bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12816: Cellular Iron Transport Protein, Transferrin Receptor 1 Plays a Role in the Pathophysiology of Pulmonary Arterial Hypertension
Authors: Hosokawa Manani , Naito Yoshiro , Sawada Hisashi , Oboshi Makiko , Iwasaku Toshihiro , Okuhara Yoshitaka , Morisawa Daisuke , Eguchi Akiyo , Hirotani Shinichi , Mano Toshiaki , Tsujino Takeshi , Masuyama Tohru
Published: July 2021

Introduction:
Cellular iron transport protein, transferrin receptor 1 (TfR1) is required for the uptake of transferrin-bound iron into the cells. Some reports have shown that iron deficiency is reported to be prevalent in patients with pulmonary arterial hypertension (PAH); however, the role of TfR1 in the pathophysiology of PAH remains unknown.

Hypothesis:
We hypothesiged that TfR1 plays a role in the pathophysiology of PAH. Here, we investigate TfR1 in the experimental models of PAH.

Methods:
Male Sprague-Dawley rats were subcutaneously injected with monocrotaline (60 mg/kg). Saline-injected rats were served as controls. In addition, we knocked down TfR1 expression in human pulmonary arterial smooth muscle cells (hPASMCs) and primary cardiomyocytes prepared from neonatal rats using its siRNA.

Results:
Monocrotaline-injected rats showed pulmonary vascular remodeling, increased right ventricular pressure, and right ventricular hypertrophy. Of interest, TfR1 expression was increased in the pulmonary remodeled artery and the hypertrophied right ventricle of monocrotaline-injected rats, as compared with the controls. Meanwhile, iron content did not differ in the pulmonary artery and right ventricle between the control and monocrotaline-injected rats. Transfection of hPASMCs and cardiomyocytes with TfR1 siRNA significantly reduced TfR1 gene expression. Importantly, TfR1 silencing suppressed platelet-derived growth factor (PDGF)-induced proliferation of hPASMCs. Moreever, TfR1 silencing attenuated phenylephrine-induced increase in cell size of cardiomyocytes.

Conclusions:
These results indicate that TfR1 plays a role in the pathophysiology of pulmonary artery remodeling and right ventricular hypertrophy in PAH.
Abstract 12830: Primary Prevention of Atrial Fibrillation With Angiontensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Patients of End-Stage Renal Disease- A Nationwide Cohort Study Using Insurance Claims Database
Authors: Lin Ting-Tse , Liao Min-Tsun , Lin Lian-Yu
Published: July 2021

Background:
Current evidence suggests that angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARB) reduce the incidence of new atrial fibrillation (AF) in a variety of settings including the treatment of left ventricular dysfunction or hypertension. This study was to assess whether ACEIs and ARB could decrease incidence of AF in patients of end stage renal disease (ESRD).

Materials and Methods:
We identified all patients who developed ESRD through January 1998 to December 2008 from the National Health Insurance Research Database, Taiwan. The primary endpoint was new onset of AF and the median duration of follow up was 1499 days. The control group was patients not prescribing ACEIs or ARB. Hazard ration of both ACEIs vs. control and ARB vs. control were analyzed.

Results:
Among 102688 patients, 14926 (14.5%) were prescribed with ACEIs, 16282 (15.9) with ARB but 71480 (69.6%) were not prescribed ACEIs or ARB. Overall, patients treated with ACEIs (adjusted hazard ratio [HR] 0.587, 95% confidence interval [CI] 0.519-0.633, P<0.001 ) or ARB (adjusted HR 0.542, 95% CI 0.461-0.637, P<0.001 ) had a reduced incidence of AF. The preventive effect between two classes of drugs was favored ARB (P<0.001). The longer patients taking ACEIs or ARB, the better prevention of AF are. The similar reduction of AF is also noted in stratified analysis of age, gender, hypertension, congestive heart failure and diabetes.

Conclusion:
Both ACEIs and ARB appear to be effective in the primary prevention of AF in ESRD patients. This analysis supports the concept of renin-angiotensin system inhibition as an emerging treatment for the primary prevention of AF.
Abstract 12836: Low-Intensity Pulsed Ultrasound Ameliorates Left Ventricular Dysfunction in a Porcine Model of Chronic Myocardial Ischemia -Potential Involvement of Mechanotransduction
Authors: Shindo Tomohiko , Ito Kenta , Hanawa Kenichiro , Aizawa Kentaro , Shiroto Takashi , Ogata Tsuyoshi , Nishimiya Kensuke , Hasebe Yuhi , Tsuburaya Ryuji , Miyata Satoshi , Hasegawa Hideyuki , Yasuda Satoshi , Kanai Hiroshi , Shimokawa Hiroaki
Published: July 2021

Purpose:
Despite recent progress in the management of ischemic heart disease (IHD), the number of patients with severe IHD is increasing. In this study, we aimed to develop low-intensity pulsed ultrasound (LIPUS) therapy for the treatment of IHD and to elucidate the underlying molecular mechanisms for the LIPUS-induced angiogenesis.

Methods and Results:
We first confirmed that the LIPUS up-regulated mRNA expression of vascular endothelial growth factor (VEGF) with a peak at 32-cycle in cultured human vascular endothelial cells (HUVECs). Then, we examined the in vivo effects of LIPUS in a porcine model of chronic myocardial ischemia with reduced left ventricular ejection fraction (LVEF) (n=28). The heart was treated with either sham or LIPUS (32-cycle, 20 min) at 3 different short axis levels (n=14 each). Four weeks after the therapy, LVEF was significantly improved in the LIPUS group (46±4 to 57±5%, P<0.05), whereas it remained unchanged in the control group. Capillary density and regional myocardial blood flow in the ischemic region were also increased in the LIPUS group but not in the control group. The protein expressions of VEGF, eNOS and bFGF in the ischemic area were enhanced in the LIPUS group compared with the control group. To further examine the signaling pathways responsible for the LIPUS-induced angiogenesis, HUVECs were transfected with siRNA or scrambled siRNA of either β1 integrin or caveolin-1. Knockdown of either β1 integrin or caveolin-1 with siRNA suppressed the LIPUS-induced up-regulation of VEGF. siRNA-mediated suppression of either focal adhesion kinase (FAK) or Fyn also inhibited the LIPUS-induced up-regulation of VEGF. Knockdown of these molecules with siRNA was confirmed with real-time PCR.

