bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14688: TREK-1 Modulates Fibrosis & Diastolic Dysfunction Through Activation of Stress-Activated Kinases
Authors: Abraham Dennis M , Lee Teresa E , Watson Lewis J , Mao Lan , Chandok Gurangad , Wolf Matthew J , Rockman Howard A
Published: July 2021

Introduction:
Heart failure with preserved ejection fraction (HFpEF) is a major public health problem because of its high prevalence and the current lack of effective therapies. HFpEF is thought to develop through diastolic dysfunction caused by diminished ventricular compliance, which is strongly influenced by cardiac fibrosis. Our work identifies TWIK related potassium channel-1 (TREK-1) as a novel modulator of diastolic dysfunction and cardiac fibrosis.

Methods & Results:
TREK-1 is expressed in mammalian cardiac tissue, although its role in cardiac function is poorly understood. To assess the role of TREK-1 in mammalian cardiac function, we interrogated cardiac function in response to pressure overload in global TREK-1 knockout (KO) mice. TREK-1 KO mice showed normal cardiac function in the basal state. However, TREK-1 KO mice developed exaggerated concentric hypertrophy in response to pressure overload. Despite developing exaggerated hypertrophy, TREK-1 KO mice maintained normal systolic and diastolic function as measured by serial echocardiography and invasive hemodynamics. Invasive hemodynamics showed preservation of ventricular compliance in pressure overloaded TREK-1 KO mice, which was associated with significantly attenuated cardiac fibrosis. The limited fibrosis in the heart was indicative of a general impairment of the fibrotic response as measured by impairments in in vivo cutaneous wound healing and in vitro fibroblast migration assays.

To determine the mechanism for how TREK-1 modulates fibrosis, we investigated the activation of signaling pathways in lung fibroblasts harvested from TREK-1 KO mice. In response to the profibrotic ligands TGF beta and TNF alpha, TREK-1 KO fibroblasts showed a significantly attenuated activation of the stress-activated kinases p38 alpha and c-Jun N-terminal kinase (JNK), known mediators of myofibroblast activation. These data suggest a critical role for TREK-1 in fibroblast function via the activation of stress-activated kinases.

Conclusions:
We identified TREK-1 as being critical to the development of diastolic dysfunction and chamber compliance by modulating the signaling pathways involved in the tissue fibrotic response.
Abstract 14713: SIRT6 Blocks Differentiation of Cardiac Fibroblasts into Myofibroblasts by Inactivation of the TGFβ1 Signaling
Authors: Sundaresan Nagalingam R , Gupta Madhu , Gupta Mahesh P
Published: July 2021

Introduction:
Cardiac fibrosis contributes to adverse cardiac remodeling which is precursor to heart failure. At the cellular level, fibrosis occurs because of differentiation of quiescent cardiac fibroblasts (CF) into myofibroblasts (myoFB), an activated fibroblast-like cell-type capable of synthesizing excessive extracellular matrix. Activation of TGFβ-signaling is considered to be a major contributor of this process. This study was undertaken to examine the role of SIRT6, an anti-aging molecule, on the differentiation of CF to myoFB and the development of cardiac fibrosis.

Methods and Results:
Cardiac fibroblasts obtained from human failing hearts were analyzed for expression levels of SIRT6 and myoFB markers like, smooth muscle α-actin (SMA), fibronectin and collagen1 (Col1) by western blotting. Expression levels of SMA, fibronectin and Col1 were increased, whereas SIRT6 levels were decreased in CF prepared from failing hearts, compared to control hearts. To test whether SIRT6 deficiency contributed to activation of myoFB markers, we analyzed hearts of SIRT6 (+/-) mice. There was robust activation of myoFB markers and Mason-trichome blue positive staining for fibrosis in SIRT6 (+/-) hearts, compared to controls. To understand the mechanism involved, we analyzed different components of TGFβ-Smad3 signaling in SIRT6 deficient hearts. Expression levels of both pro- and mature-TGFβ1 and Smad3 were significantly elevated in SIRT6 (+/-) hearts, compared to controls. By using siRNA approach we also knocked down SIRT6 (SIRT6-KD) levels in human control CF, and analyzed sensitivity of these fibroblasts to pro-fibrotic agonists, Ang-II. SIRT6-KD fibroblasts had significantly higher levels of TGFβ1, and they were highly sensitive to Ang-II stimulation in terms of synthesizing myoFB markers. Over expression of SIRT6 blocked the synthesis of TGFβ1 and the fibrotic response to Ang-II, both in control and in SIRT6-KD fibroblasts, thus demonstrating anti-fibrotic activity of SIRT6.

Conclusions:
These data indicate that SIRT6 is capable of blocking fibroblast differentiation into myofibroblasts by suppressing the synthesis of TGFβ1, and signify that SIRT6 could serve as a therapeutic target for the treatment of cardiac fibrosis and heart failure.
Abstract 14722: Dual-Targeted Microbubbles Improve the Detection of Previously Ischemic Myocardium by Echocardiography
Authors: Lin Dan , Tian Yikui , Klibanov Alexander L , Hossack John A , French Brent A
Published: July 2021

Introduction:
Echocardiography using targeted microbubbles (MB) has been shown to detect previously-ischemic regions of myocardium by molecularly targeting cell adhesion molecules that are displayed on the activated endothelial surface after ischemia/reperfusion injury. We hypothesized that the accuracy and sensitivity of detection could be improved by constant infusion and dual-targeting, respectively.

Methods:
Ischemia/reperfusion injury was induced in 8 male C57BL/6 mice with 15-min LAD occlusions. After 2h of reperfusion, hearts of the closed-chest mice were imaged in long-axis with a Sequoia 15L8 transducer at 14 MHz. Each mouse received 3 of 4 MB preparations in random order: Sialyl Lewis X MB (MBX), anti-VCAM MB (MBV), Sialyl Lewis X + anti-VCAM MB (MBD), and isotype control MB (MBI). MB concentrations were approximately 200x10^6/mL, and 100 μL were infused at a constant rate of 25 μL/min via tail vein catheter. After imaging, mouse hearts were excised and stained with TTC/Phthalo blue dye to assess area at risk, and compared to regional time intensity curve (RTIC) retrieved from video data (Panel A).

