tbuckley/cabot-search huggingface dataset:
Abstract 14308: Lamotrigine Inhibits the Inward Fast Sodium Current (I <sub>Na</sub> ) in Epileptic Rat Cardiomyocytes
Authors: Juan Antonio Contreras Vite, Robert Dumaine
Journal: Circulation (2021)

Introduction: Lamotrigine (LTG) is widely prescribed to treat neurological disorders such as migraine, neurophatic pain, and epilepsy. Recently, LTG has been linked to Brugada síndrome (BrS) ECG associated with a reduction in sodium current (I Na ) amplitude. Experimental studies have revealed that LTG blocks voltage gated sodium channels (VGSC). Hypothesis: Therefore, disrupting the depolarizing fast sodium inward current is a potential cause for arrhythmias. Recently our laboratory has shown that epilepsy induces molecular remodeling of the cardiac ventricle characterized by neuronal sodium channels overexpression, so it would be very plausible that LTG can cause important alterations on I Na in epileptic individuals. Methods: We used Patch-Clamp technique to test the effect of LTG on I Na in sham and epileptic rat ventricular cardiomyocytes. Results: We found that LTG inhibited I Na in a single dose-response manner with an IC 50 =326.35μM in sham rats. In epileptic rat cardiomyocytes the inhibitory effect was biphasic way with an IC 50 (1)=8.09 μM, which is close to the therapeutic range (between 12 and 50 μM), and a IC 50 (2)=333.66 μM. Moreover, LTG also altered sodium channels availability in biphasic manner with Vh(1)=-76.36 ± 0.31 mV and Vh(2)=-121.42 ± 1.38 mV, suggesting that LTG reduced the number of ion channels contributing to I Na . Conclusions: These findings may explain in part how LTG induce a Brugada pattern on the ECG of epileptic patients.
Abstract 13168: Total Lipoprotein Lipase Deficiency Does Not Impact Atherosclerosis Development in Low Density Lipoprotein Receptor Deficient Mice
Authors: Debapriya Basu, Jenny E Kanter, Maria Concepcion Izquierdo, Ainara Gonzalez, Lesley-Ann Huggins, Yunying Hu, Adam E Mullick, Edward A A Fisher, Karin E Bornfeldt, Ira J Goldberg
Journal: Circulation (2021)

Introduction: Elevated LDL cholesterol (LDL-C) is a major causal factor for CVD. However, the importance of elevated triglyceride rich lipoproteins (TRLs) on CVD is still being investigated. Lipoprotein lipase (LpL) is the rate limiting enzyme hydrolyzing circulating very low density lipoprotein (VLDL) and chylomicrons. The effect of increased TRLs as an independent factor on atherosclerosis is not known, in part, because hypertriglyceridemia associates with low levels of LDL-C. Objective: We tested whether whole body LpL deficiency in mice combined with LDL receptor (LDLR) deficiency and an atherogenic diet affects lesion formation. Hypothesis: LpL deficient mice will not show increased atherosclerosis progression as compared to control mice, despite severe dyslipidemia, due to reduced infiltration of atherogenic lipids into the aortic endothelium. Methods: Induced global LpL deficiency (i Lpl -/- ) was created by tamoxifen injection to activate beta actin-driven cre. To knock down hepatic LDLR we utilized anti sense oligonucleotides (ASOs) as well as a PCSK9 expressing AAV. Results: i Lpl -/- mice on chow diet have elevated plasma triglycerides, increased VLDL cholesterol, lower LDL-C and lower high density lipoprotein cholesterol (HDL-C) compared to control Lpl fl/fl mice. However, when hepatic LDLR was knocked down with using LDLR ASO or AAV PCSK9, iLpl -/- mice displayed elevated LDL-C of about 150 mg/dl, similar to the levels seen in control mice with LDLR knockdown. When i Lpl -/- mice were fed an atherogenic Western diet for 16 weeks, i Lpl -/- mice developed severe hypertriglyceridemia (1500-8000 mg/dl) and increased total cholesterol to ~1500 mg/dl. LDL-C levels were similar to those of control mice with LDLR knockdown; ~200 mg/dl. HDL-C was lower in i Lpl -/- mice compared to the controls (~10 mg/dl vs ~30 mg/dl). i Lpl -/- mice had slightly smaller lesions in brachiocephalic arteries but macrophage content was similar to the controls. Aortic root lesion size was similar in both groups of mice. Conclusion: Despite severe hypertriglyceridemia, hypercholesterolemia and low HDL-C, iLpL -/- mice did not exhibit altered atherosclerosis progression, likely because of the absence of LpL-derived atherogenic lipids or remnant lipoproteins.