Conclusions:
These results suggest that the LIPUS therapy is promising as a new, non-invasive therapy for IHD and that β1 integrin and caveolin-1 may be involved in underlying molecular mechanisms for the beneficial effects of the LIPUS.
Abstract 12880: Up-Regulation of Microrna-208b Contributes to Diabetic Myocardial Fibrosis in Mouse
Authors: Shan Zhi Xin , Guo Lin lin , Zhu Jie ning , Lin Qiu xiong , Deng Chun yu , Zou Xiao , Liang Ye you , Zhu Wen si , yu Xi yong , Wu Shu lin
Published: July 2021

MicroRNAs play important roles in myocardial fibrosis during diabetic cardiomyopathy. The present study aimed to investigate the role of microRNA-208b (miR-208b) in diabetic myocardial fibrosis. Compared to the db/m control mice, Smad3 was activated , fibrosis-related genes expression were significantly up-regulated, and miRNAs were dysregulated in the myocardium of the 16-week-old diabetic db/db mice. miR-208b was confirmed up-regulated in the db/db diabetic myocardium
in vivo
and in mouse cardiomyocytes and cardiac fibroblasts after treatment with Ang-II, TGF-β and high glucose/glucose oxidase (HG/Go)
in vitro
, respectively. By using recombinant adenovirus expressing CD63-GFP, rAd-CD63-GFP, we infected neonatal mouse cardiomyocytes with rAd-CD63-GFP and tracked the secreted exosomes with GFP. We found that miR-208b was increased in the secreted exosomes from HG/Go-treated cardiomyocytes, and the exosomes with increased miR-208b could enhance fibrosis associated Col1a1, α-SMA and CTGF expressions in cardiac fibroblasts. Transfection of miR-208b mimic could increase Col1a1, α-SMA and CTGF expression in a dose-dependent manner in cardiac fibroblasts. However, blockage of miR-208b could inhibit fibrosis related genes expression. Mtf2 and Pgrmc1 were verified modulated by miR-208b at post transcriptional level
in vitro
. Consistently, Mtf2 and Pgrmc1 expressions were decreased in the diabetic myocardium, and knockdown of Mtf2 or Pgrmc1could increase fibrosis related genes expression in cardiac fibroblasts. Smad3 inhibitor, Naringenin, could dramatically inhibit miR-208b expression in cardiac fibroblasts. Taken together, we demonstrated that miR-208b was up-regulated in diabetic fibrotic myocardium, Mtf2 and Pgrmc1 mediated the effect of miR-208b on enhancing Col1a1, α-SMA and CTGF expression in diabetic myocardial fibrosis.
Abstract 12899: A New Prognostic Marker for Functional Deterioration in Heart Failure: Coronary Vascular Resistance
Authors: Cetin Mehmet S , Ozcan Cetin Elif H , Canpolat Ugur , Aydin Selahattin , Akin Guray Yesim , Aras Dursun , Temizhan Ahmet , Aydogdu Sinan
Published: July 2021

Introduction:
Heart failure (HF) is a challenging clinical syndrome with complex pathophysiology. Previous studies demonstrated that coronary flow reserve assessed by PET technique was impaired in HF. Transthoracic echocardiography (TTE) can provide reliable data for myocardial blood flow (MBF) which can be measured from coronary sinus (CS). In relation with MBF, coronary vascular resistance (CVR) can be evaluated. In this study, we aimed to evaluate the association of MBF and CVR with clinical data in HF.

Methods:
The MBF was measured in 100 patients (80 patients with HF (LVEF<30%) and 20 healthy control subjects. MBF was measured from anterograde CS flow TVI at PLAX RV inflow view and CS diameter at A2C view (2Πr2*TVI*heart rate) and indexed to left ventricular mass index. Patient group was categorized based on NYHA functional classes (NYHA FCs).

Results:
There was an incremental trend for MBF with advancing NYHA FCs (β=0.253, p=0.015). MBF was similar among HF patients due to NYHA FCs. However, MBF was higher in NYHA FC 4 group compared to healthy subjects (p=0.029). Also, CVR was lower in HF patients than the control group (11.15±6.54 vs.24.84±7.29, p<0.001). In the subgroup analysis, CVR was not statistically different between non-ischemic and ischemic etiology of HF (6.91±1.38 vs. 6.31±0.89, p=0.249). Additionally, CVR was significantly lower in NYHA FC 4 compared to other study groups. CVR was positively correlated with peak VO2 (β=0.596, p<0.001), and Seattle Heart Failure Model derived life expectancy (β=0.476, p<0.001) and negatively correlated with serum BNP level (β=-0.450, p=0.001), troponin I (β=-0.366, p=0.001) and serum uric acid level (β=-0.503, p<0.001). In multivariate analysis, CVR is an independent predictor of mortality (HR:0.763 95%CI:0.624-0.933 P=0.008). In ROC analysis, a cut of value 6.73 for CVR has a 74% sensitivity and 66.7 % specifity for prediction of mortality in HF(AUC 0.825 P<0.001).

Conclusion:
Our results showed that CVR was reduced with advancing FC in HF patients, despite MBF was similar among different FCs. In addition, CVR was significantly correlated with various prognostic markers in HF patients. Therefore, evaluation of MBF hemodynamics, particularly CVR, with TTE may utilize prognostic assessment of HF patients.
Abstract 12910: Safety and Utility of Cardiac Catheterization in the Early Postoperative Period Following Congenital Cardiac Surgery
Authors: Mills Kimberly I , Bergersen Lisa B , Jolley Matthew , Teele Sarah A , Mayer John E , Salvin Joshua W
Published: July 2021

Introduction:
In patients with clinical concern for residual anatomic or physiologic lesions after congenital cardiac surgery, the risk to benefit ratio of early postoperative cardiac catheterization (EPOC) remains unclear.

Methods:
Retrospectively, patients undergoing EPOC (catheterization ≤42 days after surgery and prior to discharge) were identified from a single institutional database between 1/1/06 to 10/31/13. Patient, procedural and high-severity adverse event (HSAE) data were obtained from the Congenital Cardiac Catheterization Outcomes Project. Univariate analysis identified risk factors for HSAEs and a multivariable model was created to describe their relationship. Utility of EPOC was determined by re-intervention (surgical and/or catheter-based).