Results:
Example RTIC for MBD shows enhanced MB signals during and after MB infusion in the anterior apical region of the heart (Panel A). In Panel B, normalized intensities are significantly higher for MBD, MBX, and MBV, compared to MBI (p<0.05). Furthermore, normalized intensity for MBD is higher than both MBX and MBV (p<0.05). Receiver operating curve analysis using blue dye as the gold standard showed accurate detection of both ischemic and non-ischemic regions using MBD (AUC = 0.90), MBX (AUC = 0.89), and MBV (AUC = 0.97).

Conclusions:
Molecular imaging of endothelial cell adhesion molecules in closed-chest mice is possible using constant infusion of MB. Dual-targeted MB yield greater MB signals than single-targeted MB when delivered using constant infusion, improving both the sensitivity and accuracy of this technique to measure risk regions in intact mice.
Abstract 14727: Late Sodium Current Plays a Role in Ventricular Arrhythmias Associated With Increased Intracellular Calcium Concentration
Authors: Wei Xiaohong , Huo Yong , Huang Sihui , Yang Qiaomei , Ren Lu , Wu Lin
Published: July 2021

Objective:
An increase in intracellular calcium concentration is associated with the prolongation of action potential duration (APD) and polymorphic ventricular tachycardia (PVT). Recent studies indicated that late sodium current inhibitor is effective in preventing ventricular arrhythmias in patients with long QT syndrome 8. The objective of the study was to determine the role of late sodium current in calcium related ventricular arrhythmias.

Methods:
Hearts from New Zealand female rabbits were perfused in a Langendorff mode. The atrioventricular nodal area was thermally ablated to produce complete atrioventricular block, and then heart was paced at stated frequency. Multiple channel monophasic action potentials (MAP) and pseudo 12-lead electrocardiograms (ECGs) were recorded. Calcium transient and myocyte contraction were determined in rabbit ventricular myocytes.

Results:
Bay-K 8644 (10-300 nM) increased both epi- and endo- cardial MAPD90 of left ventricle in concentration dependent manners, from (176±6) to (222±13) ms, and (201±6) to (246±10) ms (n=15, p<0.05 vs control), respectively. In the presence of 1 nM ATX-II, Bay-K 8644 caused a greater prolongation of epi-MAPD90 which was increased from (182±6) to (342±21) ms (n=9, p<0.05 vs control). The prolongation of MAPD90 caused by Bay-K 8644 were reversed by 1 μM TTX in both absence and presence of ATX-II. Additionally, the incidence of PVT evoked by Bay-K 8644 was also greater in the presence compared to the absence of ATX-II. 200 nM Bay-K 8644 caused few arrhythmias in absence of ATX-II. In contrast, PVT occurred in 7/9 (77.78%) of hearts treated with 200 nM Bay-K 8644 in the presence of ATX-II. These arrhythmias could be abolished by 1 μM TTX in the continued presence of Bay-K 8644. TTX (1 μM) attenuated the increase by 200 nM Bay-K 8644 of intracellular calcium transient and myocyte contraction amplitude by 10.8% and 14.6%, respectively (n=6, p<0.05).

Conclusion:
Both endogenous and enhanced late sodium current contributes to the ventricular arrhythmias with increased intracellular calcium concentration. Inhibition of late sodium current may be effective in preventing or treating calcium overload-related ventricular arrhythmias and dysfunction of myocardial contraction.
Abstract 14746: Dynamic SIRTUIN1-modulated Lysine Acetylation of P66shc Governs Vascular Endothelial Oxidative Stress and Dysfunction of Diabetes
Authors: Kumar Santosh , Kim Young Rae , Vikram Ajit , Naqvi Asma , Kumar Ajay , Bachschmid Markus , Jacobs Julia S , Irani Kaikobad
Published: July 2021

The SIRTUIN1 lysine deacetylase (SIRT1) ameliorates diabetic vascular dysfunction by epigenetically suppressing endothelial expression of the oxidative stress protein p66shc. However, whether SIRT1 modulates the oxidative function of p66shc by directly targeting it for lysine deacetylation is not known. Here we show that the oxidative function of p66shc is dynamically modulated by lysine acetylation. Mass spectroscopy identified lysine 81 in the unique CH2 domain of p66shc as the residue targeted by SIRT1. High glucose and SIRT1 knockdown stimulates acetylation of lysine 81 of endothelial p66shc. Compared to WT p66shc, non-acetylatable (K81R) p66shc is significantly handicapped in promoting endothelial hydrogen peroxide production stimulated by high glucose. Compared to WT p66shc, K81R p66shc is also less prone to serine 36 phosphorylation by high glucose, which is essential for the oxidative function of p66shc. Moreover, in contrast to WT p66shc which worsens endothelial dysfunction, expression of K81R p66shc does not impair endothelial function in wild type mice and rescues endothelium dysfunction of diabetic db+/db+ mouse aortas . These findings show that lysine 81 acetylation promotes the oxidative role of p66shc in hyperglycemic conditions, and is essential for p66shc-mediated endothelial dysfunction.
Abstract 14766: Short-Term Dual Antiplatelet Therapy Following Bare Metal Stent Increases the Risk of Ischemic Events- A Meta-Analysis of Randomized Clinical Trials
Authors: El-Hayek Georges , Casso Dominguez Abel , Tamis-Holland Jacqueline , Herzog Eyal , Benjo Alexandre , Bangalore Sripal
Published: July 2021

Background:
Bare metal stents (BMS) are a reasonable option even in the modern era of superior outcomes with 2nd generation drug eluting stents mainly because of the need for short term dual antiplatelet platelet therapy (DAPT). Current guidelines recommend a minimum of 1 month of DAPT following BMS use. The safety of limiting DAPT to one month has not been clearly established.