Abstract 13166: Paraoxonase-3 Regulation of Cardiotonic Steroids Mediates Renal Injury and Dysfunction in a Dahl Salt Sensitive Model of Chronic Kidney Disease
Authors: Chrysan J Mohammed, Sabitri Lamichhane, Prabhatchandra Dube, Sophia Soehnlen, Jacob Connolly, Andrew Kleinhenz, Dhilhani Faleel, Dragan Isailovic, Deepak Malhotra, Steven Haller, David J Kennedy
Journal: Circulation (2021)

Background: Paraoxonases (Pons) belong to a family of hydrolytic enzymes with 3 distinct isoforms: Pon 1, 2, and 3. While the physiologic substrates for Pons are unclear, their lactonase activity is considered central to their native physiological role. We have previously demonstrated an association between diminished Pon lactonase activity and worse clinical outcomes in volume expanded states such as chronic kidney disease (CKD). Furthermore, we have identified a novel reno-protective role for Pon3 in hypertensive renal disease. However, the underlying mechanism(s) are unknown. Cardiotonic steroids (CTS) are natriuretic hormones that are increased in CKD and promote renal inflammation and fibrosis via binding of their 17β-lactone ring to the alpha-1 subunit of the Na + /K + -ATPase (NKA-α-1). Therefore, we tested the hypothesis that reduction of Pon3 lactonase activity would lead to increased renal injury and dysfunction in a CTS induced rat model of CKD. Methods/Results: Experiments were performed on Dahl salt-sensitive rats (SS rats) and Pon3 knock-out rats on the Dahl salt-sensitive background (SS- Pon3 KO). First, CTS levels in the urine of SS control and SS- Pon3 KO rats were quantified using mass spectrometry. We found that SS- Pon3 KO rats had 59 times greater increase in 24-hour urine CTS levels vs SS rats. Next, to examine the role of Pon3 in mediating CTS induced renal injury, ten-week-old, age-matched male SS control and SS- Pon3 KO rats were administered the CTS telocinobufagin (TCB, 100 μg/kg/day s.q) for four weeks followed by assessment of blood pressure (tail cuff plethysmography) and renal function. We found that SS- Pon3 KO rats following TCB administration had significantly increased 24-hour urinary protein excretion (UPE) (50.73 ± 3.59vs 25.29 ± 2.07, p&lt;0.0001), as well as decreased FITC-Sinistrin monitored glomerular filtration rate (GFR) (0.80 ± 0.10 vs 1.16 ± 0.05, p&lt;0.01) compared to SS control rats, despite similar degrees of hypertension. Conclusion: These findings suggest that Pon3 plays a critical role in regulating CTS mediated renal dysfunction in vivo.