Results:
In the cohort, 561 EPOCS occurred on median POD 10 (5, 19) in 413 subjects with median age of 4.6 mos (3.2, 9.9) and weight 4.4 kg (0.8, 18.2). The majority of cases were not elective (92%), performed on inotropes (62%) and mechanically ventilated (96%). Residual defects were found in 75% of the cases: 50% requiring catheter-based interventions, 15% necessitating re-operation and 10% underwent both catheter-based intervention and re-operation. There were 70 HSAEs (12.5%) including 1 death, 2 emergent surgeries and 5 ECMO cannulations. Vascular tears occurred at surgical anastomotic sites in 11 of 198 (6%) cases involving angioplasty. HSAEs were associated with low patient weight (p=0.02), interventional procedures (p=0.03), greater number of interventions (p<0.01), higher procedure risk group (p=0.03), blood transfusion (p<0.01) and longer case duration (p<0.01). In multivariable analysis, HSAEs were associated with case duration (OR 1.008, 95% CI 1.003-1.012), blood transfusion (OR 0.431, 95% CI 0.25-0.745) and male gender (OR 0.573, 95% CI 0.331-0.992). Time from surgery to EPOC was not associated with an increased rate of HSAEs (p=0.5).

Conclusions:
EPOC carried an increased rate of HSAEs with no association between POD and the rate of HSAEs. EPOC identified significant residual defects in the majority of patients necessitating re-intervention. EPOC should be considered in patients with unexpected cardiopulmonary concerns following congenital cardiac surgery.
Abstract 12912: Model of End-Stage Liver Disease Excluding INR (MELD-XI) Scoring System Predicts Mode of Death in Patients Admitted With Acute Decompensated Heart Failure
Authors: Yamada Takahisa , Morita Takashi , Furukawa Yoshio , Tamaki Shunsuke , Iwasaki Yusuke , Kawasaki Masato , Kikuchi Atsushi , Kondo Takumi , Kawai Tsutomu , Takahashi Satoshi , Ishimi Masashi , Hakui Hideyuki , Ozaki Tatsuhisa , Satoh Yoshihiro , Seo Masahiro , Fukunami Masatake
Published: July 2021

Backgrounds:
Cardiohepatic interactions have been a focus of attention among heart failure. A model of end-stage liver disease excluding INR (MELD-XI) is a robust scoring system of liver dysfunction, and a high score has been shown to be associated with poor prognosis in patients with heart failure. Prediction of mode of death (sudden cardiac death (SCD) and pump failure death (PFD)) in patients with heart failure may facilitate decisions about specific medications or devices. However, there is no information available on the prognostic significance of MELD-XI in patients admitted with acute decompensated heart failure (ADHF), from the viewpoint of mode of death.

Methods and Results:
We studied 303 consecutive patients admitted with ADHF and discharged with survival. MELD-XI score was calculated by the following formula: 5.11[[Unable to Display Character: ･]]ln(bilirubin)+11.79[[Unable to Display Character: ･]]ln(creatinine)+9.44. During a follow-up period of 5.0±4.3 yrs, 37 patients had SCD and 27 patients had PFD. At multivariate Cox analysis, MELD-XI score was significantly independently associated with SCD (p=0.002) and PFD (p=0.003). Receiver-operator curve analysis revealed that MELD-XI of 11 and 13 was fair discriminators for SCD (AUC 0.667(95%CI 0.575-0.758), p=0.001; sensitivity 78% and specificity 48%) and PFD (AUC 0.764(95%CI 0.683-0.845; sensitivity 74% and specificity 69%), p<0.0001), respectively. Patients with higher MELD-XI score had significantly a higher risk of not only SCD (17% vs 6%, p=0.0005, adjusted HR: 3.19 (95%CI 1.44-7.08) but also PFD (20% vs 3%, p<0.0001, adjusted HR: 4.53 (95%CI 1.72-12.07)), compared to those with lower MELD-XI score.

Conclusion:
A MELD-XI scoring system might predict not only sudden cardiac death but also pump failure death in patients admitted with ADHF.
Abstract 12925: Combination of Cardiac I-123 Metaiodobenzylguanidine Imaging Findings and Early Repolarization Pattern Improve the Predictive Power of Sudden Cardiac Death in Patients With Chronic Heart Failure
Authors: Kikuchi Atsushi , Yamada Takahisa , Morita Takashi , Furukawa Yoshio , Tamaki Shunsuke , Iwasaki Yusuke , Kawasaki Masato , Kondo Takumi , Kawai Tsutomu , Takahashi Satoshi , Ishimi Masashi , Hakui Hideyuki , Ozaki Tatsuhisa , Sato Yoshihiro , Seo Masahiro , Fukunami Masatake
Published: July 2021

Background:
Identification of patients with chronic heart failure (CHF) at risk for sudden cardiac death (SCD) is an important objective. Cardiac I-123 metaiodobenzylguanidine (MIBG) imaging findings provide prognostic information in patients with CHF. On the other hand, early repolarization pattern (ERP) is associated with life-threatening arrhythmia events. Moreover, it has been shown that ERP would be associated with an increased risk of SCD in CHF patients. However, there is no information available on the long-term prognostic value of combining cardiac MIBG imaging findings and ERP for the prediction of SCD in CHF patients.

Methods:
We studied 92 CHF outpatients (NYHA class: 2.1±0.6) with LVEF < 40% [30±7%) in our prospective cohort study. We performed MIBG scintigraphy, and measured the heart-to-mediastinum ratio on the delayed image (HMRd), of which the abnormal value was defined as < 1.7. Furthermore, we obtained the standard 12-lead electrocardiogram at enrollment. ERP was defined as J-point elevation ≤ 0.1 mV in at least 2 inferior or lateral leads.

