tbuckley/cabot-search huggingface dataset:
Abstract 4140427: Potassium-sparing Diuresis and Natriuresis With a Novel Renal Outer Medullary Potassium Channel Inhibitor, in Healthy Adult Participants
Authors: Sharif Soleman, Justin Schumacher, Beqing Wang, Juan Maya, Paul Levesque, Atif Mohammad, Lisa Christopher, Pitchumani Sivakumar, marc Kozinn, Chang Wang, Johnny Ma, Anh Bui, Veena Rao, Jeffrey Testani, Francisco Ramirez-Valle, Bindu Murthy, Samira Merali, Frederic Baribaud, Philippe Costet
Journal: Circulation (2024)

Introduction: Persistent congestion and edema remain an unmet need in heart failure (HF). BMS-986308, a novel inhibitor of the Renal Outer Medullary Potassium Channel (ROMK), is predicted to enhance potassium-sparring diuresis and natriuresis in HF patients with persistent congestion and edema despite SOC treatment. We present pharmacodynamics and biomarkers of kidney function and injury from a first-in-human study of BMS-986308 (NCT04763226). Method: Thirty-two adult healthy participants were assigned to 1 of 4 dose cohorts (3, 10, 30, and 100 mg) and randomized (6:2) to receive a single dose of BMS-986308 oral solution or matching placebo. Diuresis and natriuresis were measured in intervals over 24 h post dose and baseline-adjusted using matching intervals at Day -1. Serum creatinine, cystatin C, electrolytes (K, Ca, Cl, Mg), aldosterone, renin activity; and urinary protein and albumin to creatinine ratios (UPCR, APCR); and biomarkers of kidney injury Kim1, NAGASE, OPN, CLUST were measured up to Day 5. Statistical significance between BMS-986308 treatment groups and placebo was assessed using unpaired t tests. Results are mean (±SD). ** P&lt;0.01, *** P&lt;0.001 Results: BMS-986308 increased natriuresis and diuresis in a dose-dependent manner starting at the 30 mg dose. The table below presents change from baseline (CFB). No significant change in kaliuresis was observed (mean placebo and 100mg dose respectively 0.08 ± 0.03 and 0.05 ± 0.01 mmol/min over 24h). Aldosterone and renin activity peaked at 24h at 30 mg and 100 mg (CFB 132 ± 102% and 405 ± 129%***, 121 ± 130% and 783 ± 282%** respectively). A transient rapid dose-dependent increase in serum creatinine was observed at the 100 mg dose (CFB 44 ± 12% at 6h***, 28 ± 13% at Day2***, 11 ± 9% at Day4**, 100 mg dose) as well as a less pronounced increase in serum cystatin C (peak at 30 ± 6% at 12h***, 100 mg dose). No meaningful change was observed for the other biomarkers tested. Conclusion: BMS-986308 significantly increased diuresis and natriuresis in healthy participants while sparing potassium. In line with the substantial natriuresis, activation of the RAAS pathway and transient elevations of serum creatinine and cystatin C (with no change in kidney injury markers) was observed.
Abstract 4140562: Cardiopulmonary Measures in Those With Chronic Obstructive Pulmonary Disease: E-Cigarettes vs. Combusted Cigarettes
Authors: Brian Katz, Norman Medina, Shannon OConnor, Sulamunn Coleman, Charlie Irvin, David Kaminsky, Katherine Menson, Diann Gaalema
Journal: Circulation (2024)

