time in the absence of MACE, risk factors or risk modifying interventions. Aim: To evaluate the natural history of atherosclerosis in healthy populations on serial CCTA. Methods: NATURE-CT retrospectively selected 205 participants from two sites in Los Angeles. Subjects underwent at least two CCTA scans, the initial scan showing CAC ≤100, absence of MACE, not placed on lipid modifying therapy in the first and last scan, and at least 2 years apart. Patients with diabetes, familial hypercholesterolemia or chronic kidney disease were excluded. FDA cleared automated software Cleerly Labs (Cleerly.Inc, NY, NY) quantified plaque and stenosis. Primary outcome will be the observed annualized rate of change in the atherosclerotic plaque during the observation period. Results: At baseline visit, the mean age of the cohort was 54.9±10.2 (years), 72% (147) being white males, 0% had DM, 0% had lipid modifying therapy, 24% (49) had hypertension, 28% (57) reported hyperlipidemia and 15% (30) were ever smokers. Mean LDL was 111.6±32.0 mg/dl and the average time between CCTA scans was 4.9±2.2 years. Over half (54%) of the cohort had a CAC=0 at the baseline visit. At baseline, total non-calcified plaque volume was (median and IQR in mm3) [27.5 (10.1, 55.5)] versus at follow-up [53.5 (24.0, 97.9)], with a calculated annualized median change of [4.9 (1.4, 9.6)] in non-calcified plaque. Total calcified plaque volume was [0.3 (0.0, 5.7)] and at follow-up [3.2 (0.1, 18.2)], with a calculated annualized median change of [0.4 (0.0, 2.4)] in calcified plaque. At baseline, 9% (19 subjects) had low attenuation plaque greater than zero, and at follow-up, 23% (48 subjects). 6 subjects had annual change in PAV&gt;=1% (3%) and 23 subjects had annual change in PAV &gt;=0.59% (11%). Conclusions: Atherosclerotic plaque in the absence of MACE, risk factors or risk modifying interventions progresses overtime. The burden of non-calcified plaque has greater progression than calcified plaque. In healthy subjects, the presence of low attenuation plaque is infrequent. When observed, its progression is present overtime. Rapid plaque progression is present in some healthy subjects.
Abstract 4138935: Lp(a) and LDL-Cholesterol Interaction Association with Aortic Valve Calcium and Severe Aortic Stenosis
Authors: Christopher Chew, Natalie Marrero, Kunal Jha, Alexander Razavi, Omar Dzaye, Matthew Budoff, Jerome Rotter, Roger Blumenthal, Harpreet Bhatia, Sotirios Tsimikas, Michael Blaha, Seamus Whelton
Journal: Circulation (2024)

Introduction: Calcific aortic valve disease (CAVD) is the most common valvular disorder with aortic valve calcification (AVC) as a principal underlying mechanism. Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] are risk factors for AVC and aortic stenosis (AS). However, whether an interaction between LDL-C and Lp(a) exists in CAVD is not well studied, which may have implications for trials investigating novel Lp(a) lowering therapies. Methods: Cardiac computed tomography (CT) was used to quantify AVC in participants free of known cardiovascular disease at Multi-Ethnic Study of Atherosclerosis (MESA) Visit 1 and subsequent visits. Incident severe AS was adjudicated through chart review of hospital visits and echocardiogram data. Participants were categorized into four groups based on the cutpoints of LDL-C 160mg/dL and Lp(a) 50mg/dL. We examined the association of the four LDL-C and Lp(a) groups with incident AVC and incident severe AS using multivariable adjusted Cox Hazard models. We also tested for the presence of a multiplicative interaction between LDL-C and Lp(a). Results: In this analysis, 6,603 participants were included. The mean age of participants was 62 years old and 52% were women. Incident AVC occurred among 416 participants and during a median follow-up time of 17 years, 84 participants developed severe AS. At baseline, AVC &gt;0 was present in 11.9% of participants with LDL-C &lt;160mg/dL and Lp(a) &lt;50mg/dL compared to 21.6% participants with LDL-C ≥160mg/dL and Lp(a) ≥50mg/dL (p=&lt;0.01). Compared to participants with LDL-C &lt;160 mg/dL and Lp(a) &lt;50mg/dL, those with LDL-C ≥160 and Lp(a) ≥50 mg/dL had a 2.3-fold higher risk for incident AVC [HR 2.27 (1.34-2.85)] ( Table 1) . There was a statistically significant multiplicative interaction between Lp(a) and LDL-C as continuous variables for both incident AVC (p=0.002) and severe AS (p=0.036). Conclusion: Participants with both an elevated LDL-C and Lp(a) had the highest risk for incident AVC. There was a significant interaction between LDL-C and Lp(a) for both incident AVC and incident AS. Thus, individuals with elevated LDL-C and Lp(a) may be most likely to benefit from novel Lp(a) lowering therapies and/or combined LDL-C and Lp(a) lowering.