bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12971: Oxidative Stress in Children With Left to Right Shunt Congenital Heart Disease
Authors: Ishikawa Takamichi , Uchiyama Hiroki
Published: May 2021

Background:
Oxidative stress has recently been noted as a factor involved in myocardial remodeling and has been reported to be a predictor of heart failure severity and cardiac death in adults. However, its relevance in the pediatric field is unclear.

Objective:
This study aimed to investigate the reference range of oxidative stress dynamics and evaluate the role of oxidative stress in children with left to right shunt congenital heart disease (CHD).

Methods:
The subjects consisted of 40 patients (CHD group) with left to right shunt CHD who underwent cardiac catheterization at Hamamatsu University Hospital and 105 healthy children. The oxidative stress markers were measured in blood derivatives of reactive oxygen metabolites (ROM; adult reference value 250-300 U. CARR). We examined the dynamics of ROM in healthy children and then compared the various parameters, including ROM, in 40 age- and sex-matched healthy controls (control group).

Results:
The median age of the CHD group (21 boys and 19 girls) was 9.5 months (interquartile range: 2.8-32.0 months). CHD consisted of 27 cases of ventricular septal defect, 8 cases of atrial septal defect, 4 cases of patent ductus arteriosus, and 1 case of atrioventricular septal defect. In the healthy children, ROM showed a significant positive correlation with age (r = 0.482, p <0.001). The blood ROM of the CHD group (292 ± 84 U.CARR) was significantly higher (p <0.001) than that in the control group (199 ± 82 U.CARR), and the ROM showed a significant positive correlation with the pulmonary-to-systemic blood flow ratio (r = 0.333, p = 0.022), the percentage of left ventricular end diastolic volume (r = 0.503, p <0.001), and the percentage of right ventricular end diastolic volume (r = 0.771, p <0.001). The area under ROC curve of ROM for pulmonary-to-systemic-blood-flow ratio > 1.5 was 0.741 (95% CI: 0.576-0.906, p=0.026), with a cut-off value of 293 U.CARR.

Conclusions:
ROM, an indicator of oxidative stress, showed a gradual upward trend with age in childhood, and this transition was confirmed to differ from that of NT-proBNP, which decreases to a steady state after marked elevation in the early neonatal period. These findings suggest that ROM is a biological marker reflecting at least the volume load in left to right shunt CHD.
Abstract 12986: Geriatric Nutritional Risk Index Provides the Additional Long-term Prognostic Information to Gwtg Heart Failure Risk Score in Acute Decompensated Heart Failure Patients With and Without Reduced LVEF
Authors: Yamada Takahisa , Watanabe Tetsuya , Morita Takashi , Furukawa Yoshio , Tamaki Shunsuke , Kawasaki Masato , Kikuchi Atsushi , Kawai Tsutomu , Seo Masahiro , Nakamura Jun , Kayama Kiyomi , Kawahira Masatsugu , Ueda Kumpei , Kimura Takanari , Sakamoto Daisuke , Fukunami Masatake
Published: May 2021

Backgrounds:
The Get with The Guidelines (GWTG) heart failure (HF) risk score was developed in the GWTG inpatient HF registry to predict in-hospital mortality and has been recently reported to be associated with post-discharge long-term outcomes. Malnutrition is associated with poor outcome in ADHF patients. However, there is no information available on the long-term prognostic significance of the combination of GWTG-HF risk score and malnutrition in patients admitted for ADHF, relating to reduced left ventricular ejection fraction (LVEF).

Methods:
We studied 303 ADHF patients discharged with survival (HFrEF(LVEF<40%); n=180, HFpEF(LVEF≥40%;n=123). At the admission, we evaluated GWTG-HF score and nutritional status. Variables required for the GWTG-HF risk score were race, age, systolic blood pressure, heart rate, serum levels of blood urea nitrogen and sodium, and the presence of chronic obstructive pulmonary disease. Nutritional status was evaluated by Geriatric Nutritional Risk Index (GNRI) calculated as follows: 14.89 · serum albumin (g/dl) + 41.7 · BMI/22, and malnutrition was defined as GNRI<92. The study endpoint was cardiovascular-renal poor outcome (CVR), defined as cardiovascular death and the development of end-stage renal disease requiring renal replacement therapy.

Results:
During a follow-up period of 4.2±3.3 yrs, 86 patients had CVR. At multivariate Cox analysis, GWTG-HF risk score and GNRI were significantly and independently associated with CVR, in both HFrEF and HFpEF groups. The patients with both greater GWTG-HF score (>median value=35) and malnutrition had a significantly increased risk of CVR than those with either and none of them ([HFrEF] 60% vs 32% vs 16%, p<0.0001, [HFpEF] 45% vs 18% vs 12%, p<0.0001, respectively)

Conclusion:
Malnutrition assessed by GNRI would provide the additional long-term prognostic information to GWTG-HF risk score in patients admitted for ADHF, irrespective of the presence of reduced LV function.
Abstract 12999: Correcting the Current: Modeling the Hemodynamic Impact of Transcatheter Aortic Valve Replacement in Multiple Valvular Heart Disease Precipitating Cardiogenic Shock
Authors: Brener Michael I , Patel Amisha , Vahl Torsten , Hamid Nadira , Yuzefpolskaya Melana , Burkhoff Daniel , Kodali Susheel K
Published: May 2021

Introduction:
Multiple valvular heart disease (mVHD) caused by mixed stenotic and regurgitant lesions involving at least two valves is a common condition which is poorly understood and challenging to manage. Herein, we simulate the hemodynamics of a patient with mVHD before and after transcatheter aortic valve replacement (TAVR) to better understand the physiology of this complex disease.