Background: E-cigarettes may be less harmful than combustible cigarettes, though results from research with objective outcomes are limited. Comparisons of the cardiopulmonary effects of e-cigarettes and combustible cigarettes in controlled settings are necessary. Aims: Examine cardiopulmonary effects of combustible cigarettes vs. e-cigarettes using a within-subjects design in individuals with chronic obstructive pulmonary disease (COPD) who smoke. Hypothesis: Cardiopulmonary measures will improve following e-cigarette use compared to combustible cigarette use. Methods: Twenty-one individuals ≥40 years old who smoke (≥5 cigarettes/day for ≥1 year) while diagnosed with COPD underwent two consecutive randomly ordered 2-week phases: a cigarette phase (usual-brand cigarettes) and nicotine-containing e-cigarette phase (combustible-cigarette abstinence with 3% and/or 5% nicotine tobacco-flavored JUUL available). During the e-cigarette phase, participants earned monetary incentives for CO readings ≤6ppm to promote cigarette abstinence. Pulmonary (spirometry, oscillometry, COPD Assessment Test [CAT], Saint George’s Respiratory Questionnaire for COPD [SGRQ-C]) and cardiac (heart rate, blood pressure) measures were completed at baseline and after each phase. Changes in pulmonary and cardiac measures across assessments were analyzed using a mixed-model repeated-measures ANOVA. Results: Fourteen participants (66.66%) maintained cigarette abstinence during the e-ciguarette condition. There were no significant differences in objective (spirometry, oscillometry) or self-reported (CAT, SGRQ-C) by condition. Of the cardiac measures, diastolic blood pressure significantly differed by condition (F(2,40) = 3.87, p &lt; 0.05), with higher measures after the completion of the cigarette phase ( p = 0.02). Conclusions: Participants were largely able to conform to the study conditions. However, cardiopulmonary changes were minimal with only diastolic blood pressure differing by condition. Nonetheless, the absence of impairments in pulmonary and cardiac health during this 2-week e-cigarette phase suggests evaluations of longer durations of e-cigarette exposure, with concurrent cigarette abstinence, are warranted to determine the safety of e-cigarettes as a potential replacement for combustible-cigarettes.
Abstract 4140540: Difference of escalation and de-escalation strategies and outcome in cardiogenic shock patients supported with Impella; acute myocardial infarction versus de novo heart failure versus acute on chronic heart failure
Authors: Hidetoshi Hattori, Noriko Kikuchi, Yuki Ichihara, Satoshi Saito, Shinichi Nunoda, Hiroshi Niinami, Junichi Yamaguchi, J-PVAD investigators .
Journal: Circulation (2024)

Background: Timely initiation of temporary mechanical circulatory support (tMCS), escalation and de-escalation strategies are key components for treatment of cardiogenic shock (CS). However, little is known about tMCS strategies and outcomes based on etiology of CS and chronicity of heart failure. We evaluated differences of tMCS strategies and outcome in patients supported with Impella in acute myocardial infarction related CS (AMI-CS), de novo heart failure related CS (de novo HF-CS), and acute on chronic heart failure related CS (acute on chronic HF-CS). Methods and Results: The Japan Registry for Percutaneous Ventricular Assist Device (J-PVAD) is multicenter, observational registry enrolling all consecutive patients treated with Impella in Japan. We conducted a retrospective analysis of patients with Impella in J-PVAD between February 2020 and December 2022. Among 3678 CS patients supported with Impella. 2418 (65.7%) patients were presented with AMI-CS, 758 (20.6%) patients with de novo HF-CS, and 502 (13.7%) patients with acute on chronic HF-CS. The median time from hospital entry to initiation of Impella were 127 min, 339 min, and 1117 min in AMI-CS, de novo HF-CS, and acute on chronic HF-CS, respectively (P &lt; 0.001 for each). 2233 (92.4%) patients with AMI-CS underwent percutaneous coronary intervention during index hospitalization with median door-balloon-time of 108 min. Patients treated with multiple mechanical circulatory supports were 51.4%, 64.2%, and 55.2% in AMI-CS, de novo HF-CS, and acute on chronic HF-CS, respectively. Using de novo CS-HF as a reference, the risk for in-hospital mortality for AMI-CS and acute on chronic HF-CS were: odds ratio (OR) 1.24 [95% confidence interval (CI) 1.04–1.50], P = 0.02 and OR 1.43 (95% CI 1.12–1.81), P = 0.004, respectively. Conclusions: In CS patients supported with Impella, time course and utilization of tMCS varied in AMI-CS, de novo HF-CS, and acute on chronic HF-CS. De novo HF-CS had significantly better mortality relative to AMI-CS and acute-on-chronic CS. Further research is required for tMCS strategies based on etiology of CS and chronicity of heart failure.
Abstract 4139988: Optimal Unipolar and Bipolar Electrode Separation for Recording Atrial Fibrillation in Patients
Authors: Miguel Rodrigo, Samuel Ruiperez-Campillo, Sanjiv Narayan
Journal: Circulation (2024)

