tbuckley/cabot-search huggingface dataset:
Abstract 4139981: Protective Effects of Cell Cycle Inhibition on Tubular Metabolism in Chronic Kidney Disease
Authors: Safaa Hammoud, Justin Kern, Yosuke Osaki, Steven Funk, Craig Brooks, Leslie Gewin
Journal: Circulation (2024)

Introduction: Chronic kidney disease (CKD) is a significant healthcare challenge globally and renal proximal tubules (PT) are key targets of injury. Others have shown that patients with CKD have a dysregulated cell cycle in PT, but it remains unclear whether cell cycle progression in CKD is adaptive or maladaptive. Our recent findings indicate that inhibiting cyclin-dependent kinases 4/6 (CDK4/6) is protective in CKD. However, the underlying mechanisms remain incompletely understood. Research questions and aims: Cell cycle progression is linked to metabolism, and we aim to investigate how CDK4/6 inhibition can alter metabolism. Mitochondrial function is closely intertwined with metabolism, and chronic kidney injury is associated with both impaired mitochondrial function and decreased oxidative metabolism. However, mitophagy, the clearance of dysfunctional mitochondria, protects against CKD progression. This raises the question of how CDK4/6 inhibition affects metabolism, mitochondrial function and mitophagy. Methods: To define how cell cycle alters metabolism, we measured respirometry using a Seahorse bioflux analyzer on primary PT treated with palbociclib, a CDK4/6 inhibitor. Additionally, we injured mice with uninephrectomy/angiotensin II (UniNx/AngII) +/- palbociclib. To measure glucose oxidation, we incubated injured kidney tissues with 14 [C]-pyruvate and measured the production of 14 CO 2 . We analyzed mitochondrial structure in injured kidneys +/- palbociclib using structure illuminated microscopy (SIM). To assess the effect of CDK4/6 inhibition on mitophagy, we used a reporter mouse model “Mito-QC” injured by UniNx/AngII. Mito-QC mice have tandem mCherry-GFP tag fused to the mitochondrial outer membrane protein, but GFP is pH sensitive and is quenched during mitophagy. Results: Our data indicate that blocking CDK4/6 with palbociclib enhances mitochondrial oxygen consumption in primary PT. Additionally, palbociclib increases glucose/pyruvate oxidation in injured kidneys. Palbociclib preserves mitochondrial connectivity in response to UniNx/AngII-induced kidney injury, as detected by SIM. Moreover, palbociclib-treated mice had increased mitophagy following kidney injury. Conclusion: Our study shows that CKD4/6 inhibition increases oxidative metabolism and improves mitochondrial function. These effects may be mediating some of the protective effects of palbociclib in chronic renal injury.
Abstract 4139898: A Non-invasive <i>In Vivo</i> Experimental Model of Heart Failure Using Optogenetic Tachypacing in Larval Zebrafish
Authors: Emma Savoie, Ahmed Ramadan, Katherine Purvis, Matthew Stoyek, Alex Quinn
Journal: Circulation (2024)

Background: Tachycardia can drive heart failure (HF). Traditionally, this is experimentally modeled using an implantable pacemaker, an invasive, technically demanding, and low-throughput methodology. Genetically-expressed light-activated ion channels (‘optogenetics’) provide an alternative approach for in vivo cardiac stimulation, which if applied in transparent zebrafish embryos, may be used for non-invasive, cost-effective, high-throughput HF and drug screening studies. Objective: Establish a non-invasive in vivo experimental model of HF using optogenetic tachypacing in larval zebrafish. Methods: Larval zebrafish expressing cation-nonspecific channelrhodopsin-2 (ChR2), chloride-specific anion channelrhodopsin-1 (ACR1), or green fluorescent protein (GFP, as a light-exposed, non-paced control) in cardiomyocytes were exposed to intermittent tachypacing (15s on, 15s off) by programmed light pulses from 2-7 days post fertilization (dpf). At 7 dpf: (i) in vivo atrial and ventricular mechanical function was assessed by end-diastolic area (EDA), end-systolic area (ESA), and ejection fraction (EF) with video