bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 11277: Comparison Among Drug-Eluting Balloon, Drug-Eluting Stent, and Plain Balloon Angioplasty for Treatment of In-Stent Restenosis: A Network Meta-Analysis of 11 Randomized Controlled Trials
Authors: Park Jonghanne , Lee Joo Myung , Kang Jeehoon , Jeon Ki-Hyun , Jung Ji-hyun , Lee Sang Eun , Han Jung-Kyu , Kim Hack-Lyoung , Yang Han-Mo , Park Kyung Woo , Kang Hyun-Jae , Koo Bon-Kwon , Kim Hyo-Soo
Published: July 2021

Objective:
The optimal treatment option for in-stent restenosis (ISR) is not established. We performed a Bayesian network meta-analysis comparing the efficacy and safety of drug-eluting balloon (DEB), drug-eluting stent (DES) or plain old balloon angioplasty (POBA) for treatment of ISR.

Design:
Systemic review and Bayesian network meta-analysis using random-effects model. The primary outcome was target lesion revascularization (TLR). The secondary outcomes were myocardial infarction (MI), all-cause mortality or major adverse cardiovascular events (MACE). The pairwise posterior median odds ratio (OR) with 95% credible interval (CrI) was the effect measure.

Data Sources:
PubMed, EMBASE, BioMed Central, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, conference proceedings through February 2014.

Eligibility Criteria for Selecting Studies:
Randomized controlled trials (RCTs) comparing DEB, DES, or POBA for treatment of ISR.

Results:
This analysis included 2,059 patients from 11 RCTs. The risk of TLR was markedly lower in patients treated with DEB (OR 0.22, 95% CrI 0.10-0.42) or DES (OR 0.24, 95% CrI 0.11-0.47) than in those treated with POBA. The risk of TLR (OR 0.92, 95% CrI 0.43-1.90) was similar between DEB and DES. The risk of MI or all-cause mortality was lowest in the DEB group compared with DES or POBA, which did not meet statistical significance. The risk of MACE was significantly lower in DEB (OR 0.24, 95% CrI 0.12-0.39) or DES (OR 0.28, 95% CrI 0.14-0.53) than in POBA, but it was similar between DEB and DES group (OR 0.84, 95% CrI 0.45-1.50). The probability to be ranked as the best treatment were 59.9% (DEB), 40.1% (DES), and 0.1% (POBA) in terms of TLR, whereas, 63.0% (DEB), 35.3% (POBA), and 1.7% (DES) in terms of MI.

Conclusions:
DEB or DES was markedly better than POBA in preventing TLR, but not for MI or mortality in treatment of ISR. DEB resulted in less MI than DES without statistical significance.
Abstract 11314: Statin and Aspirin Use in a High Risk CHD HMO Population Modeled to Prevent 4,930 Ascvd Events and Save the Health Care System up to $123 Million in 3 Years
Authors: Dudl Robert J , Shah Roshan , Chan Wiley , Scott Ronald D
Published: July 2021

We assessed the use of statin and aspirin treatment in patients with CHD risk >10% vs. patients with CHD risk >20% and the potential reduction in ASCVD events and health care costs. We utilized ARCHeS and the Archimedes Model, a large bio-mathematical model built with randomized controlled trial data for predicting responses to therapies, for the simulations and analyses. In measuring financial effects, we used Medicare data to predict processes and costs of care for the events. Patients selected were from Kaiser Permanente (KP) aged 20-79 years old who had a calculated Framingham CHD risk score of ≥10% or ≥20% and were not on a statin according to the KP drug database. We assumed 80% adherence & 80% eligibility after other exclusions such as cancer, frailty, and refusing therapy.

RESULTS:
This resulted in 19,610 members with CHD risk >20% and 156,986 with CHD risk >10% that would be offered the treatment. Compared to standard of care, ASCVD events were reduced by 5.88%, 20.1%, and 33.2% in the >20% risk group and by 3.14%, 12.5%, and 24.88% in the >10% risk group at 3, 10, and 20 years, respectively. This resulted in prevention of adverse events for patients which in turn drove medical care system savings per person of $1,638, $6,453, and $9,288 for the >20% risk group, and $999, $4,871 and $9,672 for >10% risk group, respectively. Population extrapolations are shown below.

CONCLUSIONS:
These data suggest the treatment would improve patient outcomes by reducing ASCVD events and decrease medical care system resource use within 3 years by treating members at 20% CHD risk levels. However, significantly more event savings would occur if the 10% CHD risk group were included and continued in both groups for at least 20 years.
Abstract 11317: Outcomes of Atrial Arrhythmia Surgery for Atrial Tachyarrhythmias in Patients With Repaired Tetralogy of Fallot
Authors: Chang Jiwoon , Patel Sajan , Grogan Tristan R , Aboulhosn Jamil A
Published: July 2021

Background:
Atrial tachyarrhythmia is common in adults with tetralogy of Fallot (TOF) due to surgical scarring from repairs and atrial enlargement. The maze procedure refers to surgical ablation within the right atrium to disrupt arrhythmogenic circuits and is sometimes performed concomitantly during reoperation on repaired TOF patients. Our study aims to evaluate the effectiveness of maze in TOF patients.

Methods:
We performed a retrospective chart review that identified 30 TOF patients who underwent a pulmonary valve replacement (PVR) with maze and 38 TOF patients who underwent a PVR without maze from 1994 to 2011 and had at least 2 years of post-surgical follow-up at the Ahmanson/UCLA Adult Congenital Heart Disease Center. Preoperative and postoperative arrhythmia status and management were compared in maze and non-maze groups.

