bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 11839: Obesity Related Heart Rate Changes among Young Hispanic Women with Metabolic Syndrome
Authors: Jose Mini M
Published: July 2021

Introduction:
Visceral adiposity and metabolic syndrome have an earlier onset among Hispanic women due to genetic susceptibility. This study aimed to determine the association between changes in BMI, body weight and heart rate (HR) among Hispanic women aged 31-49years who met the ATP III criteria for metabolic syndrome and Obesity.

Hypotheses:
1. There is a positive relationship between changes in BMI and Basal Heart rate 2. Patients with higher BMI will have a higher heart rate.

Methods:
In this retrospective study conducted in a community clinic, patient records meeting eligibility criteria were screened for three complete readings of anthropometric measurements and Vital signs. The readings taken when the patients had elevated temperature, respiratory rate, Blood pressure or when they were on Beta blockers were excluded. Final sample consisted of 61 records.

Results:
The sample BMI varied from 25 to 55 (Mean 34; SD 6) and the body weight ranged from 118lbs to 282lbs (Mean 188lbs; SD 35). The BMI change was between -4 to +4 (mean 1.15; SD 1.6), body weight change was from-30lbs to 22lbs (Mean 6.08 and SD 8.7) and the HR varied from -12 to 25 (mean 4.76; SD 8.38) Over 34 months. First hypothesis was accepted because Spearman Rho showed a significant positive correlation (r.298 p<.05) between changes in BMI and HR and between changes in body weight and HR (r.304 p<.05). A BMI change of one point raised the heart rate by 2beats/minute or 120beats/ hour accounting for 2,880 times/day. There was a no significant correlation between BMI and HR at all three data points leading reject the second hypothesis and conclude that the patients with highest BMI may not have the highest HR.

Conclusions:
The data showed that patients with metabolic syndrome and obesity suffer significant sympathetic stimulation raising basal HR, even when their blood pressure is controlled causing deleterious effect on already compromised heart with hypertension and atherosclerosis in metabolic syndrome. Patients with highest BMI may not have the highest HR due to failure to evoke an adequate sympathetic response and autonomic neuropathy signaling progressive chronic illnesses.
Abstract 11852: Role of Lox-1 in Mitochondrial Dna Damage and NLRP3 Inflammasome Activation
Authors: Ding Zufeng , Pant Sadip , Deshmukh Abhishek , Mehta Jawahar L
Published: July 2021

Objective:
This study tested the hypothesis that mitochondrial DNA damage could trigger NLRP3 inflammasome activation during inflammation, and LOX-1 may play a critical role in this process.

Methods and Results:
We performed studies in cultured human THP1 macrophages exposed to ox-LDL or LPS,which are often used as inflammation stimuli
in vitro
. We examined and confirmed the increase in LOX-1 expression when cells were treated with ox-LDL or LPS. Parallel groups of cells were treated with LOX-1 Ab to bind LOX-1. In accordance with our previous studies in endothelial cells and smooth muscle cells, LOX-1 Ab markedly reduced ox-LDL- as well as LPS-stimulated LOX-1 expression. To assess mitochondrial ROS generation, MitoSOX™ Red mitochondrial superoxide indicator was used. Both fluorescence staining and flow cytometry analysis showed that LPS induced (more than ox-LDL) mitochondrial ROS generation. Pretreatment with LOX-1 Ab significantly attenuated mitochondrial ROS generation in response to ox-LDL or LPS. Then we observed mtDNA damage in THP1 cells exposed to ox-LDL or LPS. Importantly, pretreatment with LOX-1 Ab protected mtDNA from damage in response to both stimuli. This was also confirmed by q-PCR (mtDNA/nDNA ratio) analysis. Further, ox-LDL or LPS induced the expression of phos-NF-kB p65, caspase-1 p10 and p20, and cleaved proteins IL-1β and IL-18. Of note, NLRP3 inflammasome was activated in response to ox-LDL or LPS in a similar manner. Pretreatment of cells with LOX-1 Ab treatment blocked or significantly attenuated these inflammatory responses.

Conclusions:
These observations based on
in vitro
observations indicate that LOX-1 via ROS generation plays a key role in mtDNA damage which then leads to NLRP3 inflammasome activation during inflammation.
Abstract 11863: Enhanced Adventitial Vasa Vasorum Formation in Patients With Vasospastic Angina -Assessment With Optical Frequency Domain Imaging-
Authors: Nishimiya Kensuke , Matsumoto Yasuharu , Takahashi Jun , Kato Takeshi , Oyama Kazuma , Hironori Uzuka , Odaka Yuji , Nihei Taro , Hao Kiyotaka , Tsuburaya Ryuji , Ito Kenta , Shimokawa Hiroaki
Published: July 2021

Background:
We have previously demonstrated that adventitial inflammation, including enhanced formation of adventitial vasa vasorum (VV), is involved in the pathogenesis of coronary spasm in porcine models and that optical frequency domain imaging (OFDI) allows us to visualize adventitial VV in humans in vivo. However, it remains to be elucidated whether adventitial VV is also involved in the coronary hyperconstriction in patients with vasospastic angina (VSA). In this study, we thus examined the extent of VV formation in VSA patients and control subjects by using OFDI.

Methods:
OFDI image acquisition of the left anterior descending coronary artery (LAD) was performed along the LAD at every 10 mm length after intracoronary administration of isosorbide dinitrate in 21 patients with acetylcholine-induced spasm and 10 control subjects without the spasm.

Results:
Patient characteristics were comparable between VSA patients and control subjects, including sex, age, cardiovascular risks and medications. OFDI and reconstructed 3D-OFDI images clearly visualized enhanced VV formation in VSA patients as compared with control subjects (Figure). Quantitative analysis showed that VV area was significantly larger in VSA patients than in control subjects (VSA, 0.093±0.006 vs. control, 0.040±0.006 mm
2
, P<0.0001), whereas vessel diameter, wall thickness and coronary lesion types were all comparable between the 2 groups.