Case:
A 67-year-old man with celiac enteropathy presented to a local hospital with dyspnea, hypotension, and oliguria. Echocardiography revealed a dilated left ventricle (end-diastolic diameter [LVEDD] 6.7 cm) with an ejection fraction (EF) of 20% and multiple severe valvulopathies, including aortic stenosis (AS), aortic regurgitation (AR), and mitral regurgitation (MR). Right heart catheterization revealed a low cardiac index (1.76 L/min/m
2
) and a high wedge pressure (36 mmHg) with V-waves exceeding 50 mmHg. The patient’s severe AR precluded mechanical circulatory support, so TAVR was emergently performed in the setting of worsening cardiogenic shock (CS) with a 29 mm self-expanding bioprosthesis via transfemoral access. Valve deployment was successfully guided by fluoroscopy and transthoracic echocardiography alone. CS resolved in the subsequent 48 hours, and at 3-month follow-up, his LV EF returned to 55% and LVEDD decreased to 4.4 cm. LV pressure-volume loops pre- and post-TAVR were generated using a cardiovascular physiology simulator (Fig. 1). TAVR’s correction of the patient’s severe AS and AR produced immediate energetic benefits, with pressure-volume area declining 13% and cardiac power output increasing 2.24-fold.

Conclusions:
This challenging case and the accompanying pressure-volume analysis affirms the feasibility of emergent TAVR in highly selected patients, the procedure’s ability to immediately improve ventricular performance, and the LV’s capacity to remodel when operating under more physiologic loading conditions.
Abstract 13010: Endothelin-1 Increases ACVRL-1 Expression at the Transcriptional and Post-transcriptional Levels in Human Pulmonary Arterial Endothelial Cells via Gi, RhoA and Rho Kinase Pathway With Involvement of Sp-1
Authors: Sugimoto Koichi , Yokokawa Tetsuro , Misaka Tomofumi , Yokokawa Sayoko , Nakazato Kazuhiko , Ishida Takafumi , Takeishi Yasuchika
Published: May 2021

Backgrounds:
Pulmonary arterial hypertension (PAH) is characterized by pulmonary vasoconstriction and organic stenosis due to abnormal proliferation of pulmonary vascular cells. Endothelin (ET)-1 induces pulmonary vasoconstriction hyperplasia and plays a pivotal role in the pathogenesis of PAH. The germline mutations of activin receptor-like kinase (ACVRL)-1, a serine/threonine kinase and receptor for TGF-β, have been reported in idiopathic and hereditary PAH. However, the relationship between ET-1 and ACVRL-1 in the pathogenesis of PAH is largely unknown. Thus, we investigated the molecular mechanism of ACVRL-1 expression induced by ET-1 in human pulmonary arterial endothelial cells (hPAECs).

Methods:
ACVRL-1 expression levels were measured using Western blotting and quantitative real-time polymerase chain reaction. The promoter activity of ACVRL-1 was evaluated using dual luciferase assay. hPAECs were pretreated with pertussis toxin (PTX), cell-permeable C3 toxin (C3T) and Y27632 to inhibit Gi, RhoA and Rho kinase, respectively. GTP-RhoA, an active form of RhoA, was assessed using pull-down assay.

Results:
ET-1 increased mRNA and protein expression of ACVRL-1 in hPAECs (1.8±0.2 folds, P<0.05; 1.5±0.4 folds, P<0.05, respectively). The pull-down assay showed that ET-1 induced GTP-loading of RhoA. ET-1-induced RhoA activation was suppressed by PTX pretreatment. Furthermore, PTX, C3T, and Y27632 suppressed ET-1-induced ACVRL-1 expression. The transcriptional activity of the ACVRL-1 promoter was increased by ET-1 by 1.2±0.17 folds (P<0.05 vs. control). Moreover, ACVRL-1 mRNA was stabilized by ET-1 treatment, and the effect was canceled by Y27632. Finally, the expression of Sp-1, one of known transcriptional factors for ACVRL-1, was increased with a peak at 15 min after ET-1 treatment, and PTX, C3T and Y27632 significantly inhibited the Sp-1 induction by ET-1.

Conclusion:
These data indicate that ET-1 increases ACVRL-1 expression both at transcriptional and post-transcriptional mechanisms via the Gi/RhoA/Rho kinase/Sp-1 axis in human PAECs.
Abstract 13015: First-degree Atrioventricular Block is Associated With Incident Atrial Fibrillation in the Japanese General Population Aged ≥ 40 Years
Authors: Tanaka Yoshihiro , Patel Ravi B , Tada Hayato , Hayashi Kenshi , Takamura Masayuki , Kawashiri Masa-aki , Greenland Philip
Published: May 2021

Introduction:
First-degree atrioventricular block (fAVB) is a common cardiac conduction disorder diagnosed by prolongation of the PR interval ≥220 msec. Although it is generally considered benign, some previous studies demonstrated that fAVB was associated with incident atrial fibrillation (AF). However, evidence is scarce regarding the association between fAVB and incident AF in older populations.

Hypothesis:
We hypothesized that fAVB was significantly associated with incident AF in older populations.

Methods:
Eligible participants were residents in Kanazawa City who aged ≥ 40 years and underwent 12-lead ECG at the national Japanese health checkups in 2013. Participants with AF detected at the baseline exam and with no follow-up examinations between 2014 and 2018. fAVB was defined as PR interval ≥ 220 msec based on the Minnesota code (6-3). Incident AF was defined as the first episode of AF detected by 12-lead ECG at the annual health checkups. The cumulative incidence of AF was estimated by the Kaplan Meier curve analysis, and statistical significance was evaluated by the log-rank test. Unadjusted and adjusted hazard ratios (HRs) were computed by the Cox proportional hazard model. HRs were adjusted using three models in which conventional risk factors for AF were included (Table).

Results:
37,730 participants (mean age, 72.3 ± 9.6 years; Male, 37%) were included. Baseline fAVB was observed in 667 (1.8%) participants. During the median follow-up period of 5 years (interquartile range, 4.0 - 5.0 years), 691 cases of incident AF were observed. Kaplan Meier curve showed that a 5-year cumulative incidence of AF was significantly higher in fAVB (+) group compared with fAVB (-) group (6.8% vs 2.1%, p < 0.01). In the fully adjusted model, fAVB was significantly associated with incident AF (HR, 1.75; 95% confidence interval, 1.25 - 2.45; p-value < 0.01) (Table).

