bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12750: Atrial Tissue MicroRNAs 411-5p, 21-5p, 409-3p and 320a Are Associated With Atrial Fibrillation
Authors: Kinno Menhel , Esa Nada , Velagaleti Raghava S , Shaikh Amir Y , Lin Honghuang , Tanriverdi Kahraman , Mandapati Divakar , Tam Stanley , Okike Okike N , Keaney John F , Donahue J. Kevin , Freedman Jane E , McManus David D
Published: July 2021

Introduction:
Atrial Fibrillation (AF) is the most common arrhythmia in clinical practice. MicroRNAs (miRs) are small RNAs that play a role in regulating cardiac remodeling and have been implicated in cardiac arrhythmogenesis. However, few studies have examined the association of atrial miR expression to AF.

Hypothesis:
Changes in miR expression (estimated as fold-difference in the delta cycle threshold compared to global mean) in human atria can be associated with AF.

Methods:
Thirty-one consecutive patients undergoing elective cardiac surgery were divided into 2 groups: those with history of AF (n=19) and those with no history of AF who stayed in sinus rhythm post-operatively (n=12). Atrial tissue samples were obtained from the right atrium in all but one (left atrium). Based on pilot data and prior literature, the expression of 82 miRs was assessed using high-throughput quantitative reverse-transcriptase polymerase chain reaction. We used logistic regression adjusting for age and sex to detect the associations between levels of atrial miRs and AF.

Results:
The mean age of the sample was 65 years (±13) and 71% were men. A history of coronary artery disease and heart failure was present in 42% and 36%, respectively. Among AF subjects, the age- and sex- adjusted odds ratios for the expression of miRs 411-5p, 21-5p, 409-3p and 320a were 0.08 (p= 0.02), 0.20 (p=0.02), 0.13 (p= 0.04) and 0.04 (p=0.048), respectively, compared to no AF. The fold-difference in atrial expression of miRs 411-5p, 21-5p, 409-3p and 320a were -0.567, -0.588, -0.375 and -0.427, respectively, in those with AF compared to no AF.

Conclusion:
In our study, the atrial expression of miRs 411, 21, 409 and 320 was lower in AF patients compared to those with no AF. Notably, these miRs regulate genes involved in atrial fibrosis, apoptosis, and ion channel function. Our findings further implicate miRs as important mediators of pathological atrial remodeling and suggest their usefulness as biomarkers in detecting AF.
Abstract 12777: High Sensitivity Troponin T is Associated With Increased Heart Failure Risk in Metabolic Syndrome in the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Pokharel Yashashwi , Sun Wensheng , Villarael Dennis , Selvin Elizabeth , Virani Salim , Ndumele Chiadi , Hoogeveen Ron , Coresh Josef , Boerwinkle Eric , Butler Kenneth , Solomon Scott , Pankow James , Bozkurt Biykem , Ballantyne Christie , Nambi Vijay
Published: July 2021

Background:
Metabolic syndrome (MS) is associated with higher CVD risk. High sensitivity troponin T (hsTnT) is a marker of myocardial injury and an emerging marker for heart failure (HF) risk prediction. We examined whether hsTnT is associated with increased HF risk in people with similar number of MS components present at baseline in 10316 ARIC participants without prevalent HF.

Methods:
We used Wald Chi-square test to assess the interaction between MS and hsTnT and Cox model for the association of incident HF hospitalization by hsTnT categories across groups created by the number of MS components after adjusting for risk factors and NT-proBNP (Table).

Results:
The mean age of the study population was 63 (SD, 6) years (56% women). Mean hsTnT levels were higher with increasing MS components (Table). There were 1353 HF hospitalizations over a median of 14 years. The interaction of MS with hsTnT for HF was borderline significant (p-interaction 0.059). Compared to individuals without MS and hsTnT<5 ng/L the HRs (95%CIs) were 1.7 (1.4-2.1) in those without MS and hsTnT≥5 ng/L; 1.7 (1.3-2.1) in MS and hsTnT<5 ng/L; and 3.6 (3.0-4.4) in MS and hsTnT≥5 ng/L. In groups with 1-5 MS components present, increasing hsTnT was significantly associated with higher hazards for HF in each group with the highest HR in those with all 5 MS components (Table).

Conclusion:
Presence of higher MS risk components was associated with increasing subclinical myocardial injury as assessed by higher hsTnT. The hazards for HF were numerically similar in individuals without MS but detectable hsTnT (>5 ng/L) as to those with MS but undetectable hsTnT. In people with similar number of MS components higher hsTnT levels were associated with increased HF hazards suggesting that in MS hsTnT could be a useful marker for identifying those at higher risk for incident HF.
Abstract 12781: NF-κB Activity is Required for Heart Regeneration
Authors: Karra Ravi , Knecht Anne , Poss Kenneth D
Published: July 2021

Objectives:
In contrast to humans, zebrafish recover from cardiac injury through a robust regenerative response. Recent work suggests that the mammalian heart is able to undergo low-grade cardiomyocyte turnover in response to injury. However, this level of turnover in not sufficient for cardiac recovery. A better understanding of the mechanisms that contribute to zebrafish heart regeneration can instruct approaches to achieve therapeutic heart regeneration in humans.

Methods and Results:
We performed expression profiling of regenerating zebrafish hearts by RNA-Seq to identify factors that modify heart regeneration. Expression levels for members of the NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) pathway were significantly enriched in regenerating hearts. Using a transgenic reporter strain for NF-κB activity, we found NF-κB to be induced in cardiomyocytes following injury. Moreover, NF-κB activity overlaps with the activation of
gata4
regulatory sequences that are induced in regenerating cardiomyocytes. We subsequently developed a transgenic zebrafish strain to conditionally inhibit NF-κB signaling in cardiomyocytes by expression of mutant IκBα. Zebrafish hearts with loss of NF-κB activity scar following injury, indicative of impaired regeneration.