Methods:
We searched PubMed, Scopus and ClinicalTrials.gov databases till May 2014 for randomized clinical trials (RCTs) that compared short (<6 months) versus long DAPT duration (> 6 months) after BMS. Risks ratios (RRs) with 95% confidence interval (CI) for the composite outcome of cardiac death or myocardial infarction (MI) and for major bleeding were calculated using random-effects model.

Results:
We included 3 RCTs in this analysis. A total of 2654 patients received short term DAPT and 2612 patients received long term DAPT (9 to 24 months). The rates of cardiac death or MI were significantly higher in the short-term DAPT group (9.1%) compared to the prolonged DAPT group (7.0%)which corresponds to a 30% increase in the risk of cardiac death or MI (RR: 1.30, 95% CI: 1.08 to 1.57; p=0.005, figure). On the other hand, short-term DAPT was associated with numerically lower major bleeding events (4.0% vs 5.0%) when compared with prolonged DAPT but this did not reach statistical significance (p=0.06).

Conclusion:
Short-term DAPT as compared with prolonged treatment is associated with an increased risk of cardiac death or MI.
Abstract 14769: The Relationship Between Regular Physical Exercise and Nocturnal Blood Pressure in Korean Ambulatory Blood Pressure Monitoring Study
Authors: Kim Bae Keun , Yonggu Lee , Young-Hyo Lim , Shin Jinho
Published: July 2021

Introduction:
There have been many reports showing that regular physical exercise can reduce the blood pressure (BP). Thus physical exercise is one of the important components of lifestyle modification of hypertension. It is known that nocturnal BP is an independent factor for the cardiovascular event but there are few studies for the relationship between physical exercise and nocturnal BP.

Hypothesis:
Hypothesized regular physical exercise reduced nocturnal BP, therefore, we aimed to analyze the relationship between regular physical exercise assessed by a questionnaire (7-day physical activity recall) and nocturnal BP in the general population.

Methods:
Among 4145 subjects whose data for both clinical data and ambulatory blood pressure monitoring (ABPM) data file from the 5308 Korean ABPM (KorABP) study subjects, 3689 subjects were analyzed. The exclusion criteria was age less than 20 years (n=84), missing data for the questionnaire for physical exercise (n=372). Physical exercise was defined as regular structured exercise which intensity was heavier than the fast walking for 30 minutes. The count was recorded as the number per week.

Results:
Age was 55.5 ± 14.1 years and female was 45.9 %. Prevalence of hypertension, antihypertensive medication (AHM), diabetes and cardiovascular diseases were 58.9%, 32.5%, 13.0%, and 21.1%, respectively. Daytime and nighttime systolic BP was 138.5 ± 17.2 mmHg and 126.3 ± 18.8 mmHg. When adjusted for age, sex, BMI, and AHM, exercise frequency was independently decreased daytime systolic BP (β = -0.52 mmHg per ex-ercise, p = 0.02). For the nighttime systolic BP further adjusted by daytime systolic BP and sleep quality, ex-ercise frequency was an independent factor (β = -0.26 mmHg per exercise, p = 0.002). The statistical significances were observed even for only for 1 times per week. When further adjusted by smoking, exercise frequency was in-dependent for nocturnal dipping (β = 0.18% per exercise, p = 0.015).

Conclusions:
Regular physical exercise is independently associated with lower nocturnal BP also lower daytime BP and with increased nocturnal dipping, which was independent of AHM status.
Abstract 14771: Iron Plays a Role in the Thrombus Formation of a Rat Model of Deep Vein Thrombosis
Authors: Oboshi Makiko , Naito Yoshiro , Sawada Hisashi , Iwasaku Toshihiro , Okuhara Yoshitaka , Morisawa Daisuke , Eguchi Akiyo , Hirotani Shinichi , Mano Toshiaki , Tsujino Takeshi , Masuyama Tohru
Published: July 2021

Introduction:
Deep vein thrombosis (DVT) is a major cause of pulmonary thromboembolism. On the other hand, iron is an essential element for maintaining physiological homeostasis in the body, whereas excess iron leads to toxicity and free radical damage. Hence, iron accumulation is associated with the pathogenesis of several cardiovascular diseases. We have previously reported that dietary iron restriction (IR) prevents the development of hypertension and chronic kidney disease (CKD) in animal models of several cardiovascular diseases. In addition, we have shown that intracellular iron transport protein, transferrin receptor 1 (TfR1), is involved in the mechanism of several cardiovascular diseases. In this study, we hypothesized that iron and TfR1 play roles in the pathogenesis of DVT. We investigate the effects of dietary IR on the thrombus formation and resolution in a rat model of DVT.

Methods:
We performed the ligation of inferior vena cava to induce DVT in 8-week-old male Sprague-Dawley rats. After the ligation, rats were given either a normal diet (DVT group) or iron-restricted diet (DVT+IR group). The thrombus was harvested at 5days after the ligation.

Results:
At first, TfR1 expression was increased in the thrombus of a rat model of DVT, suggesting that iron and TfR1 play roles in the pathogenesis of DVT. Interestingly, dietary iron restriction reduced the thrombus size compared with the DVT group (180±17 mg/cm vs 135±13 mg/cm, DVT vs DVT+IR ; p < 0.05). Intrathrombotic collagen content was diminished in the DVT+IR group compared with the DVT group. Intrathrombotic gene expression and activity of matrix metalloproteinase (MMP)-9 were increased in the DVT+IR group compared with the DVT group. In addition, the numbers of CD68 positive cells in the thrombus were fewer in the DVT+IR group than in the DVT group. Furthermore, intrathrombotic gene expression of urokinase-type plasminogen activator and tissue-type plasminogen activator was higher in the DVT+IR group than in the DVT group.

