tbuckley/cabot-search huggingface dataset:
Abstract 12838: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) and m.3243A&gt;G Mutations Have Higher Prevalence of Wolff-Parkinson-White Syndrome
Authors: Jia Yue Liu, mohammed T Numan, Mary Kay Koenig
Journal: Circulation (2023)

Background: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the most common mitochondrial disorders. Cardiovascular involvement has been reported in up to 30% of MELAS patients with varying clinical presentations from non-specific cardiogenic abnormalities to conduction abnormalities, cardiomyopathies, heart failure, fatal arrhythmias and cardiac death. Although conduction defects are a known complication, the frequency of Wolff-Parkinson-White (WPW) Syndrome among MELAS patients and mutations associated with MELAS is uncertain, and their association with cardiomyopathy and treatment outcomes have rarely been reported. Methods: A retrospective chart review of 50 MELAS patients from January 2007 to December 2022 from the Neuroscience Institute at University of Texas Houston was conducted. Medical histories, genetic testing, electrocardiograms, echocardiograms, and electrophysiology studies were reviewed. Results: 43 patients were included (mean age 23.8, median age 18.5, range 2-58). Eight of 43 patients with MELAS (20 %), inclusive of one of 3 patients with m.4317A&gt;G (33.3%) and seven of 40 patients with m.3243A&gt;G variants had electrocardiographic findings consistent with WPW. Other conduction abnormalities were noted in ten of 20 patients (50%) with m.3243A&gt;G with neurological involvement and six of 20 patients (30%) with m.3243A&gt;G mutation without strokes. Four patients required electrophysiology studies with ablation (mean age 8.5, range 7-10), one for inappropriate sinus tachycardia resistant to several medications, and three patients with WPW syndrome all of whom required repeat ablations. Conduction abnormalities had a positive correlation with higher heteroplasmy levels (mean 35 % vs 51%, 95% CI -30.2 to -2.88, p=0.019). Six patients with MELAS had cardiomyopathy of varying severity which were all associated with conduction abnormalities, including two patients with WPW syndrome (p=0.014). Conclusion: The prevalence of WPW in patients with MELAS syndrome and the m.3243A&gt;G variant appears much higher than in the normal population and may require multiple electrophysiology studies ablations to treat. Routine cardiology screening is recommended for early detection.
Abstract 12379: AT1-AA (Angiotensin II Type 1 Receptor Autoantibody) Aggravates Abdominal Aortic Aneurysm Through Activating AT1R/Gq Allosterically
Authors: Xi Zhang, Suli Zhang, Meili Wang, Huirong Liu
Journal: Circulation (2023)

Background: Angiotensin II type 1 receptor (AT1R) is a key mediator of the rennin-angiotensin-aldosterone system (RAAS). Autoantibodies against AT1R (AT1-AA), as an activator of AT1R, was found in abdominal aortic aneurysm (AAA) related diseases, such as hypertension and atherosclerosis. However, the role of AT1-AA in AAA is still unclear. Methods: We used angiotensin II (AngII)-infused male ApoE -/- mice model of AAA. Ultrasonography measurement, histological assessment, western blot, qRT-PCR and RNA sequencing were used to assess the severity of AAA. Nanoluciferase-based bioluminescence resonance energy transfer (NanoBRET) assay, radio assay of receptors and homogeneous time resolved fluorescence (HTRF) were used to measure the activation feature of AT1R and the affinity of AT1R with AT1-AA or AngII. Results: AT1-AA increased the incidence of AAA (vehicle vs. AT1-AA: 47% vs. 81%; P&lt;0.05), which can be attenuated by AT1R blocker Candesartan. Furthermore, AT1-AA greatly increased severity of AAA, due to augmenting the diameter of abdominal aorta and the degradation of elastin by enhancing the expression of MMP2/9 (matrix metalloproteinase) and the accumulation of inflammatory cells. And AT1-AA could induce phenotypic switch of smooth muscle cells. But AT1-AA does not increase the plasma level of AngII. Mechanically, AT1-AA enhanced AngII-induced recruitment of Gq, but not β-arrestin1/2. AT1-AA potentiated the AngII-mediated Gq-dependent inositol phosphate (EC50 shift=3.829 nM) and the activation of PKC and ERK1/2. The responses were abolished by AT1R blocker and Gq inhibitor. The affinity of AT1-AA for the AT1R in cells was calculated to be 75.49 ± 4.7 nM. AT1-AA cannot compete for the binding of AngII to AT1R. However, AT1-AA significantly potentiated the binding of AngII with AT1R allosterically (mean K D ± SEM: 34.11 ± 0.9765 nM at 0 nM AT1-AA vs. 25.63 ± 1.826 nM at 100 nM AT1-AA; p&lt;0.05), without altering the maximum binding. Conclusion: AT1-AA, as an allosteric activator of AT1R, promotes AAA through increasing the affinity of AngII with AT1R and activating Gq biasedly.
Abstract 12726: Novel, Potent, and Highly Selective Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Inhibitors Reduce Substrate Phosphorylation in Rat Hearts and Prolong Survival in a Mouse Model of Severe Heart Failure
Authors: Shuichi Takagahara, Mioko Harada, Mari Asada, Masataka Harada, Masao Hirakata, Howard K Surks, Michael Mendelsohn, Shota Ikeda
Journal: Circulation (2023)