Conclusions:
NF-κB mediates an early transcriptional response to injury in cardiomyocytes that is required for heart regeneration.
Abstract 12813: Assessment of Coronary Artery Disease Severity and Prognostic Factors for Cardiovascular Events in Patients With Lower Limb Artery Disease
Authors: Hikita Hiroyuki , Yamakami Yosuke , Kojima Keisuke , Sagawa Yuichiro , Ohtani Hirofumi , Hishikari Keiichi , Sugiyama Tomoyo , Kimura Shigeki , Takahashi Atsushi , Isobe Mitsuaki
Published: July 2021

Introduction:
Cardiovascular mortality in patients with lower limb artery disease is higher in critical limb ischemia (CLI) than in intermittent claudication (IC). We sought to evaluate differential characteristics of coronary artery disease severity and prognostic factors for cardiovascular events between CLI and IC patients.

Methods:
Coronary and lower limb angiography was performed on 242 patients (age 73±8 years, mean±sd, men 186) without cardiac symptoms and with symptoms of either CLI or IC. From the coronary angiogram of each study patient, Gensini Score as an index of coronary angiographic severity and an incidence of significant stenosis (AHA classification, ≥75% stenosis) in at least one of major coronary arteries were evaluated. High sensitivity troponin T (hs-TnT), eicosapentaenoic acid-arachidonic acid ratio (EPA/AA), and lipoprotein (a), as biomarkers for prognostic factors, were measured from blood samples at rest in the fasting state.

Results:
The study patients were divided into CLI-group (42 patients) and IC-group (200 patients). Coronary angiography showed that Gensini Score and an incidence of significant stenosis (AHA classification, ≥75% stenosis) in at least one of major coronary arteries were higher in the CLI-group than in the IC-group (39±32 vs 8±8, p<0.001, 59.5% vs 22.0%, p<0.001, respectively). Hs-TnT and lipoprotein (a) values were higher in the CLI-group than the IC-group (0.15±0.19 ng/ml vs 0.05±0.09, p<0.001, 45.9±23.3 mg/dl vs 26.2±27.7, p<0.001, respectively) and EPA/AA was lower in the CLI-group than in the IC-group (0.22±0.11 vs 0.38±0.29, p<0.005, respectively).

Conclusions:
Greater coronary artery disease severity, higher hs-TnT and lipoprotein (a), and lower EPA/AA were observed in the CLI patients, which may explain higher cardiovascular events in CLI patients than IC.
Abstract 12842: Both Hyponatremia and Elevated Plasma Renin Activity Are Independent and Additive Cardiovascular Risk Factors in Patients With Angiographically Proven Coronary Artery Disease (CAD): The Intermountain Heart Collaborative Study
Authors: Bair Tami L , Anderson Jeffrey L , May Heidi T , Horne Benjamin D , Muhlestein Joseph B
Published: July 2021

Background:
Several studies have documented an increased risk of future major adverse cardiovascular events (MACE) among CAD patients with elevated baseline plasma renin activity (PRA). One of the proposed mechanisms of elevated PRA is sodium depletion - hyponatremia. However, the relationship between PRA and hyponatremia is not well defined.

Methods:
A total of 1,781 pts with angiographic CAD (>50% stenosis) enrolled in the Intermountain Heart Collaborative Study were evaluated. Pts were excluded if they had a history of myocardial infarction (MI), heart failure (HF), left ventricular ejection fraction (EF) <45% or were discharged on beta blocker therapy. Baseline sodium levels were stratified between low (<135 mm/L) and normal (≥135 mm/L), and PRA between elevated (>2.3 ng/ml/h) and low (≤2.3 ng/ml/h) risk categories. The independent associations between these categories and MACE (death, MI, HF hospitalization, stroke and new onset renal failure) at five years were determined by multivariable Cox hazard regression analysis.

Results:
The mean pt age was 65.5 years; most pts were men (73.2%) and hypertensive (70.4%). Overall, PRA was elevated in 940 (52.8%) of the pts and sodium was low in 42 (2.4%) of the pts. The prevalence of elevated PRA was greater among pts with low sodium (66.7% versus 52.4% [p=0.07]). Five-year incidence of MACE was higher among pts with low sodium (61.9% versus 40.7%, p=0.006) and also among those with elevated PRA (43.7% versus 38.3%, p=0.02). After adjustment for baseline characteristics, among pts with low sodium, elevated PRA did not predict an increase in MACE (adjusted hazard ratio (HR)=0.72, p=0.53). However, among those with normal sodium, elevated PRA trended toward an association with MACE (HR=1.14, p=0.08).

Conclusion:
Among stable pts with angiographically documented CAD, both hyponatremia and elevated PRA are independently associated with future adverse cardiovascular events, although much of the adverse effect of elevated PRA may be explained by the concomitant presence of hyponatremia. The underlying physiology of these findings and its potential implications to future medical management of these pts deserves further study.
Abstract 12865: Predictors of “Visual-Functional Mismatch” in Contemporary Practice -The Lesion Characteristics Associating With Mismatch Between Angiographic Stenosis and Fractional Flow Reserve
Authors: Arashi Hiroyuki , Yamaguchi Junichi , Kamishima Kazuho , Haruki Shintarou , Otsuki Hisao , Nakao Masashi , Okayama Dai , Sashida Yukiko , Minami Yuichirou , Hagiwara Nobuhisa
Published: July 2021

Background:
The benefit of fractional flow reserve (FFR) guided percutaneous coronary intervention (PCI) in patients with coronary artery disease compared with angio-guided PCI has shown recently. However, the argument for mismatch (angiographic diameter stenosis ≧ 50% and FFR > 0.80) or reverse-mismatch (angiographic diameter stenosis < 50%, FFR ≦ 0.80), so called, “visual-functional mismatch”, is remains to be solved in contemporary practice. In the present study, we examined the association of the lesion characteristics and “visual-functional mismatch”.