Results:
Before the procedure, the most common pre-operative arrhythmias in the maze group were a history of atrial fibrillation (AFib)(n=16), atrial flutter (AFL)(n=10), and other supraventricular tachycardia (SVT)(n=6). Isolated right atrial maze was performed in 26 patients, and combined right and left atrial maze-cox procedure was performed in 4 patients. Of the 16 patients in the maze group with pre-op Afib, 6 had recurrent Afib within the first 2 years of follow-up (62.5% relative reduction, p=0.012). Of the 10 patients with pre-op AFL, only 1 had recurrence (90% relative reduction, p=0.012). Of the 6 patients with pre-op SVT, 4 had recurrence (33.3% relative reduction, p=0.727). There was no significant arrhythmia status change in the non-maze group at 2 years. Comparing patients with and without maze, the average cardiopulmonary bypass times were 155 minutes and 97 minutes, respectively (p=0.064), and aortic cross clamp times were 122 minutes and 64 minutes, respectively (p=0.004). On average, patients with maze spent 3.7 more days in the hospital compared to those without maze (p=0.001).

Conclusions:
Performing a concomitant maze procedure in patients undergoing TOF repair was associated with a moderate improvement in atrial tachyarrhythmia burden over 2 years. TOF patients who had the concomitant maze procedure required longer cardiopulmonary bypass time, aortic cross clamp time, and total hospital stay.
Abstract 11423: Mitochondrial Calcium Flux Modulates Pacemaker Activity in Mouse Stem Cell Derived Cardiomyocytes
Authors: Xie An , Zhou Anyu , Liu Hong , Shi Guangbin , Boheler Kenneth R , Dudley Samuel C
Published: July 2021

INTRODUCTION:
Ca2+ release from sarcoplasmic reticulum (SR) is known to contribute to the pacemaker activity in embryonic stem cells (ESC) derived cardiomyocytes (CMs). Mitochondria are known to participate in Ca2+ cycling. Nevertheless, the role of mitochondria in pacemaker activity is unclear. We studied the role of mitochondrial Ca2+ flux in spontaneously activity of ESC derived CMs.

METHODS:
CMs were derived from Wt and ryanodine receptor type 2 knockout (RYR2-/-) mouse ESC. Action potentials (APs) were recorded by perforated whole-cell current-clamp. Cytoplasmic and mitochondrial Ca2+ transients were determined by Fluo-4 and Rhod-2 respectively. Mitochondrial Ca2+ uniporter (MCU) siRNA was used. The mRNA level was evaluated by qPCR.

RESULTS:
As predicted, SR Ca2+ handling inhibitors, 10 μM ryanodine and 2 μM 2-APB, reduced spontaneous beating rate to 56% and 73% respectively in Wt CMs. Inhibition of mitochondrial Ca2+ flux by 10 μM Ru360 showed a similar inhibition effect on the pacemaker activity as 2 μM 2-APB in Wt CMs.

To isolate the mitochondrial component, we used RYR2-/- CMs. In these cells, MCU inhibition by pharmacological or molecular biological means reduced beating rate. The MCU mRNA decreased by 96% after MCU siRNA silence 72 hrs (p<0.01). AP and mitochondrial Ca2+ transient synchronous recording revealed that the reduction of spontaneous beating rate accompanied with the depressed mitochondrial Ca2+ uptaking and releasing.

In RyR2-/- CMs, 2 μM 2-APB could significantly lower the spontaneous beating rate. While 2 μM 2-APB was applied to MCU silenced RyR2-/- CMs, the beating rate couldn’t be slowed down further. This indicated IP3 receptors reduced spontaneous beating rate via MCU. Thapsigargin could substantially slow down beating rate like 2-APB. Caffeine depletion experiments showed other ryanodine receptor subtypes didn’t contribute Ca2+ release in RyR2-/- CMs. A L-type Ca2+ channel block, 10 μM nifedipine, couldn’t reduce beating frequency. This indicated spontaneous beating rate is Ca2+ influx independent in RyR2-/- CMs.

CONCLUSIONS:
Mitochondrial Ca2+ handling plays an important role in decreasing spontaneous beating rate. IP3R reduced spontaneous beating rate through MCU.
Abstract 11491: Differences in the Development of Restenosis Over Time for Various Drug-Eluting Stents
Authors: Tanaga Kosei
Published: July 2021

Objective:
This study aims to compare the efficacy of sirolimus-eluting stents (SES), paclitaxel-eluting stents (PES), zotarolimus-eluting stents (ZES), and everolimus eluting stents (EES) via sequential angiographic follow-up and to reveal the development of restenosis over time.

Methods:
Patients were randomized to receive SES, PES, ZES, or EES, and follow-up angiography was performed at 6, 12 and 24months after percutaneous coronary intervention.

Results:
The baseline clinical characteristics of the patients and the coronary lesions are shown in (Table 1). In all groups, mean minimal lumen diameter decreased slightly during the 2-year period after the procedure (Figure 1). Compared with the SES group, the PES and the ZES groups showed greater late loss (LL) within 1 year. However, the SES group showed significantly greater LL compared with the other drug-eluting stents (DES) between 1 and 2 years (Figure 2).

Conclusion:
Serial angiographic analysis revealed differences in the rate of restenosis development over time for various DES. As DES are comprised of many components (metallic platform, alloy, drug and polymer), the progression of LL can be complex and affected by different factors.
Abstract 11511: Genetic Variation in Retinal Vascular Patterning Predicts Variation in Pial Collateral Extent and Infarct Volume After Middle Cerebral Artery Occlusion
Authors: Prabhakar Pranay , Zhang Hua , Chen De , Lockett Stephen , Faber James E
Published: July 2021

Introduction:
The presence of a native (pre-existing) collateral circulation in tissues lessens injury in stroke and other occlusive diseases. However, differences in genetic background are accompanied by wide variation in the number and diameter (extent) of native collaterals in mice, resulting in large variation in protection. Indirect evidence suggests a similar wide variation also exists in humans. However, methods of measurement in humans are indirect, invasive and not widely available.

Hypothesis:
We sought to determine if differences in genetic background in mice result in variation in branch-patterning of the retinal circulation, and if these differences predict differences in collateral extent and, in turn, differences in severity of ischemic stroke.

Methods:
Patterning metrics were obtained for the retinal arterial trees of 10 mouse strains (n=8 per strain) that differ widely in collateral extent in brain and other tissues. We also obtained pial collateral number and diameter, and infarct volume 24h after permanent middle cerebral artery occlusion. Forward- and reverse-stepwise multivariate regression analysis was conducted and model performance assessed using K-fold cross-validation.