Results:
At enrollment, 41 patients had abnormal HMRd and 19 patients had ERP. During a follow-up period of 7.7±4.3 yrs, 22 patients died suddenly. A multivariate Cox analysis revealed that HMRd (p=0.001) and ERP (p=0.017) were significantly and independently associated with SCD. Kaplan-Meier analysis showed that SCD was significantly more frequently observed in patients with both abnormal HMRd and ERP and those with either abnormal HMRd or ERP than those with neither abnormal HMRd nor ERP (55% vs 33% vs 7%, respectively, p<0.0001). The hazard ratio for SCD prediction in patients with both abnormal HMRd and ERP was 14.7 (95%CI 3.6 to 60.1), which was twofold of the hazard ratio in patients with either abnormal HMRd or ERP (HR 6.5 [95%CI 1.8 to 7.8])

Conclusion:
The combination of cardiac MIBG imaging and ERP would provide the incremental prognostic information for the prediction of SCD in CHF patients.
Abstract 12949: Aerobic Exercise After an ICD: Results of the 6 Month Follow-Up in the Anti-Arrhythmic Effects of Exercise After an ICD Trial
Authors: Dougherty Cynthia M , Glenny Robb , Kudenchuk Peter , Burr Robert
Published: July 2021

Introduction:
The Anti-Arrhythmic Effects of Exercise Trial reported that aerobic exercise training for 8 weeks after an implantable cardioverter defibrillator (ICD) significantly improved the primary outcome of cardiopulmonary function without ICD shocks or adverse events. This is a report on the longer term outcomes at 24 weeks of exercise maintenance that was continued after aerobic training.

Hypothesis:
When 8 weeks of aerobic exercise training is followed by aerobic exercise maintenance (50% reduction in the amount of walking), cardiopulmonary function [peak VO2, EX time, VO2 at AT, O2 pulse, METS, Maximum HR] will be maintained without an increase in ICD shocks or hospitalizations.

Methods:
160 subjects (80/group) with a prior ICD implant (40% primary and 60% secondary prevention), mean age 55 +12 years, 78% male, 84% Caucasian, 100% beta-blocked, and mean EF%=40%, entered a RCT comparing aerobic exercise to usual care (UC). At baseline, 8 and 24 weeks, participants completed cardiopulmonary exercise testing using a modified Balke treadmill protocol. Aerobic training= 8 weeks of home walking 1 hour/day on 5 days/week at 60-80% of maximum HR using the Karvonen formula, was followed by aerobic maintenance (EX)= 16 weeks of home walking for 150 min/week. ICD shocks and hospitalizations were verified with medical records. Analysis of variance was used to determine group x time effects on study outcomes.

Results:
Aerobic maintenance significantly increased peak VO2 ml/kg/min, p<0.000 (EX 26.9+7.7, UC 23.4+6.0), EX minutes, p<0.000 (EX 16:27+ 6:36; UC 13:24+4:33), VO2 at AT ml/kg/min, p=0.001 (EX 23.0+6.8; UC 19.8+5.8), O2 pulse p=0.01 (EX 18.7+5.5; UC 16.8+4.9), and METS, p<0.001 (EX 7.6+2.2; UC 6.7+1.8). Maximum HR was unchanged. The number of ICD shocks related to exercise was =1: 3 in UC and 1 in exercise received an ICD shock or ATP during follow-up. There were 11 hospitalizations in each group, none were related to exercise.

Conclusions:
Aerobic exercise maintenance for 16 weeks that followed aerobic exercise training for 8 weeks, maintained gains in cardiopulmonary function despite reducing the amount of walking by half (300 min vs. 150 min). Aerobic exercise in patients with an ICD is safe without increasing the number of ICD shocks or hospitalizations.
Abstract 12954: Impairment of the Compensatory Natriuretic Peptide Response to Myocardial Infarction in the Aged is Associated With Adverse Cardiorenal Repair and Heart Failure
Authors: Sangaralingham S. J , Ichiki Tomoko , Harders Gerald E , Chen Horng H , Burnett John C
Published: July 2021

Introduction:
The incidence of post-myocardial infarction (MI) heart failure (HF) is increasing in the elderly. Studies have demonstrated that B-type natriuretic peptide (BNP) mediates critical cardiorenal compensatory and protective actions through guanylyl cyclase receptor A and cGMP activation. Such actions include natriuresis, diuresis and suppression of adverse cardiorenal remodelling.

Hypothesis:
While the mechanism of this increased risk may be multifactorial, we hypothesized that an impairment of the compensatory protective BNP/cGMP axis in both the aged kidney and heart contributes to post-MI HF.

Methods:
20 month old Fischer rats were randomized into two groups: Sham-operated (S) and MI(produced by left coronary artery ligation). Cardiorenal structure and function were assessed at 4 weeks and included mean arterial pressure(MAP), LV EF, LV chamber dimension, proteinuria, sodium (Na) excretion and fibrosis by picrosirius red staining. Plasma BNP and cGMP levels were assessed by RIA. Data presented as mean±SE,*P<0.05.

Results:
LV EF (S:78±2, MI:46±3 %*) was significantly reduced in aged MI rats, despite no difference in LV fibrosis in the remote region and no change in MAP compared to aged sham rats. Post-MI HF was evident and characterized by a significant reduction in Na excretion (S:0.20±0.03, MI:0.13±0.01 mEq/day*) as well as significant increases in LV dilatation (S:7.2±0.1, MI:8.3±0.2 mm*) and cardiac hypertrophy (S:2.78±0.06, MI:3.25±0.16 mg/g*) in aged MI rats. Notably, plasma BNP (S:9±1, MI:11±2 pg/ml) failed to increase and plasma cGMP (S:44±6, MI:27±3 mm*) was significantly reduced in the MI group. Importantly, MI in the aged rat resulted in a significant loss in total renal mass (S:2739±83, MI:2351±68 mg*), consistent with renal atrophy, while no changes in proteinuria or renal fibrosis were observed.

Conclusions:
Post-MI dysfunction of the protective BNP/cGMP axis in the aged rat was associated with various cardiorenal abnormalities including renal atrophy, which may contribute to the pathophysiology of HF. This pre-clinical model provides new insights into post-MI HF and may be used to examine therapeutic strategies using natriuretic peptides to protect the heart and kidney in the elderly post-MI population.
Abstract 12978: Incident Atrial Fibrillation is Similar in Blacks and Whites With Congestive Heart Failure
Authors: Patel Parin J , Borovskiy Yuliya , Killian Anthony , Marchlinski Francis E , Deo Rajat
Published: July 2021

Introduction:
Clinical studies have demonstrated that blacks have a lower prevalence and incidence of atrial fibrillation (AF) compared with whites. Given the strong biologic associations between AF and congestive heart failure (CHF), we hypothesized that the racial disparity for incident AF is attenuated in CHF patients.