Background: Ablation is an increasingly preferred treatment for patients with atrial fibrillation (AF), yet the optimal catheter configuration to record electrical activity (electrograms) is undefined. It is unclear what electrode spacing includes local activity or remote colliding waves. This may affect the certainty that potentials near pulmonary vein or other targets are local, or truly eliminated by ablation, for different catheter designs. Hypothesis: We hypothesized that unipolar and bipolar electrograms in AF are impacted differently by electrode spacing, and that even adjacent bipolar electrograms may vary and reflect direction more than local activity. Methods: We studied 35k electrograms in N=22 patients referred for AF ablation (67±10 y.o, 3 female, 15 non-paroxysmal), collected with both grid-type (3 mm spacing; Abbott) and basket (6-8 mm spacing; Abbott) catheters. For each patient, we precisely measured separation in electroanatomic 3D shells from (x,y,z) coordinates for all electrode pairs (adjacent, next adjacent…) within and between catheters (N=12 patients had simultaneous grid/basket; fig. A). We compared similarity of AF electrograms for 1 to 20 mm distances using the Pearson correlation coefficient (CC), for unipolar and bipolar configurations, in 500ms cycle length windows. Results: Unipolar electrograms in AF were more similar over distance than bipoles. For unipoles, Fig B shows that AF electrograms had CC~0.8-0.9 for electrodes &lt;2-3 mm apart, within a grid sizes, and CC&gt;0.8 for spacing up to ~6 mm, within basket sizes. For distance &gt; 6 mm, CC dropped in a semi-linear fashion with exponential increase in variability (p&lt;0.05). For bipolar electrograms (fig. C), consistency was observed only partially even for very close electrodes (CC &gt;0.8 for &lt;2mm spacing), then fell rapidly with exponential variability (3-10mm). Fig C shows examples where even for relatively close bipoles, EGM traces showed different activation sequences (black arrows). Conclusions: Mapping in AF is very sensitive to unipolar or bipolar electrode configuration. Unipolar electrograms are similar for 2-6 mm separation, while bipolar electrograms vary for spacing &gt;2 mm which may reflect direction more than local activity. Future studies should calibrate these findings against optical recordings of wave propagation or results from prospective guided ablation.
Abstract 4139852: Plozasiran and Triglyceride Levels in Hypertriglyceridemia: Long-Term Efficacy and Safety Data From Subjects in an Open-Label Extension Trial
Authors: Christie Ballantyne, Gerald Watts, Robert Rosenson, Szilárd Vasas, Denes Pall, Peter Clifton, Stephen Nicholls, Masoud Azizad, Ran Fu, Maan Muhsin, Stacey Melquist, Jennifer Hellawell, Daniel Gaudet
Journal: Circulation (2024)

Despite current modestly effective triglyceride (TG) lowering therapies, the availability of more effective agents for persistently lowering elevated TGs and risk of acute pancreatitis remains a continuing need. More recently identified triglyceride-rich lipoproteins (TRLs), specifically remnant cholesterol (RC)-rich particles, are important drivers of ASCVD risk independent of LDL-C, driving development of more effective TG-directed therapies. Apolipoprotein C3 (APOC3) raises TGs by inhibiting lipoprotein lipase (LPL) dependent and -independent pathways. Plozasiran, a RNAi agent targeting APOC3 mRNA in hepatocytes, demonstrated large reductions in circulating APOC3, TGs, TRL-RC with a good safety profile in placebo-controlled trials. Here we report extension data to characterize long term safety and efficacy of plozasiran in subjects with elevated TGs. Plozasiran was studied in subjects with mixed hyperlipidemia (entry TGs 150-499 mg/dl) and severe hypertriglyceridemia (entry TGs &gt; 500-4000 mg/dl) in separate Phase 2 trials (MUIR and SHASTA-2). Subjects completing double-blind, placebo-controlled treatment could enter this open-label extension. Endpoints included changes in fasting TG levels, other lipid and lipoprotein parameters and safety assessments for up to 24 months. Data cut-off was 5/16/24 for this analysis, (up to 15 months of follow up) in the ongoing study. 251 and 165 subjects from MUIR and SHASTA-2 entered the extension in which all received plozasiran 25 mg SQ dosed quarterly. 10, 25 or 50 mg of plozasiran under blinded conditions produced mean reductions in TGs of -52 to -64% (MUIR) and -69 to -74% (SHASTA-2), 12 weeks (trough) after the second dose. Corresponding trough reductions in the extension ranged from -44 to -73% (MUIR) and -62 to -86% (SHASTA-2) through 15 months follow-up. Common reported AEs were consistent with the index studies and patient populations and mean HbA1c did not increase, providing further evidence that long-term safety remains favorable with repeated dosing and longer observation periods. Extended open-label treatment with plozasiran in subjects with moderate to severely elevated TGs continue to show reductions of TG levels and safety consistent with the blinded index studies, demonstrating incidence rate and severity of TEAEs remain favorable with repeated dosing and longer observation. Results of additional lipid and lipoprotein parameters are also consistent with the blinded index data and will also be reported.
Abstract 4139876: Type of diet and the Dietary Antioxidant Index are related to Long-term Microvascular Endothelial Function in coronary patients: From the Cordioprev Study
Authors: Francisco Javier Delgado Lista, Gracia M. Quintana-Navarro, Carmen Estevez Delgado, Alejandro Lopez-Moreno, Juan Francisco Alcala-Diaz, José D. Torres Peña, Pablo Perez-Martinez, Jose Lopez-Miranda
Journal: Circulation (2024)