Method and Results:
We analyzed 140 consecutive patients (157 lesions) undergoing coronary angiography and FFR examination. The mean age of study population was 68.7 years old, 54.3% of them had diabetes, 87.9% of them had hypertension and 77.1% of them had dyslipidemia. In terms of lesion characteristics, ratio of LAD lesion was 58.6%, tandem or diffuse lesion was 48.4%, mean percentage of diameter stenosis was 68.2% and lesion length was 16.3mm. The study population was divided into 4 groups by angiographic stenosis (cut-off: 50%) and FFR (cut-off: 0.80). There were no differences in patients’ background among 4 groups. Mismatches were observed in 28.7% of lesions, whereas, reverse-mismatches were observed in 10.1% of lesions. Lesion characteristics causing “visual-functional mismatch” are shown in Table 1 and ROC curve s of diameter stenosis for functional significance are shown in Figure 1.

Conclusion:
Specific lesion characteristics are applicable for predicting “visual-functional mismatch”. Angiographic severity seemed to be more reliable in LAD lesions, tandem/diffuse lesions or proximal lesions. FFR measurement should be considered for angiographic 50% stenosis in LAD to perform appropriate PCI, whereas, FFR measurement should be considered for angiographic 75% stenosis in non-LAD to avoid unnecessary PCI.
Abstract 12872: External Stenting for Tracheobronchomalacia Associated With Congenital Heart Disease
Authors: Nakamoto Yuki , Ando Makoto , Hasegawa Hisaya
Published: July 2021

Introduction:
Tracheobronchomalacia (TBM) is a disease of symptomatic obstruction of tracheal or bronchial portions either related to congenital instability or secondary to vascular compression. Patients with TBM associated with congenital heart disease (CHD) often remain difficult to manage after cardiac surgery, requiring prolonged artificial respiratory support. Under these circumstances, several treatments such as aortopexy, internal stenting, or high positive end-expiratory pressure ventilation, have been attempted, although satisfactory results have not been obtained. In 2008, we started the external stenting technique using a ringed expanded polytetrafluoroethylene graft, and we have treated 39 patients with this technique. We review the results of our experience with external stenting for TBM in children.

Methods:
Clinical records of 42 procedures in 39 patients with TBM, who underwent external stenting in our institute from February 2008 to March 2014, were reviewed. The diagnosis of TBM was made by bronchoscopy or enhanced computed tomography.

Results:
Etiology of the tracheobronchial obstruction included primary TBM in 10 cases (25.6%), congenital vascular compression in 14 (35.9%), and postoperative vascular compression in 15 (38.5%). Preoperatively, 30 patients (76.9%) were failure to wean from ventilation, 9 (23.1%) were performed tracheotomy, and 5 (12.8%) were performed aortopexy. Forty-six stents were placed in 39 children, 22 boys and 17 girls, with a median age of 7 months (range, 1 months - 6 years). Sixteen stents were placed in the trachea, 25 were placed in the left main bronchus, and 5 were placed in the right main bronchus. Stenosis-free tracheobronchial expansion was achieved in 38 (97.4%) patients. Thirty five (89.7%) patients were successfully weaned from respirator, and 36 (92.3%) discharged from a hospital. Complications of the operation occurred in 4 (9.5%) of the 42 procedures. One patient died of a perioperative bleeding. Three patients were necessitated their stent removals due to bronchial perforation, bronchial stenosis, and pulmonary venous obstruction.

Conclusions:
External stenting seems to be extremely useful in the treatment of intractable TBM associated with CHD.
Abstract 12898: Serum Vascular Endothelial Growth Factor-C Levels are Inversely Associated With Major Adverse Cardiovascular Events in Patients With Arteriosclerotic Obliterans
Authors: Masunaga Nobutoyo , Wada Hiromichi , Akao Masaharu , Ura Shuichi , Yamada Akira , Abe Mitsuru , Ishii Mitsuru , Unoki Takashi , iguchi Moritake , Yamashita Yugo , Hamatani Yasuhuro , Ogawa Hisashi , Takagi Daisuke , Satoh-Asahara Noriko , Shimatu Akira , Hasegawa Koji
Published: July 2021

Background:
Vascular endothelial growth factor-C (VEGF-C), a homologue of VEGF family, plays a key role in lymphangiogenesis. Recently, we demonstrated that VEGF-C is closely associated with dyslipidemia and atherosclerosis. However, the relationship between serum VEGF-C levels and cardiovascular events in patients with atherosclerotic disease is unknown.

Methods and Results:
We performed a prospective cohort study involving a total of 209 patients with arteriosclerotic obliterans (ASO) (age, 73±8 y [SD]; male, 75%; hypertension, 88%; diabetes, 69%; dyslipidemia, 72%; history of smoking, 76%; Fontaine class, 2.1±0.8). Serum levels of VEGF-C, VEGF-A and high-sensitivity C-reactive protein (hsCRP) were determined employing specific enzyme-linked immunosorbent assays. The primary outcome was major adverse cardiac events (MACEs) defined as all-cause mortality, hospitalization due to acute coronary syndrome, stroke, congestive heart failure, aortic disease, and coronary/peripheral revascularization. Patients were followed up over a 4 year period. The median follow-up was 484 (IQR, 220-955) days. During the follow-up period, MACEs developed in a total of 86 patients (41.1 %). Patients were divided into two groups based on the median of each biomarker. In Kaplan-Meier analyses, low-VEGF-C (P=0.014, by log-rank test), but not high-hsCRP or high-VEGF-A, was significantly associated with MACEs. Multivariate Cox proportional hazard analyses revealed that serum levels of VEGF-C (hazard ratio [HR], 0.79 [per 1-SD increase]; 95% confidence interval [CI], 0.63-0.99; P=0.04), but not hsCRP or VEGF-A, were inversely and significantly associated with MACEs after adjustment for age, gender, and established risk factors. Finally, we performed stepwise Cox proportional hazard analysis including data on age, gender, established risk factors, Fontaine class and serum levels of hsCRP, VEGF-A and VEGF-C. Notably, Fontaine class (HR, 1.4; 95% CI, 1.1-1.8; P=0.002) and the VEGF-C level (HR [per 1-SD increase], 0.80; 95% CI, 0.64-0.99; P=0.045), but not other parameters, were independent predictors of MACEs.