Introduction: CaMKII is a target of longstanding interest in drug development and has been validated in multiple preclinical models of heart failure, as well as in arrhythmia diseases, including catecholaminergic polymorphic ventricular tachycardia and atrial fibrillation. We describe here the pharmacological profiles of a novel oral CaMKII inhibitor, CRD-2015. We demonstrate the ability of CRD-2015 to reduce substrate phosphorylation in rat hearts, and to strongly prolong survival in the calsequestrin transgenic (CSQ-Tg) mouse model of severe heart failure. Results: CRD-2015 is a potent (IC 50 0.62nM), highly selective CaMKII inhibitor. Oral administration of CRD-2015 dose-dependently decreased phospholamban (P-PLN) and ryanodine receptor 2 (P-RyR2) phosphorylation at their CaMKII-specific sites (Thr17 and Ser2814, respectively) in normal rat hearts, with strong correlation between the plasma concentrations (PK) and the reduction in phosphorylation (PD) (Figure, A). In CSQ-Tg mice, CRD-2015 also decreased cardiac P-PLN and P-RyR2 in a dose-dependent manner. Chronic administration of CRD-2015 prolonged survival in a dose-dependent manner (Figure, B). At the maximum dose level, all CSQ-Tg mice survived for 27 days (n=15/15) with the treatment of CRD-2015, while no mice survived past 24 days in the vehicle-treated group (n=0/15). Similar dose and concentration-dependent reductions in P-PLN and P-RyR2 and prolongation of survival in CSQ-Tg mice were also detected with a second potent (IC 50 0.40nM) and selective CaMKII inhibitor, CRD-2959. Conclusions: Our novel CaMKII inhibitor, CRD-2015 shows a clear PK/PD relationship in normal rats and prolongs survival in a mouse model of severe heart failure. These results demonstrate the successful creation of specific CaMKII inhibitors with efficacy in preclinical models and support their clinical development for the treatment of heart failure and other cardiovascular diseases.
Abstract 12670: Trends in Patients With COVID-19 and Device Related Infections: A National Inpatient Sample Trend From 2020
Authors: Bruce Ferraro, Spandan Desai, Nicholas Roma, Vivek Modi, Darren Traub
Journal: Circulation (2023)

Background: Cardiac implantable electronic devices (CIED) are essential for managing arrhythmias, improving hemodynamics, and preventing sudden cardiac death. However, device-related infections (DRI) remain a significant complication of CIED and are associated with primary adverse outcomes. However, limited data exists on concomitant Covid-19 infection and its effects on outcomes of DRI. Methods: National Inpatient Sample 2020 was used to identify patients hospitalized for DRI based on ICD-10 codes. DRIs were further stratified into concomitant Covid-19 infected patients and non-Covid-19 infected groups. Logistic regression was used to compare in-hospital outcomes. Results: In 2020, there were 59,270 admissions for DRIs. 1,890 (3.2%) DRI cases were observed to have concomitant Covid-19 infection. Racial disparities observed included higher rates of DRI and concurrent Covid-19 infection in the African American (30.6% -vs- 20.2, p=0.002) and Hispanic (18.2% -vs- 9.4%, p=0.002) population. Lead extraction rates were lower in the Covid-19 infection with DRI group (5.33% -vs- 11.17%, p&lt;0.001). Cases with DRI and concurrent Covid-19 infection also had a significantly longer length of stay (LOS, 21.6 -vs- 11.5 days, p&lt;0.001), higher total hospital cost (305,644 -vs- 172,711, p&lt;0.001), and higher mortality (23.1% -vs- 6.6%, p&lt;0.001). This group was also observed to have increased needs for ICU level of care including higher proportion of ARDS, shock, mechanical ventilation and vasopressor use as listed in Table 1. Conclusion: DRIs with concurrent Covid-19 infection had higher all-cause mortality, complication rates, LOS and total hospital costs. Further research needs to be performed to delineate long-term outcomes in this patient population.
Abstract 12323: Cardiovascular Mortality Prediction Depends on the Time Point of Blood Pressure Measurement Rather Than on the Use of European versus US Blood Pressure Categorizations
Authors: Andreas Leiherer, Wolfgang Brozek, Axel Muendlein, Hanno Ulmer, Christoph H Saely, Thomas Plattner, Alexander Vonbank, Arthur Mader, Lukas Sprenger, Maximilian Maechler, Barbara Larcher, Peter Fraunberger, Gabriele Nagel, Emanuel Zitt, Heinz Drexel, Hans Concin
Journal: Circulation (2023)

