tbuckley/cabot-search huggingface dataset:
Abstract 4141953: Genetic deficiency of flavin containing monooxygenase 3 ( <i>Fmo3</i> ) lowers circulating trimethylamine N-oxide level and protects against atherosclerosis
Authors: Maggie Han, Sarada Charugundla, Zeneng Wang, Satyesh SINHA, Zhiqiang Zhou, Hooman Allayee, Stanley Hazen, Aldons Lusis, Diana Shih
Journal: Circulation (2024)

Introduction: Our groups have previously identified trimethylamine N-oxide (TMAO) as a risk factor for cardiovascular diseases (CVD). In humans, elevated plasma TMAO levels are associated with a ~2.5-fold increased risk for major adverse cardiac events, such as death, myocardial infarction, and stroke. Bacterial metabolism of dietary choline (and L-carnitine) in the intestine leads to an intermediate, trimethylamine (TMA), which is absorbed from the gut and oxidized primarily by the hepatic flavin-containing monooxygenase 3 (FMO3) to generate TMAO. Hypothesis: We hypothesize that decreased TMAO generation caused by FMO3 deficiency in mice leads to decreased circulating TMAO levels and atherosclerosis. Approach and Results: We generated FMO3 knockout (KO) mouse on a C57BL/6J background via CRISPR/Cas9 technology. We then crossed the FMO3KO mice with LDL receptor knockout (LDLRKO) mice to generate FMO3 heterozygous (FMO3Het)/LDLRKO mice and FMO3KO/LDLRKO mice for the study. Female FMO3Het/LDLRKO and FMO3KO/LDLRKO mice were fed a 1% choline, a TMAO precursor, and 0.5% cholesterol diet for 3 months to increase circulating TMAO and total cholesterol levels. After diet feeding, FMO3KO/LDLRKO mice had 51% lower TMAO levels compared to FMO3Het/LDLRKO mice (18.3 μM vs. 38.3 μM, p &lt; 0.0001), but no effects on plasma lipids, glucose, or insulin levels. Most notably, atherosclerotic lesion at the aortic root was decreased by 24% (p &lt; 0.01) in the FMO3KO/LDLRKO mice as compared to the FMO3Het/LDLRKO mice. The mRNA levels of inflammatory genes, such as Cox2 and E-selectin, in the aorta were significantly decreased by more than 50% in FMO3KO/LDLRKO mice when compared to the control mice. Western blot analysis revealed decreased NF-κB activation in the aorta samples of the FMO3KO/LDLRKO mice as compared to those of the controls, suggesting reduced inflammation in the former. We also measured circulating IL-6 and TNF-α levels but did not observe any differences in plasma levels of these inflammatory biomarkers. Conclusions: Taken together, our data demonstrate that Fmo3 deficiency reduces TMAO levels and aortic lesion development in the context of an appropriate pro-atherogenic diet that contains also high levels of a TMAO precursor. These results also suggest that one mechanism for the pro-atherogenic effects of TMAO is through localized upregulation of inflammatory pathways at the level of the vessel wall, which do not necessarily manifest systemically.
Abstract 4141805: High Frequency of Ejection Fraction Decline in Patients with Heart Failure with Improved Ejection Fraction
Authors: Anthony Pensa, Lucia Davis, Tingqing Wu, Veronica Zheng, Rebecca Harap, Jane Wilcox
Journal: Circulation (2024)