Conclusions:
A low VEGF-C value may serve as a predictive marker of cardiovascular events in patients with ASO.
Abstract 12967: Efficacy of Combining Assessment of Right Ventricular Function and Right Atrial Remodeling as Prognostic Factor in Patients With Pulmonary Hypertension
Authors: Fukuda Yuko , Tanaka Hidekazu , Motoji Yoshiki , Ryo Keiko , Matsuzoe Hiroki , Hatazawa Keiko , Hatani Yutaka , Dokuni Kumiko , Toki Hiromi , Shimoura Hiroyuki , Ooka Junichi , Sano Hiroyuki , Sawa Takuma , Mochizuki Yasuhide , Tatsumi Kazuhiro , Matsumoto Kensuke , Emoto Noriaki , Hirata Ken-ichi
Published: July 2021

Background:
Since survival of patients with pulmonary hypertension (PH) is closely related to right ventricular (RV) function, assessment of RV function is important for patients with PH. Right atrial (RA) area and/or RA pressure have also been reported to serve as prognostic predictors for adverse outcomes for in PH patient. Accordingly, we tested the hypothesis that the addition of RA remodeling to RV function enhances the capability of the latter to predict long-term outcome for PH patients.

Methods:
We studied 82 PH patients, all of whom underwent echocardiography and right heart catheterization. RV function was calculated by averaging the three regional peak speckle-tracking longitudinal strains from RV free wall (RV-free). RA remodeling was assessed as the RA area traced planimetrically at end-systole. Pre-defined cutoffs for RV dysfunction and RA remodeling were RV-free≤19.4% and RA area of >18cm2, respectively. Long-term unfavorable outcome events were tracked for 2.0 years.

Results:
RA area correlated with mean RA pressure (r=0.62, p<0.001), as well as with tricuspid E/E’ (r=0.38, p=0.001). However, RA area with RV restrictive filling was significantly larger than with others (all p<0.05). Kaplan-Meier analysis revealed that patients with RV-free ≤19.4% had worse long-term outcomes than those with RV-free >19.4% (log-rank p=0.01), as did patients with RA area>18cm2 compared with those with RA area ≤18cm2 (log-rank p<0.05). For sequential Cox models, a model based on hemodynamic parameters of RV performance (χ2 =3.11) was improved by addition of brain natriuretic peptide, World Health Organization functional class (χ2 =9.24; p<0.05), and RV-free (χ2 =17.11; p=0.005), and further improved by addition of RA area (χ2 =21.36, p<0.05).

Conclusions:
The combined assessment of RV function and RA remodeling results in more accurate prediction of long-term outcome, and may well have clinical implications for better management of PH patients.
Abstract 12969: Rapid Nonsustained Ventricular Tachycardia Detected by Continuous Device Monitoring for Risk Stratification in Hypertrophic Cardiomyopathy: Redefining a Traditional Risk Marker
Authors: Viswanathan Karthik , Suszko Adrian M , Jackson Nicholas M , Cameron Douglas , Spears Danna A , Rakowski Harry , Woo Anna , Khurana Mamta , Chauhan Vijay S
Published: July 2021

Introduction:
Nonsustained VT (NSVT) detected by Holter (Holter +NSVT) is a major risk factor (RF) for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). We hypothesized that using a higher heart rate cut-off and prolonged monitoring for detecting NSVT would improve its accuracy in predicting sustained ventricular arrhythmias (VA).

Methods:
We prospectively enrolled 56 patients (mean 44±14 yrs) with HCM, who had a preexisting prophylactic ICD. We assessed the prevalence of rapid NSVT (+RNSVT, ≥4 beats at 167-200 bpm) detected by their ICD within the first 12 months of implant. The primary outcome was appropriate ICD therapy after implant.

Results:
The prevalence of RF at ICD implant was 50% for syncope, 57% for Holter +NSVT, 45% for +family history SCD, and 25% for septum ≥ 30mm. The prevalence of 0, 1, 2 and ≥3 RF was 2, 32, 54 and 13%, respectively. +RNSVT occurred in 19 patients (34%) of whom 4 were Holter -NSVT. When compared to -RNSVT, those with +RNSVT had less syncope (21 vs 65%, p=0.004) but more Holter +NSVT (79 vs 46%, p=0.02).

Over a median follow-up of 59 (25, 123) months after ICD implant, 8 patients had ≥1 appropriate ICD therapy from VA. According to the number of RF, the proportion of patients with VA was 0=0%, 1=6%, 2=13%, ≥3=43% (p=0.11). +RNSVT was associated with higher VA compared to Holter +NSVT (Figure 1A). +RNSVT predicted VA by Cox regression analysis, both univariate [odds ratio 10, 95% CI 1-84, p=0.03] and adjusted for differences in RF [adjusted odds ratio 11, 95% CI 1-114, p=0.046]. ROC analysis for +RNSVT (area under curve 0.78, p=0.02) showed the optimal cut-point to be RNSVT ≥2 episodes (Figure 1B) for discriminating patients with and without VA (Sensitivity 71%, Specificity 83%, PPV 38%, NPV 95%).

Conclusions:
RNSVT detected from continuous device monitoring is an independent predictor of VA in HCM patients and a better risk stratifier than Holter +NSVT. The role of implantable loop monitoring to detect RNSVT and evaluate VA risk in HCM warrants study
Abstract 13027: Periostin Cre-mediated Hypoxia-inducible Transfroming Growth Factor-β Receptor Deletion in Pulmonary Artery Attenuates the Progression of Pulmonary Arterial Hypertension in Mice
Authors: Seki Mitsuru , Koitabashi Norimichi , Arakawa Hirokazu , Kurabayashi Masahiko
Published: July 2021

Introduction:
Mutations in the bone morphogenetic protein type II receptor, transforming growth factor-β (TGF-β) receptor superfamily member, are responsible for heritable pulmonary arterial hypertension (PAH). Although this mutation is associated with TGF-β signal activation, the precise role of TGF-β signaling still remains uncertain in pathogenesis of PAH. Under hypoxic condition, Periostin(Pn) which usually expresses in fibroblasts protein has been shown to express on vascular smooth muscle cell. Therefore, Pn-Cre-loxP system may work as conditional inhibition in hypoxic pulmonary arterial smooth muscle cells.