Introduction: Blood pressure (BP) is a predictor of cardiovascular risk but it changes during lifetime. Hypothesis: We hypothesize that there are differences in the value of systolic and diastolic blood pressure (BP) at different stages of life for predicting cardiovascular mortality risk, an issue which was addressed in this observation study (OS). Methods: At the baseline of the OS, BP was measured in 1497 cardiovascular disease patients at a median age of 65 years, and their outcome was recorded over 21 years. Fifteen years prior to the OS, the identical patients had participated in a health survey (HS) comprising BP measurement. The value of earlier (HS) vs. recent (OS) BP measurements for risk prediction was addressed using both guideline-defined BP categorizations from Europe (ESC/ESH) and the US (ACC/AHA). Results: BP at HS was a significantly better predictor of cardiovascular mortality than BP at OS (NRIESC/ESH=0.29, p&lt;0.001; NRIACC/AHA=0.30, p&lt;0.001). Each 10mm Hg increase was significantly positively associated with cardiovascular mortality for both systolic and diastolic blood pressure (HR=1.17 [1.11-1.23] and 1.20 [1.09-1.32], respectively) when measured at HS. In contrast, regarding systolic BP recorded at OS, the significant association with cardiovascular mortality (HR=1.04 [0.98-1.10]) was abrogated, and with diastolic BP the association has reversed (HR=0.82 [0.74-0.92]. In contrast, ESC/ESH and ACC/AHA BP categorizations were comparably valuable predicting cardiovascular mortality (NRIHS=0.04, p=0.563; NRIOS=0.02, p=0.817). Conclusions: Irrespective of categorization differences between European and US BP guidelines, earlier-in-life BP readings are valuable risk predictors for cardiovascular mortality and they outperform BP readings done at a more advanced age.
Abstract 12253: Occludin as a Key Mediator in Adiponectin-Mediated Diabetic Vascular Protection
Authors: Yanru Duan, Yunhui Du
Journal: Circulation (2023)

Background: APN exerts its vascular protective effects through APPL1. However, the downstream target genes that mediate the protective effects of this signaling axis on diabetic vascular endothelium remain unclear. Methods and Results: APPL1knock-out mice were fed normal or high-fat-diet (HFD) for 10 weeks. 8 weeks after HFD, mice were randomized to receive vehicle or APN treatment for another two weeks. Aortic vessels were prepared for transcriptome analysis. Bioinformatics analysis indicates that the Tight Junction (TJ) pathway exhibited the most prominent changes. Using a global signaling transduction network showed that TJ-related genes had the highest degree values. Among these genes, PCR results indicated that Occludin was the sole gene inhibited in endothelial cells treated by HG/HL and promoted by APN treatment in an APPL1-dependent manner. The protein level of Occludin was reduced in diabetic condition, and APN treatment upregulated the expression of Occludin in APPL1-mediated manner in vivo and vitro. Endothelial specific OCLN knockdown blunted APN-mediated blood flow recovery after femoral artery ligation in vivo , and abolished APN’s effects upon HG/HL-induced permeability, and apoptosis in vitro . Mechanically, transcription factor expression and activity assay kits, and mass spectrometry techniques were employed to identify transcription factors involved in mediating the APN/APPL1 signaling axis. Through a comprehensive analysis, we discovered MYB, HDAC1, and FOXO1 play a role in the regulation of Occludin. This finding was validated by CHIP-QPCR. Western blot analysis revealed that the APN-induced increase in Occludin protein level was abolished after knockdown of MYB and FOXO1. However, knockdown of HDAC1 in endothelial cells did not alter the expression of Occludin mediated by APN. Finally, CHIP-qPCR showed that both MYB and FOXO1 participate in the enrichment of Occludin promoters mediated by APN. Conclusion: Our findings firstly indicate that the APN/APPL1 signaling axis promotes the expression of Occludin through MYB and FOXO1, ultimately exerting a protective effect on vascular endothelium.
Abstract 13950: Real-World Effectiveness and Safety of Evinacumab in Pediatric and Adult Patients With Homozygous Familial Hypercholesterolemia: A Multi-Site US Perspective
Authors: Michael J Wilkinson, Priyesha Bijlani, Michael H Davidson, P B Duell, Mary Horan, Mary J Malloy, Ron Newfield, Pallavi Pradeep, Colleen Sam, Prediman K Shah, Eveline O Stock, Bruce Warden, Matthew K Ito
Journal: Circulation (2023)