Methods:
The University of Pennsylvania Atrial Fibrillation Free-Congestive Heart Failure (PAFF-CHF) Cohort is a large, multi-hospital retrospective cohort of individuals with clinical CHF and without AF at index visit. Baseline demographic and clinical parameters were obtained, and medical records were queried for incident outcomes. The primary outcome was incident AF, which was defined as a clinical or ECG diagnosis of AF on any follow up encounter.

Results:
Of 5,131 patients in PAFF-CHF, there were 2,037 blacks (40%) and 3,094 whites (60%). Median follow up time was 4.5 years (1.8, 5.9), with blacks having significantly longer follow up (4.7 v 4.2 yr, p < 0.001). During this follow-up, 851 subjects (16%) developed AF, with rates of 5.1 per 100 person years in whites and 4.9 per 100 person years in blacks (p = 0.8). Time independent risk factors for developing AF included male gender (OR 1.42 [95% CI 1.22 - 1.65], p < 0.001); LBBB on index ECG (1.32 [1.01 - 1.72], p = 0.04); and black race (OR 1.31 [1.13 - 1.52], p < 0.001). In a regression model of traditional risk factors for AF including age, gender, hypertension, coronary artery disease, diabetes, and renal insufficiency, black race remained an independent risk factor for AF (OR 1.45 [1.23 - 1.70], p < 0.001). Finally, time to event analysis showed no difference in freedom from AF and no difference in freedom from AF or death (Figure).

Conclusions:
In a large cohort of HF patients, incident AF was similar in blacks and whites. Although prior studies have indicated a low prevalence and incidence of AF in blacks compared with whites, the development of AF appears to be a common finding in both races after a diagnosis of CHF.
Abstract 12981: Does Volume Overload Predict Failed Antitachycardia Pacing Therapy for Ventricular Tachycardia in Patients With an Implantable Cardioverter-Defibrillator?
Authors: Hosseini-khalili Alireza , Kluger Jeffrey
Published: July 2021

Introduction:
Decompensated heart failure (HF) increases the risk of Implantable Cardioverter-Defibrillator (ICD) therapy. Patients with failed antitachycardia pacing (ATP) for ventricular tachycardia (VT) termination, requiring ICD shock, have been reported to have worse outcomes compared to patients with effective ATP. Thoracic impedance (TI) is a diagnostic parameter found in many ICDs. In Medtronic devices, TI is transformed into a OptiVol index, which when elevated, may represent volume overload and can predict increased HF events.

Hypothesis:
Whether an elevated OptiVol index is associated with failed ATP for VT termination in ICD patients.

Method:
Retrospective review of a prospectively collected database of patients followed in a dedicated ICD clinic, enrolled in remote ICD monitoring and who received therapy for VT termination by an OptiVol-capable ICD. The level of OptiVol was measured near the time of VT events. VT events were divided into two groups: OptiVol index <100 and OptiVol≥100, and distributions of successful and unsuccessful ATP were compared.

Results:
We analyzed 121 VT episodes that occurred in 39 ICD patients who received ATP or shock to terminate VT. Mean age of patients was 68.4 +/- 10 years and 32 patients (78%) were male. Ischemic cardiomyopathy was present in 20 patients (48.8%). Successful ATP was more likely when the VT event was associated with an OptiVol index <100 (74.5% successful vs 25.5% unsuccessful, P<0.001); whereas a VT event associated with an OptiVol≥100 was more likely to be unresponsive to ATP compared with ATP success (66.7% unsuccessful vs 33.3% successful, p<0.001).

Conclusions:
Failed ATP, requiring shock therapy for VT, is associated with a measure of volume overload (OptiVol) and could explain the worse outcomes observed in patients who require ICD shocks.
Abstract 12999: Senescence Marker Protein 30 Protect the Cardiac Injury From After Ischemia Reperfusion
Authors: Kadowaki Shinpei , Shishido Tetsuro , Narumi Taro , Honda Yuki , Nishiyama Satoshi , Takahashi Hiroki , Arimoto Takanori , Miyamoto Takuya , Watanabe Tetsu , Takeishi Yasuchika , Kubota Isao
Published: July 2021

Background:
Successful myocardial reperfusion is effective therapy for improving the clinical outcome after acute myocardial infarction, nevertheless reperfusion injury can paradoxically induces cardiomyocyte dysfunction. Moreover, recovery of cardiac function is impaired with aging. Glycogen synthase kinase-3β (GSK-3β) and p70 ribosomal S6 kinase (p70S6K) are cardioprotective against I/R via mitochondrial dysfunction. Senescence marker protein-30 (SMP30), which regulates mitochondrial quality and decreases with aging, is an organ-protective protein; however the protective role of SMP30 against ischemia/reperfusion (I/R) has not been clearly determined yet.

Methods and Result:
Firstly, we confirmed that SMP30 expressions in the heart were progressively decreased with aging. In vitro study, we also found that reactive oxygen species decreased expression levels of SMP30 in neonatal cardiomyocyte. Depletion of SMP30 increased apoptotic cardiomyocyte death after hydrogen peroxide stimulation. To evaluate the cardioprotective role of SMP30, we induced 30 min ischemia and 24-hr reperfusion (I/R) in WT and SMP30 KO mice. Phosphorylation levels of p70S6K and GSK-3β in the heart were increased after IR in WT mice; however those phosphorylation were attenuated in SMP30 KO mice. SMP30 KO mice after I/R had significantly larger numbers of apoptotic cardiomyocyte than WT mice ( 10.5± 5.7% vs. 4.0± 1.7%, p < 0.05), that correlated with a significant expansion in infarct size and a significant reduction of left ventricular fractional shortening (37.3± 4.3% vs 43.4± 5.1%, p < 0.01).