Conclusion:
fAVB was independently associated with incident AF in this predominantly elderly Japanese population.
Abstract 13017: Administration of Intramyocardial Chemokine Induce Myocardial Recovery by Modulating the Acute Inflammatory Response to Ischemia
Authors: Arora Rohan Shad , Pedroza Albert J , Quach Nicolas , Fong Robyn , Kong Sandra , Kasinpila Patpilai , Callon Kate M , Howland Julian , Fischbein Michael P , Hiesinger William
Published: May 2021

Introduction:
We have previously shown that the exogenously injected chemokines induce robust myocardial recovery and angiogenesis after a myocardial infarction (MI). Angiogenesis, however, is a late response, and the acute cellular drivers of chemokine induced recovery remain elusive. Recently it has been shown that an acute macrophage response is central to post-MI recovery after stem-cell injections. As many chemokines act as immunomodulators, we hypothesized that both angiogenic chemokines (SDF-1) and non-angiogenic chemokines of viral origin (vMIP-II) can similarly elicit a macrophage response.

Methods:
MI was surgically induced in 39 male and female C57BL/6 mice (6-8 weeks old) by ligation of the left anterior descending coronary artery. Mice were randomly assigned to receive intramyocardial injections of PBS (saline), SDF-1, or vMIP-II. Two hearts from each treatment group were explanted at post-operative day 3 (P3) for single cell suspension preparation. Viable cells were used for single cell RNA sequencing (scRNAseq). Echocardiography was performed for all remaining mice at P7 to assess for functional recovery, and hearts were explanted for histology at P14.

Results:
Treatment with both SDF-1 and vMIP-II led to significant functional recovery assessed via echocardiography at P7, one week in advance of arteriolar collateralization (Ejection Fraction 0.38 ± 0.14 and 0.50 ± 0.15 in SDF-1 and vMIP respectively; 0.27 ± 0.13 in PBS; t-test adjusted p = 0.023). scRNAseq of 7918 captured cells showed a robust acute inflammatory macrophage response at P3 across treatment groups. A robust expansion of Arginase-1 (Arg1+) macrophages - a known M2 anti-inflammatory subtype - was seen specifically in chemokine treated mice at P3 (9% in PBS vs 16.5% in both SDF-1 and vMIP-II).

Conclusions:
We show that vMIP-II triggers myocardial recovery similar to SDF-1. Furthermore, we show a robust and consistent Arg1+ macrophage response present in both treatment groups.
Abstract 13068: Epsilon and Inverted T Waves in Right Side Precordial Leads in Pulmonary Hypertensive Patients With or Without Right Ventricular Hypertrophy or Fibrosis on Cardiac Computed Tomography
Authors: FUNABASHI Nobusada , Ozawa Koya , Kobayashi Yoshio
Published: May 2021

Introduction:
Epsilon and inverted T waves on V1-3 leads are known as specific ECG findings in patients with arrhythmogenic right ventricular (RV) cardiomyopathy (ARVC), which suggests the presence of RV conduction delay. Right bundle branch block (RBBB) is often observed in ARVC. In patients with pulmonary hypertension (PH) due to RV pressure load, the occurrence of RV hypertrophy and fibrosis are frequently observed, which may also lead to the occurrence of RV conduction delay and epsilon waves.

Hypothesis:
We hypothesized that there were epsilon and inverted T waves in right side precordial leads on ECG in PH patients with RV hypertrophy and/or RV fibrosis, both confirmed on cardiac CT.

Methods:
We retrospectively analyzed 43 patients (33 females, 55 ± 15 years, 31 chronic thromboembolic PH, 7 idiopathic pulmonary arterial hypertension) with proven PH by right heart catheterization. On CT, RV fibrosis was defined as a contrast defect in the early phase and a conversely abnormal enhancement in the late phase.

Results:
32 and 9 patients had RV hypertrophy and RV fibrosis, respectively; of these, 4 had both. Of 32 PH patients with RV hypertrophy, 2 had complete RBBB and 8 had incomplete RBBB. Of 22 PH patients with RV hypertrophy but without any RBBB, only one (5%) had typical epsilon waves and 2 (9%) had waves with abnormal small upward spikes after the QRS wave that were more marked in II and aVF leads than V1 and 2 leads; these were not typical epsilon waves. 14 had a negative T wave in V1-3 leads (5 had only a V1 lead, one had only V1 and 2 leads, 4 had only V1-3 leads, and 4 had V1-4 leads, respectively). Of 9 PH patients with RV hypertrophy, one had complete RBBB and one had incomplete RBBB. Of 7 PH patients with RV fibrosis but without any RBBB, none (0%) had epsilon waves in V1-3 leads. All 7 had a negative T wave in V1-3 leads (3 had only a V1 lead, one had only V1 and 2 leads, 2 had only V1-3 leads, and one had V1-4 leads).

Conclusions:
In a total of 37 PH participants with an organized RV myocardial change, such as RV hypertrophy and fibrosis confirmed on cardiac CT, only one (3%) had typical epsilon waves that are frequently found in patients with ARVC. The mechanism of epsilon waves occurring predominantly in V1-3 leads seems not only to be caused by an organised RV myocardium, but also by other factors.
Abstract 13069: NLRP3 Inflammasome Promotes Vasculitis of Kawasaki Disease
Authors: Anzai Fumiya , Kimura Hiroaki , Takeishi Yasuchika , Takahashi Masafumi
Published: May 2021

Introduction:
Kawasaki disease (KD) is a systemic febrile syndrome which causes coronary arteritis.
Candida albicans
water-soluble fraction (CAWS) is a mannoprotein-β-glucan complex obtained from the culture supernatant of
Candida albicans
, and frequently used as a murine KD model, because administration ofCAWS induces coronary arteritis. NLRP3 inflammasome is a large multiprotein complex (NLRP3, ASC and caspase-1), and regulates the release of the potent inflammatory cytokine IL-1β. We hypothesized that NLRP3 inflammasome-mediated IL-1β had a pivotal role in the pathogenesis of CAWS-induced vasculitis.

Methods and Results:

In vivo

:
The protein level of IL-1β in the hearts was increased by CAWS administration. Activation of caspase-1 was detected around the coronary arteries by FLICA assay. Histological study showed that incidence and severity of CAWS-induced vasculitis, macrophage infiltration, and fibrosis were suppressed in NLRP3-, ASC- and IL-1β-deficient mice (Fig. A).