Results:
Twenty-one metrics varied significantly with genetic strain (p<0.01). Ten metrics (eg, vessel caliber, bifurcation angle, lacunarity, optimality, branch length) strongly predicted collateral number and diameter across 7 regression models. The best models closely predicted (p<0.0001) collateral number (K-fold R
2
=0.83-0.98), diameter (0.73-0.88) and infarct volume (0.85-0.87).

Conclusions:
Differences in retinal tree patterning are specified by genetic background and closely predict genetic variation in pial collateral extent and, in turn, stroke severity. If these findings can be confirmed in humans, and given that genetic variation in cerebral collaterals extends to other tissues at least in mice, a similar “retinal predictor index” could be developed as a biomarker for collateral extent in brain and other tissues. This could aid prediction of the risk-severity of tissue injury in occlusive disease as well as stratification of patients for treatment options and enrollment in clinical studies.
Abstract 11514: Adverse Events in Patients With Rheumatic Mitral Valve Disease in Sinus Rhythm
Authors: Kim Hyun-Jin , Cho Goo-Yeong , Kim Yong-Jin , Kim Hyung-Kwan , Lee Seung-Pyo , Kim Hack-Lyoung , Park Jin Joo , Yoon Yeonyee E , Zo Joo-Hee , Sohn Dae-Won
Published: July 2021

Introduction:
Patients with rheumatic mitral stenosis (RMS) and atrial fibrillation (AF) have revealed a high incidence of systemic embolism. Current guidelines do not recommend anticoagulation in patient with RMS and sinus rhythm.

Hypothesis:
The predictors of clinical events may facilitate adverse outcome in RMS patients with sinus rhythm.

Methods:
A total 1,019 patients who diagnosed with RMS were evaluated retrospectively between March 2003 and June 2013. Of these, patients with past or present AF (n = 447), who used anticoagulants or had prior thromboembolism (n = 154), or who performed mitral valve replacement within 9-month after diagnosis (n = 125) were excluded. A total of 293 patients were included. The clinical events were defined as all cause death and systemic embolism.

Results:
During the mean follow-up period of 68.2 ± 36.6 months, clinical events were developed in twenty-one patients (7.2%; embolism 12, all cause death 9) with 2.1% of average annual event rate. In the Cox-proportional hazard regression analysis, age was independent predictor of clinical events (HR 1.07 (95% CI 1.01-1.13),
p
= 0.026) after adjustment of confounding factors. LA dimension ≥ 47 mm showed borderline significance to predict events (HR 2.45 (95% CI 0.98 - 6.15),
p
= 0.057). Mitral valve area was not associated with events. In middle and old aged group (age ≥ 50), LA dimension ≥ 47 mm was a good prognosticator (HR 2.97 (95% CI 1.05 - 8.36),
p
= 0.040). During follow-up, sixty patients (20.5%) were developed AF with 3.5% annual event rate. LA dimension ≥ 47 mm was an independent predictor of composite all events including clinical events and development of AF.

Conclusions:
New onset AF was frequently developed in patients with RMS and sinus rhythm. Because of high risk of embolism of valvular AF, we need careful follow up in these patients group. In middle and old age group, enlarged LA dimension was closely related with all cause death or systemic embolism.
Abstract 11532: Randomized Trial of the Association Between Low Dose Statins and Nutraceuticals in High intensity Statin. intolerRant patiENts With Very High Risk Coronary Artery disease (ADHERENCE)
Authors: marazzi giuseppe , pelliccia francesco , volterrani maurizio , campolongo giuseppe , rosanio salvatore , massaro rosalba , cacciotti luca , quattrino silvia , sposato barbara , rosano giuseppe
Published: July 2021

Background:
Several trials have shown that in patients (pts) with atherosclerotic cardiovascular disease, reduction of LDL-C level with statin is associated with significant reductions in mortality and cardiovascular events. In clinical practice, however, high dose statin (HDS) treatment is often discontinued by pts due to side effects. Indeed, in statin intolerant pts alternative therapies such as nutraceuticals are available.

Purpose:
The primary objective of this study is to compare the efficacy and tollerability of low dose statin (LDS) therapy vs the association between a LDS and a nutraceuticals in HDS intollerant pts with CAD deemed to be at high risk.

Methods:
A randomised, prospective, parallel group, double blind trial was designed. The inclusion criteria were pts with CAD that underwent to PCI and that do not achieved at least a 50% reduction in LDL C and were HDS intolerant in treatment with LDS. These pts were randomized 1:1 in 2 groups: group NS received an association with LDS and a commercially available nutraceutical pill (1 tablet/day containing red yeast rice 200 mg, policosanol 10 mg and berberine 500 mg) and group S continued LDS (10 to 20 mg/day of simvastatin or 5 to 10 mg/day atorvastatin or 5 mg/day rosuvastatin). At baseline and after 3 months all pts underwent to clinical evaluation and blood exams.

Results:
100 pts were consecutively enrolled. Baseline clinical features and lipid profiles were similar between groups. At the 3° month, the 2 groups significantly differed for LDL-C, total cholesterol and triglycerides, with lower levels in the NS group than in the S group; also, the 2 groups differed for HDL-C values but not significantly, with higher levels in the NS group than in the S group (Table 1). Morever, in both group the treatment tolerance was high: in each groups only 3 pts discontinued therapy.

Conclusion:
In pts with CAD and HDS intolerant, a treatment with LDS and Nutraceuticals can be a reliable treatment option. (clinicaltrials.gov: NCT02001883)
Abstract 11534: HMG-CoA Reductase Inhibition Enhances Renoprotective Effects of Angiotensin Receptor1 Antagonism in Salt-Sensitive Hypertensive Rats
Authors: HU Lina , Cheng Xian Wu , Huang Zhe , Sasaki Takeshi , Inoue Aiko , Wu Hongxian , Zhu Enbo , Kuzuya Masafumi , Murohara Toyoaki , Okumura Kenji
Published: July 2021

Introduction:
The mineralocorticoid receptor has been implicated in the pathogenesis of chronic cardiorenal disease. 3-hydroxy-3methylgutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, improved renal dysfunction in patients with proteinuric kidney disease.