Conclusions:
These results suggest that reduction of SMP30 levels with aging is associated with age-related dysfunction after ischemia-reperfusion through disability to phosphorylate p70S6K and GSK-3β. Thus, SMP30 might be a novel therapeutic target for the treatment of acute myocardial infarction in elderly patient.
Abstract 13016: Tissue Mitral Annular Displacement (TMAD) Predicts Long-term Prognosis in Heart Failure Patients Receiving Cardiac Resynchronization Therapy
Authors: Iwakura Katsuomi , Okamura Atsunori , Koyama Yasushi , Date Motoo , Inoue Koichi , Nagai Hiroyuki , Toyoshima Yuko , Tanaka Koji , Oka Takafumi , Tanaka Nobuaki , Yamanaka Yuko , Yamasaki Tomohiro , Okada Tomoaki , Sotomi Yohei , Azuma Kohei , Orihara Yoshiyuki , Kameda Satoshi , Iwamoto Mutsumi , Ota Yoshihiro , Fujii Kenshi
Published: July 2021

Introduction:
Assessment of left ventricular (LV) dyssynchrony by echocardiography has only a limited ability to predict response to cardiac resynchronizing therapy (CRT) because of high variability of the measurement.Tissue mitral annular displacement (TMAD) is a rapid and robust method for the assessment of left ventricular (LV) longitudinal deformity. We previously reported that TMAD predicts good responders to CRT among patients with severe heart failure (AHA scientific meeting 2012). In the present study, we investigated whether TMAD could predict the long-term prognosis after CRT implantation.

Methods:
We performed echocardiography study in 41 patients with dilated cardiomyopathy (DCM) before and at 6 month of CRT, using iE33 (Philips Medical Systems). TMAD was measured on an apical 4-chamber image using QLAB software (Philips Medical Systems) to assess the movement of septal- and lateral part of mitral annulus toward apex. We measured the interval between QRS complex to peak of displacement on both regions, and calculated the differences in time-to-peak (dTTP). We defined good response to CRT as decrease in LV end-systolic volume (LVESV) > 15% at 6 month of CRT. We followed the patients to observe cardiovascular events including death, myocardial infarction, stroke and hospital admission for heart failure.

Results:
The 27 good responders (65.8%) had significantly longer dTTP than the non-responders (156±64 vs. 63±61 msec, p<0.0001). Using 104 msec as a cutoff value, TMAD detected CRT responders with sensitivity of 79% and specificity of 78% (AUC=0.83). We observed 20 cardiac events during follow-up period of 1182±635 days. We found that dTTP was significantly associated with cardiovascular events (p=0.048 by Cox proportional hazard model), and that patients with dTTP≥104ms had better prognosis than others (Figure).

Conclusion:
TMAD is a promising method for predicting long-term prognosis in patients with DCM receiving CRT.
Abstract 13030: Post-systolic Shortening and Early Systolic Lengthening in the Ischemic Segment are Affected by the Contractility in its Adjacent Segment
Authors: Sakurai Daisuke , Asanuma Toshihiko , Masuda Kasumi , Oka Masamichi , Kotani Koichiro , Inoue Katsuji , Nakatani Satoshi
Published: July 2021

Background:
Post-systolic shortening (PSS) and early systolic lengthening (ESL) are sensitive markers of acute myocardial ischemia and the magnitude of these deformation is considered proportional to the severity of ischemia. Theoretical and mathematical models have suggested these deformation is caused by the difference of contractility between the ischemic and its adjacent normal segments. However, it has not been fully confirmed in an in vivo model yet. The aim of the study was to investigate whether PSS and ESL are affected by the contractility of its adjacent segment in an animal model which underwent left anterior descending coronary artery (LAD) occlusion (ischemic segment) followed by left circumflex coronary artery (LCx) occlusion (adjacent segment).

Methods:
In 6 open-chest dogs, left ventricular short-axis images with frame rate of over 90 fps (GE Vivid E9) and hemodynamics data were acquired at 3 conditions: (1) at baseline, (2) during LAD occlusion, and (3) during both LAD and LCx occlusion. Circumferential strain was analyzed in the LAD and LCx segments by speckle tracking software. End-systolic strain (ε
ES
) and the amplitude of PSS and ESL (ε
PSS
and ε
ESL
) were measured.

Results:
During LAD occlusion, ε
PSS
and ε
ESL
in the LAD segment significantly increased compared with baseline (ε
PSS
, 1.2 ± 1.1% vs. 9.5 ± 2.7%, p<0.05; ε
ESL
, 1.3 ± 1.0% vs. 8.5 ± 4.2%, p<0.05). During both LAD and LCx occlusion, ε
ES
in the LCx segment decreased, and both ε
PSS
and ε
ESL
in the LAD segment significantly decreased compared with during LAD occlusion (ε
PSS
, 9.5 ± 2.7% vs. 2.8 ± 1.3%, p<0.05; ε
ESL
, 8.5 ± 4.2% vs. 2.3 ± 1.9%, p<0.05) (figure).

Conclusions:
PSS and ESL diminished with the decrease of contractility in its adjacent segment. This suggests PSS and ESL occur based on the interplay of contraction between ischemic and adjacent segments and do not always reflect the severity of ischemia.
Abstract 13044: Serum Vascular Endothelial Growth Factor-C Levels are Inversely Associated with the Risk of Cardiac and Cerebrovascular Events Following Drug-eluting Stent Implantation
Authors: Unoki Takashi , Wada Hiromichi , Akao Masaharu , Ura Shuichi , Yamada Akira , Takabayashi Kensuke , Yamashita Yugo , Hamatani Yasuhiro , Masunaga Nobutoyo , Ishii Mitsuru , Iguchi Moritake , Ogawa Hisashi , Takagi Daisuke , Satoh-Asahara Noriko , Shimatsu Akira , Hasegawa Koji
Published: July 2021

Background:
Vascular endothelial growth factor-C (VEGF-C) plays a key role in lymphangiogenesis. Recently, we demonstrated that VEGF-C is closely associated with dyslipidemia and atherosclerosis. However, the prognostic value of VEGF-C levels after drug-eluting stent (DES) implantation is unknown.