In vitro

:
Bone marrow-derived dendritic cells (BMDCs) produced IL-1β by CAWS stimulation, which was suppressed by the anti-Dectin-2 antibody or caspase-1 inhibitor. The CAWS-induced IL-1β production was also suppressed in NLRP3-, ASC-, and caspase-1-deficient BMDCs (Fig. B). CAWS induced mitochondrial reactive oxygen species (mtROS) production, and Mito-TEMPO, a mtROS inhibitor, suppressed CAWS-induced caspase-1 activation (Fig. C) and IL-β production. In addition, CAWS-induced mtROS production was suppressed by Syk or JNK inhibitor. Furthermore, Syk or JNK inhibitor suppressed CAWS-induced NF-κB activation and subsequent IL-1β production.

Conclusion:
These findings demonstrated that NLRP3 inflammasome activation through Dectin-2/Syk/JNK-mediated mtROS plays a pivotal role in CAWS-induced vasculitis. CAWS also induced priming signal through Dectin-2/Syk/JNK/NF-κB pathway. Our finding indicates NLRP3 inflammasome as a new therapeutic target of KD.
Abstract 13075: A Novel Senolytic Drug, Seno-7284 Ameliorates Aging and Age-related Cardiometabolic Disorders
Authors: Katsuumi Goro , Suda Masayoshi , Shimizu Ippei , Yoshida Yohko , Hayashi Yuka , Nakao Masaaki , Furuuchi Ryo , Hsiao Yang-Ting , Minamino Tohru
Published: May 2021

Introduction:
Recent studies have shown elimination of senescent cells, so-called "senolysis" has the potential to become a novel therapy for aging and age-related disorders. However, there is no senolytic drug available in clinical settings currently.

Purpose:
The present study was aimed to identify a novel senolytic reagent effective for cardiometabolic disease among compounds already available in clinical settings. Here we identified a compound called "seno-7284" which exhibits senolytic effect in murine models of aging and age-related cardiometabolic disorders.

Methods:
We generated diet-induced obese(DIO) mice model by imposing high-fat diet, atherosclerotic mice model by imposing western diet to ApoE knockout mice. We administered seno-7284 mixed in the diet (0.03% w/w) to each mouse model for 1, 2 or 4 weeks. We harvested tissue samples for molecular biological analysis after measuring glucose/insulin tolerance. We also administered seno-7284 to Zmpste24 homozygous knockout mice as a progeroid mice model from 12-week-old to measure lifespan and to wild-type mice from 1-year-old for 20 weeks to measure physical function.

Results:
Seno-7284 reduced accumulation of senescent cells in visceral adipose tissue of DIO mice as senescence-associated beta-galactosidase (SA-beta-gal) staining exhibits (figure(fig) a), resulting in improvement of glucose metabolism (fig b). We also found seno-7284 reduced accumulation of senescent cells in the aorta of atherosclerotic mice model (fig c) and inhibited advancing atherosclerosis (fig d). Furthermore, Seno-7284 improved lifespan of progeroid mice (fig e) and physical function of aged mice (fig f). Further analysis including RNA-seq speculated seno-7284 stimulates endogenous senolytic function of immune cells.

Conclusion:
Our results indicate that seno-7284 would become a promising senolytic drug that exhibits novel therapeutic machinery for aging and age-related cardiometabolic diseases.
Abstract 13092: Regulation of SARS-CoV-2, Viral Entry Proteins ACE2 and TMPRSS2, and Interferon Genes by Host MicroRNAs
Authors: Pierce Jacob B , Simion Viorel , Icli Basak , Perez-Cremades Daniel , Cheng Henry , Feinberg Mark W
Published: May 2021

Introduction:
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019, can cause myocardial injury, heart failure, and death. MicroRNAs (miRNAs) have emerged as important regulators of viral pathogenesis, but the impact of host miRNAs on SARS-CoV-2 infectivity remains unknown.

Hypothesis:
Bioinformatic analysis of host miRNAs targeting the SARS-CoV-2 genome, viral entry proteins ACE2 and TMPRSS2, and their upstream regulators the interferons (IFNs) will reveal high-probability miRNAs that may regulate myocardial injury during SARS-CoV-2 infection.

Methods:
Using validated bioinformatic prediction algorithms, we generated a prioritized atlas of host miRNAs predicted to bind to SARS-CoV-2 genome, ACE2, TMPRSS2, and IFNs. We validated the biologic plausibility of these binding interactions by investigating their expression in established miRNA profiling datasets from cell lines susceptible or resistant to SARS-CoV-2 infection and in human tissue samples.

Results:
Phylogenetic analysis of 820 SARS-CoV-2 genomes revealed high homology and, after iterative filtering, 288 predicted binding miRNAs. Overlay of these miRNAs in susceptible and resistant cell lines identified miRNA binders to ORFs (miR-23a (1ab), miR-29a, -29c (1ab, N), miR-151a, -151b (S spike), miR-4707-3p (S spike), miR-298 (5’-UTR), miR-7851-3p (5’-UTR), miR-8075 (5’-UTR)) that may be important for viral infectivity. We also highlight miRNAs predicted to regulate critical host factors during infection including the receptor ACE2 3’-UTR (miR-9-5p, miR-218-5p), the serine protease TMPRSS2 3’-UTR (let-7d-5p, -7e-5p, miR-494-3p, miR-382-3p, miR-181c-5p), and the IFNs such as IFN-α 3’-UTR (miR-361-5p, miR-410-3p). Given the known roles for several of these miRNAs in cardiovascular injury (e.g. miR-23a, -29a, -29c, -494, and let-7), we discuss a framework for further interrogation of these miRNAs in patients and disease-based models.

