Abstract Background Smoking predisposes individuals to endothelial dysfunction. Both flow-mediated dilation (FMD) and reactive hyperemia peripheral artery tonometry (RH-PAT) are used to assess endothelial function. However, there are differences in the physiology of vascular beds being tested and in the response of conduit and resistive vessels to RH. Therefore, whether smoking cessation demonstrates comparable effects on endothelial function evaluated by FMD and by RH-PAT remains unclear. Purpose We aimed to evaluate the effects of smoking cessation on endothelial function evaluated simultaneously by FMD and RH-PAT. Methods Thirty-eight consecutive current smokers (mean±standard deviation; age, 65±10 years) who visited our smoking cessation outpatient department and succeeded in smoking cessation with varenicline were enrolled. Clinical variables, FMD, and natural logarithmic transformation of the reactive hyperemia index (Ln-RHI) were examined before and 20 weeks after treatment initiation. Fifteen current smokers who failed in smoking cessation were enrolled as age- and sex-matched controls. The Spearman's rank correlation coefficient and intraclass correlation coefficient (ICC) for a two-way mixed effects model were performed to assess the agreement of changes in FMD and Ln-RHI. Multivariate logistic regression analysis was performed to examine the associations between the presence of increase in FMD or Ln-RHI and clinical variables. Results FMD significantly improved after smoking cessation (3.42%±1.96% to 4.45%±2.28%; p=0.019), whereas Ln-RHI did not (0.53±0.25 to 0.59±0.21; p=0.223). The Spearman's rank correlation coefficient between changes in FMD and Ln-RHI was −0.013, and the ICC was −0.002 (p=0.506). In the multivariate logistic regression analysis, an increase in FMD or Ln-RHI was predicted based on the baseline FMD (odds ratio = 0.54, p=0.013) or Ln-RHI (odds ratio = 0.36, p=0.012), respectively, after adjusting for age and sex. Conclusions There was significant improvement in the endothelial function assessed by FMD, but not by Ln-RHI, after smoking cessation. In addition, there was disagreement between changes in FMD and those in Ln-RHI. Smoking cessation may have varying effects on the endothelial function of the conduit and digital vessels. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grant-in-aid for scientific research from the ministry of education, science and culture of Japan

Background and Aims: Vascular endothelial dysfunction is the earliest stage of the development of atherosclerosis and recognized as a trigger of cardiovascular events. Eicosapentaenoic acid (EPA) has been reported to ameliorate endothelial dysfunction and reduce cardiovascular events. However, the factors associated with the benefits have not been fully clarified in patients with hypertriglyceridemia and no evidence of coronary artery disease (CAD). We investigated the factors associated with EPA administration that led to improve endothelial function.

Abstract Background Epicardial adipose tissue (EAT) has been recognized to contribute inflammatory activity and atherosclerosis. On the other hand, it has been reported that the volume of EAT is lower in non-ischemic heart failure (HF) patients than healthy individuals. However, the difference in regional muscle-adipose distribution including EAT between HF with preserved ejection fraction (HFpEF) and HF reduced ejection fraction (HFrEF) has not been investigated. In addition, we investigated whether distribution of body composition contributed to exercise capacity. Methods The study included 105 non-ischemic HF patients diagnosed by cardiac catheterization between September 2017 and November 2019. Epicardial, abdominal and thigh muscle and adipose tissue volume were measured by computed tomography (CT), and exercise tolerance was evaluated by symptom-limited cardiopulmonary exercise test. Results Patients were divided into 2 groups according to the left ventricular ejection fraction, ≥40% as HFpEF (n=28) or <40% as HFrEF (n=77). There was no significant difference comorbidity, including hypertension, dyslipidemia, chronic kidney disease, and body mass index. Plasma B-type natriuretic peptide level was significantly higher in HFrEF than HFpEF group (146.2 vs 393.2 pg/ml, p<0.01), whereas, high-sensitive troponin T level was not different between two groups. Although there was no significant difference in BMI between two groups, the volume of EAT was significantly higher in HFpEF than HFrEF group (81.8 vs 136.4 ml, p=0.01). On the other hand, HFpEF had more thigh adipose tissue compared with HFrEF group (54.6 vs 42.1 ml, p=0.03). There were negative correlations between EAT volume and parameters of exercise capacity such as anaerobic threshold (r=−0.42, p<0.01) and peak VO2 (r=−0.32, p<0.01). Muscle volume itself does not corelate with these parameters. Conclusion In patient with nonischemic HF, the pattern of regional adipose distribution may have important role in pathologically. HFpEF and HFrEF has different pattern despite similar body mass index. These differences may be related to impaired exercise tolerance in these 2 different types of HF. Correlation between EAT and AT, peak VO2 Funding Acknowledgement Type of funding source: None

