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Aims To examine the effects of a 24-month treatment with ipragliflozin on carotid intima-media thickness (IMT) in type 2 diabetes patients. Methods and results In this multicenter, prospective, randomized, open-label, and blinded-endpoint investigator-initiated clinical trial, adults with type 2 diabetes and haemoglobin A1C (HbA1c) of 6.0–10.0% (42–86 mmol/mol) were randomized equally to ipragliflozin (50 mg daily) and non-sodium-glucose cotransporter-2 (SGLT2) inhibitor use of standard-care (control group) for type 2 diabetes and were followed-up to 24 months. The primary endpoint was the change in mean common carotid artery IMT (CCA-IMT) from baseline to 24 months. A total of 482 patients were equally allocated to the ipragliflozin (N = 241) and control (N = 241) groups, and 464 patients (median age 68 years, female 31.7%, median type 2 diabetes duration 8 years, median HbA1c 7.3%) were included in the analyses. For the primary endpoint, the changes in the mean CCA-IMT from baseline to 24 months were 0.0013 [95% confidence interval (CI), −0.0155–0.0182] mm and 0.0015 (95% CI, −0.0155–0.0184) mm in the ipragliflozin and control groups, respectively, with an estimated group difference (ipragliflozin-control) of −0.0001 mm (95% CI, −0.0191–0.0189; P = 0.989). A group difference in HbA1c change at 24 months was also non-significant between the treatment groups [−0.1% (95% CI, −0.2–0.1); P = 0.359]. Conclusion Twenty-four months of ipragliflozin treatment did not affect carotid IMT status in patients with type 2 diabetes recruited in the PROTECT study, relative to the non-SGLT2 inhibitor-use standard care for type 2 diabetes.

Background Subcutaneous implantable cardioverter–defibrillator (S-ICD) represents an efficient alternative to transvenous ICD in patients who do not require pacing. The intraoperative defibrillation test (DFT) is recommended during S-ICD implantation to confirm appropriate sensing and successful 65-J termination of induced ventricular fibrillation (VF). However, few cases of oversensing of noise inhibiting therapies have been reported. Case summary We report the case of a 50-year-old man who underwent S-ICD implantation for secondary prevention of sudden cardiac death. Immediately after S-ICD implantation, VF was induced using a 50-Hz burst; however, shock was not delivered owing to sustained noise on the electrogram in the primary vector. Therefore, an external rescue shock was needed at 150 J. We changed the sensing vector from primary to secondary and performed a second DFT. The S-ICD could deliver an appropriate shock and was able to successfully terminate VF without noise markers in the secondary vector. During the second DFT, one back-up pacing was delivered after the shock; the sensing vector then automatically switched from the secondary to the alternate vector. However, noise was observed in the alternate vector despite sinus rhythm restoration. Discussion The present case demonstrated that noise was recorded in two different vectors during DFT, possibly supporting the hypothesis that the muscle spasm of the diaphragm induced by the 50-Hz burst causes oversensing of noise by the S-ICD.

Background Skeletal muscle atrophy is an independent prognostic predictor for patients with chronic heart failure, and the concept of sarcopenia is drawing attention. Furthermore, the importance of not only muscle mass but also intramuscular fat (IMF) has been pointed out. However, there is a lack of consensus on the implications of ectopic fat for the prognosis in patients with non-ischemic cardiomyopathy. Purpose We investigated whether ectopic fat in the thigh affects the prognosis with non-ischemic cardiomyopathy. Methods We recruited 105 patients who were diagnosed with non-ischemic cardiomyopathy by cardiac catheterization and echocardiographic date between September 2017 and November 2019. Finally 73 patients with reduced EF (EF 40% or less) enrolled in this prospective study. Functional status was evaluated by using cardiopulmonary exercise test at baseline. All patients were measured quantity of epicardial fat and thigh IMF percentage (%IMF) using computed tomography scan. Demographic, laboratory and echocardiographic date were collected from the patients' medical records. Clinical endpoints were unexpected readmission. Results During the follow-up period 18 patients had adverse events. The %IMF was significantly higher in the group with adverse events than without (5.57±5.70 and 3.02±2.44%, respectively; p Conclusions In non-ischemic cardiomyopathy patients with reduced EF, %IMF may have important adverse consequences such as increased cardiac-related events. Kaplan-Meier curves Funding Acknowledgement Type of funding source: None

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 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

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 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 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

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

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 Conclusions Self-expandable valves were associated with increased numbers of HIA on DW-MRI after TAVI in patients with severe aortic stenosis.