Conclusions:
These results demonstrate for the first time that adventitial VV formation is enhanced at the spastic coronary segment in VSA patients, suggesting the important role of adventitial VV in the pathogenesis of coronary spasm.
Abstract 11911: Comparison of Late Catch-Up Phenomenon Between Sirolimus-Eluting Stent and Everolimus-Eluting Stent During 3 Years Follow-Up - a Propensity Matched Study -
Authors: Kobayashi Norihiro , Muramatsu Toshiya , Tsukahara Reiko , Ito Yoshiaki , Ishimori Hiroshi , Hirano Keisuke , Nakano Masatsugu
Published: July 2021

Background:
Recent studies have suggested the possibility of late catch-up phenomenon after implantation of sirolimus-eluting stent (SES) for coronary artery disease (CAD) compared to bare metal stent. However, little is known about the incidence of late catch-up phenomenon after implantation of everolimus-eluting stent (EES).

Methods:
Between April 2007 and May 2011, 1234 patients with CAD were treated with SES and 502 patients were treated with EES in our institution. We used a propensity score matching method with 1:1 matching, including 495 patients treated with SES and 495 patients treated with EES. Late catch-up phenomenon which was defined as target lesion restenosis (1 year to 3 years) were compared between the 2 groups.

Results:
After the propensity matching, no difference was seen in baseline characteristics between the 2 groups. Cumulative incidence of TLR at 3 years was 7.1% in EES group and 13.5% in SES group (P=0.001, log-rank test). Incidence of late catch-up phenomenon was 4.2% in EES group and 7.8% in SES group (P=0.020, log-rank test). Multivariate Cox’s proportional hazard analysis revealed that sirolimus eluting stent usage (HR 4.7, 95%CI 2.8-7.9, P<0.001), hemodialysis (HR 2.7, 95%CI 1.5-4.9, P=0.001), 2 stent use for bifurcation (HR 2.1, 95%CI 1.1-4.1, P=0.028), IVUS usage (HR 0.41, 95%CI 0.27-0.62, P<0.001), and ACS (HR 1.9, 95%CI 1.0-3.4, P=0.038) were independent predictors of late catch up phenomenon.

Conclusions:
EES was significantly superior to SES in the incidence of late catch-up phenomenon.
Abstract 11924: Phenotypes of Heart Failure Identified via Cluster Analysis Do Not Recapitulate Hemodynamic Profiles: Insights From the ESCAPE Trial
Authors: Ahmad Tariq , Dunning Allison , Schulte Phillip , Rogers Joseph , O’Connor Christopher , Felker Michael , Patel Chetan
Published: July 2021

Background:
Heart failure (HF) classification criteria do not adequately describe disease state. We used cluster analysis to identify distinct phenotypes of patients in the pulmonary artery catheter (PAC) arm of the ESCAPE trial, and examine association of clusters with hemodynamic profiles.

Methods:
Cluster analysis was performed on baseline clinical variables and PAC measurements in a cohort of 172 subjects from the ESCAPE trial, a randomized study examining PAC versus usual care in advanced systolic HF patients. ANOVA examined association between patient clusters and clinically determined hemodynamic profiles (warm/cold/wet/dry); association with clinical outcomes was assessed using Cox proportional hazards models.

Results:
Four HF clusters were identified with the following general characteristics: Cluster 1(n=75): Male Caucasians with ischemic cardiomyopathy, multiple comorbidities, lowest BNP levels; Cluster 2 (n=33): Females with non-ischemic cardiomyopathy, few comorbidities, most favorable hemodynamics; Cluster 3 (n=29): Young African American males with non-ischemic cardiomyopathy, most adverse hemodynamics and advanced disease; Cluster 4 (n=25): Older Caucasians with ischemic cardiomyopathy, concomitant renal insufficiency, and highest BNP levels. We noted no association between hemodynamic profiles and clusters (P=0.70). Cluster 4 patients had the highest risk of all adverse clinical outcomes, whereas cluster 2 had the lowest. Compared to patients in cluster 4, patients in other clusters had 45-70% lower risk of all-cause mortality.

Conclusions:
Using a novel approach that clusters patients according to similar clinical variables and PAC measures, we identified 4 clinically relevant phenotypes of HF patients, with no discernable relationship to hemodynamic profiles. Our analysis suggests that HF classification can be enhanced by simultaneous considerations of etiology, comorbid conditions, and biomarker levels.
Abstract 11928: Cardiospecific Overexpression of Carnosine Synthase Attenuates Myocardial Ischemia Reperfusion Injury
Authors: Baba Shahid , zhang Deqing , Hoetker David , Guo Yiru , Bhatnagar Aruni
Published: July 2021

Even though myocardial ischemia/reperfusion (I/R) remains the leading cause of death, the underlying mechanisms remain incompletely understood. Increased formation of reactive carbonyl has been shown to be a common biochemical feature of I/R injury. These carbonyls are generated from the oxidation of proteins and membrane lipids. Reactive carbonyls such as methylglyoxal are generated from increased glycolytic activity during ischemia. Previous work in our lab has shown that the endogenous dipeptide carnosine (β-alanine-histidine) quenches both protein and lipid derived carbonyls. It can also buffer changes in intracellular pH and chelate metals that catalyze ROS production. In the heart, carnosine is synthesized by the ATP grasp enzyme (ATPGD1). Hence, we examined whether overexpression of ATPGD1 could increase carnosine synthesis in the heart and attenuate I/R injury. To overexpress ATPGD1, we generated mice in which the expression of the transgene was driven by cardiospecific α-MHC promoter. Two different ATPGD1Tg mouse lines were generated, which showed 10-15 fold higher abundance of ATPGD1 protein in the heart compared with their wild-type (WT) littermates. Cardiac levels of the histidyl dipeptides anserine and carnosine were approximately 100 fold higher in the ATPGD1Tg than WT mice hearts (WT: anserine 1.8±0.3 pmoles/mg protein, carnosine 6±1 pmoles/mg protein; ATPGD1-Tg: anserine 114±15 pmoles/mg protein, carnosine 615±44 pmoles/mg protein). No changes in the levels of these dipeptides were observed in other tissues of the ATPGD1Tg mice. Echocardiographic analysis showed that ATPGD1 overexpression did not affect cardiac function. When subjected to 30 min of coronary occlusion followed by 24 h of reperfusion, the infarct size was significantly lower in ATPGD1Tg than WT mice. Infarct size as the area of risk of left ventricle was 59±3.02% in WT mice and 38±2.73% in the ATPGD1-Tg mice (p<0.05 vs WT; n=7-8), indicating that increasing carnosine levels attenuates myocardial I/R injury. These findings reveal a novel cardioprotective role of endogenous histidyl dipeptides in decreasing I/R injury and suggest that treatment with such peptides may be a potential therapy for decreasing myocardial I/R injury and its progression of heart failure.
Abstract 11940: Mineralocorticoid Receptor Dysregulation by MicroRNA-135a in Bradycardic Arrhythmogenic Remodeling
Authors: Duong Eric , Xiao Jiening , Le Quang Khai , Naud Patrice , Shi Yan- F , Tardif Jean- C , Dobrev Dobromir , Nattel Stanley
Published: July 2021