Abstract Background Recently, there are some reports that hypo-attenuated leaflet thickening (HALT) following transcatheter aortic valve implantation (TAVI) is incidentally detected by multi-slice computed tomography. It is believed that valve thrombosis causes HALT, because oral anticoagulation therapy (OAC) is effective for HALT regression. Furthermore, it is reported that d-dimer level increases in patients with HALT, and might be a key biomarker to detect HALT. Purpose We sought to investigate the predictors related to increased d-dimer level at 6 months after follow-up TAVI. Methods We enrolled 124 consecutive patients who underwent successful TAVI between 2016 and 2018. Study patients were classified into two groups according to antithrombotic therapy resume (OAC therapy or anti-platelet therapy).We set the primary endpoint as the d-dimer levels at 6 months after TAVI. To evaluate the risks of the primary endpoint, we employed a multivariable linear regression model, setting the primary endpoint as an objective variable and patient and clinical backgrounds as explanatory variables. Furthermore, we set the secondary endpoint as one-year bleeding event. Results The median age of patients was 83 years old (quartile 80-87). Patients who had taken OAC at 6 months follow-up after TAVI were 29.8%. The median d-dimer level at 6 months after TAVI was 1.3 (1.0-2.2) µg/ml, and OAC group had statistically lower d-dimer level at 6 months follow-up than those in non-OAC group (p = 0.020). Uni-variable liner regression model demonstrated that increased d-dimer level at follow-up had significant relationship with large effective orifice area (EOA) (p = 0.002) and low left ventricular ejection fraction (LVEF) (p = 0.048) after TAVI. Furthermore, large EOA (p = 0.003) and OAC therapy (p = 0.027) were independently associated with increased d-dimer level in multivariate analysis. Kaplan-Meier estimates revealed that there were no significant difference regarding one-year bleeding event between OAC group and non-OAC group (long-rank p = 0.167). Conclusions This study suggests that large EOA after TAVI is associated with increased d-dimer levels at 6 months after TAVI, and OAC therapy might have a potential to decrease d-dimer level after TAVI without increase of bleeding events. Abstract P107 Figure: One-year bleeding event