Conclusions:
These results suggest that iron plays a role in the pathogenesis of DVT.
Abstract 14784: Effect of Lifestyles of Children and Their Parents on the Levels of Cardiovascular Risk Factors in Elementary School Children
Authors: Yoshinaga Masao , Miyazaki Ayumi , Aoki Machiko , Ito Yoshiya , Kubo Toshihide , Hamajima Takashi , Horigome Hitoshi , Takahashi Hideto , Iwamoto Mari , Ogata Hiromitus , Tokuda Masakuni , Tachikawa Tomoko , Koriyama Nobuyuki , Hara Mitsuhiko , Shinomiya Masaki , Nagashima Masami , Nagashima Masami
Published: July 2021

Background and Objectives:
Recently, the prevalence of obese children is declining in Japan; however, longitudinal studies showed that the prevalence of obesity is still increasing during elementary school periods. Therefore, the present study aimed to evaluate the effect of lifestyles of children and their parents on the levels of cardiovascular (CV) risk factors in elementary school children.

Subjects:
The study have conducted since 2012 and announced through the local boards of education in seven areas in Japan. The study was included 1114 healthy volunteers (540 boys, 574 girls) aged from 6 to 12 years with a medical examination and a questionnaire. The medical examination included the measurement of height, weight, waist circumference, and blood pressures, and blood sampling for CV risk factors. The questionnaire collected data on the lifestyles of the subjects and their parents. Screen time included time spent watching TV and playing games. The subjects were asked to walk with pedometer for 7 days. Obesity in the present study was defined using the age- and sex-specific International Obesity Task Force standard.

Results:
Multivariate regression analyses showed that number of steps by pedometer measurement, screen time, sleeping time, and parental BMI were significantly and independently associated with the levels of one or more CV risk factors in elementary school children. Among these, screen time had a profound adverse effect on CV risk factor levels. Number of steps was positively associated with sleeping time and negatively associated with screen time. Screen time in children was strongly associated with parental screen time. The risk of obesity in boys was associated with paternal obesity (p=0.000), but not with maternal obesity (p=0.95). On the other hand, the risk of obesity in girls was associated with both paternal and maternal obesity (both p=0.000).

Conclusions:
Increase in number of steps and sleeping time and decrease in screen time may be the first-line approach for elementary school children to maintain favorable CV risk factor levels. An association between childhood obesity and paternal or maternal obesity and differs between genders in Japan; thus, approaches focusing on parents should take the gender of children into consideration.
Abstract 14862: Gender Differences in Impact of CYP2C19 Polymorphism and Low Grade Inflammation on Coronary Microvascular Disease
Authors: Akasaka Tomonori , Hokimoto Seiji , Tabata Noriaki , Sakamoto Kenji , Tsujita Kenichi , Kojima Sunao , Kaikita Koichi , Ogawa Hisao
Published: July 2021

Background:
Specific CYPs localized in vascular smooth muscle and endothelium contribute to the regulation of vascular tone and homeostasis. CYP2C19 two loss-of-function alleles (PM) were found to be an independent risk factor for diabetic retinopathy, and PM is associated with the coronary spasm especially in female. However, it is unknown whether CYP2C19 genotype is associated with the coronary microvascular disease. The aim was to evaluate the impact of CYP2C19 genotype on coronary microvascular disease.

Methods:
We examined CYP2C19 genotype in patients with microvascular disease (n=40) who were diagnosed by intra-coronary acetylcholine infusion test and healthy subjects (n=455) as control group. We defined the coronary microvascular disease that have no epicardial spasm and have angina, ischemic ECG changes, reduced coronary blood flow, or inversion of lactic acid level between intra-coronary and coronary sinus. CYP2C19 genotypes were divided into 3 groups; (1) CYP2C19*1/*1: EM, (2) one loss-of-function allele (*1/*2, *1/*3: IM), and (3) two loss-of-function alleles (*2/*2, *2/*3, *3/*3: PM).

Results:
The ratios of CYP2C19 genotype (EM, IM, and PM) were 33, 35, and 32% in microvascular disease group, and 32, 49, and 19% in control group. In short, PM frequency was significantly higher in microvascular disease group (32%vs19%,P=0.039). In microvascular disease group, the ratios of CYP2C19 genotype (EM, IM, and PM) were 44, 38, and 19% in male, and 25, 33, and 42% in female, respectively. Briefly, the PM frequency was significantly higher in female than in male (42%vs19%,P=0.011). Moreover, the level of hs-CRP was significantly higher in microvascular disease group (0.37±0.908 vs 0.10±0.240, P<0.001). Multivariate analysis for microvascular disease indicated that gender, high age, smoking, hypertension, and the high level of hs-CRP are predictive factors among all subjects. PM is a predictive factor for microvascular disease in female group only (OR3.214, 95%RI 1.286-8.034, P=0.012), but not in male (OR0.909, 95%RI 0.251-3.285, P=0.884).

Conclusion:
The CYP2C19 two loss-of-function alleles (PM) and low grade inflammation may be associated with pathophysiology of coronary microvascular disease, especially in female.
Abstract 14867: Wnt11 Over-expressing Mesenchymal Stem Cells Promote Cardiomyocyte Proliferation by Paracrine Signaling
Authors: Wang Jingcai , Liu Honghai , Yu Bin , Gong Min , Wang Yigang , Ashraf Muhammad , Xu Meifeng
Published: July 2021

Objective:
The regenerative capacity of the heart is very limited and consequently, the heart cannot regenerate adequately after injury. Our previous studies showed that the paracrine factors released from mesenchymal stem cells (MSCs) overexpressing Wnt11 protected cardiomyocytes (CM) after myocardial infarction. Here, we hypothesized that these factors also stimulate CM proliferation.