microscopy; (ii) cardiac structure was measured by atrial and ventricular area in fixed larvae with fluorescent imaging; and (iii) gene expression of cardiac-specific HF biomarkers (atrial and brain natriuretic peptide [ anp , bnp ], atrial- and ventricular-specific myosin heavy chain-a and -b [ myh6 , myh7 ], and a-smooth muscle actin [ acta2 ]) was quantified by qPCR. Values across groups were compared by one-way ANOVA, with Šídák post hoc tests. Results: In vivo , atrial and ventricular EDA were greater in ChR2 (+191%, p &lt;0.0001; +66%, p &lt;0.0001) and ACR1 (+58%, p =0.005; +40%, p =0.0004) hearts compared to control, as was ESA (ChR2: +245%, p &lt;0.0001; +67%, p &lt;0.0001 and ACR1: +89%, p &lt;0.0001; +53%, p &lt;0.0001). Atrial EF was lower in ChR2 (-26%, p =0.0006) and ACR1 (-26%, p =0.0032) hearts, while ventricular EF was unchanged. Atrial and ventricular area were also greater in fixed ChR2 hearts (+191%, p &lt;0.0001; +35%, p =0.0005), while only atrial area was greater in ACR1 hearts (+55%, p =0.0236). Expression of anp , bnp , and myh6 were greater in both ChR2 (11x, 22x , 58x; p &lt;0.05 for each) and ACR1 (6x, 4x, 15x; p &lt;0.05 for each) hearts. Conclusion: Intermittent optogenetic-tachypacing with either ChR2 or ACR1 induces HF in larval zebrafish, which may represent novel experimental models for insight into HF mechanisms and as pre-clinical tools for the development of new HF therapies.
Abstract 4140462: Effects of Right Ventricular vs. Conduction System Pacing on Left Ventricular Systolic and Diastolic Function Reserve and Pulmonary Gas Exchange During Exercise Stress in Pacemaker Dependent Patients with Normal Left Ventricular Ejection Fraction
Authors: Songnan Wen, Courtney Wheatley-Guy, Jordan Parks, Catherine T. Wingler, Rose A. Simpson, Monique Silva, Hicham El Masry, Tasneem Naqvi
Journal: Circulation (2024)

Background: Right ventricular pacing (RVP) can have adverse cardiac effects and cause pacing induced cardiomyopathy (PiCM). His bundle pacing (HBP)&amp;Left Bundle Branch area pacing (LBBAP) mimic physiologic conduction (PhysioP) and maintain biventricular synchrony. Hypothesis and Aims: Reduced left ventricular (LV) systolic function reserve in the presence of normal baseline LV ejection fraction (EF) could precede development of RV PiCM. Our aim was to compare the effects of RVP vs. PhysioP on bicycle exercise cardiopulmonary performance in patients with normal LVEF who required pacing for bradyarrhythmias. Methods: Patients with sinus rhythm and RVP or PhysioP&amp;ventricular pacing burden of &gt;70% who completed cardiopulmonary exercise test and simultaneous stress echocardiography (SE) were included. Pulmonary gas exchange was calculated using Ventilation/CO2 production at rest and during exercise. Changes in LV size, EF, longitudinal strain and diastolic function and gas exchange parameters were compared post and pre exercise in the 2 groups. Results: 25 of 29 patients completed the study [68 ± 23 yrs, 48% M; LVEF 56±5%, 11 RVP, 14 PhysioP]. There was no difference in baseline demographic&amp;clinical variables, exercise duration, rest and peak heart rate and blood pressure between 2 groups. Pacing duration was 2.61±1.48 yrs in RVP vs. 0.84±0.67 yrs (p=0.003) in the Physio group. Resting echocardiographic parameters ( Table 1A) were comparable. Compared to RVP, reduction in LV end-diastolic volume (EDV) 3.4±14.1 ml vs. -23.1±18.1ml, p=0.006)&amp;LV end-systolic volume (ESV -5.7±11.6 ml vs. -18.0±9.5ml, p=0.01) was more pronounced in the PhysioP group. Changes in LVEF, LV strain&amp;diastolic function were not different between the 2 groups ( Table 1B ). There were no significant differences in changes in pulmonary gas exchange parameters in the 2 groups. Conclusions: In patients with normal LVEF and pacemaker dependent, RVP is associated with impaired but PhysioP with preserved LV systolic function reserve, which can be detected by exercise SE. SE may help identify patients at risk for RV PiCM. Benefit of PhysioP needs to be determined by larger studies with longer follow-up.