Introduction: Homozygous familial hypercholesterolemia (HoFH) is an autosomal co-dominant disorder characterized by extreme elevations in LDL-C and early onset ASCVD. Unfortunately, patients with HoFH generally experience poor LDL-C lowering with standard lipid-lowering therapy and rarely achieve LDL-C goals. Evinacumab is a monoclonal antibody administered by monthly IV infusion that binds angiopoietin-like 3 and when added to standard lipid-lowering therapies lowers LDL-C by ~50% in clinical trials involving patients with HoFH. Real-world effectiveness and safety of evinacumab is unknown. Methods: We performed retrospective chart review to assess effectiveness and safety of evinacumab in patients with HoFH in clinical practice at six US academic medical centers. The primary efficacy endpoint was the percent change in LDL-C from baseline to first follow-up and to most recent follow-up after evinacumab initiation. Secondary efficacy endpoints were percent change in non-HDL-C, triglycerides, total cholesterol, HDL-C, and achievement of an LDL-C &lt;70 mg/dL. Adverse events were recorded. Results: Twenty-four patients (mean age 38 yrs; range 5-75) with HoFH were followed for a median of 63 weeks. Fifty percent were female, 66.7% had ASCVD, 87.5% were on a statin, 83.3% on ezetimibe, 66.7% on a PCSK9i, 24% on lomitapide, and 33.3% were undergoing lipoprotein apheresis. Significant reductions in LDL-C, non-HDL-C, total cholesterol, triglycerides, and HDL-C were observed both at first follow-up (4 weeks) and most recent follow-up (63 weeks) (p &lt; 0.001 for all) (Table). Significantly more patients achieved LDL-C &lt;70 mg/dL after evinacumab was added. No serious adverse events occurred and evinacumab was generally well-tolerated. Conclusions: Across six US academic medical centers, evinacumab was generally well-tolerated by patients with HoFH and lowered LDL-C by ~50%, consistent with results from clinical trials.
Abstract 12019: The Psychometric Performance of the Kansas City Cardiomyopathy Questionnaire-12 in Symptomatic Obstructive Hypertrophic Cardiomyopathy
Authors: Andrew J Sauer, Charles F Sherrod, Kensey L Gosch, Suzanne V Arnold, Matthew Reaney, Yue Zhong, Jenny Lam, Kathleen W Wyrwich, John A Spertus
Journal: Circulation (2023)

Background: A treatment goal for obstructive hypertrophic cardiomyopathy (oHCM) is to reduce symptom burden and improve health status, which can be measured with the 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ-23). While the KCCQ-23 has been validated in oHCM, the shorter 12-item version (KCCQ-12) is more feasible in clinical care but has not been validated. Hypothesis: The construct validity, reliability, and responsiveness of the KCCQ-12 will support its use for patients with oHCM. Aims: To validate the psychometric performance of the KCCQ-12 in patients with oHCM and its interpretability categorized by Patient Global Impression of Change (PGIC). Methods: The psychometric properties of the KCCQ-12 and domains were tested in 196 participants with symptomatic oHCM from the EXPLORER-HCM trial. Construct validity was assessed against clinical and patient-reported standards using Spearman Correlation coefficients. Reliability was assessed by Cronbach’s alpha (&gt; 0.70). Test-retest reliability was determined using intra-class correlation (ICC) coefficient (good correlation being ICC &gt; 0.70) and paired t-tests of clinically stable patients (defined as no change in PGIC from baseline to 6 weeks and no change in Patient Global Impression of Severity from 18-30 weeks). Responsiveness and interpretability were assessed within categories of the 6-week PGIC. Results: KCCQ-12 domains and summary scores had moderate to strong correlations with most clinical standards (NYHA class, exercise duration, pVO 2 ) and patient-reported scales (Table 1). The KCCQ-12 showed strong internal and test-retest reliability (Table 2). All KCCQ-12 scores demonstrated significant and proportional changes of different magnitudes of clinical change delineated by the PGIC (Table 3). Conclusion: The KCCQ-12 demonstrates good psychometric performance for patients with oHCM and can be confidently used to monitor the health status of patients with oHCM in clinical practice.
Abstract 13732: A Mobile Intervention to Support Self-Care of Patients With Coronary Artery Disease: Preliminary Analysis of a Randomized Controlled Trial
Authors: Polly Wai Chi Li, Doris S yu
Journal: Circulation (2023)