Conclusions:
Overall, this study provides insight into potential novel regulatory mechanisms of SARS-CoV-2 by host miRNAs and lays the foundation for future investigation of these miRNAs as potential therapeutic targets or biomarkers for myocardial injury.
Abstract 13100: Rescue Myocardial Aging Caused a Progressive Decline in Cardiac Function and β-Adrenergic Reserve With a Selective Beta3-Adrenergic Receptor Antagonist, but Not Beta1-Adrenergic Receptor Blocker in a Murine Model
Authors: Cheng Che , Sun Xiaoqiang , Cao Jing , Liu Yixi , Chen Zhe , Zhou Peng , Masutani Satoshi , Kitzman Dalane , Zhao David , Cheng Heng Jie
Published: May 2021

Background:
Cardiac aging (CA) leads to the progressive decline in cardiac function- increasing risk for heart failure (HF) and cardiac mortality. Both down-regulation of β
1
-adrenergic receptors (AR) and up-regulation of a newly-described inhibitory pathway mediated by β
3
-AR may play a crucial role in the development of CA. β-AR blockers are a mainstay in the therapy of several cardiovascular diseases, including HF. However the therapeutic effects of different β blockers in CA are unknown. We tested the hypothesis that up-regulation of cardiac β
3
-AR with enhanced negative inotropic actions, rather than the desensitization of β
1
-AR, is the critical determinant of the dysfunctional β-AR regulation that occurs in CA. Thus, β
3
-AR antagonists (β
3
ANT), but not β
1
Blockade, may reverse the progression of age-associated deficits in LV myocyte functional performance.

Methods:
LV myocyte basal and isoproterenol (ISO)-stimulated functional and [Ca
2+
]
i
transient ([Ca
2+
]
iT
) responses were compared in 4 groups (7/group) of wild-type (WT) mice: 1)
YWT
, young (Y, 6 mo); 2)

Aβ
3
ANT

, aged (A, 26 mo) treated with β
3
ANT (L-748,337, 10
-7
M/kg/day, mini-pump) for 12 weeks (W);3)

Aβ
1
Blockade

, metoprolol XL (1.5 mg/kg/day, po), a selective β
1
blocker was given for 12 W and 4)
AWT
, aged sham control.

Results:
Compared with YWT, AWT myocytes had about 30% decreases in basal cell contraction (dL/dt
max
, 85.9 vs 122.3 μm/s) and relaxation (dR/dt
max
, 69.4 vs 99.2 μm/s) with reduced the peak [Ca
2+
]
iT
(0.17 vs 0.21). ISO (10
-8
M)-stimulated increases in dL/dt
max
(33% vs 69%), dR/dt
max
(31% vs 62%) and [Ca
2+
]
iT
(15% vs 34%) also significantly reduced. In Aβ
1
Blockade group, metoprolol therapy failed to improve basal dL/dt
max
(86.3 μm/s), dR/dt
max
(68.9 μm/s) and [Ca
2+
]
iT
(0.18). ISO-stimulated increases in dL/dt
max
(34%), dR/dt
max
(35%) and [Ca
2+
]
iT
(17%) remained attenuated. By contrary, Aβ
3
ANT myocytes showed normal basal cell contraction (131.0 μm/s), relaxation (101.9 μm/s) and [Ca
2+
]
iT
(0.21) with preserved ISO-stimulated increases in dL/dt
max
(68%), dR/dt
max
(59%) and [Ca
2+
]
iT
(32%).

Conclusions:
Chronic β
3
-AR antagonist, but not β
1
-AR blocker leads to the preservation of myocyte function, [Ca
2+
]
iT
, and β-adrenergic responsiveness in a murine model of cardiac aging.
Abstract 13134: A Novel Device for Detecting Anaerobic Threshold Using Sweat Lactate Acid During Exercise
Authors: Seki Yuta , Nakashima Daisuke , Toshinobu Ryuzaki , Ikura Hidehiko , Miura Kotaro , Shiraishi Yasuyuki , Fukuda Keiichi , Katsumata Yoshinori
Published: May 2021

Background:
Continuous monitoring of lactate acid (LA) levels during exercise has not been possible. We aimed to visualize real-time changes in LA levels in sweat during exercise and to investigate the relationship between the lactate threshold in sweat (sLT) and LT in blood (bLT) and the ventilatory threshold (VT).

Methods:
Twenty-three healthy subjects (age: median; 20 [interquartile range; 20, 21] years old) and 22 consecutive patients (age: 65 [57, 73] years old) with cardiovascular diseases (CVDs) underwent exercise tests with a RAMP protocol ergometer, simultaneously monitoring changes in the LA values in sweat using a wearable lactate sensor. The sLT was identified as the first significant increase in LA above baseline based on the graphical plots and change finder scores calculated by the Change Finder algorithm using the time-series data of the LA values during exercise. We applied the Bland-Altman method to verify similarities for each threshold.

Results:
During exercise, the dynamic changes in LA values in sweat were successfully visualized in real-time with a sharp continuous increase up to volitional exhaustion and a gradual decrease in the recovery period. In healthy subjects, the work rate (WR) at the sLT (WR-sLT) was substantially correlated with the WR at the bLT (r=0.90). The Bland-Altman plot described a strong agreement (the mean difference: -3.0 watt). Among 22 patients, there were 8 patients whose LA values in sweat were not measured due to a non-response in the sensor. In the remaining 13 cases, except for a patient in whom the VT could not be detected, the sLT was well correlated with bLT and VT (r=0.81 and 0.65, respectively); the mean differences were -8.3 and 3.4, and there was no bias between the mean values. Finally, the logistic regression analysis revealed that a non-response in the sensor was associated with NYHA 3/4 and low peak VO2 (Odds ratio [OR] 0.01 [95% confidence interval (CI); 0.00-0.13], OR 1.45 [95% CI; 1.09-2.20], respectively)

Conclusions:
Our wearable device enabled a continuous and real-time LA measurement in sweat during incremental exercise in a subset of patients with CVDs as well as healthy subjects. This can provide additional information for detecting the VT.
Abstract 13139: Sleep Duration, Inflammation and Cardiovascular Mortality in Ambulatory Us Adults: Insights From the National Health and Nutrition Examination Survey
Authors: Gupta Kartik , Nagalli Shivaraj , Kalra Rajat , Pate Mike , Gupta Rishab , Zhou Wunan , Prabhu Sumanth D , Bajaj Navkaranbir S
Published: May 2021

Introduction:
Sleep disturbance is associated with higher inflammation and cardiovascular mortality. The interplay between sleep duration and inflammation as an effect modifier for cardiovascular risk is unknown.

Hypothesis:
We sought to evaluate the association between sleep duration, C-reactive protein (CRP), and cardiovascular mortality.

Methods:
We used data from the National Health and Nutrition Examination Survey (NHANES) 2005-2010 linked with the cause of death data from the National Center for Health Statistics for adults aged ≥18 years. The associations between short (<6 hours), adequate (6-9 hours), and long (>9 hours) sleep duration with inflammation (CRP) and cardiovascular mortality were explored using linear, Poisson and Cox proportional hazard modeling.