Objective:
We aimed to clarify the potential effect of a statin to enhance the inhibitory effect of an angiotensin type1 receptor blocker (ARB) on renal injury and the cellular mechanism of the effect of ARB on renal remodeling and proteinuria.

Methods and Results:
Dahl salt-sensitive (DS) rats on a high-salt diet were randomly assigned to four groups (n = 10 for each group) that were treated with either vehicle (0.5% carboxymethyl cellulose), a low or high dosage of olmesartan (1 or 3 mg/kg/d), or pitavastatin (1 mg/kg/d) plus olmesartan (1 mg/kg/d) from 12 to 19 weeks of age. Rats fed a low-salt diet served as age-matched controls. Rats on the high-salt diet developed massive proteinuria and glomerulosclerosis, and these changes were attenuated by olmesartan in a dose-dependent manner. The amounts of mRNAs for AT1R, mineralocorticoid receptor (MR), osteopontin, monocyte chemoattractant protein-1 and collagen type I, and the activities for matrix metalloproteinase-9 and cathepsin S were significantly higher in the failing kidneys of vehicle-treated rats than in the age-matched control rats; olmesartan significantly attenuated these changes. Olmesartan attenuated both the decrease in the ratio of reduced glutathione to oxidized glutathione and the increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity apparent in the kidney cortex of vehicle-treated rats. Furthermore, olmesartan inhibited kidney cortex vascular inflammation and renal fibrosis. The addition of pitavastatin significantly enhanced these beneficial effects by AT1R antagonism via anti-inflammation and anti-proteolysis.

Conclusions:
The beneficial renal effects of AT1R antagonism are likely attributable, at least in part, to the attenuation of renal oxidative stress and renal vascular inflammation induced by the AT1R-MR signaling interaction. The combination of statin with ARB may be a potential therapeutic strategy for renal injury with proteinuria.
Abstract 11535: A Triple-Targeting Strategy for Characterization of Plaque Inflammation in Mice and Humans Using Molecular Imaging
Authors: Krohn-Grimberghe Marvin , Bartmann Katharina , Hummel Hannes , Neudorfer Irene , von Elverfeldt Dominik , Merkle Annette , Wernli Bettina , Schoellhorn Joachim , Gawaz Meinrad , Bode Christoph , von zur Muhlen Constantin
Published: July 2021

Introduction:
Molecular imaging using inflammatory markers might offer additional information for plaque characterization. Here, we present a novel triple-target imaging strategy for the diagnosis and characterization of inflamed plaques using antibodies against vascular cell adhesion molecule 1 (VCAM1), lectin-like ox-LDL receptor (LOX1), and glycoprotein VI (GPVI).

Methods:
Antibodies against VCAM1, LOX1, GPVI, as well as control antibodies were conjugated to three different fluorescent dyes for imaging with the IVIS spectrum. As a model of atherosclerosis, we used ApoE-/- mice which were divided into three groups and fed 3 months of western type diet (WTD), 6 months of WTD, or 3 months of WTD with daily high-dose atorvastatin, respectively. Afterwards, their aortic arches were removed and imaged after incubation with the antibodies. To transfer our findings into a human model, we use carotid endarterectomy specimens for IVIS as well as magnetic resonance imaging (MRI). For MRI, we coupled our antibodies to microparticles of iron oxide (MPIO), a hypo intense contrast agent, and imaged the plaques using a small animal 9.4 T MRI after incubation under flow conditions.

Results:
The VCAM1, LOX1, and GPVI antibody constructs showed specific binding to atherosclerotic plaques in mice (p<0.05 for all three; n=4-5 per group) at both time points in comparison with their controls. The additional treatment with Atorvastatin led to a reduction for the signals of all three receptors (all p<0.05). After 6 in comparison to 3 month of WTD, an increase of LOX1 (p<0.05), a reduction of VCAM1 (p<0.05) and no significant changes of GPVI (p=0,81) were seen. Perfusion of the endarterectomy specimens with the MPIO-labeled contrast agent led to a significant signal reduction in MRI in comparison with their controls (n=8 per group; VCAM1 p=0.02; GPVI p=0.03). Our preliminary data for LOX1 show a tendency towards reduction (n=4; p=0.15) while not reaching significance yet.

Conclusion:
In this approach, we apply a new strategy of molecular MRI by targeting three different inflammatory markers in murine and human atherosclerosis for the noninvasive characterization of this disease, which might help to improve early detection and therapy of vulnerable atherosclerotic plaques.
Abstract 11542: Prognostic Significance of Insulin Treatment and Glucose Control Status on Clinical Cardiovascular Outcomes in Diabetic Patients Who Underwent Elective PCI Using Drug-Eluting Stents
Authors: Kunimura Ayako , Uetani Tadayuki , Kataoka Takashi , Takeshita Masataka , Harada Kazuhiro , Okumura Satoshi , Shinoda Norihiro , Harada Ken , Kato Bunichi , Kato Masataka , Marui Nobuyuki , Nanki Masahiro , Matsubara Tatsuaki , Ishii Hideki , Amano Tetsuya , Murohara Toyoaki
Published: July 2021

Background:
The aim of this study was to evaluate prognostic impact of insulin treatment and glucose control status on cardiovascular outcomes in diabetic patients after elective coronary intervention using drug-eluting stents (DES).

Methods:
A total of 198 consecutive diabetic patients undergoing elective percutaneous coronary intervention (PCI) with DES in Chubu Rosai Hospital from October 2005 to March 2008 were enrolled. The median HbA1c value of the patients was 7.5%. Patients were divided into four groups based on the presence or absence of insulin treatment and the HbA1c value at baseline (<7.5% or ≧7.5%). The endpoint of this study was major adverse cardiac event (MACE) defined as the composite of cardiovascular death, non-fatal myocardial infarction and any revascularization.