Abstract 13133: Heterogeneous Uptake of [ <sup>99m</sup> Tc]microspheres and <sup>201</sup> Tl in Skeletal Muscles in Porcine Model of Hindlimb Ischemia
Authors: Supum Lee, Pedro Gil de Rubio Cruz, Stephanie Thorn, Zhao Liu, christi hawley, Marina Mamarian, Tymoteusz Turlejski, Ling Jian Meng, Chi Liu, Albert Sinusas
Journal: Circulation (2021)

Introduction: There is a need for quantitative methods to evaluate skeletal muscle blood flow in PAD patients. We assessed skeletal muscle blood flow heterogeneity at rest or vasodilator stress using 99m Tc-microspheres (HSA), that do not cross the capillaries, and 201 Tl, a freely diffusible radiotracer, in a pig hindlimb ischemia model. Methods: Following acute right femoral artery ligation, pigs (n=8) were injected with either 201 Tl or HSA at rest (n=2 per tracer) or under adenosine-stress (n=2 per tracer). Ex vivo SPECT/CT imaging was performed on excised ischemic (I) and non-ischemic (NI) gastrocnemius (GM) and soleus (SM) muscles. SPECT images were analyzed for the ischemic/nonischemic (I/NI) activity ratio, tracer heterogeneity as indicated by the coefficient of variance (CV) of signal intensity and image intensity histograms. Results: The rest 201 Tl I/N ratio for SM was higher (0.86±0.08) compared to stress (0.64±0.16), with no difference in GM. In contrast, the I/N ratio for HSA was near normal in both muscle groups at rest (GM: 0.80±0.21, SM: 1.06±0.45) although decreased during stress (GM: 0.70±0.04, SM: 0.71±0.12). Rest 201 Tl displayed uniformly low CV in both I (GM: 0.43, SM: 0.43) and NI muscles (GM: 0.37, SM: 0.43). Corresponding CV for stress 201 Tl were similar (I - GM: 0.41, SM: 0.42; NI - GM: 0.41, SM: 0.46). Rest HSA CV were higher in I (GM: 0.92, SM: 1.03) and NI (GM: 0.67, SM: 0.69) muscle, although there was greater heterogeneity in the I muscles assessed with HSA. Stress HSA CV decreased in both I (GM: 0.60, SM: 0.73) and NI (GM: 0.52, SM: 0.51). Figure displays representative count histograms. Conclusions: 201 Tl displayed less heterogeneity than HSA. 201 Tl appears to be more sensitive at detecting reduced blood flow at rest, due to changes in microcirculation. There was no change in the I/NI ratio during 201 Tl stress due to capillary recruitment, although HSA did demonstrate a decrease in the I/NI ratio with vasodilation, reflecting proximal vascular occlusion.
Abstract 13171: The Role of Novel Brugada Syndrome Gene <i>MAPRE2</i> in Maintaining Normal Cardiac Electrophysiology
Authors: David Y Chiang, Arie Verkerk, Babet van der Vaart, Nakul Narendran, Rachelle Victorio, Ashmita KC, Jianing Wang, James Sampognaro, Eva P Buys, Tuomas O Kiviniemi, Anna Akhmanova, Connie R Bezzina, Calum Macrae
Journal: Circulation (2021)

Introduction: Brugada syndrome (BrS) is a significant cause of sudden cardiac death yet only ~20% of patients are found with a loss-of-function variant in SCN5A encoding the cardiac Na + channel, leaving ~80% genetically undiagnosed. A recent genome-wide association study found 12 loci associated with BrS, including one in MAPRE2 encoding microtubule end-binding protein 2 (EB2). Hypothesis: MAPRE2 loss-of-function contributes to BrS and is necessary in maintaining normal cardiac electrophysiology (EP). Methods: Using CRISPR/Cas9, we generated two mapre2 loss-of-function mutants in zebrafish: a full knock-out and a mutant lacking the unique N-terminus of EB2 (delN). Cardiac EP was assessed using optical mapping in larvae, surface ECG in adults, and patch clamping in ventricular myocytes. Cardiac structure was assessed using videomicroscopy, histology, and confocal microscopy. Transcriptional changes were assessed using RNA-seq. Results: No gross changes in cardiac structure were observed with mapre2 loss-of-function. However, in both mutants, voltage mapping showed decreased ventricular conduction velocity and action potential upstroke velocity (V max ) and ECGs showed prolonged QRS, P wave, and corrected QT. Patch clamp of delN ventricular myocytes revealed reduced Na + current density without changes in gating properties consistent with the reduced V max . RNA-seq of larvel hearts suggested disruption of cell adhesion, confirmed by confocal microscopy, whereas Ca 2+ imaging found an increase in Ca 2+ transient amplitude. RNA-seq of adult hearts showed disruption in the Wnt signaling pathway and treatment with GSK3β inhibitor SB217673 rescued mutant ECG abnormalities. Conclusions: Our study supports MAPRE2 as a novel contributing gene in BrS pathogenesis and conduction slowing in general. Beyond its effect on Na + channel function, mapre2 and in particularly its unique N-terminal segment may play a broader role in cellular organization via the microtubule network affecting cellular EP in multiple ways. Our study also implicates for the first time the Wnt signaling pathway in BrS, suggesting not only shared biology with arrhythmogenic cardiomyopathies, but also the possibility of GSK3β modulation as a novel therapeutic approach.