Abstract 4140060: Impact of SGLT2 Inhibitors on Mortality Risk in Type 2 Diabetes Mellitus and Coronary Artery Disease: A Systematic Review and Meta-Analysis
Authors: Antony Gonzales, Nicole Collantes-Silva, Sebastian Arambulo-Castillo, Zhamanda N. Ortiz-Benique, Juan Manuel Munoz-Moreno, Esteban Alarcon
Journal: Circulation (2024)

Introduction: Type 2 diabetes mellitus (T2DM) is a major risk factor for coronary artery disease (CAD). SGLT2 inhibitors (SGLT2i) are effective in reducing cardiovascular mortality in T2DM patients, but their benefits for those with both CAD and T2DM are uncertain. Objective: The primary outcome was to evaluate the efficacy of SGLT2i compared to other hypoglycemic agents or placebo in reducing the risk of all-cause mortality in patients with T2DM and CAD. Secondary outcomes included cardiovascular death, fatal or non-fatal stroke, and fatal or non-fatal myocardial infarction. We hypothesize that SGLT2i are more effective in mortality risk reduction in patients with T2DM and concomitant CAD. Methods: A systematic review following PRISMA-2020 guidelines was conducted across four databases to evaluate the efficacy of SGLT2i in reducing mortality risk in diabetic patients with CAD. Quantitative analysis using Stata v18 employed a random-effects model (Restricted Maximum Likelihood) with Hazard Ratios (HR) as the measure of association. Results: Out of 853 studies identified, 5 publications were included in the final quantitative analysis, which included 5225 patients. The Newcastle-Ottawa Quality Assessment Form showed all included cohort studies had a low risk of bias. Those patients taking SGLT2i had a significant reduction in 38% the risk of all-cause mortality (HR 0.62 [0.47, 0.80]), this same effect was observed when compared with each subgroup vs. other hypoglycemic agents, HR 0.52 [0.29, 0.93]; vs. placebo, HR 0.64 [0.46, 0.90]. Results show very low heterogeneity. In overall cardiovascular death analysis, a significantly greater reduction was observed with SGLT2i (HR 0.61 [0.46, 0.81]), as well as when compared with placebo (HR 0.64 [0.47, 0.86]). In contrast, when compared with other hypoglycemic agents, there was a reduction, but this was not significant (HR 0.45 [0.19, 1.03]). No statistically significant decrease in the risk of fatal or non-fatal stroke and myocardial infarction was found with SGLT2i. Conclusion: SGLT2i demonstrates a greater significant benefit in reducing all-cause and cardiovascular mortality in patients with T2DM and CAD.