Methods:
We established TGF-β type I receptor knockout mice specifically in periostin expressing cell (PnCre/Alk5flox model mice). A mouse model of hypoxia-induced PAH was used for this study. We evaluated right ventricular systolic pressure, function, hypertrophy, and vascular remodeling of pulmonary artery after 3 weeks of exposure to 10% of oxygen.

Results:
Those mice were induced proliferation of pulmonary arterial smooth muscle cells and perivascular fibrotic change, causing pulmonary hypertension. Right ventricular pressure measured by pressure catheter was significantly decreased in PnCreAlk5flox model mice compared with wild-type mice (44.8±7.8 vs 55.0±9.7mmHg, p<0.05). Right ventricular function and right ventricular weight showed no significant difference between both mice. Histological analysis revealed inhibition of medial thickening of pulmonary artery and perivascular fibrotic change in PnCreAlk5flox model mice compared with wild-type mice (% muscularization of pulmonary artery ; 52.0±14.3 vs 78.4±11.5%, p<0.05).

Conclusions:
These results indicate that TGF-β signaling in fibroblasts and smooth muscle cells has a critical role on pathogenesis of PAH, suggesting the usefulness of therapy by targeting TGF-β signaling.
Abstract 13054: Thymosin Beta-4-Treated Endothelial Progenitor Cells Improve Cardiac Function and Vasculogenesis in Diabetic Obese Rats with Myocardial Infarction
Authors: Lee Poay Sian S , Ye Lei , Chen Yei-Tsung , Khoo Eric Yin Hao , Yeo Tiong Cheng , Tan Huay Cheem , Richards Arthur Mark , Poh Kian Keong
Published: July 2021

Introduction:
Diabetes and obesity are associated with endothelial dysfunction and may impair circulating endothelial progenitor cells (EPCs). Thymosin beta-4 (Tβ4), a novel peptide with angiogenic properties, may improve EPC number and function.

Hypothesis:
We aim to transplant allogenic Tβ4-treated EPCs in Zucker Diabetic Fatty (ZDF) rats with myocardial infarction (MI) and hypothesize that Tβ4-treated EPCs may improve cardiac function, vasculogenesis and upregulate angiogenic cytokines and genes, compared to non-treated EPCs and controls.

Methods:
The left anterior descending coronary artery was permanently ligated to induce experimental MI on ZDF rats (n=19), divided into MI+saline(n=6); MI+EPCs (n=6) and MI+Tβ4-treated EPCs (n=7). Peripheral blood mononuclear cells were harvested from ZDF rats and isolated using Ficoll density gradient centrifugation and grown on fibronectin-coated plates. EPCs were treated with Tβ4 (1μg/mL) on day 7. At day 10, allogenic EPCs were harvested and transplanted into the peri-infarcted myocardium. Echocardiographic examination including strain assessment, immunohistological assessments and assays of angiogenic cytokines were performed 6 weeks after surgery.

Results:
Left ventricular (LV) ejection fraction was improved in Tβ4-treated EPCs (72.0±7.6%) and non-treated EPCs rats (80.5±5.9%) compared to control MI rats (64.8±19.7%) (P=0.04). Similar improvement was observed in LV radial strain rate in rats with Tβ4-treated EPCs (-7.22±1.24 1/s) and non-treated EPCs (-6.67±2.66 1/s) compared to MI only (-4.08±3.75 1/s) (P<0.01). Vascular density (CD31) and c-kit density (CD117) were significantly upregulated in Tβ4-treated EPCs rats compared to MI (P=0.03; P=0.005 respectively) and non-treated EPCs rats (P=0.04; P=0.04 respectively). Angiogenic cytokines of PDGF-BB, IGF-1 and VEGF levels were increased by 1.5 fold in Tβ4-treated EPCs and supported by similar trend in mRNA levels compared to non-treated EPCs (P<0.01).

Conclusions:
ZDF rats with Tβ4-treated EPCs had significant improvement in cardiac function, increased vasculogenesis and upregulation of angiogenic cytokines and genes. This suggests that Tβ4 may be beneficial in enhancing efficacy of EPCs in cell-based therapies.
Abstract 13061: Trends in Incidence, Management and Outcomes of Heart Failure Patients with Cardiogenic Shock
Authors: Gupta Navdeep , Aggarwal Saurabh , Gaglianello Nanzio , Bangalore Sripal , Cinquegrani Michael P
Published: July 2021

Background:
Patients with heart failure who develop cardiogenic shock or have Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) 1 profile have high mortality. However, trends in incidence, management and outcomes of these patients are not well defined.

Methods:
We analyzed patients in the Nationwide Inpatient Sample (NIS) between 2002-2011 with primary discharge diagnosis of Heart Failure (CHF) and secondary diagnosis of cardiogenic shock. Primary outcome was trend in cardiogenic shock complicating CHF. Secondary outcome was trends in in-hospital mortality. We excluded discharges with co-diagnosis of Acute Myocardial Infarction (AMI) from our analysis.

Results:
Among 10,475,927 weighted discharges with primary diagnosis of CHF, 349,292 discharges with AMI were eliminated. Of the remaining 10,126,635 discharges, cardiogenic shock was present in 56,314(0.6%). During the study period there was a steady increase in percentage of CHF patients with cardiogenic shock (0.4% in 2002 to 1.0% in 2011, p<0.001). Among patients with cardiogenic shock, the rates of heart transplant showed a steady increase from 2002 at 10.1% to peak in 2008 at 17.8% declining to 14.4% in 2011. Similarly, the rates of left ventricle assist device (LVAD) use showed a steady increase from 1% in 2002 to 11% in 2011. During the same period in-hospital mortality decreased from 44.2% to 26.1% (p<0.001).