Background: Heart failure with improved ejection fraction (HFimpEF) is defined by prior HF with reduced EF (HFrEF) and evidence of systolic improvement and is associated with improved outcomes. Despite this, HFimpEF patients remain at risk of future adverse events, including EF decline. However, little is known about factors associated with EF trajectory in this population. Question: Are baseline clinical characteristics associated with future EF decline in HFimpEF? Goals: To describe the EF trajectory in HFimpEF and to identify if clinical characteristics are predictive of eventual EF decline. Methods: This was a retrospective observational study of 115 patients in our HFimpEF registry. Inclusion criteria were a history of HFimpEF (prior HFrEF [EF ≤40%] with subsequent EF improvement ≥10% and resulting EF &gt;40%) and at least one follow-up echocardiogram after improvement. The primary outcome was EF decline (EF drop ≥10% from peak improvement EF). Cox proportional hazard models were built using baseline factors at time of HFrEF diagnosis to identify predictors of EF decline. Results: The median time from initial HFrEF diagnosis to development of HFimpEF was 0.61 years (IQR 0.26-1.17). Most patients (77%) continued to have EF improvement after HFimpEF diagnosis, and the peak EF was 60% (IQR 54-65%). Over a mean follow-up of 4.7±3.2 years, 35 (30%) HFimpEF patients developed EF decline. Baseline characteristics were similar between those with sustained EF and EF decline ( Table 1 ), as was peak EF (60.0% vs 60.3%, p=0.571). Indexed end-systolic dimension (1.78 vs 1.93 cm/m 2 , p=0.014) was smaller at time of HFimpEF diagnosis in those with sustained EF. In multivariate analysis, current/former tobacco use was associated with EF decline (HR 2.60, 95% CI 1.02-6.63, p=0.045; Table 2 ). Conclusions: Many HFimpEF patients develop EF decline, highlighting the need for continual clinical follow up in this high-risk patient population.
Abstract 4141919: Differential Association of Atrial Myopathy Subtypes with Incident Atrial Fibrillation: The Atherosclerosis Risk in Communities Study (ARIC)
Authors: Ethan Moser, Ruoyu He, Wendy Wang, Jeremy Van't Hof, Daokun Sun, Chunxiao Zhang, Michael Zhang, Lap Sum Chan, Scott Solomon, Amil Shah, Wei Pan, Lin Chen
Journal: Circulation (2024)

Background: Atrial myopathy—characterized by abnormal left atrial (LA) function or size— is independently associated with cardiovascular outcomes such as atrial fibrillation (AF) and stroke. One obstacle to the discovery of strategies to prevent atrial myopathy-related outcomes is its heterogeneity. Objective: Resolve heterogeneity of atrial myopathy by identifying distinct subtypes of atrial myopathy with differential risk of AF using an unsupervised machine learning clustering analysis. Methods: We included ARIC participants at visit 5 (2011-13) with atrial myopathy—defined using LA reservoir strain (Female: &lt;28.6%, Male: &lt;26.4%)—and no prevalent AF. We considered 52 clinical, demographic, ECG, and echocardiographic candidate variables for the clustering analysis. Random forest imputation was used for missing data. LASSO regression of atrial myopathy was used to select pertinent variables. Selected variables were standardized, and clusters were identified using model-based clustering with mClust , based on the Bayesian Information Criterion. Multivariable Cox regression model was used to evaluate the association between final clusters and incident AF. Results: In total, 1,415 (mean age ± SD, 77 ± 5 years, 70% Female, 26% Black) participants with atrial myopathy were included in the clustering analysis, and 5,209 participants in the Cox regression analysis. There were 22 variables selected, and 3 clusters identified ( Table 1 ). Over a mean follow-up of 6.3 years, 712 incident AF cases occurred. Compared to those with no atrial myopathy, all three clusters had differentially increased risk of incident AF ( Table 2 ). Conclusion: Clustering analysis of individuals with atrial myopathy identified 3 unique clusters that were differentially associated with incident AF providing evidence of the heterogeneity of atrial myopathy. The clustering scheme may be used to select high-risk patients for clinical trials aimed at preventing outcomes related to atrial myopathy.
Abstract 4141925: Impact of Chemotherapy Exposure on New-Onset Cardiovascular Disease Risk in Cancer Survivors
Authors: Gabriel Raab, Whitney Underwood, Xiaoyue Ma, Joseph Wallins, Jessica Scott, Jennifer Liu, Lee Jones, Anthony Yu
Journal: Circulation (2024)