Results:
During the median follow-up of 1454 days, total 87 events occurred. MACE occurred more frequently in insulin-treated group with HbA1c<7.5% (78.9%) than in the other groups (log-rank p < 0.0001). The incidence of cardiac death or non-fatal myocardial infarction (p=0.022) and any revascularization (p=0.025) were significantly increased in insulin-treated group with HbA1c<7.5% than the other groups. In cox analysis, after adjustment for conventional risk factors (age, sex, body mass index, smoking status, hypertention, dyslipidemia) and duration of diabetes, fasting blood glucose, hemodialysis, the hazard ratio for MACE relative to non-insulin-treated group with HbA1c<7.5% was 2.91 (95% confidence interval 1.09 - 7.81, p = 0.034) in insulin-treated group with HbA1c<7.5%. Compared with insulin-treated group with HbA1c≧7.5%, the hazard ratio was 3.83 (95% confidence interval 1.01 - 14.54, p = 0.049) in insulin-treated group with HbA1c<7.5%.

Conclusion:
Insulin treatment with lower HbA1c value was proven to be an independent predictor of MACE in diabetic patients after PCI using DES.
Abstract 11611: Muscle Superoxide Dismutase and Augmented Autonomic Responsiveness in Rats With Peripheral Artery Disease
Authors: Xing Jihong , Lu Jian , Liu Jiahao , Li Jianhua
Published: July 2021

Background:
During exercise, responses of sympathetic nerve and blood pressure are amplified in patients with peripheral artery disease (PAD). This worsens the restricted blood flow directed to the limbs in this disease. The purpose of this study was to determine the role played by muscle oxidative stress in regulating the augmented autonomic responses to static exercise in PAD. Superoxide dismutases (SOD) is a class of enzymes to catalyze the dismutation of superoxide into oxygen and hydrogen peroxide, and considered as an important antioxidant. Thus, our specific hypothesis was that limb ischemia impairs muscle SOD and thereby leads to abnormal autonomic responsiveness observed in PAD.

Methods and Results:
We used a rat model of femoral artery ligation to study PAD. Note that all data are presented as mean ± SE. First, western blot analysis shows that 72 hours of femoral occlusion significantly decreased the protein levels of SOD in the oxidative muscle (optical density: 1.02±0.03 in control
vs.
0.21±0.02 after ligation,
P<
0.05;
n
= 6 in each group) and glycolytic muscle (optical density: 1.03±0.03 in control
vs.
0.65±0.04 after ligation,
P<
0.05;
n
= 6 in each group). Additional immunofluorescence study demonstrates down-regulation of SOD in the ischemic hindlimb muscles. Second, the reflex blood pressure response to static muscle contraction was examined in control rats (n=5) and rats with 72 hours of femoral occlusion (n=6). The data show that the augmented reflex pressor response to muscle contraction was significantly attenuated after compensating SOD in ischemic muscles by chronic administration of tempol (a mimetic of SOD, 30 mg over a period of 72 hours) into the hindlimb. In the ligated rats, mean arterial pressure response was 26±3 mmHg with no tempol (n=6) and 12±2 mmHg with tempol application (
P<
0.05
vs.
group with no tempol; n =5).

Conclusions:
Muscle SOD is blunted in the ischemic limbs and supplement of SOD mimetic for anti-oxidation improves the augmented blood pressure response during static exercise, which is beneficial to the restricted blood flow to the limbs in PAD patients.
Abstract 11661: A Family History of Premature Coronary Artery Disease is Associated With Location and Severity of Angiographically Defined Coronary Artery Stenosis
Authors: Hammadah Muhammad , Patel Riyaz S , Eapen Danny J , Samman Tahhan Ayman , Ghasemzadeh Nima , Al Kassem Hatem , Khayata Mohamed , Manocha Pankaj , Awad Mosaab , Kassas Ibrahim , Alkhoder Ayman , Veledar Emir , Quyyumi Arshed A
Published: July 2021

Introduction:
A family history (FH) of premature coronary artery disease (CAD) is an important prognostic risk factor. Emerging evidence suggests that CAD location as well as severity may be heritable. We sought to investigate the association between a FH of premature CAD with the location and severity of angiographically phenotyped CAD.

Methods:
2854 patients undergoing coronary angiography were enrolled from the Emory Cardiovascular Biobank. A FH of CAD was defined as having any male or female relative with history of CAD at age ≤55 or ≤65 year old respectively. Coronary angiograms were phenotyped using a 17 segment AHA model. Proximal disease was defined as having ≥70% lesion in the left main or proximal portion of any of the three major epicardial arteries, while CAD severity was assessed by counting the number of vessels with ≥70% stenosis.

Results:
Among this population (mean age 63±12, male 67%, diabetes 33%), 21% reported a positive FH of premature CAD. After adjustment for age, gender, and traditional cardiovascular risk factors, those with a positive FH were more likely to have significant CAD than those without a positive FH (OR 1.3 (1.1-1.7)). They were 40% more likely to have single vessel (OR 1.4(1.1-1.7)) and up to 80% more likely to have multi-vessel disease (OR 1.8 (1.4-2.4)). In addition, they were also much more likely to have left main (OR 1.9 (1.3-2.8)) and proximal vessel involvement (OR 1.5 (1.2 - 1.9)), but not distal vessel stenosis (OR 1.1 (0.9-1.4)).