Introduction:
Complete atrioventricular block (CAVB) causes arrhythmogenic remodeling and increases the risk of Torsades de Pointes (TdP) arrhythmias. MicroRNAs (miRs) are key regulators of gene expression that contribute to cardiac remodeling. Here, we assess microRNA changes after CAVB and their potential significance in arrhythmogenic cardiac remodeling.

Methods:
CAVB was induced in mice via His bundle ablation. Expression of miRs was evaluated by pan-microRNA microarray with qPCR confirmation on samples from controls and at 24 hrs and 4 wks post-CAVB. Arrhythmias were detected by continuous monitoring. MicroRNA target prediction algorithms were used to identify potential target genes. Biological confirmation of targets was by luciferase assay and overexpression (OE) studies in HEK and H9c2 cells respectively.

Results:
TdP occurred within 24 hrs in 6/17 CAVB mice, vs no controls. Ventricular tachyarrhythmia episodes were frequent at 4 wks CAVB (212±83 per 24 hrs) and were not seen in controls. CAVB was followed by increased left ventricular (LV) dimension (by 31%, ***p<.001), LV mass (by 33%, *p<.05) and LV fractional shortening (by 33%*) at 4 wks. Of >400 miRs assayed, only miR-135a was altered at 24 hrs (downregulated by 96%***, Fig. A), with 70% decrease at 4 wks. TargetScan predicted miR-135a regulation of the mineralocorticoid receptor (MCR), encoded by the
NR3C2
gene. miR-135a OE suppressed
NR3C2
3’UTR reporter activity 3.2-fold* (n=5, Fig. B). miR-135a OE did not affect
NR3C2
mRNA (Fig. C) but significantly reduced
NR3C2
protein expression (n=4, Fig. D). Coexpression with anti-miR-135a eliminated the
NR3C2
downregulating effect of miR-135a OE.

Conclusions:
The mineralocorticoid receptor, encoded by the
NR3C2
gene, is translationally regulated by miR-135a, a microRNA that is downregulated in the heart following CAVB in mice. These results implicate miR-135a/mineralocorticoid modulation in arrhythmogenic ventricular remodeling caused by CAVB.
Abstract 11959: Cardiac Denervation Appears Before Becoming Myocardial Tissue Fibrosis in Patients With Cardiac Involvement Sarcoidosis and Active Inflammation Using C-11 Hydroxyephedine PET/CT and Cardiac Magnetic Resonance
Authors: Yoshinaga Keiichiro , Tsujino Ichizo , Manabe Osamu , Tomiyama Yuuki , Sato Takahiro , Oyama-Manabe Noriko , Ohira Hiroshi , Nishijima Ken-ichi , Birnie David , Beanlands Rob S , Nishimura Masaharu , Tamaki Nagara
Published: July 2021

Background:
Cardiac involvement sarcoidosis (CS) has increased risk of arrhythmia linked to sudden death. Cardiac sympathetic nervous (SNS) dysfunction may play an important role for these events. However, the association between the SNS dysfunction and active inflammation or tissue fibrosis has not been studied. The aim of this study was to evaluate the left ventricle (LV) SNS dysfunction measured by C-11 hydroxyephedrine (HED) positron emission tomography (PET)/CT and its association with tissue fibrosis measured by cardiac magnetic resonance (CMR) in patients with CS and active inflammation.

Methods:
Eleven patients with CS based on the JMHW guidelines (1993) were enrolled. CS (age 59±16 y) and preserved LVEF (64±14 %) underwent HED PET, FDG PET, and CMR. Ten healthy controls underwent HED PET. LV wall was divided into 17 segments. Reduced HED uptake, focal FDG uptake, and late gadolinium enhancement (LGE) on CMR were defined as positive for the visual assessment. In addition, whole LV and regional HED uptake was quantitatively assessed by retention index (RI). Standard uptake value (SUV) was measured in the FDG positive segments.

Results:
CS had reduced global LV HED RI compared to control (0.09±0.04 vs. 0.15±0.03 %/min, P<0.001). FDG positive group (n=7) had lower global HED RI than FDG negative group (n=4) (0.065±0.027 vs. 0.130±0.040 %/min, P=0.010). In contrast, there was no significant difference in LGE positive segments numbers between the two groups (3.14±2.79 vs. 1.25±0.96, P=0.46). In segmental analysis, the percentage of abnormal segments were trend to higher in HED than LGE (P=0.19). In addition, there was no correlation between regional FDG SUV and HED RI (n=42 segments, R=-0.11, P=0.50).

Conclusions:
Cardiac involvement sarcoidosis with active LV inflammation and preserved LVEF showed global LV cardiac sympathetic nervous dysfunction. Denervation area was tended to be larger than tissue fibrosis. Furthermore, no association was seen between FDG uptake and HED retention index in regional level. These findings may imply that multiple factors other than inflammatory process and tissue fibrosis may be involved in the cardiac sympathetic nervous dysfunction in cardiac involvement sarcoidosis.
Abstract 11972: Venous Thromboembolism Recurrence Rate and Risk Factors in a European Population
Authors: Hamilton Melissa , Goren Amir , Gupta Shaloo , Auziere Sébastien , Claflin Abigail , Phatak Hemant
Published: July 2021

Introduction:
This study estimated venous thromboembolism (VTE) recurrence and risk factors in a European population, given limited data in this region.