Background: Although cardiac rehabilitation is beneficial to all patients with coronary artery disease (CAD), due to the cost implications, such services are confined to those with an acute coronary event or heart failure exacerbation, which limits their accessibility and scalability. Hypothesis: Patients with CAD who receive the internet-based CArdiac Rehabilitation Enhancement (i-CARE) intervention would report better changes in self-care, functional status, health-related quality of life (HRQoL) and physiological biomarkers than those who receive usual care. Aims: This randomized controlled trial aimed to examine the effects of the i-CARE intervention on self-care behaviors, functional status, HRQoL, blood pressure, waist-to-height ratio and cholesterol level in patients with CAD. Methods: CAD patients were recruited in the cardiac clinic of two hospitals in Hong Kong. The intervention consisted of a single face-to-face orientation session and a mobile app consisting of three key user interfaces, including a self-monitoring dashboard with personalized interface according to their own risk profile, an interactive e-library covering various CAD-related self-care dimensions and a chat room for the nurse to provide continuous coaching. The control group received usual care. Results: A total of 132 patients with CAD were randomly allocated to the intervention (n = 68) or control group (n = 64). Compared to the control group, the intervention group showed greater improvements in self-care behaviors (β = 5.532, 95% CI: 1.735 - 14.241, p = 0.012), functional status (β = 2.235, 95% CI: 1.092 - 8.286, p = 0.033), HRQoL (β = 6.135, 95% CI: 1.830 - 12.843, p = 0.012), and blood pressure control (β = 12.584, 95% CI: 10.050 - 29.221, p = 0.041) at 12 weeks follow-up. No significant changes in cholesterol level and waist-to-height ratio were found. Conclusions: The i-Care intervention improves self-care behaviors, HRQoL, functional status and blood pressure control in patients with CAD. It is warranted to examine the longer-term effects of the i-CARE intervention.
Abstract 12194: Clinical Application of Virtual Antiarrhythmic Drug Test Using Digital Twins in Patients Who Recurred Atrial Fibrillation After Catheter Ablation
Authors: Taehyun Hwang, Oh-Seok Kwon, BYOUNGHYUN LIM, Sohyun Yang, Daehoon Kim, Je W Park, Hee Tae Yu, Tae-Hoon Kim, Jae-sun Uhm, BOYOUNG JOUNG, Moon Hyoung LEE, Hui-Nam Pak
Journal: Circulation (2023)

Introduction: We previously reported that a computational modeling-guided antiarrhythmic drug (AAD) test was feasible for assessing diverse AADs in patients with atrial fibrillation (AF). In this study, we took the virtual AAD test (V-AAD) in patients who took AADs after AF catheter ablation (AFCA). Hypothesis: Patients using an effective drug in the VAAD test will have fewer AF recurrences than patients using an ineffective drug. Methods: This single-center retrospective study included 246 patients (72.8% male, 60.7±10.2 years of age, 38.6% paroxysmal AF) prescribed AADs within 3 months after AFCA. Using realistic computational modeling, we evaluated the effects of five AADs (amiodarone, sotalol, dronedarone, flecainide, and propafenone; 2 doses for each drug). Clinical AADs (C-AAD) were chosen at the discretion of the physicians blinded to the V-AAD test. We defined the effective V-AAD as the V-AAD that terminated AF or converted AF to atrial tachycardia (AT) and the best V-AAD as the V-AAD that ended virtual AF the fastest. We compared AF recurrence rates after the AAD prescription depending on the results of the V-AAD test. Results: The ineffective and best V-AAD were administered in 64 (26.0 %) and 70 patients (28.5%). The recurrence rate within a year after using the ineffective, effective, and best V-AAD were 46.9%, 35.7%, and 25.7%, respectively (log-rank p=0.013). The recurrence rate within a year in patients with at least one V-AAD terminating AF and those without was 33.9% and 50.0%, respectively (log-rank p=0.034). The use of best V-AAD (OR 0.43, 95% CI [0.18-0.96]; p=0.042, vs. ineffective V-AAD) is an independent predictor of AF recurrence within a year of using AAD after AFCA. Conclusions: The digital twins-guided V-AAD test was feasible for evaluating the efficacy of multiple AADs in patients with AF who had a high chance of recurrence after AFCA. We need a prospective randomization study to assess the prediction power of the V-AAD test.