Abstract Background Atherosclerotic cardiovascular disease including acute myocardial infarction (AMI) has become one of major co-existing diseases in cancer patients due to their improved survival rate. Current guideline recommends dual-antiplatelet therapy (DAPT) in patients with AMI. Given that the presence of cancer elevates not only coagulability but bleeding risks, these substrate may further worsen cardiovascular outcomes and bleeding risks in cancer subjects with AMI receiving DAPT. Methods We retrospectively analyzed 712 AMI patients treated by primary PCI with drug-eluting stent and DAPT between 2007 and 2017. The diagnosis of cancer was determined through medical record review. Clinical characteristics, thromboembolic (=all-cause death+non-fatal MI+stroke) and bleeding events were compared in AMI subjects with vs. without cancer. Results Cancer was identified in 11.1% (=79/712) of study subjects. Of these, around 40% of them had gastrointestinal cancer (=35/79), followed by lung cancer (=5/79) and breast cancer (=8/79). Cancer patients were more likely to be older (77±7 v. 69±13 years, p<0.001) with a history of Af (25 v. 10%, p<0.001), CKD (eGFR<60: 60 v. 42%, p=0.002), anemia (hemoglobin: 12.8±1.8 v. 13.9±1.8 g/dl, p<0.001). Under anti-thrombotic (DAPT=86%, triple-antiplatelet therapy=14%) and optimal medical therapies (ACE-I=90%, beta-blocker=76%, statin=96%), more frequent occurrence of thromboembolic events was observed in patients with cancer (34.2 v. 12.6%, p=0.004, Picture). Furthermore, the presence of cancer was associated with more than four times greater risk of bleeding events compared to non-cancer subjects (18.9 v. 4.3%, p<0.001, Picture). In particular, the frequency of both major (10.1 vs. 3.3%, p=0.003) and minor (8.9 vs. 0.9%, p<0.001) bleeding events was significantly higher in patients with cancer. In multivariate analysis, cancer independently predicted bleeding events (Table). Conclusions Under the use of guideline recommended DAPT, the concomitance of cancer in AMI subjects was a predictor for thromboembolic as well as bleeding events. In particular, the relationship between cancer and bleeding was significant. These observations underscore the appropriate selection and duration of anti-thrombotic agents in AMI subjects with cancer. Cardiac/Bleeding Events in AMI Subjects Funding Acknowledgement Type of funding source: None

Abstract Background Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are well-known for preventing cardiovascular disease. Among n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) play key roles in preventing cardiovascular diseases. However, the effects of n-3 PUFAs have been examined under conditions of simultaneous administration of EPA and DHA in the majority of clinical investigations and the effect of purified EPA is still controversial. EPA has been reported to improve endothelial dysfunction. Although several mechanisms underlying the effects of EPA on endothelial function have been demonstrated such as the modulation of lipid metabolism including increases in high-density lipoprotein (HDL) and/or decreases in triglyceride (TG) levels, decreases in cytokine production, and inhibition of inflammatory processes, the main mechanisms ameliorating endothelial function have not been fully determined. Purpose We sought to clarify the main factors associated with EPA administration that led to improved endothelial function. Methods Fifty-one consecutive patients with hypertriglyceridemia (mean ± SD age, 60±13 years) with no evidence of coronary artery disease (CAD) were prospectively enrolled and administered purified EPA (1800 mg/day). Forty-eight patients who were not administered EPA were enrolled as age- and sex-matched controls. Clinical variables such as body mass index, HbA1c, fasting glucose level, HDL, low-density lipoprotein, TG, systolic blood pressure, diastolic blood pressure, heart rate, interleukin-6, baseline diameter of the brachial artery, intima-media thickness of the brachial artery, and flow-mediated dilation (FMD) were examined before and after 6 months of treatment. Univariate and multivariate regression analyses were performed to examine the associations between FMD changes and clinical variables. Results FMD was significantly improved from 4.16% ± 1.88% to 6.30% ± 2.24% (p<0.0001) in the EPA group. The change in FMD was positively correlated with the change in EPA/arachidonic acid (AA) ratio (r=0.34, p=0.014). The multivariate regression analysis showed that the change in EPA/AA ratio alone was significantly associated with the change in FMD (p=0.010). Conclusions EPA treatment improves endothelial dysfunction in patients with hypertriglyceridemia without evidence of CAD. The change in FMD was associated with the change in EPA/AA ratio alone. These finding suggest that a direct effect of EPA on the endothelium may be the predominant factor ameliorating endothelial function. Acknowledgement/Funding This study was supported, in part, by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (15K08649).