Conclusions:
A FH of CAD is associated with a greater likelihood of multi-vessel and proximal anatomical disease. Whether site specific disease is genetically mediated remains to be explored.
Abstract 11675: Influence of Donor-Transmitted Lesions on Vessel Remodeling and Plaque Progression in Coronary Artery After Heart Transplant Recipients: Serial Three-Dimensional Intravascular Ultrasound Analysis
Authors: Watanabe Takuya , Seguchi Osamu , Nishimura Kunihiro , Yanase Masanobu , Sato Takuma , Sunami Haruki , Nakajima Seiko , Hisamatsu Eriko , Sato Takamasa , Kuroda Kensuke , Kobayashi Takashi , Nakao Yoko , Nakai MIchikazu , Takegami Misa , Higashiyama Aya , Watanabe Makoto , Kokubo Yoshihiro , Hata Hiroki , Fujita Tomoyuki , Miyamoto Yoshihiro , Nakatani Takeshi
Published: July 2021

Introduction:
The association between the presence of donor-transmitted lesions (DL) and the progression of cardiac allograft vasculopathy (CAV) including coronary vessel remodeling has been still controversial. The purpose of present study was to elucidate the influence of DL on coronary artery morphology after heart transplantation (HTx).

Methods:
Serial three-dimensional intravascular ultrasounds (3D-IVUS) analyses were performed in 50 HTx recipients at 9.0±3.6 weeks after HTx and annually thereafter for 5 years. Sites at baseline with maximum intimal thickening≧0.5 mm of anterior descending artery (LAD) were defined as DL. Significant functional narrowing by IVUS was defined as %plaque area (plaque area/vessel area) >40%. A mixed-model repeated-measures analysis was used.

Results:
DL was present in 54.0% in all recipients. In the first year after HTx, plaque volume significantly increased from 2.04±1.22 to 2.59±1.54 mm
3
/mm (p<0.01) in recipients with DL. Furthermore, the increase of plaque volume during 1 year after HTx was significantly higher in recipients with DL (0.62±0.85 vs 0.16±0.50 mm
3
/mm, p=0.048). Vessel volume in recipients with DL were greater than without DL at 1 year after HTx (12.84±3.15 vs 10.84±2.78 mm
3
/mm, p=0.024). Thereafter, the vessel volume decreased in both groups during 5 years. Consequently, the incidence of functional narrowing up to 5 years was higher in recipients with DL than in without DL (66.7% vs 30.4%, p=0.001). Cox proportional hazard model showed that the presence of DL increased the risk of functional narrowing (hazard ratio:HR3.38, 95% confidence interval 1.35-8.45) after adjusting for donor age, donor sex and the level of high density lipoprotein at 1 year.

Conclusions:
The presence of DL influenced not only the increase of plaque volume during the first year but also the vessel remodeling during 5 years. Recipients with DL have a higher incidence of significant functional narrowing by IVUS.
Abstract 11684: Impaired Cortical Pain Processing in Patients With Silent Myocardial Ischemia
Authors: Di Franco Antonino , Lanza Gaetano A , Valeriani Massimiliano , Villano Angelo , Russo Giulio , Sestito Alfonso , Virdis Daniela , Pazzaglia Costanza , Sarullo Filippo M , Rossini Paolo M , Crea Filippo , Vollono Catello
Published: July 2021

Purpose:
In the present study, we investigated whether the function of brain areas specifically devoted to nociception presents any abnormalities in patients with silent myocardial ischemia (MI), as compared to those with symptomatic MI.

Methods:
We studied 3 groups of individuals: 1) 11 asymptomatic, non-diabetic patients with documented obstructive coronary artery disease (CAD) (67±10 years, 6 men; group 1); 2) 10 patients with obstructive CAD and a clinical pattern of chronic stable angina (66.5±10 years, 6 men; group 2); 3) 14 apparently healthy subjects matched for age and gender to patients (63.2±9 years, 8 men; group 3). Patients with any chronic pain syndrome other than anginal chest pain were excluded. Cortical nociception function was assessed by cortical laser evoked potentials (LEPs) recording in response to chest skin stimulation by cutaneous CO2 laser pulses. Specifically, the N2/P2 wave of LEPs, which reflects cortical pain processing, was measured. Three sequences of painful stimuli (at the intensity of 2.5 times the individual sensory threshold) were applied, separated by 5-minute intervals.

Results:
N2/P2 amplitude during the first sequence of chest skin stimuli was 9.3±4.0, 14.0±7.3 and 15.5±6.4 μV in group 1, group 2 and group 3, respectively (p=0.03). N2/P2 amplitude decreased across the three sequences of pain stimuli in group 2 (-37.5±14 %) and group 3 (-23.0±15 %), but not in group 1 (-0.14±37 %) (comparison among groups, p=0.015).

Conclusion:
CAD patients with silent MI show a reduced amplitude of N2/P2 LEP component and inadequate habituation to painful stimuli, compared to symptomatic angina CAD patients and healthy controls. This pattern is likely due to thalamic gate modulation of pain signals and can contribute to the lack of pain perception during MI in these patients.
Abstract 11710: Plasma Mid-Regional Pro-Atrial Natriuretic Peptide and N-terminal Pro-Brain Natriuretic Peptide Can Discriminate Between Paroxysmal and Persistent Lone Atrial Fibrillation
Authors: Chang Ian C , Chong Jenny P , Austin Erin , Quay Chwee N , Gong Lingli , Richards Arthur M , Ling Lieng H , Chen Lin Y
Published: July 2021

Purpose:
The progression from paroxysmal to persistent atrial fibrillation (AF) is associated with an increased prevalence of cardiovascular comorbidities. Plasma atrial and B-type natriuretic peptides are increased in atrial fibrillation. We sought to determine whether mid-regional pro-ANP (MRproANP) and N-terminal pro-brain natriuretic peptide (NTproBNP) can discriminate between paroxysmal vs. persistent lone AF.

Methods:
We enrolled patients with lone AF (patients aged <60 years without hypertension, diabetes, or structural heart disease). Biomarkers were measured in normal sinus rhythm. We compared the ability of MRproANP versus NTproBNP in discriminating between paroxysmal and persistent lone AF by estimating the area under the ROC curve (AUC).