Background: Five-year survivors of cancer are at excess risk of non-cancer competing morbidity and mortality including cardiovascular disease (CVD). However, whether excess risk differs based on exposure to specific chemotherapy treatments is unclear. We compared risk of CVD among 5-year cancer survivors with or without prior chemotherapy exposure. Methods: Using a retrospective cohort design, we identified 25,535 pan-cancer survivors with ≥5 years follow-up at MSKCC. New onset CVD events (i.e., heart failure [HF], myocardial infarction [MI], stroke) were ascertained based upon administrative billing codes. Cumulative incidence rates (CIR) were estimated, accounting for the competing risk of death, and differences between groups with and without chemotherapy treatment were evaluated using Gray’s test. Multivariable Fine and Gray proportional hazard models estimated sub-distribution hazard ratios (sHR) and 95%CIs for survivors treated with versus without chemotherapy. Subgroups of survivors treated with an individual class of chemotherapy were also examined. Results: Median follow-up was 116.2 (IQR, 80.6-162.0) months (Table). Compared to survivors with no chemotherapy exposure, survivors with prior chemotherapy treatment had higher CIR of HF (7.62% vs. 2.77%, P&lt;0.01) and stroke (5.44% vs. 3.06%, P&lt;0.01), but not MI (3.92% vs 3.49%, P=0.20). In multivariable models, survivors who received chemotherapy had higher risk of HF (sHR: 4.08; 95% CI: 3.47-4.80), MI (sHR: 1.61; 95% CI: 1.36-1.91), and stroke (sHR: 2.64; 95% CI: 2.20-3.15). Risks of CVD varied based upon type of chemotherapy received (Figure 1). Conclusion: Cancer survivors who received chemotherapy had higher risks of CVD compared with survivors without chemotherapy exposure, with variation based upon type of chemotherapy. These findings underscore the need for aggressive CVD risk factor modification and prevention in cancer survivors, especially those who received chemotherapy associated with increased CVD risk.
Abstract 4141859: Impacts of the COVID-19 era Practice of Preventing Bypass of the Emergency Department for ST-Segment Elevation Myocardial Infarction Patients Identified in the Field by Emergency Medical Services on In-Hospital Mortality and Other Performance Metrics
Authors: Catherine Benziger, Richard Mullvain, Krysta Kaas, RAMIN ARTANG, Colleen Renier
Journal: Circulation (2024)

Background: Field activation of patients with ST-segment elevation myocardial infarction (STEMI) by Emergency Medical Services (EMS) during the COVID-19 (COVID) pandemic era involved a change in policy whereby patients underwent COVID-19 testing in the emergency department (ED) prior to Percutaneous Coronary Intervention (PCI) versus bypassing the ED to the Catheterization (Cath) Lab. Research Question: We aimed to compare In-Hospital Mortality and other performance metrics of field activated STEMI patients at a large rural health system during the COVID era to pre and post pandemic periods. Methods: Retrospective single-center (Essentia Health, Duluth, MN, USA) cohort study of consecutive patients with STEMI activation identified in the field by EMS prior to the COVID era (5/27/2018–3/26/2020), during the 22 months of the COVID testing policy (3/27/2020–1/25/2022), and post-COVID when ED bypass resumed (1/ 26/2022–11/26/2023). The main outcomes of this study were in-hospital mortality and common STEMI system performance metrics. Results: A total of 373 consecutive field activated STEMI cases were included (pre COVID [N =132], COVID [N = 104], post COVID [N = 137]). Pre COVID, 40.9% of EMS activated STEMI cases stopped in the ED prior to the Cath Lab, 97.1% during the COVID era, and 51.1% in the post-COVID era (p&lt;0.0001 between pre COVID and COVID era). The median door to device time was increased from 32.5 (15-75 total range) 39 (18-122) min p= 0.042. The time from symptom onset to device placement was increased from 140 (63-806) to 170 (63-934) min p=0.0054. The time from 1 st positive EKG to device time was increased from 80 (32-157) to 94 (43-197) min p=0.046. The first medical contact to device, 911 call to device, and symptoms onset to 911 call times during COVID era showed increasing trend as compared to pre-COVID times but were not statistically significant. The unadjusted In-hospital mortality rates for EMS identified STEMI during the pre-COVID era, COVID era, and post-COVID era were 6.1%, 8.7%, and 7.3%, respectively (p=ns). Most times metrics returned to the pre-COVID levels in the post-COVID phase. Conclusion: In the rural setting, EMS activated STEMI patients had longer times to reperfusion during the COVID-19 era as compared to pre COVID due to the stop at the ED. The delayed reperfusion did not significantly reflect in in-hospital mortality, likely due to low number of events. Larger cohort multi-center studies on this issue is warranted.
Abstract 4141937: Long Noncoding RNA SNRKAS as a SNRK Inhibitor Triggers Endothelium Senescence
Authors: Qiulun Lu, Sanjiv Shrestha, Ping Song
Journal: Circulation (2024)