Results:
There were 17,635 eligible participants. The mean age was 47.5±19.2 years with 51% women and 47% self-identified non-Hispanic Whites. There were 2,755 (15.6%), 14,340 (81.3%), and 540 (3.1%) participants in the short, adequate, and long sleep duration groups, respectively. There were 60 (2.2%), 268 (1.9%), and 22 (4.1%) cardiovascular deaths in the short, adequate, and long sleep duration groups, respectively. The adjusted hazard of cardiovascular mortality was 24% (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.05-1.47, p=0.012) and 78% (HR 1.78, 95% CI 1.37, 2.30, p<0.001) higher among participants with short and long sleep duration, respectively, compared to adequate sleep duration (Figure, panel A). A similar U-shaped trend was observed between log-transformed CRP with higher CRP among participants with short (b=0.06, p=0.01) and long (b=0.26, p<0.001) sleep duration versus adequate sleep duration (Figure, panel B).

Conclusions:
Short and long sleep duration are independently associated with a higher hazard of cardiovascular mortality and CRP. These findings suggest an association between circadian rhythm, mortality, and inflammation.
Abstract 13146: Clinical Significance of Left Ventricular Diastolic Function on Exercise Capacity and Prognosis: Comparisons Among Heart Failure Patients With Reduced, Preserved and Mid-range Ejection Fraction
Authors: Sato Takamasa , YOSHIHISA Akiomi , Ishida Takafumi , Takeishi Yasuchika
Published: May 2021

Introduction:
American Society of Echocardiography and European Association of Cardiovascular Imaging have proposed the estimation of left ventricular (LV) filling pressures and grading LV diastolic function in patients with heart failure (HF). However, the associations of LV diastolic dysfunction (LVDD) grade with exercise capacity and prognosis have not been fully elucidated among HF patients with reduced LV ejection fraction (HFrEF, LVEF ≤40%), preserved EF (HFpEF, LVEF ≥50%) and mid-range EF (HFmrEF, LVEF 41% to 49%). We aimed to determine the differences in the associations of LVDD grade with parameters of cardiopulmonary exercise testing (CPX) and prognosis in patients with HFrEF, HFpEF and HFmrEF.

Methods and Results:
We analyzed data on 891 hospitalized patients with HF and sinus rhythm (SR), who had discharged alive and undergone CPX at stable condition in prior to discharge. Of 891 patients, 38.9% had HFrEF, 40.6% had HFpEF and 20.4% had HFmrEF. The HFrEF group had higher rates of adverse cardiac events, defined as cardiac death and re-hospitalizations for worsening HF, than HFpEF and HFmrEF groups. In HFrEF group, the patients with LVDD grade 1 had the highest peak oxygen uptake (peak VO
2
), the lowest minute ventilation and carbon dioxide production (VE/VCO
2
slope), the highest oxygen uptake efficiency slope (OUES) and the lowest adverse cardiac event rates. However, there was no difference in CPX parameters and adverse cardiac event rates between patients with LVDD grade 2 and 3. In HFpEF group, the patients with LVDD grade 1 had the highest peak VO
2
, the lowest VE/VCO
2
slope and the highest OUES. In contrast, CPX parameters did not differ between patients with LVDD grade 2 and grade 3. Patients with LVDD grade 3 had the highest adverse cardiac event rates, followed by patients with grade 2 and 1. In HFmrEF group, the patients with LVDD grade 1 had the highest peak VO
2
, the lowest VE/VCO
2
slope and the highest OUES. Patients with grade 1 had the lowest adverse cardiac event rates. However, CPX parameters and adverse cardiac event rates did not differ between patients with grade 2 and 3.

Conclusions:
LVDD grade was associated with poor exercise capacity and adverse prognosis in patients with HF and SR, regardless of their LVEF.
Abstract 13148: Clinical Importance of Left Atrial Infiltration in Cardiac Transthyretin Amyloidosis
Authors: Bandera Francesco , Martone Raffaele , Chacko Liza , Ganesananthan Sharmananthan , Lane Thirusha , Martinez-Naharro Ana , Wheland Carol , Quarta Cristina , Rowczenio Dorota , Ponticos Markella , Gilbertson Janet A , Lachmann Helen , Wechelakar Ashutosh , Brown James , Knight Daniel , James Moon , Petrie Aviva , Cappelli Francesco , Guazzi Marco , Potena Luciano , Leone Ornella , Hawkins Philip N , Gillmore Julian D , Fontana Marianna
Published: May 2021

Introduction:
The clinical significance of left atrial (LA) involvement and dysfunction in ATTR amyloidosis cardiomyopathy (ATTR-CM) has not been characterized. We sought to study: 1) LA pathology in heart specimens from ATTR-CM patients 2) LA stiffness and mechanics using echocardiographic speckle tracking (EST) in cardiac ATTR-CM 3) the association between parameters of atrial function and mortality.

Methods:
Congo red staining and immunohistochemistry was performed to assess amyloid in the atria from 5 ATTR-CM heart specimens. 2D EST was used to assess LA reservoir, conduit, contractile function and stiffness in 906 ATTR-CM patients (551 wt ATTR; 93 T60A ATTR; 241 V122I ATTR; and 21 other gene variants).

Results:
There was extensive ATTR amyloid infiltration in the 5 atria, with loss of normal architecture, infiltration and remodelling of vessels, capillary disruption and subendocardial fibrosis. EST demonstrated increased atrial stiffness [median (25th-75th quartile) 1.83 (1.15-2.92)] that remained independently associated with reduced survival, after adjusting for known prognostic variables (lnLA stiff: HR= 1.26, CI 1.07-1.57; p=.009). There was substantial impairment of the three phasic functional atrial components [reservoir 8.86(5.94-12.97)%; conduit 6.5(4.53-9.28)%; and contraction 4.0(2.29-6.56)%]. Atrial contractile function was absent in 21.6% of patients whose ECG showed sinus rhythm (SR)-atrial electro-mechanical dissociation (AEMD). AEMD was associated with a poorer prognosis compared to SR patients who had effective mechanical contraction (p <.0001). AEMD conferred a similar prognosis to patients in AF.