Conclusions:
Cardiogenic shock complicating heart failure has a low but increasing incidence with time. There is a steady increase in the rates of heart transplant and LVAD use in these patients with a steady decline in in-hospital mortality over the ten-year period.
Abstract 13102: Brain Angiotensin II Type1 Receptor Blockade Ameliorates the Development of Atrial Fibrillation via Sympathoinhibition Independent of Depressor Response in Hypertensive Rats
Authors: Nagayama Tomomi , Hirooka Yoshitaka , Kishi Takuya , Mukai Yasushi , Inoue Shujiro , Chishaki Akiko , Sunagawa Kenji
Published: July 2021

Background:
Previous studies demonstrated that the pathophysiology of atrial fibrillation (AF) with hypertension is associated with sympathoexcitation or the renin-angiotensin system. Conventional therapies, however, do not sufficiently prevent the development of AF. We reported that sympathoexcitation via brain angiotensin type1 receptors (AT1R) plays an important role in hypertension. Here we examined the hypothesis that brain AT1R-induced sympathoexcitation contributes to the development of AF in hypertension.

Methods and Results:
Sixteen-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar Kyoto rats (WKY) were divided into 4 groups and administered treatment for 2 weeks, as follows: 1) SHRSP treated with intracerebroventricular infusion (ICV) of vehicle, S-VEH; 2) SHRSP treated with ICV of the AT1R blocker, losartan (1 mg/kg/day), S-LOS; 3) SHRSP treated with oral administration of hydralazine (100 mg/L in drinking water), S-HYD; 4) WKY treated with ICV of vehicle, W-VEH. Systolic blood pressure was significantly lower in both S-LOS and S-HYD than in S-VEH (201.0±1.7 and 172.4±4.0 vs. 233.0±3.5 mmHg, n=7-8/group, respectively, P<0.05). Urinary norepinephrine excretion for 24 hours as an indicator of sympathoexcitation was significantly reduced in S-LOS, but increased in S-HYD despite the larger depressor response. The induction rates of AF by transesophageal burst pacing were higher in S-VEH and S-HYD than in S-LOS and W-VEH (96±2% and 92±4% vs. 74±6% and 71±9%, n=7-8/group, respectively, p<0.05). AF duration was markedly inhibited in S-LOS, but not in S-HYD (Figure). Interstitial atrial fibrosis and echocardiographic parameters did not differ among SHRSP groups.

Conclusions:
Blockade of brain AT1R lowered the inducibility and sustainability of AF via sympathoinhibition independent of depressor response in hypertensive rats. We conclude that brain AT1R is a potential target of treatment for AF with hypertension.
Abstract 13106: Exercise Tests Cannot Be Used as a Diagnostic Tool for Detection of Coronary Microvessel Dysfunction
Authors: Dose Nynne , Michelsen Marie M , Mygind Naja D , Pena Adam A , Prescott Eva
Published: July 2021

Introduction:
Current guidelines indicate that patients with angina, a positive exercise test and no obstructive coronary artery disease (CAD) should be suspected of coronary microvessel dysfunction (CMD). The aim of this study was to investigate if exercise tests can identify patients with CMD.

Methods:
Women with angina pectoris and no obstructive CAD (<50% stenosis on CAG) were consecutively included in the study (n=763). Coronary flow reserve (CFR) was assessed by TTE during dipyridamole infusion (0.84 mg/kg) and information regarding results from exercise test ≤6 months prior to CAG and risk factors were obtained. Results were categorised as 1) positive based on occurrence of ECG changes or typical angina pectoris symptoms 2) negative or 3) inconclusive.

Results:
Exercise test had been performed prior to CAG in 283 of 642 patients (44 %). Patients lacking information were excluded (n=121). Patients with or without exercise test did not differ in CFR, age, smoking status, years of smoking, type-2 diabetes, BMI, hypertension, hypercholesterolemia or CAG result (all p>0.05).There were no significant differences in mean CFR between patients with a positive, inconclusive or negative test and the proportion with CMD (cut off 2.0 and 2.5, respectively) did not differ. Age, smoking status, type-2 diabetes, hypercholesterolemia or CAG results was similar (table). There was a tendency towards less hypertension in the group of patients with a negative test (p=0.051). Furthermore patients with a negative test had been smoking significantly less than patients with an inconclusive or positive test (p=0.04)

Conclusions:
No difference in CFR for patients with a positive, inconclusive or negative exercise test was observed. This lack of difference did not seem to be explained by an uneven distribution of risk factors between groups due to selection bias. Exercise tests cannot be used as diagnostic method for CMD, which supports the need for developing novel methods for diagnosing CMD.
Abstract 13108: Optimal Duration of Dual Antiplatelet Therapy after Drug-Eluting Stent Implantation for Off-Label vs. On-Label Indications
Authors: Park Duk-Woo , Ahn Jung-Min , Lee Cheol Whan , Yun Sung-Cheol , Yoon Sung-Han , Park Hyun Woo , Chang Mineok , Lee Pil Hyung , Choi Hyo In , Roh Jae-hyung , Choi Hanul , Lee Jong-Young , Kang Soo-Jin , Lee Seung-Whan , Kim Young-Hak , Park Seong-Wook , Park Seung-Jung
Published: July 2021

Introduction:
The risks and benefits of long-term dual antiplatelet therapy (DAPT) beyond 12 months in patients receiving drug-eluting stents (DES) and with high-risk clinical and angiographic features are unclear.

Hypothesis:
We try to determine whether extended use of DAPT is beneficial among patients with off-label use of DES.