Methods:
This retrospective cohort study included data collected from physicians recruited from an online panel in France, Spain, Italy, and Germany. Physicians completed case report forms for the next 3-4 patients seen in consultation for any reason who had an initial VTE event in the prior 3 to 24 months (i.e., patients who survived 90 days since their initial VTE). Included were 376 general practitioners and 307 specialists, providing 2,184 patient records and information on patient demographics, comorbidities, and VTE recurrence. Kaplan-Meier estimation provided cumulative incidence survival functions accounting for censored data (patient records varied from 3-24 months post-initial VTE). Risk factors for VTE were assessed.

Results:
Patients’ mean age was 61.3 years (SD=14.3) and 47.4% were female. Of 2,184 patients, 379 developed recurrent VTE over 1,298 person-years of follow-up. The table shows cumulative incidence of VTE in the overall population and by risk categories. The 6-month cumulative incidence of VTE recurrence was 11.7%; the 12-month cumulative incidence was 27.6%. VTE cumulative incidence did not differ by age, gender or initial VTE type. However, it was higher in patients with moderate-to-strong vs. weak Anderson & Spencer summary risk scores (p=.001); e.g., 12-month rates of 33.8%, vs. 20.9%, respectively.

Conclusions:
VTE recurrence is high in this European population and increases with time since initial VTE event, suggesting the need for targeted anticoagulant treatment following an initial VTE event and longer term prevention of VTE recurrence. Among risk factors investigated, Anderson & Spencer scores help differentiate patients more likely to experience recurrence within 12 months of initial VTE.
Abstract 11988: Next Generation Sequencing of Cardiac Gene Expression Changes Associated With Heart Failure in Chronic Inflammation Inhibition
Authors: Matsumoto Takehiro , Wada Atsuyuki , Fujii Masanori , Taniguchi Atsuhi , Mori Kousuke , Tamagawa Yuichiro , Isono Takahiro , Horie Minoru
Published: July 2021

Since a variety of gene alternations are involved in heart failure (HF), identifying key functional molecules associated with HF is a challenging task. Therefore, we investigated the global transcriptome analysis of left ventricle (LV) from tachycardia induced HF dogs using next generation genome sequencers. The mRNA sequence reads aligned with ~15000 of the 21407 genes using the human genome19 database. The analysis identified significantly up-regulated genes associated with inflammation such as Rel A, STAT 3, RIPK2, CDKN1, TNF-alpha, interleukin (IL) and p53 related pathways and collagen type 4, which regulate cell cycles of inflammatory cells and fibroblast. These data suggest chronic inflammation induced by those novel genes may affect cardiac remodelling and inhibition of these effects may become one of the strategies to treat HF. Thus, we focused on cardiac chymase activity that is stored in the mast cells recruited by stem cell factor and affects chronic inflammation closely linked with cardiac remodelling. We examined therapeutic effects of a chymase inhibitor (ChyI 0.3mg/kg/day, n=7) on cardiac structural changes and gene expressions in failing dogs’ heart. In HF, the number of chymase-degranulated cells evaluated by chymotrypsin staining increased in the LV compared with the normal group, however, ChyI significantly decreased that cell density. ChyI significantly suppressed the IL-6, Rel A, STAT 3, CDKN1, RIPK2, TNF-alpha and p-53 mRNA levels in the cardiac tissue. Not only collagen type 1,3 but also type 4 mRNA involved in maintaining the structural integrity were decreased compared with the vehicle. ChyI suppressed fibrosis in LV evaluated with picrosirius red stain (% collagen volume fraction; 1.1, Normal; 4.6, ChyI; vs 7.1%, Vehicle; P<0.05, respectively). Despite no significant differences in blood pressure, ChyI shortened the prolongation of tau (22, Normal; 35, ChyI; vs 50 msec, Vehicle; P<0.05, respectively) and decreased LV end-diastolic pressure. We can conclude that the global transcriptome analysis can provide new insights into cellular mechanisms and therapeutic effects of ChyI in HF.
Abstract 12067: Serum Immunoglobulin G4 Level is a Useful Marker for the Assessment of Low-Density Coronary Plaque
Authors: Sakamoto Aiko , Ishizaka Nobukazu , Ando Jiro , Uehara Masae , Nagai Ryozo , Komuro Issei
Published: July 2021

Objective:
Rupture of atherosclerotic coronary plaque is the most frequent cause of acute coronary syndrome. Although an immuno-inflammatory process is recognized to play a crucial role in the pathogenesis of atherosclerosis, it remains unclear whether immunoglobulin G4 (IgG4)-related immuno-inflammation is associated with coronary plaque vulnerability. The association between serum IgG4 levels and low-density plaque (LDP) was analyzed.

Methods:
We measured serum levels of IgG4 and high-sensitivity C-reactive protein (hsCRP) in 325 patients (193 males; mean age, 68.2 ± 10.8 years) who underwent 320-slice coronary computed tomography angiography (CCTA). The presence or absence of LDP was evaluated, and epicardial fat volume (EFV) was also calculated.

Results:
A total of 130 patients (40.0%) were judged to have LDP by CCTA. Serum levels of IgG4 and hsCRP were both significantly higher in patients with LDP than in those without (IgG4, 32.4 mg/dL [interquartile range, IR 18.6-81.2] vs. 24.0 mg/dL [IR 13.2-49.0], P=0.002; hsCRP, 0.10 mg/dL [IR 0.05-0.23] vs. 0.07 mg/dL [IR 0.03-0.15], P=0.008). The median of EFV was significantly greater in patients with LDP than in those without (112 mL [IR 78-148] vs. 94 mL [IR 74-127], P=0.011). EFV had a significant association with serum levels of IgG4 (R=0.117, P=0.035) and hsCRP (R=0.200, P<0.001). In logistic regression analysis using age, gender, EFV, serum hsCRP levels, estimated glomerular filtration rate (eGFR), smoking, hypertension, dyslipidemia, and diabetes as covariates, the fourth quartile of IgG4 (≥56.7 mg/dL) was significantly associated with LDP with an odds ratio of 2.15 (95% confidence interval 1.07-4.34, P=0.032).