Methods and Results:
MSCs harvested from rat bone marrow were transduced with Wnt11 (MSC
Wnt11
) or EGFP empty vector (MSC
GFP
). Conditioned medium (CdM ) were obtained from MSC
GFP
(CdM
GFP
) or MSC
Wnt11
(CdM
Wnt11
) under normal and hypoxic culture for 36 hours. CM obtained from neonatal and adult rat ventricles were cultured in CdM
GFP
, CdM
Wnt11
or CdM
Wnt11-H
medium for 3 and 7 days. Cultured CM were stained with BrdU, Ki67, and Aurora B, respectively and identified by staining with α-actinin. Some CM were positive for these proliferative markers (
Fig. 1
). The expression of proliferating cell nuclear antigen (PCNA), cyclin D2, Nkx2.5, b-myosin heavy chain (b-MHC), atrial natriuretic factor (ANF), troponin I type 1 (Tnni1), troponin I type 3 (Tnni3), sarco-/endoplasmic reticulum Ca
2+
-ATPase (SERCA2), and desmin was analysed (
Fig. 2
). Although PCNA was downregulated in CM treated with CdM, other cardiac specific markers were significantly upregulated in CM treated with CdM
Wnt11
or CdM
Wnt11-H
obtained from MSC
Wnt11
exposed to hypoxia for 24 hours. Moreover, CdM
Wnt11
also increased adult CM mitosis, cytokinesis, and CM numbers compared to CdM
GFP
. In addition, CdM significantly improved the contractile dyskinesis of adult CM caused by 7 days culture in non-serum M199 medium (
Fig. 3
).

Conclusions:
Our studies support the hypothesis that paracrine factors released from MSC promote CM re-entry cell-cycle and proliferation. Wnt11 may serve as a positive regulator of CM proliferation.
Abstract 14886: The Association Between Acculturation and Hypertension Prevalence among South Asian Immigrants in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study
Authors: Kong Allison , Shoham David A , Kramer Holly , Kandula Namratha
Published: July 2021

Introduction:
South Asians are the second fastest growing ethnic minority group in the US. Despite a modest body mass index, South Asians have a high and early prevalence of cardiovascular disease risk factors, including high blood pressure (BP). The majority of South Asians are immigrants, thus behavior and lifestyle changes may play a role in the development of elevated BP. This paper examines the hypothesis that greater acculturation is associated with hypertension (HTN) in US South Asians.

Methods:
We examined baseline data (2010 to 2013) of 906 subjects (54% male; mean age 55 ± 9 years) in the Mediators of Atherosclerosis in South Asians Living In America study. HTN was defined by: systolic BP ≥ 140 mmHg, diastolic BP≥ 90 mmHg, and/or use of hypertensive medication. Acculturation was defined by 4 proxy variables and 1 summary score: place of birth, English language proficiency, length of US residency, traditional South Asian beliefs scale, and a summary score of all 4 variables ranging from 0 to 6 (higher score=more acculturated). Multiple logistic regression was used to study the associations between measures of acculturation and HTN, adjusted for sex, age group and education. Interaction with adjustment variables and significant main effects were examined. Likelihood ratio tests were used for statistical significance.

Results:
The cohort’s overall prevalence of HTN was 41%. We did not find significant associations between HTN and any acculturation measures except English language proficiency, which was associated with lower odds of HTN (OR=0.70; 95% CI: 0.52-0.95; p=0.02). There were evidence of interactions between English proficiency and age (p=0.08), and English proficiency and education (p=0.09): the odds of HTN were lower in older adults who were proficient in English compared to younger adults who were not (OR=0.69; 95% CI: 0.49-0.98; p=0.038) and in South Asians who were English-proficient and had higher education compared to non-fluent speakers who were less educated (OR=0.55; 95% CI: 0.35-0.87; p=0.011).

Conclusion:
English language proficiency was associated with lower adjusted odds of HTN in older and more highly educated South Asians. The mechanisms through which language and CVD risk factors are linked deserve further exploration.
Abstract 14994: How Low Should You Go in Secondary Prevention Treatment of LDL Cholesterol: Observational Insights from the Intermountain Heart Collaborative Study
Authors: Muhlestein Joseph B , May Heidi T , Lappé Donald L , Bair Tami L , Le Viet T , Anderson Jeffrey L
Published: July 2021

Introduction:
Epidemiologic studies have identified high LDL cholesterol levels as an independent risk factor for cardiovascular (CV) disease, and randomized trials with statin therapy have demonstrated added clinical benefit when LDL levels are reduced to at least 70 mg/dL. However, whether targeting significantly lower secondary prevention LDL levels is beneficial, or perhaps actually may be unsafe, is not known.

Methods:
Patients undergoing coronary angiography who were documented to have significant (≥50% stenosis) coronary artery disease (CAD), discharged on statin therapy with an LDL level <100 mg/dL and had ≤3y clinical follow-up were studied. Patients were stratified, according to on-statin LDL levels, into ultra low (<40 mg/dL [n=221]), very low (40-69 mg/dL [n=1,684]) and low (70-99 mg/dL [n=3,317]) categories and followed for the long-term endpoints of all-cause death, cardiac death, non-cardiac death, MI, stroke, coronary revascularization (CR) and MACE (death, MI, stroke, CR). Hazard ratios (HRs) comparing the three LDL groups were calculated by Cox regression, adjusting for 17 baseline variables.

Results:
A total of 5,222 patients (age = 66±12 yrs, men = 72%, hypertension = 69%, diabetes = 30%, smokers = 29%, ACS presentation = 69%) were studied. Follow-up for the ultra low, very low and low LDL categories was 6.1±4.3, 6.4±3.9 and 7.3±4.1 yrs respectively. Event rates and adjusted HRs are shown in the Table.

Conclusions:
In a large secondary prevention population with significant CAD on statin therapy, treating LDL cholesterol levels to <70 mg/dL compared to 70-99 mg/dL was not associated with superior long-term CV outcomes. From a non-CV standpoint, LDL levels down to 40 mg/dL appeared to be safe, but ultra low LDL levels (<40 mg/dL) were associated with a significantly increased risk of non-CV death. Based on this information, very aggressive secondary prevention treatment of LDL cholesterol to levels below 40 mg/dL may require further study.
Abstract 15: Increasing Compression Rate and Depth Positively Correlate with End-Tidal Carbon Dioxide During Actual CPR Performance
Authors: Sheak Kelsey , Wiebe Douglas J , Babaeizadeh Saeed , Yuen Trevor C , Zive Dana , Owens Pamela C , Edelson Dana P , Daya Mohamud , Idris Ahamed H , Abella Benjamin S , Leary Marion
Published: July 2021

Background:
Current resuscitation guidelines suggest the use of continuous capnography to monitor the effectiveness of CPR. While laboratory data support this concept, little published clinical data exist to support this recommendation. The quantitative relationship between chest compression (CC) delivery and capnographic measurement (specifically, end-tidal CO
2
(ETCO
2
)) is poorly understood, and has important implications for CPR quality assessment.