Methods and Results:
We performed a prospective cohort study involving a total of 443 patients (age, 71.7±9.0 y [SD]; male, 73.8%; number of lesions, 1.6±0.8) who underwent successful DES implantation. Patients were recruited between January 2010 and October 2013, and were followed up over 3 years. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE) defined as cardiovascular death, hospitalization due to acute coronary syndrome, stroke, heart failure, and coronary revascularization. The median follow-up was 617 (inter-quartile range, 320-937) days. Pre-procedural serum levels of high-sensitivity C-reactive protein (hsCRP), vascular endothelial growth factor-A (VEGF-A), and VEGF-C were measured. During the follow-up period, MACCE developed in a total of 106 patients (23.9%). Patients were divided into two groups based on the median of each biomarker. In Kaplan-Meier analyses, low-VEGF-C (P=0.0005 by log-rank test), but not high-hsCRP (P=0.3) or high-VEGF-A (P=0.3), was significantly associated with the risk of MACCE. Multivariate Cox proportional hazard analyses revealed that levels of VEGF-C (hazard ratio [HR], 0.77 per 1-SD increase; 95% confidence interval [CI], 0.62-0.94; P=0.011), but not hsCRP (HR, 1.05; 95% CI, 0.86-1.25; P=0.6) or VEGF-A (HR, 1.04; 95% CI, 0.86-1.23; P=0.6), were inversely and significantly associated with MACCE after adjustment for age, gender, and established risk factors, the number of lesions, and type of DES. Finally, we performed stepwise multivariate Cox proportional hazard analysis including data on age, gender, established risk factors, the number of lesions, type of DES, and VEGF-C levels. Notably, the only independent predictor of MACCE was the VEGF-C level (HR, 0.74 per 1-SD increase; 95% CI, 0.61-0.91; P=0.0042), followed by diabetes (HR, 1.47; 95% CI, 0.98-2.21; P=0.060).

Conclusions:
A low VEGF-C value may serve as a predictor of MACCE after DES implantation.
Abstract 13049: Microrna-33, Located Within Srebf2 Intron, Regulate Fatty Acid Synthesis via Targeting SREBP-1 in vivo
Authors: Nishino Tomohiro , Horie Takahiro , Baba Osamu , Kuwabara Yasuhide , Nakao Tetsushi , Nishiga Masataka , Usami Shunsuke , Izuhara Masayasu , Ide Yuya , Nakazeki Fumiko , Koyama Satoshi , Yokode Masayuki , Kita Toru , Kimura Takeshi , Ono Koh
Published: July 2021

Introduction:
MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote degradation. Recent reports, including ours, indicated that miR-33 located within the intron of sterol regulatory element binding protein (SREBP) 2 controls cholesterol homeostasis and can be a possible therapeutic target for treating atherosclerosis. Unexpectedly, miR-33 deficient (miR-33
-/-
) mice fed high fat diet (HFD) developed severe fatty liver and the mechanisms were investigated.

Methods and Results:
The liver weight of miR-33
-/-
mice were about 1.5 times heavier than that of miR-33
+/+
mice and histological examination revealed that miR-33
-/-
mice developed severe fatty liver under HFD feeding. In order to determine the cause of the fatty liver observed in miR-33
-/-
mice fed HFD, we analysed the gene expression profiles using the liver of miR-33
+/+
and miR-33
-/-
mice fed normal chow at the age of 16 weeks when they didn’t show fatty liver. As a result, genes involved in fatty acid metabolism were upregulated in miR-33
-/-
mice. Among them we found SREBP-1 as a new potential target gene of miR-33
in silico
and confirmed that miR-33 targets the 3’UTR of SREBP-1
in

vitro
. The expression of SREBP-1 and
de novo
fatty acid production were significantly increased in the liver of miR-33
-/-
mice. We further intercrossed miR-33
-/-
mice with
Srebf1
+/-
mice and fed them HFD. Hepatic steatosis was reversed in miR-33
-/-
Srebf1
+/-
mice compared with miR-33
-/-
Srebf1
+/+
mice by histological analysis and measurement of triglyceride levels. The expression levels of genes involved in fatty acid synthesis, including
Scd1, Fasn, Acc1
, and
Pparg
were increased in miR-33
-/-
Srebf1
+/+
mice compared with miR-33
+/+
Srebf1
+/+
mice, and those increase were reversed in miR-33
-/-
Srebf1
+/-
mice.

Conclusions:
miR-33 regulates lipogenic pathway via regulating SREBP-1 as a novel target
in vivo
. In sterol-depleted conditions, acetyl-CoA might be preferred as a substrate for cholesterol production and not for fatty acid production by the downregulation of SREBP-1 through the upregulation of miR-33. Conversely, in cholesterol-rich condition, acetyl-CoA might be preferred as a substrate for fatty acid production through the downregulation of miR-33.
Abstract 13093: The Inducible Nuclear Protein IκBζ Plays a Pivotal Role in the Transition From Adaptive to Maladaptive Cardiac Hypertrophy During Pressure Overload
Authors: Higashikuni Yasutomi , Fukuda Daiju , Sata Masataka , Komuro Issei
Published: July 2021

Background:
Inflammation has been implicated in the pathophysiology of both adaptive and maladaptive cardiac hypertrophy in response to pressure overload. However, it remains unclear how chronic inflammation contributes to the transition from adaptive to maladaptive cardiac hypertrophy. Interleukin-1β (IL-1β) has been shown to induce Akt phosphorylation, which plays an important role in cardiac adaptive response to pressure overload, whereas chronic IL-6 signaling has been reported to inhibit Akt phosphorylation through induction of suppressor of cytokine signaling (SOCS) 3. IκBζ, encoded by the NFKBIZ gene, is an inducible nuclear protein which regulates the transition from IL-1β expression to IL-6 expression in the NF-κB system. This study was performed to clarify the role of IκBζ in pressure overload-induced cardiac hypertrophy.

Methods and Results:
Pressure overload was induced in

Nfkbiz
+/+

and

Nfkbiz
+/-

mice by transverse aortic constriction (TAC). In

Nfkbiz
+/+

mice, TAC-operated hearts showed adaptive cardiac hypertrophy until 2 weeks after the operation, whereas at 4 weeks after TAC, impaired systolic function with left ventricular dilatation was observed (n=10). TAC-operated

Nfkbiz
+/-

hearts showed similar adaptive cardiac hypertrophy to TAC-operated

Nfkbiz
+/+

hearts until 2 weeks after the operation (n=10). However, at 4 weeks after TAC,

Nfkbiz
+/-

hearts showed preserved systolic function with attenuated LV dilatation compared with

Nfkbiz
+/+

hearts. Real time PCR revealed that IL-1β mRNA expression levels were higher in

Nfkbiz
+/-

hearts than in

Nfkbiz
+/+

hearts at 4 weeks after TAC (n=5), whereas mRNA expression levels of IL-6 and SOCS3 were higher in

Nfkbiz
+/+

hearts that in

Nfkbiz
+/-

hearts. Western blot analysis demonstrated that Akt phosphorylation levels were higher in

Nfkbiz
+/-

hearts that in

Nfkbiz
+/+

hearts at 4 weeks after TAC.