Conclusions:
Serum levels of IgG4 were significantly associated with LDP, and this relationship was, at least in part, independent of traditional cardiovascular risk factors and serum hsCRP levels. IgG4-related immuno-inflammation may affect coronary plaque vulnerability.
Abstract 12117: The Cardioprotection of Trimetazidine Against Ischemic Injury is Mediated by AMPK and ERK Signaling Pathway
Authors: Liu Zhenling , Ma Yina , Kuznicki Michelle , Chen Xingchi , Sun Wanqing , Zhu Ping , Li Ji
Published: July 2021

Introduction:
Trimetazidine (TMZ) is an anti-anginal drug that has been widely used in Europe and Asia. The TMZ can optimize energy metabolism via inhibition of long-chain 3-ketoacyl CoA thiolase (3-KAT) in the heart, with subsequent decrease in fatty acid oxidation and stimulation of glucose oxidation. However, the mechanism by which TMZ aids in cardioprotection against ischemic injury has not been characterized.

Hypothesis:
AMP-activated protein kinase (AMPK) is an energy sensor that control ATP supply from substrate metabolism and protect heart from energy stress. TMZ changes the cardiac AMP/ATP ratio
via
modulating fatty acid oxidation, thereby it may trigger AMPK signaling cascade that contribute to protection heart from ischemia/reperfusion (I/R) injury.

Methods:
The mouse
in vivo
regional ischemia and reperfusion by the ligation of the left anterior descending coronary artery (LAD) were used for determination of myocardial infarction. The infarct size was compared between C57BL/6J WT mice and AMPK kinase dead (KD) transgenic mice with or without TMZ treatment. The
ex vivo
working heart perfusion system was used to monitor the effect of TMZ on glucose oxidation and fatty acid oxidation in the heart.

Results:
TMZ treatment significantly stimulates cardiac AMPK and extracellular signal-regulated kinase (ERK) signaling pathways (p<0.05 vs. vehicle group). The administration of TMZ reduces myocardial infarction size in WT C57BL/6J hearts, the reduction of myocardial infarction size by TMZ in AMPK KD hearts was significantly impaired versus WT hearts (p<0.05). Intriguingly, the administration of ERK inhibitor, PD 98059, to AMPK KD mice abolished the cardioprotection of TMZ against I/R injury. The
ex vivo
working heart perfusion data demonstrated that TMZ treatment significantly activates AMPK signaling and modulating the substrate metabolism by shifting fatty acid oxidation to glucose oxidation during reperfusion, leading to reduction of oxidative stress in the I/R hearts.

Conclusions:
Both AMPK and ERK signaling pathways mediate the cardioprotection of TMZ against ischemic injury. The metabolic benefits of TMZ for angina patients could be due to the activation of energy sensor AMPK in the heart by TMZ administration.
Abstract 12127: Integrated Flow-Mediated Vasodilation Response Predicts Cardiovascular Events in Elderly Patients at Cardiovascular Risk Factor
Authors: Kabutoya Tomoyuki , Hoshide Satoshi , Ogata Yukiyo , Eguchi Kazuo , Kario Kazuomi
Published: July 2021

Introduction:
The integrated flow-mediated vasodilation (FMD) response was shown to be associated with cardiovascular risk factors, but the association between the integrated FMD response and consequent cardiovascular events has been unclear.

Hypothesis:
We assessed the hypothesis that the integrated FMD response predicts consequent cardiovascular events.

Methods:
We enrolled 575 patients who had at least one cardiovascular risk factor (hypertension, dyslipidemia, diabetes, or smoking). We measured the FMD magnitude of the percentage change in peak diameter (ΔFMD), and we measured the integrated FMD response calculated as the area under the dilation curve during a 120-sec dilation period (FMD-AUC
120
) using a semiautomatic edge-detection algorithm. The primary outcome was defined as any cardiovascular event (a composite of cardiovascular death, and hospitalization for myocardial infarction, stroke, or heart failure).

Results:
The mean duration of follow-up was 35±22 months (range: 1-74 months). During the follow-up period, 34 cardiovascular events were recorded. Among the elderly patients (age[[Unable to Display Character:  ]]≥[[Unable to Display Character:  ]]65 yrs, n[[Unable to Display Character:  ]]=[[Unable to Display Character:  ]]281), the patients with the lowest tertile of FMD-AUC
120
(FMD-AUC
120
<[[Unable to Display Character:  ]]5.6) suffered a higher incidence of cardiovascular events compared with the patients with the higher two tertiles (FMD-AUC
120
≥[[Unable to Display Character:  ]]5.6) (log rank 4.16, p=0.041). The association remained significant after adjusting for age, gender and office systolic blood pressure (hazard ratio 1.25, p=0.039). In the younger patients (age[[Unable to Display Character:  ]]<[[Unable to Display Character:  ]]65 yrs, n[[Unable to Display Character:  ]]=[[Unable to Display Character:  ]]294), cardiovascular events were similar among the patients with the lowest tertile and those with the higher two tertiles of FMD-AUC
120
. Cardiovascular events were also similar in the patients with the lowest tertile and the higher two tertiles of ΔFMD in both the elderly and younger patients.

Conclusions:
The integrated FMD response, but not ΔFMD, predicted cardiovascular events in elderly patients with a cardiovascular risk factor.
Abstract 12150: Dronedarone is a Potent Cardiac and Hepatic CPT-1 Inhibitor
Authors: Chong Cher-Rin , Licari Giovanni , Westley Ian , Horowitz John D , Sallustio Benedetta C
Published: July 2021

Purpose:
Dronedarone was developed on the basis that it would represent a class III anti-arrhythmic devoid of “amiodarone-like” adverse effects. Indeed, photosensitization and iodine-related thyroid toxicity do not occur with dronedarone. However, a number of other adverse effects have emerged. We tested the hypothesis that, like amiodarone, dronedarone modifies cellular metabolism by inhibiting mitochondrial fatty acid uptake via the carnitine shuttle.