Results:
We enrolled 68 paroxysmal and 13 persistent lone AF patients (median age, 48 and 50 years; 88% and 92% male, respectively). Median MRproANP (121.5 v. 56.6 pmol/L, P<0.001) and NTproBNP (292.0 v. 48.0 pmol/L, P=0.004) were higher in persistent than paroxysmal lone AF. MRproANP (AUC [95% CI] 0.82 [0.72-0.92]) was marginally better than NTproBNP (0.76 [0.65-0.88]) in discriminating between paroxysmal and persistent lone AF, P=0.06 (Figure). The AUC of using both markers (0.85 [0.75-0.94]) was not significantly different from MRproANP alone (P=0.08), but was slightly better than NTproBNP alone (P=0.03).

Conclusions:
MRproANP and NTproBNP may be helpful in discriminating between paroxysmal and persistent lone AF. Further prospective studies are needed to assess whether these biomarkers can predict progression of paroxysmal to persistent lone AF.
Abstract 11737: Heart Failure Patients Who Have Knowledge About Their Disease but Don’t Perform Self-Care Have Worse Clinical Outcomes
Authors: Kato Naoko , Kinugawa Koichiro , Jaarsma Tiny
Published: July 2021

Introduction:
Both knowledge and self-care are related to outcomes of heart failure (HF) patients. Some HF patients do not perform self-care even if they have knowledge about the disease and might be in need for special interventions. We aimed at describing characteristics of those patients and assessing their clinical outcomes.

Methods:
A total of 163 HF outpatients were enrolled (age 64, 70% male, NYHA I or II, 95%) and followed for 2 years. HF self-care risk score was calculated by counting the number of poor adherence to five self-care behaviors (medication, a low-sodium diet, exercise, daily weighing, and help-seeking behavior) (range, 0-6). Knowledge was assessed with a Japanese HF knowledge scale (range, 0-15). Subsequently, we classified patients into 4 groups (A-D) as shown in figure. We analyzed patient’s characteristics in group C (poor self-care but good knowledge) by ANOVA and Chi-square test. To assess clinical outcomes we used Kaplan-Meier method and Cox regression analysis.

Results:
The mean HF self-care risk score was 3.1±1.6 and the mean knowledge score was 10.9±2.9. In total, 45 patients (28%) were classified into Group C [76% male, mean B-type natriuretic peptide (BNP) levels, 164 pg/mL]. Compared with other groups, patients in Group C were likely to be younger (61±13 vs. 65±11 years, p=0.059). Their self-care scores did not correlate with their knowledge scores (p=0.99). During a 2-year follow-up period, 29 patients (18%) had HF hospitalization and/or cardiac death, with a significant higher rate in Group C (30%, Fig, p=0.04). After adjustment for age, BNP, and medical therapy, patients in Group C had 2.8 times higher risk of poor outcomes than other groups (hazard ratio=2.80, p=0.01).

Conclusions:
One-third of patients have HF knowledge but they do not perform self-care, and they have worse outcomes compared with other groups. Further study is necessary to examine those patients in more detail and to provide support for them to put knowledge into action.
Abstract 11750: Inactivation of Cardiac Foxo1 by Insulin Signaling is Required for Cardiac Function and Suppression of β-Myosin Heavy Chain Gene Expression
Authors: Qi Yajuan , Wu Yuxin , Thomas Candice , Kumar Rajesh , Baker Kenneth M , Guo Shaodong
Published: July 2021

Heart failure is a leading cause of morbidity and mortality in the USA and is closely associated with diabetes mellitus. The molecular link between diabetes and heart failure is incompletely understood. We recently demonstrated that insulin receptor substrate 1, 2 (IRS1, 2) are key components of insulin signaling and their dysfunction mediates insulin resistance, resulting in metabolic dysregulation and heart failure. Loss of IRS1 and IRS2 is associated with downstream Akt inactivation and in turn activation of the forkhead transcription factor Foxo1. To determine the role of Foxo1 in control of heart failure in insulin resistance and diabetes, we generated mice lacking Foxo1 gene specifically in the heart. Mice lacking both IRS1 and IRS2 in adult hearts exhibited severe heart failure and a remarkable increase in the β-isoform of myosin heavy chain (β-MHC) gene expression, while deletion of cardiac Foxo1 gene largely prevented the heart failure and resulted in a decrease in β-MHC expression. The effect of Foxo1 deficiency on rescuing cardiac dysfunction was also observed in db/db mice and high-fat diet (HFD) mice. Using cultures of primary ventricular cardiomyocytes, we found that Foxo1 interacts with the promoter region of β-MHC and stimulates gene expression, mediating an effect of insulin that suppresses β-MHC expression. Taken together, our study suggests that Foxo1 has important roles in promoting diabetic cardiomyopathy and controls β-MHC expression in development of cardiac dysfunction. Targeting Foxo1 and its regulation will provide novel strategies in preventing metabolic and myocardial dysfunction and influencing MHC plasticity in diabetes mellitus.
Abstract 11760: The Outcomes of Children Implanted With Ventricular Assist Devices in the US: First Analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS)
Authors: Blume Elizabeth D , Rosenthal David N , Rossano Joseph W , Baldwin J. T , Eghtesady Pirooz , Morales David L , Cantor Ryan S , Conway Jennifer , Almond Christopher S , Naftel David C , Kirklin James K
Published: July 2021

BACKGROUND:
Use of pediatric mechanical circulatory support to decrease mortality has expanded dramatically. A national account of the use of FDA-approved devices in children is essential to understanding outcomes, refining patient selection, and improving quality of care.

METHODS:
PediMACs is an NIH-supported national registry for FDA-approved temporary and durable VAD usage in patients < 18 years of age. Between the launch in Sept 2012 and March 2014, 32 US hospitals enrolled patients. This first report of data from this registry analyzed pre-implant patient characteristics, survival using competing outcomes, and adverse events.

