tbuckley/cabot-search huggingface dataset:
Abstract 12421: Clinical Evidence, Electric and Fluid Dynamics Reveal Systolic Volume as the Direct Effector of RV Systolic Impedance Variations: Innovations on CLS Algorithm in Pacing
Authors: Antonella Sabatini, Marco Tomaino
Journal: Circulation (2021)

Background: Dual chamber PM-CLS algorithm, originally conceived as Rate Responsive (RR) algorithm in cardiac pacing, has been recently clinically used beyond RR, by being activated in a selected group of patients (pts) affected by severe recurrent reflex syncope and tilt-induced asystole. PM-CLS is highly effective in reducing recurrences (BIOSync CLS Trial, 2021). Methods: After Biosync Trial, PM-CLS has experienced increasing importance in the scientific community. CLS exhibits peculiar features in the context of a selected group of Neurally Mediated reflex Syncope (NMS) due to different triggers: central or orthostatic. The mechanism of PM-CLS in intrinsic disturbances and extrinsic central and orthostatic triggered NMS are depicted in Fig.1. Discussion: NMS prevalence (# of events ≥ 1, gen. population) is 50%. Only pts with severe clinical presentation may benefit from pacing. CLS functioning as RR provides compensative pacing in pts affected by intrinsic electric disturbance (sinus node disease). In NMS (normal electric conduction system but extrinsic disturbance) CLS can anticipate pacing at appropriate heart rate (HR) at reflex triggering, avoiding abrupt HR drop and preventing asystolic syncope.CLS measures intracardiac systolic Right Ventricle (RV) impedance (Z), after PM pacing/sensing, via subthreshold high-freq. current pulses. Clinical evidence (BIOSync CLS Trial), electric circuits and fluid dynamics reveal systolic volume as the direct effector of RV Systolic Z, bound by inverse proportionality (Fig.1): • Hypovolemia = High Z • Hypervolemia = Low Z Systolic Z variations activate CLS. Conclusions: Cardiac pacing with CLS is also highly effective in reducing recurring syncope. CLS highlights the importance of volemia being the direct effector of RV systolic impedance. Innovative use of PM-CLS could be exploited in other NMS conditions, dysautonomia and heart failure follow-up.
Abstract 12613: Combinatorial Treatment With Epigenetic Modifiers Reduce Endotoxemia-Induced Inflammation in Human Macrophages and Favors Anti-Inflammatory M2 Plasticity
Authors: Narasimman Gurusamy, VINOTH SIGAMANI, SHEEJA RAJASINGH, Rajasingh Johnson
Journal: Circulation (2021)

Introduction: Macrophages are key mediators of the pathogenesis of acute lung injury (ALI). During ALI, lung macrophages shift into the M1 phenotype and induce severe inflammatory responses and lung tissue damage. Recently, we have shown that pan inhibition of DNA methyl transferase (DNMT) and histone deacetylase (HDAC) abrogated the inflammation and protected the mice from endotoxemia-induced ALI. Hypothesis: We hypothesize that the treatment with a combination of DNMT1-specific inhibitor, procainamide (PRO) and HDAC6-specific inhibitor, tubastatin A (TBA) attenuates lipopolysaccharide (LPS)-induced inflammation in human macrophages via polarization of macrophages towards anti-inflammatory M2 phenotype. Methods &amp; Results: Human macrophage cell line (THP-1) was employed in this study. RNA sequencing analysis has identified a significant reduction in the mRNA expression of a panel of pro-inflammatory genes by PRO+TBA treatment in LPS-induced macrophages, and these results were validated and confirmed by qRT-PCR for the expression of TNFα and IL1β. The expression of pro-inflammatory genes IL1β, TNFα and M1 macrophage marker CD80 was significantly decreased (studied by various analysis) by PRO+TBA treatment at 24 hrs after in LPS challenged macrophages, compared to untreated or treated with either PRO alone or TBA alone (Fig. 1 and 2). On the other hand, the expression of anti-inflammatory gene TSG6 and M2 macrophage marker CD206 were significantly increased by PRO+TBA treatment at 72 hrs after LPS challenged macrophages, compared to untreated or treated with either PRO alone or TBA alone (Fig. 2). Conclusions: Our results have clearly demonstrated that the combined PRO+TBA treatment significantly reduced the expression of pro-inflammatory genes and M1 phenotype marker; and increased the expression of anti-inflammatory genes and M2 phenotype marker in human macrophages challenged with LPS.
Optimizing Treatment Approaches for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Authors: Jennifer R. Brown
Journal: Journal of the National Comprehensive Cancer Network (2021)