Methods:
We compared the efficacy of dronedarone as an inhibitor of cardiac and hepatic carnitine palmitoyl transferase-1 (CPT-1) with that of the known CPT-1 inhibitors perhexiline and amiodarone. Male 6-week old Sprague-Dawley rats were euthanized under 2% isoflurane. Hearts and livers were rapidly removed, homogenised and placed on ice. CPT-1 activity was measured by the formation of palmitoyl-carnitine, as previously described1. Samples were ultracentrifuged and supernatants were injected for detection by liquid-chromatography/mass-spectometry. Dronedarone (5, 10, 50, 100 and 500μM) was compared to amiodarone (100, 200 and 500μM), perhexiline (20, 50, 100, 150 and 200μM), and the physiological inhibitor of CPT-1, malonyl-CoA (1μM). Concentration-response curves were expressed via log(inhibitor) vs normalized responses.

Results:
(1) Malonyl-CoA inhibited CPT-1 by >90% in both heart and liver, while perhexiline was more potent than amiodarone as CPT-1 inhibitor (Table). (2) Dronedarone was equipotent (IC50 approximately 40μM) in both heart and liver, and approximately 3-fold more potent than amiodarone.

Conclusion:
Dronedarone, like amiodarone and perhexiline, inhibits cardiac and hepatic CPT-1. This has potential advantages regarding haemodynamic stability in atrial fibrillation, but may predispose to eventual hepato- and cardiotoxic effects.

Ref:

1. Kennedy JA, Unger S, Horowitz JD. Biochem Pharmacology 1996, 52, p273-280.
Abstract 12171: Biomarkers and Echocardiographic Predictors of Myocardial Dysfunction in Patients With Hypertension
Authors: Bielecka-Dabrowa Agata , Michalska-Kasiczak Marta , Gluba Anna , Rysz Jacek , Banach Maciej
Published: July 2021

Introduction:
The aim of the study was to clarify the basis of exertional dyspnea in patients with hypertension with well-controlled blood pressure and normal ejection fraction (EF).

Methods:
99 patients with hypertension of mean age 63±11 years: group A - 22 patients without symptoms; group B - 27 patients with exertional dyspnea; group C - 50 patients with overt heart failure (HF). Patients in groups A and B had normal resting echocardiography.Patients underwent echocardiography at rest and during submaximal exercise on a bicycle ergometer; cardiotrophin-1, cystatin C (CysC), syndecan-4, collagen III N-terminal propeptide (PIIINP), transforming growth factor beta (TGF-beta), tumor necrosis factor alpha (TNF-alpha), interleukin 1 receptor, type I (IL1R1), galectin-3 and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured.

Results:
In test group B the level of PIIINP was higher than in group A (2.9±0.94 vs 1.27±1.03 ng/ml; p=0.0001). Patients in groups A and B were characterized by lower levels of cardiotrophin-1, syndecan-4, NT-proBNP, and CysC than in group C. The concentration of TGF-beta was lower in group C than in A and B (p=0.000). Groups A and B had comparable echocardiographic findings at rest except isovolumic relaxation time, which was higher in group B (104.87±19 vs 89.4±26 ms; p=0.03). In exertional echocardiography the patients from group B compared with group A had lower E’ and S’ according to tissue Doppler imaging(12.83±1 vs 14.94±3, p=0.02; 9.35±2 vs 10.98±2; p=0.01) and E/E’ ratio was increased in the symptomatic group as compared to controls (6.99±1 vs 5.91±1; p=0.03). A late diastolic mitral annular velocity (A') increase was observed in group A and a reduction in group B with a significant difference in [[Unable to Display Character: ∆]]A’ between these two groups (-0.62±2.46 vs 1.22±3.41; p=0.04).

Conclusions:
PIIINP might be the first early biomarker for the development of HF in patients with hypertension. Patients with normal resting echocardiography can present exercise intolerance and breathlessness associated with reduced left atrial function, worse left ventricular relaxation and impaired function of the longitudinal fibers of myocardium on exercise. Exertional echocardiography may indicate patients with incipient HF with preserved EF.
Abstract 12193: Cardiovascular Toxicity of Carfilzomib on Vascular Tone, Vascular Reactivity and Endothelial Function
Authors: Scarabelli Tiziano , Gavazzoni Mara , Chen-Scarabelli Carol , Sahni Gagan , Saravolatz Louis , Narula Jagat , Raddino Riccardo
Published: July 2021

Background:
Carfilzomib (CFZ) is a new proteasome inhibitor used for the treatment of Multiple Myeloma (MM). Cardiac failure events (7.2%) and myocardial ischemia have occurred following administration CFZ. Infusion reactions also include chest thightness and angina of unknown mechanism.

Aim of study:
To investigate whether CFZ exerts in vitro effects on vascular tone and reactivity in an isolated experimental model of rabbit thoracic aortic-strips.

Methods and Results:
We evaluated first the effect of single injections of CFZ on the basal tone of isolated aortic strips (n= 6) placed in 10 ml organ bath at 37°C containing Krebs-Henseleit solution. Vasoconscriction, as documented by an overall increase in tension of 0.5 g, was observed with increasing concentrations of CFZ (from 1 x 10-9 to 10 -7 mol/L; p:0.041). In a second set of experiments, the effect of three different spasmogenic agents [potassium chloride (KCl) (n= 6), noradrenaline (NA) (n= 6), and angiontensin II (A) (n= 6)] on naive aortic strips (group 1) was compared to that on aortic strips pretrated for 60 minutes with CFZ at a concentration of 15 nmol/L (group 2). Pretreatment with CFZ resulted in amplified vasocostriction (2.4±0.4 g vs 2.1±0.3 g for KCl administration; 2.5±0.3 g vs 2.0±0.2 g for NA; 2.6±0.2 g vs 2.0±0.2 g for A; all p<0.005) and impaired vasodilation following administration of nitroglycerin (NTG) on the plateau of contraction induced by each spasmogenic agent (100% vs 82% for KCl; 100% vs 67% for NA and 100% vs 51% for A; all p<0.05). Finally, aortic strips pretreated with CFZ exhibited impaired relaxation, as compared to naive strips (100 % versus 40% in tension reduction; p:0.028), following administration of acetylcholine (Ach), an endothelium-dependent vasodilating agent, on the plateau of NA contraction.