Objectives:
We hypothesized that increasing rate and depth of CC will be associated in real-time with increasing ETCO
2
during both in-hospital cardiac arrest (IHCA) and out-of-hospital cardiac arrest (OHCA).

Methods:
In a multicenter cohort study, we captured time synchronized ETCO
2
and CPR quality data from resuscitation events at 4 sites between 04/2006 [[Unable to Display Character: –]] 05/2013 using CPR-sensing defibrillators (Philips Mrx-QCPR). ETCO
2
and CC rate and depth were averaged over 15-sec epochs. A linear regression analysis was performed to evaluate the relationship between CCs and ETCO
2
.

Results:
29,028 epochs were processed for analysis from 583 arrest events (227 IHCA, 356 OHCA). Average age of the entire cohort was 63.7±17.1 and 213 (37%) were female. ROSC was achieved in 42% of IHCA patients and 27% of OHCA patients. CC rate range was 95-125 per min, CC depth range was 31-59 mm and ventilation rate range was 4-48 per min. CC rate was not significantly associated with ETCO
2
. CC depth was significantly associated with increased ETCO
2
. For every 10 mm increase in depth, ETCO
2
increased by 1.4 mmHg (p<.001). Ventilation rate was inversely related to higher ETCO
2
. For every 10 breaths per min increase in ventilation rate, ETCO
2
was decreased by 3.0 mmHg (p<.001) (see table).

Conclusions:
ETCO
2
during CPR directly correlated with CC depth, supporting the possible role of capnography as an approach to monitor the quality of CPR delivery. Confounding by ventilation rate may be an important consideration for future work.
Abstract 15002: Towards Unmasking Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy in the Early Concealed Stage
Authors: Mast Thomas P , Teske Arco J , vd Heijden Jeroen F , Groeneweg Judith A , Doevendans Pieter A , Loh Peter , Hauer Richard N , Cramer Maarten J
Published: July 2021

Background:
The concealed stage of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is associated with increased risk of sudden cardiac death. However, particular at this stage disease detection is hampered by absence of criteria. Activation delay (AD) is a hallmark of arrhythmogenesis in ARVD/C. Echocardiographic tissue Doppler imaging (TDI) may unmask AD in the absence of electrocardiographic (ECG) abnormalities.

Methods:
Three groups were compared 1) symptomatic definite ARVD/C patients with a mutation in the Plakophilin-2 (
PKP2)
gene (n=37), 2) asymptomatic
PKP2
mutation carriers (n=20) and 3) healthy controls (n=30). All groups underwent full echocardiographic examination with additional TDI of the right ventricular (RV) free wall and a routine 12-lead ECG recording. As surrogate for AD the electro-mechanical interval (EMI) was measured, defined as time between local first electrical deflection and local onset of mechanical shortening. EMI was measured in the subtricuspid, mid and apical region of the RV free wall. Detailed ECG analysis of depolarization (AD analysis) and repolarization abnormalities was performed in all subjects.

Results:
EMI was prolonged in all RV segments in ARVD/C patients compared to controls. Abnormal depolarization and repolarization was recorded in respectively 23 and 27 ARVD/C patients. In asymptomatic mutation carriers EMI was significantly prolonged in the subtricuspid area (Table 1). However, the ECG showed in 5/20 subjects only prolonged terminal activation duration and no repolarization abnormalities.

Conclusion:
TDI unmasks AD in both ARVD/C patients and asymptomatic mutation carriers. In asymptomatic mutation carriers EMI is prolonged in the subtricuspid area, whereas ECG appeared normal in the large majority. AD in the subtricuspid area is an early sign of disease in the concealed ARVD/C stage and may contribute to advanced risk stratification.

Table 1: Results
Abstract 15010: Disruption of Outer Mitochondrial Membrane Protein, MitoNEET, Increases Mitochondrial Iron Content in the Heart
Authors: Furihata Takaaki , Kinugawa Shintaro , Matsushima Shouji , Takada Shingo , Fukushima Arata , Mizushima Wataru , Kadoguchi Tomoyasu , Masaki Yoshihiro , Yokota Takashi , Tsutsui Hiroyuki
Published: July 2021

Background:
Iron in the mitochondria is regulated to maintain mitochondrial physiological function. A loss of mitoNEET protein located in the outer mitochondrial membrane has been shown to increase mitochondrial iron content in adipocytes. However, the role of mitoNEET in iron homeostasis has not been determined in the heart.

Methods and Results:
MitoNEET flox/flox (mNT
f/f
) mice were generated with lox-P and homologous recombination strategies. Cardiac-specific deletion of mitoNEET was achieved using αMHC-Cre (mNT
-/-
). Mice, mNT
-/-
(n=11) and mNT
f/f
(n=10), were bred for 3 months. Mitochondrial iron content, measured by colorimetric method, was significantly increased in mNT
-/-
mice compared to mNT
f/f
mice (1.13±0.09 vs. 0.58±0.07 μg/dl/μg mitochondrial protein, P<0.001). In parallel, immunoblot analysis showed that mitochondrial ferritin, mitochondrial iron transporter, was significantly higher in mNT
-/-
than mNT
f/f
by 45%. Mitoferrin2, mitochondrial iron importer, and ATP-binding cassette transporter type B8, mitochondrial iron exporter, protein did not differ between groups. The activity of electron transport chain complex V, mitochondrial iron importer, was also higher in mNT
-/-
than mNT
f/f
(617±22 vs. 496±17 mM/min/mg mitochondrial protein, P<0.05). In contrast, frataxin, involved in the synthesis of iron-sulfur cluster (ISC), was significantly lower in mNT
-/-
by 49%. ATP-binding cassette transporter type B7, mitochondrial ISC exporter, did not differ. Body weight and heart weight were comparable between groups. Left ventricular end-diastolic diameter (2.9±0.1 vs. 2.9±0.1 mm), percent fractional shortening (55±3 vs. 55±3 %), and wall thickness (0.71±0.01 vs. 0.73±0.01 mm) measured by echocardiography were also similar.