Abstract 14316: Genetic Cardiomyopathy Heart Transplant Outcomes
Authors: Sonya John, Kimberly Hong
Journal: Circulation (2021)

Introduction: Data evaluating heart transplant (HT) outcomes in patients with genetic cardiomyopathies is limited. Cardiac features are prominent in these genetic disorders, resulting in progressive heart failure that may be lethal without cardiac transplantation. However, no single center has accumulated enough experience to investigate post-HT outcomes for these rare cardiomyopathies. The primary aim of this review is to synthesize literature investigating if HT is a viable treatment option for genetic cardiomyopathies including Duchene Muscular dystrophy (DMD), Becker’s (BMD), Limb-Girdle (LGMD), Emery Dreifuss (EDMD); mitochondrial disorders, Friederich’s ataxia (FA), Barth’s disorder and fatty acid oxidation disorders (FAOD). Methods: We performed a systematic literature search of PubMed, EMBASE, and Google Scholar identifying studies reporting HT outcomes published up to June 2021. Results: A total of 42 articles were selected for review with 118 patients reported. Patient data with age at HT, gender distribution, mean follow-up, reported survival data, and post-operative outcomes are reported in Table 1. Patients with DMD, BMD, LGMD, and EDMD had HT during the second and third decade of life and were reported to have favorable survival outcomes at one and five years. In FA, 11 patients underwent cardiac transplantation at mean age 21.2 years with reported survival of 100% at one and five years. Patients with Barth syndrome received HT at younger ages with mean age 1.6 years. Mortality in these patients as well as mitochondrial disorders were low even with longer reported follow-up time. Cardiac transplants in FAOD were rare with one female receiving HT at the age of 27 months and was reported to be complication-free after 12 years. Conclusions: This review suggests that post-transplantation outcomes in genetic cardiomyopathy patients with multisystem involvement are generally favorable, with high survival and few post-operative complications.
Abstract 14240: Disparities in Implementation of Advanced Heart Failure Therapies Among Patients With HIV: An Analysis of the NIS Database
Authors: Rafael J Hernandez, Juliann Gilchrist, Jennifer Maning, Jelani Grant, Louis T Vincent, Bertrand Ebner, Neal Olarte, Odunayo Olorunfemi, Rosario A Colombo
Journal: Circulation (2021)

Background: Highly active anti-retroviral therapy has transformed human immunodeficiency virus (HIV) infection into a chronic disease. HIV+ patients now experience increased mortality from chronic conditions such as heart failure (HF). Nonetheless, limited data has been published on the implementation of advanced HF therapies among this patient population. The aim of our study is to assess current disparities in therapies among HIV+ patients. Methods: We performed a retrospective analysis using the National Inpatient Database (NIS) from 2011 to 2018 to identify patients admitted for HF exacerbation. Patients were stratified according to HIV status. Baseline characteristics and clinical status were recorded. Primary outcome was implementation of advanced HF therapies (left ventricular assist device, LVAD and/or transplantation, HTX). Multivariate analysis models were adjusted for statistically significant differences in baseline characteristics between the groups. Results: A total of 39,527,306 HF patients were identified, of these 207,394 (0.52%) were HIV+. HF/HIV+ patients were less likely to be females (33.6% vs 49.8%, p &lt; 0.001) and obese (11.6% vs 19.1%, p &lt; 0.001). The prevalence of renal disease (50.9% vs 40.1%, p &lt; 0.001) and dialysis dependance (19.7% vs. 5.2%, p &lt; 0.001) was higher among the HF/HIV+ patients. The use of mechanical circulatory support was lower among HF/HIV+ (0.5% vs 0.7%, p &lt; 0.001), despite higher incidences of cardiogenic shock (1.9% vs 1.8%, p = 0.001) among these patients. HF/HIV+ were less likely to go for LVAD (n=65, 0% vs n=2997, 0.1%, OR = 0.245, p &lt; 0.001) or HTX (n=55, 0% vs n=21,089, 0.1%, OR = 0.266, p &lt; 0.001). Conclusions: Access to advanced HF therapies among patients with HIV-associated cardiomyopathy appears to be limited and unequal. These results should encourage further studies to evaluate the short- and long-term clinical outcomes of advanced HF therapies among HF/HIV+ patients.