Abstract 4140244: In a Murine Model of Experimental Sepsis, Cardiac-Specific Jarid2 Knockdown is Associated With Improved Myocardial Function and Survival
Authors: James Tsoporis, Yambo Wang, Jean-Francois Desjardins, Amin Ektesabi, Shehla Izhar, Youngsook Lee, Thomas Parker, Claudia dos Santos, Howard Leong-Poi
Journal: Circulation (2024)

Introduction: Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, leading to acute heart failure, decreased contractile function, and biventricular dilation. Emerging evidence suggests that the transcriptional repressor Jarid2 may play a regulatory role in sepsis. Hypothesis: We hypothesize that cardiac-specific knockdown (KD) of Jarid2 could enhance cardiac function and improve survival in response to sepsis. Methods: We generated mice with cardiac-specific Jarid2KD using an alpha myosin heavy chain-specific Cre-LoxP system. Using an in vivo model of cecal ligation and puncture (CLP) with 12-week-old wild-type (WT) and cardiac-specific Jarid2KD mice we investigated whether Jarid2 is a potential novel target for sepsis treatment. Results: In response to 48 hours of CLP, WT mice exhibited over 60% mortality vs. WT-Sham. Survivors developed bacterial peritonitis, an increased inflammatory response (left ventricle (LV): 15-fold increase in IL-6, 3-fold increase in IL-1β and TNF-α, vs. WT-Sham), and apoptosis (LV: 2.5-fold increase in apoptotic Bax/Bcl2 ratio vs. WT-Sham). Jarid2KD showed myocardial dysfunction with a 20-35% decrease in dp/dt, echo-derived ejection fraction (EF), fractional shortening (FS)), a switch from adult α-myosin heavy chain (MHC) to fetal β-MHC, and a 40-50% reduction in LV Jarid2 mRNA and protein compared to WT-Sham. In contrast, Jarid2KD mice despite a similar decrease in LV Jarid2 expression to WT-CLP mice, demonstrated resistance to CLP-induced bacterial peritonitis with cardiac function (dp/dt, EF, FS) similar to the WT-Sham. Histological staining revealed better organization of cardiomyocytes and preservation of functional ultrastructure. Furthermore, Jairid2KD displayed a survival rate of over 90%, a reduced LV inflammatory response (LV: 2-fold increase in IL-6, no change in IL-1β and TNF-α), maintenance of α-MHC, and absence of apoptosis vs. WT-CLP. Metabolic genes such as NDUFA9, Cox4il, ND1, ND4 and PGC1b were downregulated approximately 60-75 per cent in Jarid2KD vs WT-CLP suggesting an improved ability to regulate energy usage. Improved survival was observed even 7 days post-CLP (65% in WT-CLP compared to 100% in Jarid2KD). Conclusion: Cardiac-specific JARID2KD improves survival and reduces sepsis-induced myocardial dysfunction. Thus, Jarid2 may serve as a novel therapeutic target for treating sepsis-induced myocardial dysfunction.
Abstract 4140175: Association of Non-Cardiac Comorbidities With Long-Term Re-Hospitalization for Heart Failure: Contemporary Analysis of 88,528 Consecutive Cases
Authors: Giuseppe Ambrosio, Elena Tagliabue, Pierpaolo Pellicori, Lars Lund, Antonio Pontiroli
Journal: Circulation (2024)

Background: Heart failure (HF) may coexist with non-cardiac comorbidities. Yet, while relevant, the impact of non-cardiac comorbidities on long-term HF re-hospitalizations (Re-Hosp) is is not well established. Previous studies do not reflect modern HF management, often report just all-cause Re-Hosp, or are based on selected populations from randomizd trials. We investigated the association of non-cardiac comorbidities with long-term Re-Hosp for HFafter discharge for HF in a large, contemporary setting. Methods: Administrative hospital discharge data for HF (primary diagnosis) (Jan 1st 2015-Dec 31st 2019) of all &gt;10 Million residents of Lombardy (Italy); follow up through June 30th 2021. Comorbidities assessed from discharge information and/or administrative codes for chronic diseases. Re-Hosp risk for HF (primary diagnosis) after HF discharge as a function of non-cardiac comorbidities was assessed by Cox proportional-hazard models (age- and sex-adjusted). Kaplan Meier curves for HFRe-Hosp were stratified for number of non-cardiac comorbidities. Results: 88,528 consecutive patients received a HF primary discharge; over 42.8±18.3 months of follow-up, 79,533 HF Re-Hosp occurred (32.44/100 patient/year). Risk of HF Re-Hosp increased with increasing number of non-cardiac comorbidities. Adjusted by age, females with &gt;4 comorbidities had a 3.08 (CI 2.73-3.47) greater risk of Re-Hosp compared with females without comorbidities; males with &gt;4 comorbidities had a 2.62 (CI 2.39-2.87) greater risk compared with males without comorbidities. By multivariable analysis, number of comorbidities, age, and male sex, remained significantly associated with Re-Hosp risk (Figs 1, 2). Risk of all-cause death also increased with increasing number of non-cardiac comorbidities, from 1.42 for HF patients with 1-2 comorbidities to 2.20 for HF patients with &gt;4 comorbidities. Also the number of days spent in hospital because of HF after index HF discharge significantly increased with increasing number of non-cardiac comorbidities, from 19.9±19.3 days in patients without non-cardiac comorbidities to 45.4±33.0 days for patients with &gt;4 non-cardiac comorbidities (p&lt;0.0001). Conclusion: In a large, contemporary real-world series of patients hospitalized with HF, HF re-hospitalizations, all-cause mortality, and life-time spent in hospital due to worsening HF increased with number of non-cardiac comorbidities. Non-cardiac comorbidities substantially impact the clinical trajectory of HF patients.