Abstract Background Little evidence is available regarding the risk of peri-procedural stroke detected by diffusion-weighted magnetic resonance imaging (DW-MRI) after transcatheter aortic valve implantation (TAVI). Our purpose was to evaluate stroke risk after TAVI using DW-MRI by enrolling consecutive patients who underwent transfemoral TAVI and post-procedural DW-MRI. Methods We prospectively enrolled 113 consecutive patients who underwent transfemoral TAVI and post-procedural DW-MRI. We used balloon-expandable valves as first-line therapy and selected self-expandable valves only for patients with narrow sinotubular junctions or annuli. We set the primary endpoint as the number of high intensity areas (HIA) detected by DW-MRI regardless of the size of the area. To evaluate the risks of the primary endpoint, we employed a multivariable linear regression model, setting the primary endpoint as an objective variable and patient and clinical backgrounds as explanatory variables. In addition, the relationship between valve type and the number of HIAs on DW-MRI was also confirmed by the propensity score matching analysis to evaluate the robustness of the result, using a multivariable linear regression model with the protocol described in the previous manuscript. Shortly, the propensity score was calculated with a logistic regression model by setting the treatment as the response variable and baseline characteristics and procedural information that were significantly different between 2 groups (balloon expandable and self-expandable) as explanatory variables, which included age, estimated glomerular filtration rate, oversizing rate, and BAV before THV deployment. Results Median patient age was 84 years, and 36.3% were men. Ninety-three patients underwent balloon-expandable TAVI and 20 underwent self-expandable TAVI. Symptomatic stroke occurred in 6 (5.3%) whereas asymptomatic stroke occurred in 59 (52.2%) patients. The incidence of symptomatic and total stroke was higher in patients who underwent self-expandable TAVI than those who underwent balloon-expandable TAVI (30.0% vs 0.0%, p<0.001 and 90.0% vs 50.5%, p=0.001, respectively). A multivariable linear regression model demonstrated an increased primary endpoint when self-expandable TAVI was performed (p<0.001). The other covariates had no significant relationship to the primary endpoint. Akaike information criterion-based stepwise statistical model selection revealed that valve type was the only explanatory variable for the best predictive model. This result was also confirmed with the propensity score matching analysis (estimate, 2.359; 95% CI, 0.426–4.292; p=0.019) after adjustments of propensity score, in which 28 patients were matched (n=14 in each group). Conclusions Self-expandable valves were associated with increased numbers of HIA on DW-MRI after TAVI in patients with severe aortic stenosis.

Purpose: The presence of atherosclerotic plaque in the aortic arch is an independent risk factor for ischemic stroke. Although, it is well known that high prevalence of aortic arch plaques in patients with severe aortic stenosis, the underlying mechanisms have not been understood and remain still obscure. Increased day-by-day Blood Pressure (BP) variability is known to be associated with stroke, little is known on the association between day-by-day BP variability and aortic atherosclerosis. We studied the relationship between day-by-day BP variability and aortic atherosclerosis in patients with severe aortic stenosis using transesopageal echocardiograohy. Methods: The study population consisted of 63 patients (mean age 73±8 years) with severe aortic stenosis who were scheduled for aortic valve replacement. BP was measured in the morning more than 4 consecutive days (mean 6.8 days) during hospital admission. Day-by-day BP variability was expressed as the standard deviation or coefficient of variation of all readings. Large (≥4mm), ulcerated, or mobile plaques were defined as complex plaques using transesophageal echocardiography. Results: In univariate analysis, age, mean systolic BP, and day-by-day systolic BP variability were associated with complex plaque (p<0.05), whereas office systolic BP and diastolic BP variables were not associated with complex plaque. In multivariate analysis adjusted for age, sex, smoking status and history of hypertension, diabetes mellitus and hypercholesterolemia, only day-by-day systolic BP variability was independently associated with complex plaque (p<0.05). Conclusion: Day-by-day systolic BP variability is independently associated with the presence of complex plaque in patients with severe aortic stenosis. This finding may have important implications in gaining further insights into the mechanism of plaque formation and progression.