Abstract 14180: RyR2 Hyperactivity Contributes to Arrhythmogenic Triggers in the <i>ex vivo</i> Human Right Ventricle
Authors: Jaclyn A Brennan, Rokhaya N Faye, Bjorn C Knollmann, Igor R Efimov
Journal: Circulation (2021)

Introduction: Sudden cardiac death (SCD) caused by VT/VF is a major cause of mortality and morbidity, accounting for up to 20% of all deaths in the United States. Novel antiarrhythmic targets and relevant translational models of SCD are urgently needed for basic and translational arrhythmia research, and ex vivo donor human hearts are invaluable resources for such pharmacological studies. It was the goal of this study to investigate the occurrence of VT/VF in excised human hearts and to test a novel pharmacological agent to suppress arrhythmias. Hypothesis: We assessed the hypothesis that RyR2 hyperactivity contributes to arrhythmogenic triggers and substrates in the human RV, and we analyzed the antiarrhythmic effects of pharmacological RyR2 suppression. Methods: Adult human hearts (n = 10; 3F, 7M) were procured from the Washington Regional Transplant Community. The entire RV free wall was isolated, coronary perfused, and placed in an oxygenated, 37°C bath of Tyrode’s solution for optical mapping with the addition of Di-4-ANBDQBS and blebbistatin. Pseduo ECGs were recorded, and action potentials (APs) were spatiotemporally mapped using high-speed CMOS cameras. Optical recordings were taken at baseline and after exposure to the adrenergic agonist isoproterenol (ISO, 250 nM) and the adenosine antagonist caffeine (CAF, 200 μM) to elicit RyR2 hyperactivity. We also evaluated pharmacological RyR2 suppression (2 μM dantrolene) on arrhythmia inhibition. Results: ISO and ISO+CAF significantly shortened tissue APDs. ISO+CAF increased the incidence of PVCs at low pacing frequencies as well as increased the incidence of VT/VF at high pacing frequencies. We observed non-sustained arrhythmias in roughly a third of the hearts examined. No significant differences in conduction velocities were observed. While dantrolene did not return APDs to baseline conditions, it did significantly reverse the effect of caffeine on inducing PVCs. Conclusions: In conclusion, caffeine contributes to arrhythmogenic triggers in the ex vivo human right ventricle, and dantrolene may be used as a pharmacological tool to suppress RyR2 hyperactivity and thus prevent SCD.