Abstract 4140503: Artificial Intelligence Can Match Atrial Fibrillation Electrograms to Action Potential Recordings in Patients
Authors: Ricardo Carlos Abad Juan, Suhaas Anbazhakan, Samuel Ruiperez-Campillo, Miguel Rodrigo, Sanjiv Narayan
Journal: Circulation (2024)

Background: In patients with atrial fibrillation (AF), pulmonary vein isolation (PVI) improves morbidity and mortality compared to anti-arrhythmic medications, yet is suboptimal in &gt;30-40% of patients typically with persistent AF. Several promising mapping approaches are emerging for such patients, but results are inconsistent. One challenge is to reconcile differences between clinical mapping of electrograms and optical mapping, that detects local tissue action potentials. Hypothesis: We hypothesized that artificial intelligence (AI) algorithms applied to AF electrograms recorded from clinical catheters can infer onsets of action potentials, referenced to clinical MAP recordings. Methods: In N=303 AF patients at ablation (68.2±8.0 years, 17.8% females, 72.9% non-paroxysmal AF), we isolated a development cohort (N=229) and a test cohort (N=74). In the development cohort we trained a multistage AI-system to identify cycle-to-cycle activations in AF electrograms recorded from various clinical catheters. In the separate test cohort, we assessed the accuracy of the AI algorithm relative to MAP onsets, recorded at adjacent sites with dedicated catheters (N=20, MedFact, GmbH). We related accuracy to signal quality, defined from the homogeneity of distribution of activation times. Results: Figures shows unipolar AF EGMs, MAPs and AI annotation. A. Good agreement between AI timing, and MAP onsets (15 ms) for signals of high quality in a 67 year old woman. B. Good agreement between AI timings and MAP onsets (42 ms) with delay reflecting spatial separation between EGM and MAP catheters in a 72 year old woman. C. Good agreement despite difficulty in expert annotation of EGM in cases of intermediate to low signal quality in a 67 year old man. In summary, the AI system provided an average F1-score for AF timings of 0.83 relative to experts (p&lt;0.01), varying from 0.72 to 0.95 for low to high signal quality (p&lt;0.01). A similar trend was found for AI accuracy vs. MAP onsets (p&lt;.05) Conclusions: In this large registry, a novel AI-based approach accurately identified AF activation relative to tissue action potential onsets, referenced to expert labels. AI may improve characterization of AF activity within the atria, and could be a foundation for future mapping and phenotyping.