Methods:
A total of 5,045 patients were included in the DES LATE trial and stratified according to randomized treatments (aspirin-alone or dual-therapy) and whether use was standard or off-label. Off-label was defined as use in renal insufficiency, ejection fraction ≤30%, acute myocardial infarction (MI), multivessel stenting, total stent length ≥36 mm, or ostial, bifurcation, grafts, left main, restenotic, thrombus, or totally occluded lesions. The primary endpoint was a composite of death from cardiac causes, MI, or stroke at 24 months after randomization.

Results:
Off-label use occurred in 68.6% of all patients. Among patients with off-label use, the risk of primary endpoint at 2 years was similar between aspirin-alone and dual-therapy group (2.6% vs. 3.1%; hazard ratio: 0.89; 95% confidence interval: 0.59 to 1.34, P = 0.59). In addition, no significant differences were observed between 2 treatment groups for individual and combined risks of efficacy and safety endpoints (death, MI, stroke, stent thrombosis, repeat revascularization, or major bleeding). These findings were consistent in patients with on-label use of DES (Figure).

Conclusions:
Extended use of DAPT beyond 12 months was not significantly more effective than aspirin monotherapy in reducing the risk of death from cardiac causes, MI, or stroke, regardless of off-label or on-label use of DES.
Abstract 13125: Sedentary Behaviour and Physical Activity Among Older Patients Following Percutaneous Coronary Intervention Presented with Stable Angina versus Acute Coronary Syndrome
Authors: Denton Sarah J , van Hees Vincent T , Bawamia Bilal , Veerasamy Murugapathy , Quinn Louise , Dunford Joseph R , Trenell Michael I , Jakovljevic Djordje G , Kunadian Vijay
Published: July 2021

Introduction:
A wide variety of exercise regimes produce significant reductions in coronary artery disease (CAD) risk and modulate the pathogenesis of CAD. Given the ongoing burden of cardiovascular disease and an aging population, physical activity (PA) in patients with CAD needs to be emphasized in addition to the use of advanced therapeutic and pharmacological interventions in their management. It is not known whether PA levels differ among older patients following percutaneous coronary intervention (PCI) for stable angina (SA) vs. acute coronary syndrome (ACS) consisting of ST-segment elevation myocardial infarction (STEMI) and non STEMI (NSTEMI).

Hypothesis:
To determine differences in the distribution of time spent in acceleration categories reflecting sedentary behaviour and PA in older patients (≥75 years) following PCI.

Methods:
We evaluated sedentary behaviour and PA amongst patients following PCI for SA (n=20), STEMI (n=20) and NSTEMI (n=18) upon discharge from a tertiary centre over a 7-day period using wrist-worn triaxial accelerometers (GENEActiv, Activinsights Ltd, United Kingdom).

Results:
Mean ± Standard deviation age was 79±4 years (31% female). STEMI and NSTEMI patients spent more time in the lowest acceleration category (0-40mg) than SA patients (1298±59 and 1305±66 vs. 1240±92 minutes/day, p<0.05). STEMI and NSTEMI patients spent less time than SA patients in the 40-80mg acceleration category (95±35 and 94±41 vs. 132±50 minutes/day, p<0.05). These trends continued for acceleration categories 80-120mg (p<0.05) and 120-160mg (p<0.05) but only between SA and NSTEMI patients. SA patients spent more time than NSTEMI patients in the 1 (15±18 vs. 6±9 minutes/day, p<0.05) and 5 (6±10 and 1±3 minutes/day, p<0.05) minute moderate-vigorous intensity PA bouts (≥100mg category). For the higher acceleration categories (≥160 mg), no differences between the groups were observed.

Conclusions:
Patients presenting with ACS and undergoing PCI spent more time in the low acceleration category reflecting sedentary behaviour and sleep compared with SA patients. Following PCI for ACS, strategies may need to be put in place to ensure that ACS patients achieve the mid category acceleration.
Abstract 13152: A Novel Link between Energy Expenditure, Plasma Lipid Turnover, and Cardiovascular Health
Authors: Laurila Pirkka-Pekka , Soronen Jarkko , Boon Mariëtte , Taskinen Marja-Riitta , Ripatti Samuli , Rensen Patrick , Kovanen Petri , Jauhiainen Matti
Published: July 2021

We previously showed that USF1 transcription factor was associated with familial combined hyperlipidemia in Finns. In the current study, we have conducted a detailed metabolic characterization of Usf1 in mice.

We generated a congenic strain of Usf1 knockout mice, fed with high-fat diet for 5 months. The knockouts displayed both elevated cholesterol and phospholipids in their plasma HDL-fractions and lower total and VLDL-triglycerides. This was due to both enhanced TRL clearance linked to elevated LPL activity of the knockouts, and reduced hepatic VLDL secretion. The elevated HDL-C levels were associated with increased efflux capacity of HDL particles derived from Usf1-/- mice. The detailed analysis of Usf1-/- HDL composition revealed an enrichment of phospholipids, known to enhance the efflux capacity of HDL particles.

The Usf1-/- mice were protected against HFD induced obesity despite being physically less active and eating more than Usf1+/+ mice. Furthermore, they were protected against insulin resistance, atherosclerosis, and fatty liver. Multiplex measurements revealed a reduction in the cytokines representing vascular inflammation. While absorption of lipids was similar between Usf1-/- and Usf1+/+ mice, the Usf1-/- mice displayed elevated VO2 and VCO2, even in thermoneutral conditions, suggesting an increased metabolic rate. Analysis of post-injection organ distribution of [3H]triolein and [14C] cholesteryl oleate revealed a selective uptake of TRLs to brown adipose tissue in Usf1-/- mice, mediated by an LPL-dependent mechanism, as inhibiting LPL by tetrahydrolipstatin completely eliminated lipoprotein uptake to BAT. There was a dramatic 8-fold reduction in lipid droplet size as well as lipid content of BAT. The protein levels of mitochondrial complex II were elevated in the BAT of Usf1-/- mice. Furthermore, PET/CT measurements demonstrated an increased glucose uptake to BAT of Usf1-/- mice. Together, these findings demonstrate overall avidity of BAT to process energy substrates.