Conclusions:
CFZ increased the resting vasoconstricting tone and amplified the spasmogenic effect of different agents. Moreover, preincubation with CFZ decreased the anti-spasmogenic activity of NTG and reduced by over 50% the vasodilating effect of Ach, suggesting that CFZ can impair vasodilation by inducing endothelial dysfunction. Further studies are warranted to establish its clinical safety in patients with known CAD and prior history of coronary spasm.
Abstract 12196: Optic Atrophy 1 Deficiency in Skeletal Muscle Results in Progressive Mitochondrial Dysfunction, but Prevents Age-Induced Obesity and Glucose Intolerance
Authors: Pereira Renata , Li Zhonggang , Oliveira Karen , Pires Karla , Abel E. Dale
Published: July 2021

Mitochondrial dysfunction develops in skeletal muscle with aging and may contribute to insulin resistance, which increases cardiovascular risk. A link between skeletal muscle insulin resistance and perturbed mitochondrial fusion and fission has been suggested but not proven. Optic Atrophy 1 (OPA1) is an inner mitochondrial membrane protein that plays a fundamental role in mitochondrial fusion, quality control and respiratory function. OPA1 levels are reduced in muscle from elderly subjects; however, the specific roles of OPA1 in the aging muscle have not been studied. We, therefore, generated a mouse model with inducible deletion of the OPA1 gene in skeletal muscle of adult C57Bl6 mice, by crossing OPA1 floxed mice with HSA-Cre (ERT2) mice (KO). Four-week-old KO and wild-type (WT) mice were treated with tamoxifen for 5 days to induce recombination, resulting in a 60% reduction in OPA1 protein levels 8 weeks after treatment (12-wk-old mice). OPA1 deficiency resulted in altered mitochondrial cristae morphology, with preserved maximally stimulated mitochondria respirations in soleus and reduced ATP synthesis rates in KO mice, 8 weeks after recombination (12-wk-old mice). At 20 weeks, mitochondrial respiration and ATP synthesis were decreased in KO mice, concomitantly with increased AMPK and eIF2 alpha activation. Body weight was reduced in 12 and 20-week old KO mice relative to WT. At forty-weeks, body weight was increased by 40% in WT mice vs. 15% in KO mice. This increase in body weight occurred on the basis of increased fat mass (70% in WT vs. 30% in KO). Lean mass was reduced by 30% in WT mice, which was attenuated in KO mice (~10%). Glucose tolerance tests were similar between WT and KO mice at 12 and 20 weeks of age; however, 40-wk-old WT mice had severe glucose intolerance, which was prevented in KO mice. Interestingly, KO mice had a100-fold increase in FGF21 mRNA levels in muscle compared to WT mice. These data reveal that OPA1 is critical for maintaining skeletal muscle mitochondrial function in the adult muscle and suggest that reducing OPA1 levels activates signaling pathways that retard age-induced obesity and glucose intolerance.
Abstract 12199: Prognostic Value of Cardiac Time Intervals Measured by Tissue Doppler Imaging M-Mode in the General Population
Authors: Biering-Sørensen Tor , Mogelvang Rasmus , Jensen Jan Skov
Published: July 2021

Purpose:
Tissue Doppler imaging (TDI) M-mode through the mitral leaflet is an easy, fast, and precise method to estimate the cardiac time intervals from one cardiac cycle (Figure). The aim was to evaluate the usability of the cardiac time intervals in predicting major cardiovascular events (MACE) in the general population.

Methods:
In a large community based population study, cardiac function was evaluated in 1,915 participants by both conventional echocardiography and by TDI. The cardiac time intervals, including the isovolumic relaxation time (IVRT), isovolumic contraction time (IVCT), and ejection time (ET) were obtained by TDI M-mode through the mitral leaflet (Figure). IVCT/ET, IVRT/ET and the myocardial performance index (MPI=(IVRT+IVCT)/ET) were calculated.

Results:
During follow-up (median 10.8 years), 383 (20%) participants reached the combined endpoint MACE (ischemic heart disease, heart failure or cardiac death). After multivariable adjustment for clinical predictors and conventional echocardiography, only the combined indexes, including information on both the systolic and diastolic performance (IVRT/ET and MPI), remained significant prognosticators (IVRT/ET: Subdistribution Hazard Ratio (SHR) 1.16 (1.00-1.34), p = 0.047; MPI: 1.11 (1.03-1.23), p = 0.024). Adding IVRT/ET or MPI to a model already including all other echocardiographic parameters resulted in a significant increase in the Harrell’s c-statistics (p<0.05 for both). Finally, when adding IVRT/ET or MPI to the clinical predictors improved reclassification significantly (p<0.05 for both).

Conclusion:
In the general population, the combined cardiac time intervals which include information on both the systolic and diastolic function in one index (IVRT/ET and MPI) are not only powerful and independent predictors of future MACE, but provide additional prognostic information to clinical and conventional echocardiographic measures of systolic and diastolic function.
Abstract 12226: Left Atrial Structure and Function and Cardiovascular Events in Patients With Diabetes Mellitus: Results From Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Markman Timothy M , Habibi Mohammadali , Ambale-Venkatesh Bharath , Zareian Mytra , Wu Colin , Heckbert Susan R , Bluemke David A , Lima João A
Published: July 2021

Introduction:
Diabetes mellitus (DM) is associated with the development of cardiovascular disease (CVD). Morphological changes in the LA may appear before symptoms. We aimed to investigate the association between cardiac magnetic resonance imaging (CMR) measured LA structure and function and incident CVD in asymptomatic individuals with DM.