The choice of therapy for chronic lymphocytic leukemia (newly diagnosed as well as relapsed/refractory disease) depends on the disease (presence or absence of del(17p) or TP53 mutation) and patient characteristics (age, comorbidities, functional status and patient preference). Many patients can choose between continuous treatment with a Bruton’s tyrosine kinase (BTK) inhibitor or time-limited therapy with venetoclax/obinutuzumab. For patients with 17p deletions, the data support the use of continuous treatment with a BTK inhibitor, although these patients should also be referred to clinical trials evaluating novel combination therapy options with minimal residual disease monitoring. The choice of therapy for relapsed disease also depends on prior therapy and duration of response to prior therapy in addition to the disease and patient characteristics (as mentioned earlier). BTK inhibitor– or venetoclax-based regimens are recommended for patients experiencing relapse following chemoimmunotherapy. In the case of disease relapse following BTK inhibitor therapy, prospective data are available only for venetoclax-based regimens, whereas disease relapse (after a period of durable remission) following time-limited therapy with venetoclax-based regimens can be managed through re-treatment with venetoclax or a BTK inhibitor.
Abstract 9883: Outcomes of Cardiac Arrest Hospitalizations in Obese Patients with vs. without Prior Bariatric Surgery Status: A Nationwide Propensity-Score Matched Analysis
Authors: Zainab J Gandhi, Geethu Jnaneswaran, Athul Raj Raju, Waleed Sultan, Charu Agarwal, Gaurav Mudgal, Vivek Joseph Varughese, Abhimanyu Ravalani, Rupak Desai
Journal: Circulation (2021)

Introduction: Prior bariatric surgery (PBS) in obese patients curtail the risk of future cardiovascular diseases, but its role in outcomes of obese patients developing new acute cardiac events remains largely unknown. We assessed the outcomes of cardiac arrest (CA) by the effect of bariatric surgery on obese patients. Methods: Hospitalizations among adult obese patients with CA were identified using the National Inpatient Sample (2015October-2017). Propensity-matched analysis (1:1) was performed for sociodemographic/hospital characteristics to identify two cohorts, with (PBS+) or without (PBS-) status. The primary endpoint was in-hospital mortality and the secondary endpoint was healthcare resource utilization. Results: Propensity matched obese cohorts admitted for CA, PBS+ vs PBS- (n=1275 each), had patients with comparable age (mean 58 years), with a higher frequency of white (&gt;70%), females (&gt;60%), and Medicare enrollees (&gt;40%). PBS+ cohort had lower rates of diabetes (27.8% vs 36.1%), hyperlipidemia (33.7% vs 48.6%), renal failure (17.3% vs 22.0%), chronic pulmonary disease (11.8% vs 21.2%) and higher rates of anemias (18.4% vs 12.2%), liver disease (5.1% vs 2.4%) and alcohol abuse (6.7% vs 2.4%) vs. PBS- cohort (p&lt;0.05). Despite a lower burden of cardiovascular disease (CVD) risk factors in the PBS+ group, there was no significant difference in all-cause mortality (46.3% vs 45.1%, p=0.551) between the two cohorts (Table 1) . The PBS+ cohort was less often transferred routinely and had a shorter hospital stay with equivalent hospital charges compared to the PBS- cohort (p&lt;0.001). Conclusions: This propensity-matched analysis showed that the prior bariatric surgery status (irrespective of timeframe) did not improve the survival in CA admissions among obese patients. Preventive strides are warranted to control persistent CVD risk factors that could hinder the benefits of surgery in obese patients and worsen outcomes of future cardiac events.
Abstract 10111: How Do Patients with Heart Failure Perceive Their Symptoms?
Authors: Solim Lee, Amy Nolan, Julie Guerin, Brittany Koons, Lea Ann Matura, Corrine Y Jurgens, Victoria V Dickson, Barbara Riegel
Journal: Circulation (2021)