Abstract 4140280: The Association of the Muscle Mass with Exercise Capacity and Childhood Opportunity Index in Patients with Fontan Circulation
Authors: Abigail Tercek, Kevin Smith, Brock Karolcik, Gaurav Arora, Jacqueline Kreutzer, Laura Olivieri, Adam Christopher, Tarek Alsaied
Journal: Circulation (2024)

Background: The Child Opportunity Index (COI) is a validated, comprehensive measure of social context, comprised of 29 indicators of child neighborhood opportunity, split into three domains (education, health and environment, and socioeconomic). Our previous work showed that low COI is associated with a 10% lower percent of predicted peak VO 2 post-Fontan. Exercise intolerance is a known prognostic factor for this patient population. Previous studies have shown that health inequities in education, environment, and socioeconomics factor into worse exercise outcomes. Cardiac MRI (CMR) measured muscle mass is a novel practical technique to evaluate muscle mass. We hypothesized that lower muscle mass by CMR is associated with lower exercise capacity and lower COI z-scores. Methods: A retrospective, single-center study was performed, analyzing 75 post-Fontan patients who had CMR completed between 2010 and 2022. The anterior and paraspinal muscles were measured (Figure). COI z-scores were split into low and high levels, and univariate analyses were subsequently performed to determine associations between COI levels, exercise capacity and muscle mass. Results: The mean age of the population was 19.09 years ± 8.58 with the majority being male (65.3%). Most patients underwent an extracardiac conduit repair (65.3%) (Table). There was a positive correlation between anterior (r=0.36, p=0.007) and paraspinal (r=0.34, p=0.01) muscle mass to peak VO 2 . There was no significant difference in paraspinal (p=0.15) or anterior (p=0.72) muscle mass between COI groups. Similarly, there were no significant associations between muscle mass and specific COI domains. Conclusion: Muscle mass correlated with exercise capacity in our population and is easy to measure by CMR. There was no correlation between COI level and muscle mass in this study, suggesting that the COI impact on exercise capacity is not directly mediated by lower muscle mass and that other factors should continue to be explored.
Abstract 4140480: The Relationship Between Obesity Status and Change in NT-proBNP with Angiotensin-Neprilysin Inhibition in Patients with Mildly Reduced or Preserved Ejection Fraction and Recent Worsening Heart Failure Event: Results from the PARAGLIDE-HF Trial
Authors: Josephine Harrington, Robert Mentz, Kirkwood Adams, Adrian Hernandez, Anuradha Lala, Alexander Peikert, Scott Solomon, Randall Starling, Eric Velazquez, Jonathan Ward, Kristin Williamson, Shelley Zieroth, Kavita Sharma
Journal: Circulation (2024)

Background: In PARAGLIDE-HF, patients with heart failure with mildly reduced or preserved ejection fraction (HFpEF) and a recent worsening HF event randomized to sacubitril/valsartan (sac/val) vs val had a significantly larger reduction in NT-proBNP and were numerically more likely to derive clinical benefit as assessed by a win ratio. Patients with obesity and HFpEF may represent a unique phenotype, characterized by a high risk for recurrent HF hospitalization and lower levels of NT-proBNP. Research Question: Does BMI category modify the relationship between sac/val vs val on NT-proBNP change and/or a win ratio among patients with HFpEF or mildly reduced EF? Methods: To assess the interaction between BMI and sac/val vs val on NT-proBNP, the time-averaged proportional change in NT-proBNP from baseline to Weeks 4 and 8 was assessed with an analysis of covariance model including the interaction of treatment-by-BMI group (obese with BMI ≥30 vs normal/overweight, BMI 18.5 to &lt;30 kg/m 2 ). A win ratio of cardiovascular death, total HF hospitalizations, urgent HF visits, and change in NT-proBNP was calculated for both BMI groups, including an interaction term with significance set at ≤0.1. Results: Overall, 65% (n=298) of patients had obesity and 35% (n=164) of patients had normal/overweight. When the interaction between BMI category and the effect of sac/val vs val on the time-averaged proportional change from baseline NT-proBNP was assessed, patients with obesity had a non-significant but numerically larger decrease in NT-proBNP ( Table ). Patients with obesity were also more likely to derive clinical benefit overall from sac/val vs val as compared to patients with normal/overweight (win ratio 1.38, 95% CI 1.01-1.90 vs 0.90, 95% CI 0.62-1.32, p interaction = 0.09). Conclusion: These preliminary data suggest that patients with HF with mildly reduced or preserved EF and obesity may experience a larger clinical benefit from sac/val than patients with normal/overweight BMI.