Conclusions:
Our results suggest that IκBζ plays a pivotal role in the transition from adaptive to maladaptive cardiac hypertrophy during pressure overload, possibly in part, through the regulation of proinflammatory cytokine expression pattern in the heart tissue, which may regulate Akt phosphorylation levels. Thus, IκBζ may be a novel therapeutic target for treating heart failure.
Abstract 13228: Nitroxyl (HNO) donated via Slow-Release Oral Pro-Drug Improves Ventriculo-Arterial Coupling in Conscious Dogs with Induced Heart Failure: Enhanced Load-Independent Mechano-Energetics
Authors: del Rio Carlos L , George Robert S , Youngblood Bradley L , Ueyama Yukie , May Jonelle R , Humphries David J , Hartman Craig , Cully Doris F , Hamlin Robert L , Reardon John E
Published: July 2021

Introduction:
Reduction of myocardial loading and energetic demand while enhancing function are primary needs for the treatment of heart failure (HF). Nitroxyl (HNO) produces cAMP-independent unloading and inotropic/lusitropic support in both laboratory animals and patients with HF. To date, however, the cardiovascular activity of HNO has only been investigated using short-acting parenteral donors.

Aim:
This study assessed the feasibility of non-parenteral (oral) HNO delivery, by evaluating the cardiovascular responses to a novel slow-release HNO prodrug given to conscious dogs with induced HF.

Methods:
Dogs were either used for pharmacokinetic assessments or chronically instrumented for arterial pressures and LV pressure-volume (LVPV) recordings; instrumented dogs had HF induced via chronic pacing (e.g., EF: 38 ± 1%, PRSW: 51.2 ± 0.9 mmHg+, EDP: 23 ± 2 mmHg and NT-proBNP > 2500 pM/L). Data were obtained before/after oral (22.5 mg/kg) and/or before/during continuous IV infusion (65 μg/kg/min) treatment with a slow-release HNO prodrug (~30min in vitro t1/2 for release of HNO); load-independent systolic/diastolic function was examined by LVPV relationships obtained for up to 180min after the onset of dosing.

Results:
The slow-release HNO prodrug was bioavailable orally (%F: 40 ± 4), presenting rapid absortion (Tmax: 0.1 ± 0.5 hr, Cmax: 3.6 ± 1.3 ug/mL) and clearance (t1/2: 0.40 ± 0.01 hr, AUCinf: 4.1±0.8 hr·ug/mL). Oral HNO reduced LV preload (EDV: -7 ± 1%*), filling (EDP: -29 ± 7%*) and end-systolic pressures (ESP: -17 ± 2 %*), without concomitant changes in heart rate (HR: -4 ± 2%). Oral HNO increased stroke volume (SV: 14 ± 3%*) and ejection fraction (EF: 22 ± 3%*), while decreasing arterial elastance (Ea: -27 ± 2 %). Oral HNO enhanced load-independent inotropy (PRSW, +12 ± 2%*) and lusitropy (tau: -15 ± 3 %*, EDPVR: -50 ± 8%*), improved ventriculo-arterial coupling and decreased estimated myocardial demand (PVA: -66 ± 4%*). These effects were comparable to those obtained via IV administration (PRSW: +12 ± 1%*, Ea: -23 ± 3%*, and PVA: -51 ± 8%*). (*: P < 0.05 vs. pre-dosing).

Conclusions:
These results demonstrate the feasibility of delivering HNO orally to improve myocardial loading and enhance systolic/diastolic function in the setting of HF.
Abstract 13245: Clinical Correlates and Heritability of Cardiac Mechanics: Insights from the HyperGEN Study
Authors: Khan Sadiya S , Kim Kwang-Youn A , Peng Jie , Aguilar Frank G , Selvaraj Senthil , Martinez Eva E , Baldridge Abigail S , Irvin Marguerite R , Sha Jin , Broeckel Ulrich , Arnett Donna K , Shah Sanjiv J
Published: July 2021

Introduction:
A genetic predisposition to abnormal cardiac mechanics may explain the familial predisposition to heart failure (HF). We hypothesized that indices of cardiac mechanics (speckle-tracking strain parameters and tissue velocities) are heritable traits.

Methods:
We performed speckle-tracking analysis on echocardiograms and measured global longitudinal, circumferential, and radial strain (GLS, GCS, GRS), early diastolic strain rate, and e’ velocities in the HyperGEN study, a family- and population-based study of hypertension (N=2058 [54% African American (AA)]). Additive genetic heritability estimates for cardiac mechanics were calculated by maximizing the likelihood variance components in SOLAR (ver.6) adjusted for age, sex, race, height, weight, systolic blood pressure (SBP), left ventricular (LV) mass, ejection fraction, reader, image quality, and institution.

Results:
Mean age was 51±14 years and HF risk factors were common: hypertension (56%), obesity (47%), and diabetes (16%). Clinical and conventional echocardiographic characteristics, including male gender, hypertension, elevated fasting glucose, higher body-mass index, and LV hypertrophy were all significantly associated with increased absolute GLS and septal e’ velocity (P<0.05). After adjustment for covariates (and correlation within the same families), genetic contributions remained significant in GLS and septal e’ velocity in all participants, a finding which persisted in race-stratified analyses (Table).

Conclusions:
Echocardiographic measures of cardiac mechanics, particularly GLS and e’ velocity, are heritable traits, even after adjustment for clinical and cardiac structural factors (e.g., SBP and LV mass, respectively) that are known to be heritable and associated with cardiac mechanics. These data support the exploration of genetics of cardiac mechanics, which may provide insight into the molecular pathogenesis of LV dysfunction and HF.