Effective symptom perception may prevent unplanned hospitalizations. However, patients with heart failure (HF) often face challenges that interfere with symptom perception. Little is known about how patients perceive their HF symptoms. Aim: To describe how patients with HF perceive symptoms through the processes of monitoring, awareness, and evaluation. Methods: Using a qualitative descriptive design, we conducted semi-structured in-person interviews with a purposeful sample of adults experiencing an unplanned hospitalization for a HF symptom exacerbation. We elicited how patients monitor, become aware of, and evaluate symptoms prior to hospitalization. Data were analyzed using directed qualitative content analysis. We identified symptom monitoring behaviors, types of symptoms experienced, and success or failure in linking the symptoms to HF. Categories/subcategories were developed by grouping codes based on similarities and differences. Themes were conceptualized at a higher level of abstraction by combining categories. Results: A sample of 40 patients (mean age 62 years, 50% male, median HF duration 6 years, 95% HF stage C/D) was enrolled. Patients demonstrated Body listening , which was the use of active and individualized symptom monitoring tactics that involved observing for bodily changes outside one’s usual range. Trajectory of bodily change involved the patterns or characteristics of bodily changes as they became apparent. Three subthemes— sudden and stunning change , gradual change , and fluctuating change emerged as different Trajectories of bodily changes were identified. The same types of bodily changes could develop in different trajectories. Patients simultaneously experienced all or some of the trajectory types of various symptoms. Patients evaluated symptoms through an Exclusionary process , sequentially attributing symptoms to a cause through a cognitive process of excluding possible causes until the most plausible cause remained. Conclusion: Three major themes emerged from an in-depth description of the complex symptom perception processes of monitoring, awareness, and evaluation. Identifying where patients have difficulties in symptom perception will facilitate the development of tailored interventions.
Trends in Transcatheter and Surgical Aortic Valve Replacement Among Older Adults in the United States
Authors: Makoto Mori, Aakriti Gupta, Yun Wang, Torsten Vahl, Tamim Nazif, Ajay J Kirtane, Isaac George, Celina M Yong, Oyere Onuma, Susheel Kodali, Arnar Geirsson, Martin B Leon, Harlan M Krumholz
Journal: Journal of the American College of Cardiology (2021)
Abstract 11621: Effect of Genotype Guided Oral P2y12 Inhibitor Selection After Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis of Randomized Clinical Trials
Authors: Rahul Gupta, aaqib malik, Abhishek Chaturvedi, Sandipan Chakraborty, pranav mahajan, Sanjay Mehta, Wilbert S Aronow, Apurva Vyas, Nainesh Patel, HASAN AHMAD
Journal: Circulation (2021)

Introduction: Clopidogrel is the most frequently used P2Y12 inhibitor as a component of the dual antiplatelet regimen in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Prior studies have shown the variable efficacy of clopidogrel due to genotypic differences in the CYP2C19 enzyme function, which converts clopidogrel to its active metabolite. Hypothesis: The aim of this meta-analysis is to evaluate the effectiveness of genotype testing-guided P2Y12 inhibitor prescription therapy to patients after PCI for ACS compared to non-genotype guided conventional treatment. Methods: A comprehensive literature search was performed in PubMed, Embase, and Cochrane to identify relevant trials. Summary effects were calculated using a DerSimonian and Laird random-effects model as odds ratio with 95% confidence intervals for all the clinical endpoints. Results: Seven studies with 9617 patients were included. Genotype-guided strategy arm included prasugrel or ticagrelor prescription to patients with loss of function (LOF) of CYP219 alleles (most commonly alleles being *2 and *3) and clopidogrel prescription to those without the LOF allele. The conventional arm included patients treated with clopidogrel without genotype testing. Comparison of genotype arm with conventional arm showed decreased major adverse cardiovascular events (MACE) (RR 0.72, 95% CI 0.55-0.95; p=0.02, I 2 =23), improved cardiovascular (CV) mortality (RR 0.62, 95% CI 0.43-0.90; p=0.01, I 2 =0) and reduced incidence of myocardial infarction (MI) (RR 0.57, 95% CI 0.41-0.97; p&lt; 0.01), and a similar stroke incidence (RR 0.65, 95% CI 0.35-1.21; p= 0.18). Regarding adverse events, the incidence of stent thrombosis was lower in the genotype arm than the conventional arm (RR 0.52, 95% CI 0.28-0.96; p=0.04). Conclusions: Our analysis illustrates the possible advantages of genotype-guided P2Y12 inhibitor prescription strategy compared to non-genotype-guided strategy with reductions in MACE, CV mortality, MI, and stent thrombosis. This analysis can be used as a stepping stone to conducting further trials determining the efficacy of this treatment strategy in various ACS subtypes.
Abstract 10590: Trends in Major Adverse Cardiac Events During the Covid-19 Pandemic in Alberta, Canada
Authors: Erin S Mackinnon, Todd J Anderson, Paolo Raggi, Jean C Gregoire, RAJVI J WANI, Millicent Packalen, Thiago Oliveira, Shirley Li, Suzanne McMullen, Tara Cowling, Shaun G Goodman
Journal: Circulation (2021)