Abstract 13183: Persistent Anemia Was Associated With Higher Long-Term Mortality in Patients With Chronic Kidney Disease Following Primary Percutaneous Coronary Intervention
Authors: Takuma Koike, Yuichi Chikata, Hiroshi Iwata, Hidetoshi Yasuda, Takehiro Funamizu, Shinichiro Doi, Jun Shitara, Hirohisa Endo, Hideki Wada, Ryo Naito, Manabu Ogita, Tomotaka Dohi, Takatoshi Kasai, Shinya Okazaki, Katsumi Miyauchi, Hiroyuki Daida, Tohru Minamino
Journal: Circulation (2021)

Background: Anemia is one of the most common complications of chronic kidney disease (CKD), renal anemia, which has a significant link with increased risk of the morbidity, as well as the mortality of cardiovascular disease. However, the prognostic implication of the temporal change of anemia status has been rarely addressed, especially in secondary prevention of coronary artery disease (CAD). Methods and Results: This long-term (median follow-up range: 5.7 years) single center observational study involved consecutive 416 patients with CKD over stage 3 (defined by eGFR&lt;60 ml/1.72/m 2 ) who underwent percutaneous coronary intervention (PCI) for the first time since 2003 to 2018. All-cause death was set as an endpoint. Participants were divided into 4 groups by the median of hemoglobin (Hb) at PCI (baseline, 12.0 mg/dl) and 8.1±2.1 months after PCI (follow-up, 12.7 mg/dl), respectively: Groups of Continuously high-Hb (n=146), Increased-Hb (n=51), Attenuated-Hb (n=61) and Persistently low-Hb (n=158). Categorized Cox proportional hazard analysis with setting Continuously high-Hb group as a reference showed a significantly increased risk of all-cause death in groups of Attenuated- (Hazard ratio (HR) 2.6, 95% confidence interval (CI) 1.3-5.2, p=0.01) and Persistently low-Hb (HR 2.6, 95%CI 1.4-4.8, p=0.002), respectively, while similar in Increased-Hb group (HR 1.1, 95%CI 0.3-3.2, p&gt;0.5) (Figure) . Conclusion: This study showed a significant association between the reduced Hb overtime and increased mortality risk in patients with CKD and CAD, which might potentially indicate a prognostic merit of the intervention for renal anemia in this population.
Abstract 14134: Relationship Between Blood Pressure and Thoracic Aortic Diameter
Authors: John DePaolo, Michael Levin, Catherine Tcheandjieu,, James Priest, Gill Dipender, Stephen Burgess, Scott Damrauer, Julio A Chirinos
Journal: Circulation (2021)

Introduction: The impact of blood pressure (BP) traits, including systolic/diastolic blood pressure (SBP/DBP), pulse pressure (PP) and mean arterial pressure (MAP), on thoracic aorta (TA) diameter remains poorly understood. Hypothesis: We hypothesize that genetic predisposition to elevated SBP, DBP, MAP and PP is related to risk of TA dilation suggesting enhanced primary and secondary prevention strategies for thoracic aortic aneurysm (TAA). Methods: We performed two-sample Mendelian randomization to investigate the effect of BP traits on TA diameter. We considered SBP, DBP, MAP, and PP in 479,103 participants of diverse ancestry from UK Biobank. We considered 32,215 participants from UK Biobank who underwent cardiac MRI for TA diameter. Genetic instruments were constructed from uncorrelated (r 2 &lt; 0.001) genetic variants associated with each BP trait at genome-wide significance (p &lt; 5 x 10 -8 ) in a pan-UK Biobank GWAS of BP traits. Results: Each of genetically-predicted MAP (beta = 0.017, 95% CI 0.013 to 0.021, p = 2 x 10 18 ), SBP (beta = 4.1 x 10 -3 , 95% CI 8.4 x 10 -4 to 7.4 x 10 -3 , p = 0.01) and DBP (beta = 0.27, 95% CI 0.022 to 0.032, p = 9 x 10 -29 ) were positively associated with increased TA diameter. PP was inversely associated with TA dimension (beta = -0.015, 95% CI -0.021 to -0.010, p = 2.4 x 10 -7 ). When considered jointly in multivariable Mendelian randomization, both genetically-predicted PP (beta = -0.037 mm/mmHg increase, 95% CI -0.045 to -0.029, p = 2 x 10 -20 ) and MAP (beta = 0.038mm/mmHg increase, 95% CI 0.031 to 0.046, p = 3 x 10 -23 ) were independently associated with TA diameter. In bi-directional analyses, increased TA diameter was associated with decreased PP and SBP, and increased DBP. Results were robust to MR methods that make different assumptions about the presence of pleiotropic variants, and using alternative genetic variants to proxy BP traits. Conclusions: These data suggest elevated BP contributes to TA diameter. Multivariable analysis suggests both steady pressure (proxied by MAP) and pulsatility (proxied by PP) directly contribute to aortic size. These findings suggest societal-level intervention to lower blood pressure to prevent TAA development and related morbidity and mortality.