Introduction: It has been described that both skin and coronary microvascular dysfunction occur in coronary heart disease patients, being a critical pathogenesis of cardiovascular diseases, mainly driven by a reduced endothelium-derived relaxing factor nitric oxide availability, the main homeostatic antioxidant in microcirculation. Various dietary factors could modulate endothelial function. Our goal was to evaluate the relationship between nutrition and long-term microvascular endothelial function in patients in secondary cardiovascular prevention. To do this, we evaluated the consumption of two healthy diets (Mediterranean Diet and Low-fat diet) and the total antioxidant content of the diet. Methods: With an analytical, longitudinal, experimental, and retrospective design, this work included all patients from the Cordioprev study who had completed endothelial function measures and dietary evaluations at the start of the study and after six years of intervention (n=520). Endothelial function (basal flow and area of reactive hyperemia) was measured using laser-Doppler flowmetry in the second phalanx of the third finger of the dominant hand. Food intake was evaluated using a food frequency questionnaire and the antioxidant quality of the diet using the dietary antioxidant index. Results: In the entire population, we observed a significant direct correlation between the evolution of the dietary antioxidant index and basal flow after 6 years of dietary intervention (p=0.024). When we studied the effect of the two diets investigated, in the Mediterranean diet group, an increase in the average dietary antioxidant index score was observed at the end of the study, and a direct relationship was also found between the dietary antioxidant index and endothelial function markers (basal flow (p=0.037); area of reactive hyperemia (p=0.015)). These findings were not observed after the low-fat diet. Conclusions: Our study indicates that, after six years of dietary intervention, changes in the total antioxidant content of the diet are directly correlated with changes in microvascular endothelial function in patients with coronary disease. These findings are especially evident with the Mediterranean Diet.
Abstract 4139853: Altering Cardiovascular Mortality in HFpEF with SGLT2i or ARNI — A Head-to-Head Analysis
Authors: Jesslyn Hariyanto, Chirag Veera, Manoela Lenzi Pinto, Anoushka Chatterjee, Sherif Eltawansy
Journal: Circulation (2024)

Background: Therapeutic options for HFpEF are continuously evolving. The latest AHA guidelines recommend ARNI with a class 2B and SGLT2i with a class 2A for HFpEF. Trials indicate that both SGLT2i and ARNI can improve clinical outcomes, but the practical implications of these costly novel agents must be considered. In this study, we assessed the effects of ARNI and SGLT2 inhibitors on cardiovascular mortality in HFpEF patients. Methods: PubMed, Scopus, and Cochrane search identified RCTs comparing ARNI with Valsartan, ACEi, or placebo, and SGLT2i with placebo. The outcome was cardiovascular mortality, comparing ARNI and SGLT2i subgroups. Heterogeneity was assessed with I^2 statistics with a random-effects model. Results: We included 8 RCTs with 15212 patients. Four studies were included with 27.6% being females with an age range of 70.9 - 72.9 years. Follow-up ranged from 8 weeks to 41 months, and mean LVEF was 57.3 ± 8%. Pooled RR for cardiovascular mortality (0.71 [95% CI: 0.47-1.09], P = 0.11) indicated no significant reduction in risk, with moderate heterogeneity (I^2 = 48%, P = 0.12) In four studies in the SGLT2i subgroup, the age range was 60 to 71.9 years, with an LVEF range of 45 - 61%, and 48.7% of the participants were female. One study found women were more likely to have EF &gt;60% than EF ≤45%. Background medication of ARNI or RAAS inhibitors was continued. Follow-up time ranged from 26.2 months to 4.2 years. Pooled RR for cardiovascular mortality (0.94 [95% CI: 0.83-1.06], P = 0.30) showed no significant reduction in risk, with low heterogeneity (I^2 = 34%, P = 0.21) Combining both ARNI and SGLT2i groups, the total number of patients was 15,212 for the treatment group and 12,426 for the control group. The overall pooled RR (0.91 [95% CI: 0.81-1.03], P = 0.13) suggested no significant difference in cardiovascular mortality, with low heterogeneity across all studies (I^2= 34%, P = 0.16) The test for subgroup differences between ARNI and SGLT2i was not significant (P = 0.22) with low heterogeneity (I^2 = 33.4%) Conclusion: In HFpEF, subgroup analysis showed no significant differences in cardiovascular mortality reduction between ARNI and SGLT2i. Further research should investigate additional clinical and functional endpoints, considering the cost-effectiveness of these treatments.
Abstract 4140617: SGLT-2 Inhibitors and Atrial Fibrillation Incidence Following Heart Failure Hospitalization in a Diabetic Population
Authors: Thomas Fretz, Onyedika Ilonze, Tanyanan Tanawuttiwat, Mithilesh Das
Journal: Circulation (2024)