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has impacted cardiovascular (CV) outcomes and care globally, although to date, limited data exist on the Canadian experience. This study aimed to describe trends in major adverse cardiovascular events (MACE)/procedures during the COVID-19 pandemic in the Province of Alberta, Canada. Methods: A repeated cross-sectional study design compared MACE from inpatient and emergency department visits among Albertan adults between March 15, 2019, and September 14, 2020. The Alberta population was 4.4 million in 2020 and all residents are part of a single payer healthcare system. The percent change between each MACE reported in the control (2019) and COVID-19 restriction periods (2020) were calculated. MACE were defined individually and as a primary composite outcome (CV death, acute coronary syndrome [ACS], ischemic stroke, or coronary revascularization procedures). These preliminary data are part of an ongoing study, measuring outcomes throughout the first year of the pandemic. Results: Compared to March-June 2019, primary MACE during the initial COVID-19 restriction period (March-June 2020) decreased by 15.6% (n=739 patients), and by 7.3% (n=342 patients) during June-September 2020, when COVID-19 restrictions were eased. Most individual MACE followed similar patterns with reduced reported events/procedures during the initial restriction period and an increase towards previous rates thereafter (Figure 1): CV death (17.7% vs 10.2%), ACS (19.1% vs 8.4%), coronary revascularization (17.0% vs 9.2%). The exception was ischemic stroke, which was not notably impacted by pandemic restrictions. Conclusions: Declines in MACE/procedures during the COVID-19 pandemic are suggestive of a substantial gap in patient management and healthcare-seeking behaviour that may have negative downstream implications. Ongoing analyses will further explore reported MACE up to one year after the pandemic began.
PATH-01. SMALL RNASEQ ANALYSIS OF MICRORNAS IN BRAIN METASTASIS
Authors: Radim Jancalek, Frantisek Siegl, Jiri Sana, Marek Vecera, Karolina Trachtova, Michal Hendrych, Vaclav Vybihal, Martin Smrcka, Marketa Hermanova, Tomas Kazda, Ondrej Slaby
Journal: Neuro-Oncology (2021)

Abstract MicroRNAs (miRNAs) are a well-known subclass of short non-coding RNAs responsible for posttranscriptional gene silencing and have been described as dysregulated in many cancers. They have also been shown to be both specific diagnostic, prognostic, and predictive biomarkers as well as therapeutic targets. Therefore, specific miRNA expression patterns of BMs of various origins could serve as a promising diagnostic tool for determining both the original tumor and the prognosis in patients with BMs of unknown origin. For identifying significantly dysregulated miRNAs among BMs (n=90) with various origin and non-tumor brain tissues (n=12), small RNAseq analyses were used. cDNA libraries were prepared using QIAseq miRNA Library Kit and purified by Qiaseq beads. The final sequencing analyses were performed by Next 500/550 High Output v2 Kit-75 cycles using the NextSeq 500 instrument. For miRNA mapping and analysis, Miraligner and MirBase were used. Bioinformatic analysis of obtained sequencing data identified 472 significantly dysregulated miRNAs (logFc &amp;gt;2, adj.p-value&amp;lt; 0.05) between BM and non-tumor samples. The comparison of BMs origin from lung BMs (n = 26) with other BMs revealed 132 significantly dysregulated miRNAs, mainly miR-4662a-5p, miR-1179, miR-211-5p, miR-146a-5p, and miR-194-5p. The most significantly dysregulated miRNAs in breast BMs were miR-4728-3p, miR-211-5p, miR-184, miR-365b-5p, and miR-2115-3p. In BMs originating from melanoma, miR-200c-3p, miR-141-5p, miR-200b-5p, miR-514a-3p, and miR-200b-3p showed the most aberrant expression. We have demonstrated that miRNA profiling could be a potent tool for the partition of brain metastases based on their origin. We found that miRNA signatures corresponding to particular origins are rather distinct from the profiles of the rest of BMs. Our results suggest that after validation, miRNA profiling can be used to identify the origin of brain metastases and potentially for the refinement of the diagnosis. Supported by the Ministry of Health of the Czech Republic, grant nr. NV18-03-00398.
Abstract 12635: Mitochondria-Targeted NOX4 Overexpression Causes Restrictive Diastolic Dysfunction in a “Two-Hit” Mouse Model of HFpEF
Authors: Andrey Lozhkin, Aleksandr E Vendrov, Marschall S Runge, Nageswara R Madamanchi
Journal: Circulation (2021)