Conclusions:
Cardiac specific deletion of mitoNEET protein increased mitochondrial iron content in mice, in association with the increase in iron importer and transporter and the decrease in frataxin, suggesting that mitoNEET may play an important role in the regulation of mitochondrial function via iron homeostasis in the heart.
Abstract 15058: Disruption of Extracellular Cytotoxic Chromatin by Acute DNase1 Administration Improves Left Ventricular Remodeling after Myocardial Infarction
Authors: Vogel Benjamin , Shinagawa Hisahito , Hofmann Ullrich , Ertl Georg , Frantz Stefan
Published: July 2021

Rationale:
Myocardial infarction (MI) leads to necrosis of multinucleated and polyploid myocytes. This causes uncontrolled release of cellular content like chromatin to the infarct area. Chromatin is mainly comprised of histones which are essential for controlling and packing of DNA but paradoxically are also known to be cytotoxic. This makes free chromatin a toxic DNA polymer creating local high concentrations of hazardous histones.

Objective:
We hypothesized that chromatin from necrotic cells accumulates in ischemic myocardium, creates local high concentrations of cytotoxic histones, and thereby potentiates ischemic damage to the heart after MI. The endonuclease DNase1 is capable of dispersing extracellular chromatin through linker DNA digestion and could decrease local histone concentrations and cytotoxicity.

Methods and Results:
After permanent coronary artery ligation in mice we found extracellular histones accumulated within the infarcted myocardium. Histone cytotoxicity towards isolated myocytes was confirmed in vitro. To reduce histone related cytotoxicity in vivo DNase1 was injected within the first 6 hours after induction of MI. DNase1 accumulated in the infarcted region of the heart, effectively disrupted extracellular cytotoxic chromatin and thereby reduced high local histone concentration. Animals acutely treated with DNase1 revealed significantly improved left ventricular remodeling as measured by serial echocardiography up to 28 days after MI (e.g. NaCl vs DNase1, papillary end diastolic area [mm
2
]: 23.26 ± 2.06 vs 18.90 ± 1.24, n=9 vs 10, p<0,05). Treatment did not influence mortality, infarct size or inflammatory parameters as determined by neutrophil infiltration and RTQ-PCR analysis of characteristic cytokines. However improved myocyte survival was discovered within the infarct region which might account for the protective effects in DNase1 treated animals (NaCl vs DNase1: 3.0 ± 0.7% vs 8.3 ± 2.3%; p<0.05; n=7 vs 8).

Conclusions:
Targeting extracellular cytotoxic chromatin within the infarcted heart by DNase1 is a promising approach to preserve myocytes from histone induced cell death and to conserve left ventricular function after MI. The efficacy of other chromatin degrading agents is now under investigation.
Abstract 15088: Scar Pattern in Chagas Heart Disease
Authors: Traina Mahmoud I , Thomas Mariam , Bradfield Jason , Hernandez Salvador , Altamirano Ufion Alvaro J , Sanchez Daniel R , Meymandi Sheba K
Published: July 2021

Introduction:
Scar in Chagas heart disease (CHD) is thought to be predominantly epicardial and requires epicardial access for ventricular tachycardia (VT) ablation. However, little data exists on scar patterns in this population. We evaluated the patterns of scar in patients who underwent magnetic resonance imaging (MRI) with delayed enhancement (DE).

Methods:
19 patients were enrolled who had evidence of DE by MRI: 4 (21.0%) patients with normal electrocardiogram (ECG) and normal echocardiogram (echo) (group 1); 3 (15.8%) patients with abnormal ECG and normal echo (group 2); and 12 (63.2%) patients with abnormal ECG and echo (group 3).

Results:
In the 19 patients, there were 110 segments (34.1%) with DE identified using a 17-segment model. Pattern of involvement is as follows: endocardial 30 (27.3%), mid-myocardial 22 (20.0%), epicardial 2 (1.8%) and transmural 56 (50.9%). Most common territories of involvement are as follows (% of patients with segment involved): Basal inferolateral (78.9%), basal anterolateral (68.4%), mid inferolateral (63.2%), mid anterolateral (52.6%), apical lateral (52.6%) and apex (42.1%).

The pattern of involvement also varied by group. In group 1, mid-myocardial 7 (50%), endocardial 6 (42.9%), transmural 1 (7.1%). In group 2, mid-myocardial 2 (18.2%), endocardial 6 (54.5%), transmural 3 (27.3%). In group 3, mid-myocardial 13 (15.3%), endocardial 18 (21.2%), transmural 52 (61.2%), epicardial 2 (2.4%).

Conclusion:
DE tends to occur most commonly in the basal and mid lateral segments. At earlier stages of disease, myocardial scar pattern tends to involve mid-myocardium and endocardium, and progress to transmural in later stages. Isolated epicardial scar was rare in this patient population, which is has potential implications for VT ablation strategies.
Abstract 15125: Percutaneous Transluminal Pulmonary Angioplasty Improves Hemodynamics and Right Ventricular Function in Patients with Chronic Thromboembolic Pulmonary Hypertension -One Year Follow-up Study
Authors: Miura Masanobu , Sugimura Koichiro , Nochioka Kotaro , Aoki Tatsuo , Tatebe Shunsuke , Yamamoto Saori , Yaoita Nobuhiro , Sato Haruka , Sato Kimio , Shimokawa Hiroaki
Published: July 2021

Objectives:
Right ventricular function (RV) is an important prognostic indicator of pulmonary hypertension. Recent studies have demonstrated that percutaneous transluminal pulmonary angioplasty (PTPA) improves pulmonary hemodynamics in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). In this study, we examined whether PTPA also improves right ventricular dysfunction in those patients.