Background: Although sucrose non-fermenting 1-related kinase (SNRK) in endothelial cells (EC) has a critical role in anti-inflammation and anti-fibrosis in the kidney, whether SNRK controls EC senescence and vascular aging, and how SNRK is regulated have never been studied. Long noncoding RNAs (lncRNAs) are involved in endothelial function and are altered during aging and in response to various senescence stimuli. However, whether lncRNA controls SNRK protein levels, which regulate EC senescence and cardiovascular diseases (CVD), is still poorly understood. Methods: Immunohistochemistry was performed on mouse aortic samples. RNA fluorescence in situ hybridization (RNA-FISH) staining was taken with young and aged arteries. Young and senescent primary human ECs were used for molecular signaling analysis, and SNRK expression was manipulated using plasmid overexpression and depletion. Senescence-associated β-galactosidase (SA-β-gal) staining was performed in vitr o and in vivo . Results: Analyzing the expression of senescence-associated lncRNAs by qRT-PCR in human endothelial cells, we identified a long noncoding antisense (AS) transcript of SNRK, SNRKAS, which was upregulated by forkhead box A2 (FOXA2) activation in senescent human EC in vitro and EC from aged human vessels in vivo . SNRKAS, acting in a cis-regulatory manner, downregulated SNRK expression via RNA-mRNA interaction in EC. The passaging of primary EC and X-ray irradiation (XRI) substantially decreased SNRK protein levels, while elevating SNRKAS levels; SNRK overexpression reversed XRI-induced protein and mRNA upregulation of p16, a cellular senescence marker. Furthermore, SNRK was required for the expression of lamin B1, while negatively regulating the stimulator of interferon genes (STING) signaling in EC. Finally, endothelial SNRK deficiency in mice promoted endothelial senescence, aortic stiffness, and atherogenesis in vivo . Conclusions: We conclude that lncRNA SNRKAS acts as a negative regulator of endothelial senescence via downregulation of SNRK.
Abstract 4141875: Individualized Ablation Strategies Optimize First Pass Isolation and Minimize Pulmonary Vein Reconnection During Atrial Fibrillation Ablation
Authors: Joey Junarta, Jessica Qiu, Austin Cheng, Chirag Barbhaiya, Lior Jankelson, Douglas Holmes, Alexander Kushnir, Robert Knotts, Felix Yang, Scott Bernstein, David Park, Larry Chinitz, Anthony Aizer
Journal: Circulation (2024)

Background: First pass isolation (FPI) improves freedom from AF, while acute pulmonary vein reconnection (PVR) predicts AF recurrence. There is little data to predict FPI or acute PVR based on individual patient characteristics. Height is a risk factor for incident AF and may be associated with AF recurrence after ablation. Hypothesis: We hypothesize that patient-specific factors can predict lack of FPI and acute PVR. If such factors are identified and used to modify ablation strategies, FPI will increase and acute PVR will reduce in those undergoing paroxysmal AF ablation. Methods: Patients were ablated utilizing CARTO3 with THERMOCOOL SMARTTOUCH SF catheters at 50W, 2mm overlapping lesions. A derivation cohort of patients were treated with standard Ablation Index (AI) targets of 450 on anterior and 350 on posterior surfaces. Subsequently, ablation strategies would be modified and outcomes were reassessed. Results: In the derivation cohort, median height (&lt;172cm vs &gt; 172cm) was the strongest predictor of FPI among all variables (age, sex, height, weight, BSA, diabetes, hypertension, sleep apnea, LA size), (B=1.68 p&lt;0.01). When patients were treated with standard AI targets, patients &gt; 172cm had reduced FPI (50/107 [47%] vs 67/99 [68%] p&lt;0.01) and increased acute PVR (24/107 [22%] vs 67/99 [11%] p=0.04) compared to patients &lt;172cm. A subsequent cohort of 56 patients &gt; 172cm were treated with augmented AI targets of 550 on anterior and 350 on posterior surfaces. When compared to patients &gt; 172cm treated with standard AI targets, FPI increased (37/56 [65%] vs 50/107 [47%] p=0.02) and acute PVR decreased (1/56 [2%] vs 24/107 [22%] p&lt;0.01). There was no difference in total procedure time (01:23:31 ± 00:20:07 vs 01:23:39 ± 00:20:05 p=0.98) or FPI time (01:05:10 ± 00:17:52 vs 01:03:01 ± 00:17:10 p=0.51) between groups. Conclusions: Height is associated with a lack of FPI and increased acute PVR. Using AI guided radiofrequency ablation, height-based adjustment of AI targets increase acute FPI and reduce acute PVR without affecting procedure times. Personalized AF ablation strategies optimize acute ablation outcomes.
Abstract 4141954: Laser Ablation to Prevent Coronary Obstruction and Sustain Coronary Access in redo-TAVR: a Feasibility Study
Authors: John Brlansky, Dong Qiu, Ali Azadani
Journal: Circulation (2024)