Heart failure with preserved ejection fraction (HFpEF) prevalence increases with age. However, the pathophysiologic mechanisms of HFpEF are unknown and no specific treatment is available. NOX4 NADPH oxidase levels, particularly in mitochondria, increase with age and induce mitochondrial dysfunction. We previously showed that diastolic dysfunction patients’ hearts had higher NOX4, ROS levels and mitochondrial damage whereas mice with mitochondria-targeted NOX4 overexpression ( Nox4 TG) had impaired mitochondrial function and pronounced diastolic dysfunction. Here we investigated the effects of increased mitochondrial NOX4 levels on the pathophysiology of HFpEF using Nox4 TG mice in a “two-hit” model. The “two-hit” mouse HFpEF model is a combination of metabolic stress from high-fat diet and dysregulation of NO after treatment with L-NAME. Compared to wild-type, Nox4 TG mice had significantly lower ATP-linked and maximal oxygen consumption rates in ventricular cardiomyocytes and showed a trend towards reduced exercise tolerance. Echocardiography analysis showed that both strains in “two-hit” model had increased E/E' versus controls, whereas Nox4 TG mice had significantly prolonged isovolumic relaxation and mitral valve deceleration time. In addition, NOX4 overexpression significantly reduced cardiac output, suggesting restrictive diastolic dysfunction. MCP1 expression was significantly higher in left ventricle (LV) lysates and the percentage of CD11b + cells was higher in LV sections of Nox4 TG mice. Myocardium flow cytometry analysis showed higher percentage of Ly6C hi macrophages with elevated TNFα expression in Nox4 TG mice. TGFβ1 and osteopontin expression was also higher in the LV lysates. Picrosirius red and collagen I staining showed increased interstitial fibrosis in Nox4 TG mice as in LV sections of patients with diastolic dysfunction. Congruently, percentage of periostin + and ACTA2 + cells was significantly higher in Nox4 TG mice, recapitulating findings in human LV sections. Together, our data show that mitochondrial dysfunction leads to restrictive diastolic dysfunction through inflammation and fibrosis, suggesting that preserving mitochondrial function in aging is a potential therapeutic strategy for HFpEF.
Abstract 9347: Biomarker-Based Risk Prediction of Adverse Outcomes in Double Valve Surgery
Authors: Yi Kei Stephanie Tse, Si-Yeung Yu, Hang Long Li, Meizhen Wu, Qingwen Ren, Shuk Yin Yu, Pui Fai Wong, Lok Yee Jane Lam, Kwan Yu LI, Ka Lam Calvin Leung, Hung Fat Tse, Kai Hang Yiu
Journal: Circulation (2021)

Introduction: Current strategies for risk assessment in patients undergoing double valve surgery are limited by suboptimal performance and a narrow focus on only symptoms and left ventricular performance. Hypothesis: We hypothesized that the application of a biomarker-based risk score would improve prognostication in patients undergoing double valve surgery. Methods: Between 2012 and 2020, 131 consecutive patients (age 64±8 years, 50% female) presenting for concomitant aortic and mitral valve surgery were prospectively included in the study. Based on optimal cut-offs derived from the Youden index, we developed an integer-based biomarker score: hsTnT ≥26pg/ml, NT-proBNP ≥258ng/ml, GDF-15 ≥290ng/ml, and galectin-3 ≥22pg/ml, with one point for each abnormal parameter. The rates of adverse outcomes (composite of all-cause mortality and heart failure [HF] hospitalization) were compared across biomarker score groups (0 to 4) using Cox proportional hazards analysis. The independent and incremental value of the biomarkers to EuroSCORE II was evaluated using Harrell’s C -statistics, continuous net reclassification improvement (cNRI), and integrated discrimination improvement (IDI). Results: Over a median follow-up of 3.8 years, 37 adverse events (23 HF hospitalizations and 14 deaths) occurred. Each biomarker result was independently associated with long-term adverse outcomes after adjustment for HF and EuroSCORE II (p&lt;0.05 for each). The biomarker score demonstrated good discrimination (C-statistic: 0.75, p&lt;0.01) and calibration (Wald χ 2 = 0.48, p=0.49). The rates of adverse events increased in a graded fashion with an increasing biomarker score, whereby a score of 1-2, 3, and 4 conferred a 3-, 7- and 19-fold increased risk of adverse outcomes, respectively. When the four biomarkers were added to EuroSCORE II, the C -Statistic improved from 0.70 to 0.78 (p&lt;0.01); significant cNRI (0.66, 95% CI 0.27-1.03, p&lt;0.01) and IDI (0.09, 95% CI 0.03-0.15, p&lt;0.01) were also observed. Conclusions: In patients undergoing double valve surgery, a novel biomarker-testing strategy comprising hsTnT, NT-proBNP, GDF-15, and galectin-3 may improve risk assessment beyond conventional risk-scoring systems.