Methods:
Tissue tracking CMR was used to measure LA size and phasic emptying fraction (EF) on all 574 MESA participants with DM and available baseline CMR, which was performed between 2000 and 2002. MESA is a population based, multi-center cohort study of 6814 healthy individuals. CVD was defined as MI, resuscitated cardiac arrest, angina, stroke, heart failure, atrial fibrillation, and any mortality secondary to CVD. Cox regression was used to assess the association of LA parameters with incident CVD adjusted for traditional risk factors, LV mass assessed by CMR, NT Pro-BNP and maximum LA volume. Adjusted Kaplan-Meier curves are based on 25th percentile cut-offs.

Results:
After a mean follow up of 7 years, 96 individuals developed CVD (mean age 64, 53%male, 79% treated). Individuals with incident CVD (mean age 66 years, 66% male vs. mean age 4 years, 50% male) had larger maximum and minimum LA volume index (LAVI) (32±13 mm3/m2 vs. 27±10 mm3/m2; 20±10mm3/m2 vs. 14 ±6 mm3/m2), and lower total and active EF than those without CVD (42±11% vs. 48±9%; 29±11% vs. 32±11%). p<0.01 for all. In the final model, there was a significant association of minimum LAVI, LA total EF, and LA active EF with incident CVD.

Conclusions:
CMR measured LA structure and function are predictive of CVD in a diabetic multi-ethnic population free of any symptomatic CVD at baseline.
Abstract 12229: Health Literacy, Adherence to Self-Care Behaviors, and Ten-Year Cardiovascular Disease Risk in Central Appalachian Residents
Authors: Wu Jia-rong , Hardin-Fanning Frances , DeWalt Darren , Moser Debra K
Published: July 2021

Background:
Appalachian Kentucky has disproportionately higher rates of cardiovascular disease (CVD) and associated risk factors than the rest of the U.S. Health literacy and adherence to CVD risk reduction self-care behaviors are important predictors of health outcomes and may play a major role in modifying CVD risk.

Objective:
To examine the relationships among health literacy, adherence to self-care behaviors and 10-year CVD risk in Central Appalachian residents.

Method:
This was a sub-analysis of baseline data of a randomized control trial in 844 Central Appalachian residents (male 25%, age 51± 14, Caucasian 95%) without major CVD (e.g., coronary artery disease, stroke). Health literacy was assessed by the Newest Vital Sign (NVS), and adherence to self-care behaviors by the Medical Outcomes Study Specific Adherence Scale. Ten-year CVD risk points were calculated from the Framingham formula based on age, high density lipoprotein, total cholesterol, systolic blood pressure (treated & untreated), smoking status, and diagnosis of diabetes. Linear regressions were used to examine the relationships among health literacy, adherence to self-care behaviors, and 10-year CVD risk.

Results:
Based on the NVS, 12% of residents had limited health literacy. Residents who had limited health literacy were more likely to have higher 10-year CVD risk than those with adequate health literacy (
p
= .014). Health literacy was not correlated with adherence to self-care behaviors. Unadjusted regressions revealed that both health literacy and adherence to self-care behaviors predicted 10-year CVD risk (
p
= .002 and < .001, respectively). After adjustment for the covariates (age, gender, ethnicity, marital status, employed status), only adherence to self-care behaviors predicted 10-year CVD risk (
p
= .012)

Conclusion:
Poor adherence to self-care behaviors predicts higher 10-year CVD risk. The lack of independent relationship between health literacy and self-care adherence, and health literacy and outcome suggests that adherence to effective self-care may be fostered despite low health literacy. It is important to design and implement effective interventions to enhance adherence to self-care behaviors to reduce 10-year CVD risks in Central Appalachian residents.
Abstract 12282: A Decrease in Mitochondrial, but Not Cytosolic, Iron Protects Against Cardiac Ischemia-Reperfusion Damage Through a Reduction in ROS
Authors: Chang Hsiang-Chun , Wu Rongxue , Ardehali Hossein
Published: July 2021

Introduction:
Iron is essential for the activity of several cellular proteins, but excess free iron can cause cellular damage through production of reactive oxygen species (ROS). Iron accumulation in mitochondria, the major site of cellular iron homeostasis, leads to cardiomyopathy. However, it is not known whether a reduction in baseline mitochondrial (as opposed to cytosolic) iron can protect against ischemia-reperfusion (I/R) injury in the heart. We hypothesized that since mitochondria are the major site of iron homeostasis and that mitochondrial iron can lead to oxidative damage, a reduction in mitochondrial iron at baseline would be sufficient to protect against I/R injury.

Results:
Transgenic (TG) mice with cardiomyocyte-specific overexpression of the mitochondrial iron export protein ATP-binding cassette (ABC)-B8 had significantly lower mitochondrial iron in the heart than nontransgenic (NTG) littermates at baseline, but their cardiac function and the expression of key antioxidant systems were similar to NTG littermates. In response to I/R, TG mice displayed significantly less apoptosis and lipid peroxidation products and better preserved cardiac function than NTG littermates, suggesting that a reduction in mitochondrial iron protects against I/R injury. To confirm these results, we next took a pharmacological approach to assess the effects of a reduction in mitochondrial vs cytosolic iron on the response to I/R using 2,2’-bipyridyl (BPD, a mitochondria-accessible iron chelator) and deferoxamine (DFO, an iron chelator that can only reduce cytosolic iron). Treating rat cardiomyoblast H9C2 cells with BPD but not DFO significantly lowered chelatable mitochondrial iron and protected against H
2
O
2
induced cell death, and pretreatment with BPD but not DFO protected mice against I/R injury and reduced ROS production, suggesting that a reduction in baseline mitochondrial, but not cytosolic, iron is sufficient to protect against I/R injury.

Conclusions:
Our findings demonstrate that selective reduction in mitochondrial iron is protective in I/R injury. Thus, targeting mitochondrial iron with selective iron chelators may provide a novel approach for treatment of ischemic heart disease.