Conclusions:
The phenotype of ATTR-CM includes clinically significant infiltration of the atrial walls characterized by progressive loss of function and increased stiffness, a strong independent predictor of mortality. AEMD emerged as a distinctive functional phenotype identifying patients in SR with poor prognosis.
Abstract 13149: Survival Benefit With Higher Dose Tafamidis in Patients With Hereditary and Wild-type Transthyretin Amyloid Cardiomyopathy
Authors: Shah Sanjiv J , Gundapaneni Balarama , Sultan Marla B , Merlini Giampaolo
Published: May 2021

Introduction:
Tafamidis was shown to be an effective treatment for patients with both hereditary/variant (ATTRv) and wild-type (ATTRwt) transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). The higher dose of tafamidis (80 mg) was shown to be the optimal dose and is approved for the treatment of ATTR-CM. We hypothesized that longer term follow up would further characterize the benefit of higher dose tafamidis.

Methods:
In ATTR-ACT, patients were randomized to tafamidis meglumine (80 mg or 20 mg) or placebo for 30 months. Patients who completed ATTR-ACT were eligible to enroll in a long-term extension study (LTE) in which placebo-treated patients were randomized to tafamidis 80 mg or 20 mg. As of 20 July, 2018, all patients in the LTE were transitioned to tafamidis free acid 61 mg (a new formulation bioequivalent to tafamidis 80 mg). All-cause mortality (as of 1 Aug, 2019) was assessed in patients treated with tafamidis 80 mg in ATTR-ACT and the LTE who transitioned to tafamidis free acid 61 mg (tafamidis 80/61 mg) compared with patients treated with placebo in ATTR-ACT who transitioned to tafamidis in the LTE (placebo/tafamidis).

Results:
There were 85 ATTRv patients (42 tafamidis 80/61 mg [median treatment duration 53.8 months]; 43 placebo/tafamidis [48.1 months]) and 268 ATTRwt patients (134 tafamidis 80/61 mg [51.7 months]; 134 placebo/tafamidis [51.6 months]).In ATTRv patients, there were 25 (59.5%) deaths with tafamidis 80/61 mg and 30 (69.8%) deaths with placebo/tafamidis; a 39.8% reduction in risk of all-cause mortality with tafamidis 80/61 mg (hazard ratio vs placebo/tafamidis [95% CI], 0.6020 [0.3473, 1.0435]; P=0.0706). In ATTRwt patients, there were 50 (37.3%) deaths with tafamidis 80/61 mg and 78 (58.2%) deaths with placebo/tafamidis; a 40.1% reduction in risk of all-cause mortality with tafamidis 80/61 mg (0.5992 [0.4186, 0.8577]; P=0.0051).

Conclusions:
While there were fewer ATTRv patients in the study, longer-term follow-up demonstrated similarly improved survival with higher dose tafamidis in both ATTRv and ATTRwt patients. These data further highlight the benefit of tafamidis (80 mg meglumine or 61 mg free acid) in all patients with ATTR-CM.
Abstract 13163: Clinical Impact of Contralateral Carotid Occlusion During Carotid Intervention in Contemporary Practice: An Analysis of the National Cardiovascular Data Registry Peripheral Vascular Intervention Registry
Authors: Krawisz Anna K , Rosenfield Kenneth , White Christopher J , Jaff Michael R , Campbell Joseph , kennedy kevin , Tsai Thomas T , Hawkins Beau M , Jones William S , Secemsky Eric A
Published: May 2021

Introduction:
Contralateral carotid occlusion (CCO) is an established high-risk feature for carotid endarterectomy (CEA) and is a reason to recommend carotid artery stenting (CAS). Recent observational data have called into question whether CCO remains a high-risk feature for CEA. We investigated the clinical impact of CCO among patients undergoing CEA and CAS in a contemporary nationwide registry.

Hypothesis:
CCO confers an elevated risk of in-hospital adverse events among patients undergoing CEA, but not CAS.

Methods:
All patients undergoing CEA or CAS from 2005-2019 in the NCDR CARE and PVI registries were included. The primary exposure was the presence of a CCO. The outcome was a composite of in-hospital death, stroke, and myocardial infarction. Analyses were stratified by treatment with CEA or CAS. Multivariable logistic regression models were used to identify factors associated with adverse outcomes.

Results:
Among 58,423 patients, 4,624 (7.9%) patients had a CCO. Of those, 68.9% (N=3,185) underwent CAS and 31.1% (N=1,439) underwent CEA. The average age of patients with CCO was 69.5±9.7, 32.6% were female, 92.8% were Caucasian, 51.7% had a prior TIA or stroke, and 45.4% had symptomatic disease. Over the study period, there was a 4.3% decline in procedures performed on patients with CCO (p <0.001), but CAS remained the primary revascularization strategy (7.8% CAS vs 3.5% CEA in 2019Q2). Unadjusted rates of the composite outcome were lower after CAS (3.2%) than after CEA (3.9%). Following adjustment, CCO was associated with a 60% increase in odds of an adverse outcome after CEA (95%CI 1.2-2.12, p=0.0013) (Figure). There was no increase in risk for patients treated with CAS (adjusted OR 0.99, 95%CI 0.79-1.22, p=0.89).

Conclusions:
In this contemporary nationwide registry analysis, CCO remains an important predictor of increased risk in patients undergoing CEA, but not CAS. These data support the continued use of CCO to guide carotid revascularization strategy.
Abstract 13165: Self-Reported Social Functioning is Responsive to Change in Functional Class in Patients With a Left Ventricular Assist Device: Findings From the Mechanical Circulatory Support Measures of Adjustment and Quality of Life Study
Authors: Hahn Elizabeth A , Cummings Peter D , Wortman Katy , Lindenfeld Joann , Teuteberg Jeffrey , Kiernan Michael S , Allen Larry A , McIlvennan Colleen K , Lee Christopher S , Denfeld Quin E , Klein Liviu , Beiser David , Murks Catherine M , Rich Jonathan D , Pham Duc T , Yancy Clyde W , Cella David , Walsh Mary N , Ruo Bernice , Buono Sarah K , Grady Kathleen L
Published: May 2021

Introduction:
Improvement in social functioning is an important goal for advanced heart failure (HF) patients (pts) who receive left ventricular assist devices (LVADs). Self-reported social functioning and its association with clinical change is understudied.