Methods:
We performed a total of 252 PTPA procedures (median 4 procedures per patient) for 56 consecutive patients with inoperable CTEPH, after stabilizing their condition using conventional pulmonary vasodilators. Among them, we enrolled 33 patients who had finished 1-year follow-up after final PTPA in the present study (female 81.8%, median age 60 yrs.). RV function was evaluated by tricuspid annular plane systolic excursion (TAPSE) on echocardiogram (42.4%, n=14) and RV ejection fraction (RVEF) on cardiac magnetic resonance imaging (39.4%, n=13) before and after PTPA.

Results:
No patient died during the PTPA procedure or during the 1-year follow-up period. Comparisons before and after PTPA showed marked improvement of WHO functional class III/IV (75.7 to 0%, P<0.001), 6-min walking distance (316 to 480 m, P<0.001), and brain natriuretic peptide level (93 to 23 pg/ml, P<0.001) and significant hemodynamic improvements for mean pulmonary artery pressure (42.3±10.7 to 24.4±5.7mmHg, P<0.001), cardiac index (2.2±0.6 to 2.7±0.6 L/min•m2, P<0.001) and pulmonary vascular resistance (786±384 to 265±93 dyn•sec•cm5, P<0.001). Furthermore, RV function was also significantly improved for both TAPSE (18.0±4.0 to 23.4±4.3mm, P<0.001) and RVEF (37.9±11.0 to 52.4±7.1%, P<0.001) (Figure).

Conclusions:
PTPA improves not only pulmonary hemodynamics but also RV function in patients with inoperable CTEPH.
Abstract 15155: Supracardiac Type (1a) Total Anomalous Pulmonary Venous Return with Right to Left Shunt Atrial Septal Defect Diagnosed by 320 Slice CT
Authors: Funabashi Nobusada , Takaoka Hiroyuki , Ozawa Koya , Kobayashi Yoshio
Published: July 2021

The first choice of imaging modality to evaluate complex congenital heart disease, especially in infants, is transthoracic echocardiogram (TTE) and magnetic resonance imaging. But to evaluate anatomic details of the heart, including coronary arteries with surrounding structures, CT is most useful.

We experienced a patient who was diagnosed as having supracardiac type total anomalous pulmonary venous return (TAPVR) with a right to left shunt atrial septal defect (ASD) by 320 slice CT.

A 63-year-old female who had palpitations and dizziness was referred to our hospital because of cardiac enlargement shown on chest X ray in a health examination. On chest X ray, enlargement of protrusion of the right first and left first aortic arches was observed. ECG revealed ectopic low part atrial rhythm, right axis deviation of the QRS wave, and incomplete right bundle branch block.

On TTE, ASD with right to left shunt was observed, presence of Eisenmenger syndrome was suspected and there seemed to be no surgical indication. But on TTE, right heart configuration seemed not due to pressure load but volume load, which is not indicative of Eisenmenger syndrome.

To evaluate the presence of other complications of anatomical cardiovascular heart disease, ECG-gated 320 slice CT (Aquilion ONE, Toshiba Medical) was performed. On CT, supracardiac type TAPVR with right to left shunt ASD could be accurately diagnosed. She then underwent TAPVR surgical repair from the superior approach in which total PV connected to the LA and ligated innominate vein and ASD pericardial patch closure. By this procedure, there was no blood flow from PV to the right heart, with blood from the PV flowing into the LA directly. Hemodynamics was normalized.

In summary, this patient had remarkable cardiac enlargement on chest X-ray, and on TTE ASD with right-to-left shunt was detected. 320 slice CT can evaluate complex congenital heart disease as well as coronary arteries accurately and provide information on blood flow.
Abstract 15161: Impact of Malnutrition Score Index on Short-term Clinical Outcome in Patients with Acute Decompensated Heart Failure
Authors: Iwakami Naotsugu , Nagai Toshiyuki , Sugano Yasuo , Yamane Takafumi , Shibata Tatsuhiro , Nakamura Kenji , Chinen Daigo , Asaumi Yasuhide , Aiba Takeshi , Noguchi Teruo , Kusano Kengo , Ishihara Masaharu , Ogawa Hisao , Yasuda Satoshi , Anzai Toshihisa
Published: July 2021

Backgrounds:
Recent studies have elucidated the association between malnutrition and poor long-term prognosis in patients with chronic heart failure (HF), using controlling nutritional status (CONUT) score, a simple and useful index for evaluating malnutrition. In this study, we aim to investigate the prognostic significance of CONUT score in patients with acute decompensated HF.

Methods:
We examined 320 consecutive patients in our prospective acute decompensated HF registry database from January 2013 to January 2014. Patients with acute coronary syndrome, in-hospital death, and without complete data-set at discharge were excluded. Finally, we selected 206 patients as a study population and malnutrition was defined as CONUT score above 3 at discharge.

Results:
112 (54%) patients showed malnutrition at discharge. Patients with malnutrition had higher age, serum creatinine and plasma brain natriuretic peptide levels, and lower serum sodium level at discharge than those without. There were no significant differences between the groups in terms of sex, blood pressure, heart rate, left ventricular ejection fraction, etiology of HF and cardiovascular medications at discharge. During the median follow-up of 192 days (interquartile range = 109-260 days), malnutrition was associated with higher short-term adverse events including death and HF admission (P = 0.008, Figure). Cox proportional-hazards model analysis demonstrated that malnutrition was independently associated with adverse events (HR 2.00, 95% CI 1.01-4.17, P = 0.047), even after adjustment among variables including age (HR 1.04, 95% CI 1.00-1.08, P = 0.03) and serum sodium level (HR 0.93, 95% CI 0.88-1.00, P = 0.04).

Conclusions:
In patients with acute decompensated HF, malnutrition at discharge was independently associated with worse short-term clinical outcomes. These findings suggest that earlier intensive nutrition management might need to be considered.