RESULTS:
One hundred and thirty pediatric pts underwent 153 VAD implantations. Etiology of heart disease included 87 (67%) pts with cardiomyopathy, 26 (20%) with congenital heart disease. Twenty pts transitioned from ECMO and 37 had prior cardiac surgery. Most pts were Intermacs level 1 (28%) and level 2 (55%) at implant, with 12% Intermacs level 3. There were 26 temporary devices. Of the durable devices, 65 (51%) were pulsatile and 62 (49%) continuous flow (CF) (compared to adult Intermacs implants: 4% pulsatile, 96% CF). Age at first implant included 22 pts (17%) < 1 yr of age, 23 (18%) 1-5 yrs, 26 (20%) 6-10 yrs and 59 (45%) 10-18 yrs. Patients were supported with LVAD alone in 99 (76%), BiVAD in 24 (18%) and total artificial heart in 2 (2%) and represented 484 months of follow-up. The 104 patients receiving primary durable devices had an actuarial survival of 90% at 6 mos. Competing risk analysis at 6 mos revealed 54% of pts transplanted, 37% alive on support, 8 % died and 1 % recovery. In the overall cohort, there were 8 early (<1mo) and 5 late deaths. Reported serious adverse events included infection (42), bleeding (40), device malfunction (37) and neurologic dysfunction (33).

CONCLUSIONS:
Pedimacs constitutes the largest single data repository with detailed information of pediatric pts implanted with all types of VADs. Initial data show a higher rate of use of pulsatile devices as compared to contemporaneous adult data. Survival rates are excellent despite varying patient characteristics and pump types. With further data collection, analysis of patient risk factors critical to improving outcomes will be possible.
Abstract 11803: Factors Associated With Delayed Diagnosis of Critical Congenital Heart Defects in Texas
Authors: Doshi Unnati , Hashmi Syed S , Marengo Lisa , Kaul Surabhi , Moulik Mousumi
Published: July 2021

Purpose:
Critical congenital heart defects (CCHD) require surgical and/or transcatheter intervention in infancy. They may or may not have ductal dependent circulation. Timely diagnosis before ductal closure is important to reduce morbidity and mortality. Our goal was to identify factors associated with delayed diagnosis of CCHD.

Methods:
This is a retrospective, population-based, observational study of liveborn infants in Texas born from 2000 - 2009 identified using the Texas Birth Defects Registry (TBDR). Inclusion required a definitive diagnosis of one of 13 selected CCHDs identified by diagnostic code and information on one of three “diagnostic” procedures: prenatal or postnatal echocardiogram or autopsy. Cases with aortic or pulmonary stenosis, coarctation of aorta, tricuspid stenosis or Ebsteins anomaly were included only if they underwent a cardiac surgical or catheterization procedure within 6 weeks of life. Stillborn infants or that died within three days of life (DOL) without evidence of an echocardiogram procedure were excluded. Date of diagnosis was defined as date of first echocardiogram. “Delayed diagnosis” was defined as any date of diagnosis after DOL3. Eligible infants with autopsy as the only “diagnostic” procedure were also classified as “delayed diagnosis”. Logistic regression models were created to identify factors that influence diagnosis delay.

Results:
A total of 5895 CCHD cases were identified. Diagnosis was delayed in 25% of cases. The CCHDs with highest rates of delayed diagnosis were critical coarctation (34%) and TAPVR (32%). In multivariate analysis, delayed diagnosis was more likely to be associated with single CCHD [adjusted odds ratio (aOR) 1.9; 95% CI 1.5-2.4], low maternal education [aOR1.7; 95% CI 1.2-2.3], prematurity <32wks [aOR 1.6; 95% CI 1.21-2.26], and rural maternal residence [aOR 1.5; 95% CI 1.22-1.94]. Presence of noncardiac defects decreased delayed diagnosis only for a few CCHD phenotypes.

Conclusions:
A quarter of all births with CCHD have a delayed diagnosis in Texas. Maternal education and residence are associated with the delay. Future studies will have to investigate each CCHD phenotype for specific risk factors.
Abstract 11815: Effects of Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers and Beta-Blockers on the Prevention of Atrial Fibrillation in Patients With Heart Failure With Preserved Ejection Fraction: A Prospective Study of Four-Years Follow-Up
Authors: Kawasaki Masanori , Tanaka Ryuhei , Minatoguchi Shingo , Watanabe Takatomo , Saeki Maki , Nagaya Maki , Ono Koji , Arai Masazumi , Noda Toshiyuki , Watanabe Sachiro , Minatoguchi Shinya
Published: July 2021

Background:
The incidence of new-onset atrial fibrillation (AF) is increasing with the prevalence of diastolic dysfunction. Diastolic dysfunction is thought to be responsible for heart failure with preserved ejection fraction (HFPEF). Effective medication for the treatment of HFPEF has been controversial, although angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs) and beta-blockers (BBs) have been proven to be effective in heart failure with reduced EF. We recently reported that pulmonary capillary wedge pressure (ePCWP) estimated by the combination of left atrial (LA) volume (V) and emptying function (EF) evaluated by speckle tracking echocardiography (STE) had a strong correlation with PCWP measured by cardiac catheterization (r=0.86-0.92).

Methods:
We screened 663 elderly (>65 years old) patients and identified 228 who had no AF history and met the criteria for diastolic dysfunction according to the Echocardiography Association of the European Society of Cardiology. These patients were prospectively followed for 4 years to identify new-onset AF. We measured echocardiographic parameters such as left ventricular (LV) mass index, LV ejection fraction, E/A, E/e’ and ePCWP at baseline. Concomitant medication was left to the discretion of the physicians in charge.

Results:
During a mean follow-up of 43 months, 63 elderly patients (age 73±6, 39 men) developed electrocardiographically-confirmed AF. There was no significant difference in the development of new-onset AF between the groups treated with and without BBs (hazard ratio (HR): 0.615, p=0.15). There was also no significant difference in new-onset AF between the groups with and without ACEIs or ARBs (HR: 0.796, p=0.46). However, in multivariate analysis that included ePCWP, LVM index, E/e’ and E/A, ePCWP at baseline independently predicted the risk of new-onset AF (HR: 1.42, 95% confidence interval: 1.29-1.57, p<0.001).

Conclusions:
ACEIs, ARBs or BBs had no beneficial effects on the prevention of new-onset AF as a marker of diastolic dysfunction in the patients with HFPEF. Estimation of ePCWP by STE had incremental value for the risk stratification of new-onset AF.