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 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).

Aims Increasing clinical evidence has emphasized the importance of coronary plaque characteristics, rather than the severity of luminal narrowing on acute coronary syndrome (ACS) outcome. Computed tomographic coronary angiography (CTCA) is a unique, non-invasive approach for assessing plaque characteristics. This study was prospectively designed to investigate the prognostic value of physiologically non-obstructive but a vulnerable coronary plaque on CTCA for predicting future ACS events. Methods and results This study consisted of 543 patients who had undergone CTCA and had normal findings on exercise-stress myocardial perfusion single-photon emission computed tomography. CTCA analysis included the presence of >50% luminal stenosis and vulnerable features including positive remodelling (PR), low-attenuation plaque, and ring-like sign. The primary endpoint was ACS events including cardiac death, non-fatal myocardial infarction, and unstable angina. The mean follow-up period was 3.4 ± 0.8 years. The 3-year cumulative event rate was 1.2% per year, and 87% of ACS events occurred in plaques with at least one of vulnerable features. In patient-based multivariate analysis, the presence of plaque with vulnerable features on CTCA was a significant predictor for future ACS events ( P = 0.001). Patients with vulnerable plaque had worse ACS outcomes compared with those without vulnerable plaques (3-year cumulative event rate; 3.2 per year vs. 0.8%, P < 0.001). Conclusion This study demonstrated that physiologically non-obstructive but vulnerable coronary plaques were associated with future ACS events. We should pay more attention to currently non-obstructive plaque but showing vulnerable morphologies on CTCA.

Aims The planimetry method using three-dimensional (3D) echocardiography is useful for providing an accurate mitral annulus area (MAA) value. However, this method is relatively unavailable. Therefore, we evaluated the accuracy of conventional methods for MAA measurement compared with that of 3D planimetry. Methods and results Two-dimensional (2D) and 3D transoesophageal echocardiography (TEE) were performed in 70 patients. The mitral annulus diameter (MAD) was measured using four standard TEE imaging planes: four-chamber (4Ch), two-chamber (2Ch), anterior–posterior (LAX), and commissure–commissure (CC). MAA was calculated using a single diameter based on that of a circle and using two diameters based on that of an ellipse. MAA measurements using the single 4Ch MAD method ( r = 0.84, P < 0.001), and two anatomically orthogonal MAD method in 4Ch/2Ch ( r = 0.93, P < 0.001) and LAX/CC ( r = 0.97, P < 0.001) planes correlated with 3D planimetric MAA measurements. Further analysis with Bland–Altman plots revealed that the LAX/CC MAD measurement exhibited the closest limits of agreement with the 3D planimetric MAA measurement. Notably, in patients showing an elliptical annulus shape, only LAX/CC MAD, but not 4Ch or 4Ch/2Ch MAD, provided results comparable with those of 3D planimetric MAA measurements. However, in patients with a circular annulus shape, reliable MAA measurements can be achieved using either single 4Ch MAD or any biplane MAD. Conclusion Conventional LAX/CC MAD can be recommended for MAA measurements in a diverse patient population. This method is applicable as an alternative to the 3D planimetric method, regardless of the mitral annulus shape.

Aims Although two-dimensional-dobutamine stress echocardiography (2D-DSE) is useful for the diagnosis of myocardial ischaemia, it requires the acquisition of multiple cross-sections at each stage. The introduction of new real-time three-dimensional echocardiography (RT3DE) offers rapid acquisition and 3D display of the entire left ventricle (LV). The purpose was to evaluate real-time three-dimensional-dobutamine stress echocardiography (RT3D-DSE) for the diagnosis of ischaemia using exercise 201Tl single-photon emission computed tomography (SPECT) as the reference standard, in comparison with 2D-DSE. Methods and results We performed DSE in 56 consecutive patients who had undergone SPECT because of suspected ischaemia. 3D images by RT3DE were acquired from the apical window after the acquisition of cross-sectional images at every stage of 2D-DSE. Wall motion analysis in RT3DE was performed from anatomical images by cropping the acquired full volume data sets. Mean scanning time for adequate image acquisition at peak stress by RT3D-DSE was shorter than that by 2D-DSE (29±4 vs. 68±6 s, P

A 67-year-old man with a history of paclitaxel-eluting stent implantation in the right coronary artery (RCA) 4 years previously needs below-the-knee amputation of the right leg due to uncontrollable foot infection. The patient had acute high fever and leukocytosis, and performed repeatedly transthoracic echocardiography (TTE) to rule out infective endocarditis. TTE revealed …