Introduction: The development of atrial fibrillation (AF) in patients with heart failure (HF) is associated with increased morbidity and mortality. Initially developed as a diabetic medication, SGLT-2 inhibitors have been shown to improve hospitalization rates and mortality in patients with heart failure. Meta-analyses of large prospective trials suggest SGLT-2 inhibitors prevent the incidence and burden of atrial fibrillation, though this specific question has not been specifically addressed by prospective trials. Hypothesis: SGLT-2 inhibitors reduce the incidence of atrial fibrillation in patients who have diabetes following heart failure hospitalization. Aims: The goal of this study was to evaluate the effect of SGLT-2 inhibitors on the incidence of atrial fibrillation in a diabetic population following hospitalization for heart failure. Methods: The study included consecutive patients with diabetes admitted to an academic tertiary care center over a 3 year time period with a primary diagnosis of heart failure exacerbation and without prior diagnosis of AF. The primary outcome is incidence of new AF within 12 months after hospitalization. Demographic, comorbidity, echocardiographic data, and medications were obtained from the medical record. Cox-regression analysis was performed to identify the predictors of AF following HF hospitalization. Results: A total of 2,300 patients were included, 24.3% of whom were prescribed SGLT-2 inhibitors. Of those included, 499 (21.7%) have HFrEF, 309 (13.4%) have HFmrEF, and 1492 (64.9%) have HFpEF. The use of SGLT-2 inhibitor demonstrated a statistically significant association with lower incidence in AF at one year following heart failure hospitalization. Patients on an SGLT-2 inhibitor had a AF incidence of 13.2% compared to an incidence of 20.2% in those not taking an SGLT-2 inhibitor. This difference was found to be statistically significant ( p&lt;0.001; RR 0.62; 95% CI: 0.48-0.80 ). Conclusion: The use of SGLT-2 inhibitors is associated with a statistically significant reduction in new-onset AF at one year following hospitalization for heart failure in patients with diabetes.
Abstract 4140528: Association of Ventricular Arrhythmias with Lamotrigine: An Observational Cohort Study
Authors: Sodam Kim, Landon Welch, Bertha De Los Santos, Przemyslaw Radwanski, KIBUM KIM, Mark Munger
Journal: Circulation (2024)

Objective: The chemical reduction of intracellular sodium through inhibition of the voltage-gated sodium channels stabilizes presynaptic neuronal membranes and inhibits presynaptic glutamate and aspartate release making lamotrigine (L) an important strategy for treating patients with Bipolar I disorder (BPI). L also slows cardiac conduction velocity introducing a potential substrate for its proarrhythmic properties. This study’s aim was to examine the association between onset of ventricular tachycardia (VT) and L in patients with BPI. Methods: A retrospective observational research study was performed using Merative MarketScan ® Commercial Claims and Medicare Supplemental Database. Analytic cohort included adult naïve VT or atrial fibrillation patients who filled a prescription for L or control agents (C), including lithium, quetiapine, valproate, or risperidone. Patients were free from arrhythmia, including atrial fibrillation or VT, during the 6-month baseline period before prescription of L or C prescription. The onset of VT was identified by the appearance of newly recorded ICD codes. Cumulative incidence of VT was calculated using Kaplan-Meier estimator, with patients being censored at the last enrollment, treatment switching, discontinuing treatment, or end of one-year follow up. We used a multivariable regression model to calculate hazard ratio for the onset of VT associated with L and C, adjusting for baseline characteristics, with a particular interest in the impact of structured heart disease (SHD). Results: The analytic cohort included 153,852 L and 213,593 C patients with respective mean year age of 37.53 (SD 13.63) and 40.85 (SD 15.74). The 1-year cumulative incidence of VT from L and C was 0.785% and 0.683%, respectively, calculating HR of 1.270 [95% CI: 1.079-1.496], p=0.0041. Figure 1) (After adjusting for the baseline characteristics, HR was 1.326 [1.122-1.568], p-value = 0.0009. From the multivariable analysis, the measure of SHD impact on the onset of VT was HR of 1.538 [1.011-2.341] (p=0.0444). Conclusions: In adult BPI patients, L has a strong potential to increase the risk of VT compared to C. Notably, baseline SHD has a significant impact on the onset of VT.