Introduction: Redo-transcatheter aortic valve replacement (TAVR) is a promising treatment for transcatheter aortic valve degeneration, becoming increasingly relevant with an aging population. In redo-TAVR, the leaflets of the initial (index) transcatheter aortic valve (TAV) are displaced vertically when the second TAV is implanted, creating a cylindrical cage that can impair coronary cannulation and flow. The risk of coronary obstruction after redo-TAVR can reach as high as 20% and is affected by several factors, including the first TAV design, implantation depth, commissural alignment, and choice of the second TAV. Preventing coronary obstruction and maintaining coronary access is essential, especially in young and low-risk patients. Hypothesis: Laser ablation of TAV index leaflets can effectively create openings to prevent coronary obstruction and ensure coronary access in at-risk patients undergoing redo-TAVR. Aim: This study aimed to develop a new leaflet modification strategy using laser ablation to prevent coronary obstruction and facilitate coronary access after redo-TAVR. Methods: To evaluate the feasibility of the leaflet modification technique using laser ablation, initially, a medical-grade ultraviolet laser was used for ablation through pericardial leaflet tissue. Following this intervention, computational fluid dynamics simulations were utilized to assess the efficacy of the resulting perforations in promoting coronary flow after sinus sequestration in redo-TAVR. These simulations played a crucial role in ensuring that these changes would facilitate the restoration of coronary circulation. Results: Laser ablation of pericardium leaflets was successful, demonstrating the feasibility of creating openings in the TAV leaflets (Fig. 1a). Flow simulation results showed that ablation of index valve leaflets can effectively mitigate the flow obstruction caused by sinus sequestration in redo-TAVR, with the extent of restoration dependent on the number and location of the ablated openings (Fig. 1b). Conclusions: Laser ablation could be a viable method for leaflet modification in redo-TAVR, serving as a new tool in interventional procedures.
Abstract 4141918: Kidney and cardiac biomarkers and risk of adverse kidney outcomes in patients with type 2 diabetes and kidney disease, cardiovascular disease, or both
Authors: Finnian Mc Causland, Brian Claggett, Scott Solomon, Nishi Chaturvedi, Dick de Zeeuw, Marcus Malachias, Martina McGrath, John McMurray, Brendon Neuen, Muthiah Vaduganathan, Marc Pfeffer
Journal: Circulation (2024)

Introduction: Kidney (estimated glomerular filtration rate [eGFR] and urine albumin/creatinine ratio [UACR]) and cardiac biomarkers (high-sensitivity troponin T [hsTnT] and N-terminal pro-B-type natriuretic peptide [NT-proBNP] predict cardiovascular (CV) and kidney outcomes in a wide spectrum of patients. However, the discriminatory ability of these biomarkers in isolation and in combination is less clear. Methods: We examined data from participants in the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE) with available baseline measurements (n=5,597). Cox models were fitted to explore the individual and collective discriminative ability of eGFR, log-UACR, log-NT-proBNP, and log-hsTnT with a kidney composite outcome (kidney failure [dialysis or transplant], kidney-related death, sustained doubling of serum creatinine). Subsequently, the combined biomarker model was additionally adjusted for clinical covariates (age, sex, race, BMI, insulin use, baseline BUN, history of stroke, amputation, or heart failure). Discriminatory capacity was assessed by differences in C-statistics. Results: Over a median follow-up of 2.7 years, 344/5,597 (6.1%) participants experienced the kidney composite outcome. At baseline, mean eGFR was 52 ±23 mL/min/1.73m 2 ; median baseline UACR, hsTnT, and NT-proBNP were 300 [62, 914]mg/g, 15 [7, 24]pg/mL and 176 [77, 430]pg/mL, respectively. For the kidney composite outcome, the C-statistic was 0.583 for eGFR alone, 0.622 for NT-proBNP, 0.686 for hsTnT, and 0.842 for UACR. The combined 4-biomarker model C-statistic was 0.847, which increased to 0.865 with the addition of clinical covariates (Table 1). Conclusion: Among participants of ALTITUDE, higher UACR was the most important prognostic biomarker of future adverse kidney events, beyond that of a multivariable clinical model. The addition of eGFR, hsTnT, and NT-proBNP to UACR marginally improved model discrimination, with further improvement by adding clinical variables.