Methods:
Adult HF pts who received LVADs at nine U.S. sites completed two measures of social functioning prior to, and 3-6 months after, surgery. Patient-Reported Outcomes Measurement Information System (PROMIS) measures were: Ability to Participate in Social Roles and Activities (Ability) and Satisfaction with Social Roles and Activities (Satisfaction). PROMIS uses T-scores standardized to a U.S. general population (mean=50; standard deviation, SD=10); higher scores represent better outcomes. New York Heart Association (NYHA) Functional Classification was assigned at both times by treating clinicians; change was subsequently categorized as Better, Same or Worse NYHA. Linear mixed effects models and least-squares means were estimated for Ability and Satisfaction.

Results:
Pts (
n
=107) were primarily male (78%) and non-Hispanic White (68%); mean age (SD)=54 (12.5) years; 74% were NYHA Class IV prior to surgery and only 18% were NYHA IV at follow-up. NYHA was better for the majority (
n
=75, 70%); 24% (
n
=26) were the same, and 6% (
n
=6) were worse. Mean Ability and Satisfaction were lower than the general population mean of 50 at both time points (Figure). Ability improved for the NYHA Better (
p
<0.001) and Same (
p
=0.030) groups, and nominally decreased for the Worse group (
p
=0.800). Satisfaction improved for the Better (
p
<0.001) group, and nominally improved for the Same and Worse groups (
p
>0.300).

Conclusions:
Self-reported social functioning measures were responsive to clinician-rated clinical change. Understanding these relationships may guide clinicians in providing targeted health-related quality of life therapies to improve social functioning.
Abstract 13191: Increased Extracellular Sodium and Intercellular Cleft Separation Synergistically Prolong Repolarization in the Long-qt Syndrome Type 3
Authors: Wu Xiaobo , HOEKER Gregory , King David Ryan , Gourdie Robert G , Weinberg Seth , Poelzing Steven
Published: May 2021

Introduction:
Long-QT syndrome type 3 (LQT3) is caused by a gain-of-function mutation in the cardiac sodium channel that increases the late sodium current and prolongs repolarization. We previously suggested that narrowing the perinexus which is adjacent gap junction conceals the LQT3 phenotype by depleting extracellular sodium ([Na]) within this nanodomain and curtails the late current and repolarization. However, it is unknown if elevating bulk [Na] alone modulates action potential duration (APD) in widened perinexi to unmask LQT3.

Hypothesis:
Elevated [Na] and widened perinexi synergistically prolong APD in LQT3.

Methods:
The dependence of APD on [Na] and perinexal width was explored with a computational model and in Langendorff-perfused guinea pig hearts. The late sodium current was induced with ATXII (7nM). Perfusate [Na] changed from 145 (145Na) to 160 mM (160Na). Perinexal expansion was induced with βadp1 (1uM). APD was quantified from whole-heart optical maps. Perinexal width was quantified by transmission electron microscopy.

Results:
A computational model, including preferential sodium channel location at the intercalated disk, predicts that combination of elevated [Na] and widened perinexus prolongs APD greater than summing the effect of the individual interventions alone. Therefore, the combination is synergistic and not additive. Isolated heart experiments are consistent with the model. Specifically, ATXII+βadp1 significantly widens perinexal width from 27.8±4.1 to 49.7±9.3 nm and prolongs APD by 18.1±5.1ms with 600ms pacing relative to ATXII alone. In the presence of ATXII, 160Na significantly prolongs APD by 12.0±5.8ms relative to 145Na. Furthermore, the combination of both interventions is synergistic. Specifically, in the presence of ATXII, 160Na+βadp1 significantly prolongs APD more than the sum of the individual effects (49.9±7.5ms vs. 30.2±5.4ms).

Conclusions:
The data demonstrate that in LQT3, enhancing sodium and perinexal width concurrently prolong APD more than the individual effects alone. This synergistic effect suggests that maintaining reduced plasma sodium level can be a simple and effective method to conceal LQT3, even in the presence of perinexal expansion associated with osmotically induced stress.
Abstract 13195: Race, Body Mass Index, and the Risk of Atrial Fibrillation: The Multi-Ethnic Study of Atheroclerosis
Authors: Singleton Matthew J , German Charles , Carnethon Mercedes R , Soliman Elsayed Z , Bertoni Alain G , Yeboah Joseph
Published: May 2021

Introduction:
Higher body mass index (BMI) is associated with an increased risk of incident atrial fibrillation (AF), but it is not known if this relationship varies based on race/ethnicity.

Hypothesis:
The relationship between BMI and incident AF will vary by race/ethnicity.

Methods:
Eligible MESA participants had no AF at baseline. The risk of incident AF as a function of baseline BMI was modelled using Cox proportional hazards. Formal tests of interaction by race/ethnicity were performed. Restricted cubic splines models were used to explore non-linear relationships.

Results:
Among 6,739 participants, 0.8% were underweight, 27.8% had normal BMI, 39.0% were overweight, 21.1% had grade I obesity, 7.6% had grade II obesity, and 3.7% had grade III obesity. Over 79,860 person-years of follow-up (median 13.8), 991 participants (14.7%) had new-onset AF. With BMI modeled as a categorical variable, only those with grade II and grade III obesity had an increased risk of AF (HR 1.48, 95% CI 1.13 - 1.94, p = 0.005 for grade II obesity and HR 2.21, 95% CI 1.11 - 4.40, p = 0.02 for grade III obesity ). The relationship between BMI and AF risk was non-linear, best characterized as J-shaped. However, the risk of AF as a function of BMI varied substantially by race/ethnicity (p-value for interaction = 0.02), with Chinese-American participants having a much higher risk of AF with higher BMI and African-American participants having minimal increased risk of AF with higher BMI (Figure 1).

Conclusions:
Obesity is associated with an increased risk of incident AF. The relationship between BMI and the risk of AF is J-shaped and this relationship differs by race/ethnicity, such that Chinese-Americans have a more pronounced increased risk of AF with higher BMI, while African-Americans have minimal increased risk. Further exploration of the differential effects of BMI by race/ethnicity on cardiovascular outcomes is needed.