Our data establish the critical role of Usf1 as a metabolic master-regulator, and demonstrate that Usf1 deficiency leads to a remarkably beneficial metabolic profile in mice. Our discoveries make USF1 appear a particularly attractive therapeutic target.
Abstract 13171: Cellular Basis of Angiotensin-(1-7) Produced Augmentation on Left Ventricular Contractile Function in Heart Failure
Authors: Zhang Xiaowei , Cheng Heng-Jie , Zhou Peng , Li Tiankai , Li Wei-Min , Cheng Che Ping
Published: July 2021

Background:
Accumulating evidence suggests that Angiotensin (A)-(1-7) exhibits cardiovascular effects that are in opposition to that of AII, thus providing protection against heart diseases. However, the exact means by which A-(1-7) affords cardioprotection are unclear. Its direct cardiac effect is not well understood. We previously showed that in heart failure (HF), AII decreases left ventricle (LV) contractility. Whether A-(1-7) may antagonize AII-induced cardiac depression, thereby contributing to its beneficial actions in HF remains to be determined. We assessed the hypothesis that A-(1-7) may produce positive modulation on [Ca
2+
]
i
regulation and LV and myocyte contraction via A-(1-7) receptors, coupled with nitric oxide (NO)/bradykinin (BK)-mediated mechanism.

Methods:
We measured LV contractility changes after A-(1-7) (650 ng/kg, iv), which produced a 20-fold increase in plasma A-(1-7) levels, mimicking the elevations caused by angiotensin-converting enzyme inhibitor therapy in HF, and compared myocyte contractile, [Ca
2+
]
i
transient ([Ca
2+
]
iT
) and I
Ca,L
responses to A-(1-7) (10
-5
M) in 14 rats with isoproterenol induced HF (3 months after 170 mg/kg sq for 2 days). In the subsets of cell contractile study, myocytes were pretreated to inhibit NO synthase (L-NAME, 10
-5
M), BK (HOE 140, 10
-6
M) or A-(1-7) receptor [D-Ala
7
]-A-(1-7), 10
-5
M) followed with A-(1-7) exposure.

Results:
Compared with baseline, after A-(1-7), E
ES
(47%, 1.0 vs 0.68 mmHg/μl) and M
SW
(49%, 94.3 vs 62.8 mmHg) were increased, indicating enhanced LV contractility. In HF myocytes, A-(1-7) increased myocyte percent shortening (28%, 6.8% vs 5.3%), the velocity of contraction (31%, 106.4 vs 74.5 μm/sec) and relengthening (41%, 74.7vs 50.1 μm/sec) accompanied by significantly-increased [Ca
2+
]
iT
(27%, 0.19 vs 0.15 pA/pF) and I
Ca,L
(24%, 6.3 vs 5.1pA/pF). L-NAME increased, HOE 140 decreased, and A-(1-7) receptor blockade prevented myocyte contractile responses to A-(1-7).

Conclusion:
In HF, clinically-relevant concentrations of A-(1-7) counteracted AII-induced cardiac depression, increased [Ca
2+
]
iT
and I
Ca,L
, and produced positive inotropic effects in both LV and myocytes. These effects are coupled with A-(1-7) receptors and involve activation of NO/BK pathways.
Abstract 13180: Impact of Cigarette Smoking on Levels on Platelet P2Y12 Mediated Platelet Inhibition in Prasugrel Treated Patients: Results of a Pharmacodynamic Study
Authors: Rollini Fabiana , Franchi Francesco , Ferrante Elisabetta , Cho Jung Rae , Dunn Elizabeth C , DeGroat Christopher , Bhatti Mona , Thano Estela , Duarte Valeria , Faz Gabriel , Alobaidi Zeina , Guzman Luis A , Zenni Martin M , Bass Theodore A , Angiolillo Dominick J
Published: July 2021

Introduction:
In patients with established vascular disease, smoking is a strong independent risk factor for adverse outcomes, including mortality. Several investigations have shown that cigarette smoking induces cytochrome P450 enzymatic activity which in turn increases clopidogrel metabolism leading to enhanced pharmacodynamic (PD) effects compared with non-smokers. These findings may explain the heightened clinical benefits of clopidogrel in smokers compared with nonsmokers. Prasugrel has superior PD and clinical effects compared with clopidogrel. The aim of this study was to evaluate the impact of cigarette smoking on platelet P2Y
12
mediated effects among patients on maintenance prasugrel therapy.

Methods:
A total of 156 patients on maintenance prasugrel therapy (10mg/qd) for at least 7-days, in addition to aspirin (81mg/qd), who previously underwent a percutaneous coronary intervention in the setting of an acute coronary syndrome were studied. An objective assessment of smoking status was performed by measuring serum levels of cotinine (the major stable degradation product of nicotine metabolite). Cotinine levels >3 ng/ml identified patients as smokers. PD assessments to determine platelet P2Y
12
activity was performed by flow cytometric assessment of vasodilator-stimulated phosphoprotein (VASP). Results were reported as platelet reactivity index (PRI). A PRI>50% identified patients with high on-treatment platelet reactivity (HPR).

Results:
According to cotinine serum levels, patients were divided into smokers (n=55) and nonsmokers (n=101). PRI values in the overall population were not normally distributed (median [interquartile range (IQR)] 30 [19.1-38.9]) and 14.6% of patients had HPR. PRI levels were not significantly different between smokers and nonsmokers (33.7 [13.6-46.9] vs 28.8 [21.7-37.3], p= 0.56). There was no correlation between PRI values and cotinine levels (r=0.03; p=0.74). Accordingly, HPR rates were similar between smokers and nonsmokers (18.2% vs 12.9%; p=0.25).

Conclusions:
In patients on maintenance prasugrel therapy, cigarette smoking status, as objectively assessed by serum levels of cotinine, does not affect the degree of platelet P2Y
12
mediated inhibition.