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Background Whether optical frequency domain imaging (OFDI) images can realize pathological diagnosis of coronary atherosclerotic plaques, and whether its diagnostic accuracy of lesion types varies depending on the personal experience of the clinician caring for coronary intervention have not been elucidated. Purpose This study investigated the interobserver variability in characterizing atherosclerotic plaque types by OFDI for multiple OFDI observers with levels of different experience. Methods Three-hundred-thirty-three histological cross-sections from 21 autopsy hearts were co-registered with the corresponding OFDI images. Histological cross-sections were classified into the following 7 lesion types according to the modified AHA atherosclerosis classification by a single experienced pathologist blinded for OCT findings: adaptive intimal thickening (AIT), intimal xanthoma (IX), pathological intimal thickening (PIT), fibrous cap atheroma (FA), fibrocalcific plaque (FC), calcified nodule (CN), and healed erosion/rupture (HER). The five OFDI observers, unaware of the histological diagnosis, provided a single diagnosis for each corresponding OFDI image. The OFDI observer 1 was an expert interventional cardiologist with sufficient experience in OFDI imaging, followed by the OFDI observer 2, 3, and 4 as middle career interventional cardiologists who had completed training ten, seven, and four years. The OFDI observer 5 was a young career interventional cardiologist. The diagnostic accuracy of lesion types for each OFDI observer was determined taking histology as a gold standard. Results On histological analysis, 13% of histological cross-sections were diagnosed as AIT, 5% as IX, 23% as PIT, 25% as FA, 27% as FC, 2% as CN, and 5% as HER. The overall agreement between OFDI diagnosis and histopathologic diagnosis for OFDI observer 1 to 5 was 77%, 62%, 61%, 56%, and 46% (k values of 0.71, 0.54, 0.54, 0.45, and 0.33), respectively. Although the performance for characterizing AIT and FC was excellent and comparable among all OFDI observers, the sensitivity and positive predictive value for characterizing IX, PIT and FA varied depending on the OFDI observers' years of experience (Table). The main causes of false-positive or -negative diagnosis of FA were IX and PIT for all OFDI observers. Conclusion The diagnostic accuracy of atherosclerotic tissue properties from OFDI images correlated with the observers' years of experience, subspecialty training in coronary imaging, which suggests that the interpretation of OFDI images requires expertise and can be challenging to a less experienced reader. Table 1 Funding Acknowledgement Type of funding source: None

The accurate identification of in-stent fibroatheroma by in vivo imaging is clinically important to preventing the late catch-up phenomenon after stent deployment. This study investigated the diagnostic accuracy of optical coherence tomography (OCT) for the detection of “in-stent fibroatheroma” following stent implantation. Fifty stented coronary arteries from the 31 autopsy hearts were examined to compare OCT and histological image findings. A histological in-stent fibroatheroma was defined as a neointima containing an acellular necrotic core generated by macrophage infiltration. OCT-derived in-stent fibroatheroma comprised a heterogeneous pattern with an invisible stent strut behind the low-signal-intensity region. A total of 122 matched OCT and histology cross-sections were evaluated. Using histological findings as the gold standard, the sensitivity, specificity, positive predictive value, and negative predictive value for OCT-derived in-stent fibroatheroma were 100%, 99%, 80%, and 100%, respectively. The only histological finding underlying the false-positive diagnosis of OCT-derived in-stent fibroatheroma was foam cell accumulation without a necrotic core on the neointimal surface. No false-negative diagnosis of OCT for in-stent fibroatheroma was apparent in this analysis. This study demonstrated the potential capability of OCT based on stent strut visualization behind low-signal-intensity regions to discriminate in-stent fibroatheroma from other neointimal tissues.

Background Muscle wasting is an important predictor of long‐term outcome in patients with cardiovascular disease, but the prognostic value of muscle wasting in patients with non‒ST‐segment‒elevation myocardial infarction is not established. The aim of this study is to investigate the prognostic value of muscle wasting, defined by psoas muscle mass index (PMI), in patients with non‒ST‐segment‒elevation myocardial infarction. Methods and Results A total of 132 consecutive patients with non‒ST‐segment‒elevation myocardial infarction were prospectively enrolled between 2015 and 2018. Primary end point was incidence of cardiovascular events including cardiovascular deaths, non‐fatal myocardial infarction, or non‐fatal stroke. Cross‐sectional area of the psoas muscle at the L3 vertebral level was obtained by computed tomography and PMI was calculated. The median follow‐up period was 2.4 years (interquartile range, 1.1–4.0 years). There were 45 cardiovascular events (34%) during the study periods. The optimal cutoff value of PMI to predict cardiovascular events was 772 mm 2 /m 2 , as assessed by receiver operating curve analysis. Patients with reduced PMI (PMI2 /m 2 ) had significantly higher cardiovascular events than those with preserved PMI (PMI≥772 mm 2 /m 2 ) (48% versus 21%; log‐rank test P P Conclusions Muscle wasting defined as PMI is a simple and useful objective marker to predict future cardiovascular outcome in patients with non‒ST‐segment‒elevation myocardial infarction. Registration Information URL: https://www.umin.ac.jp/ctr/ ; Unique identifier: UMIN000013445.

Background To date, there have been no data available regarding the diagnostic performance of optical frequency domain imaging (OFDI) for in vivo histological classification of atherosclerotic lesions. This study investigated whether OFDI can be used to diagnose and classify histological atherosclerotic lesions in the coronary artery by ex vivo histological examinations. Methods Three-hundred-fifteen histological cross-sections from 21 autopsy hearts were matched with the OFDI images. Histological cross-sections were classified into six categories: adaptive intimal thickening (AIT), pathological intimal thickening (PIT), fibrous cap atheroma (FA), fibrocalcific plaque (FC), calcified nodule, and healed erosion/rupture. The five observers with different years of experience in the interpretation of OFDI provided a single diagnosis for the OFDI scans of each cross-section according to the aforementioned six histological categories. The diagnostic accuracy and interobserver variability of lesion types for each OFDI observer were determined using histology as the gold standard. Results The overall agreement rates between OFDI and histopathologic diagnosis for OFDI observers 1–5 were 81%, 70%, 68%, 61%, and 50% (κ values of 0.75, 0.61, 0.58, 0.49, and 0.36), respectively. Although the diagnostic accuracy of OFDI for detecting AIT and FC was excellent for all five observers, the sensitivity, and positive predictive values of OFDI for detecting PIT and FA were low in proportion to years of experience. Conclusion The diagnostic accuracy of atherosclerotic tissue properties from OFDI scans correlated with the observers' years of experience, especially when lesions contained lipid components.

Background The causes of anaemia in patients with end-stage renal disease include a relative deficiency in erythropoietin production and complex clinical conditions. We aimed to investigate the underlying mechanisms of anaemia in patients with end-stage renal disease who were undergoing maintenance dialysis by measuring erythrocyte creatine levels. Methods In a cross-sectional study, we evaluated 69 patients with end-stage renal disease who were receiving haemodialysis (n = 55) or peritoneal dialysis (n = 14). Erythrocyte creatine level, a quantitative marker of mean red blood cell (RBC) age, was measured. Results The mean RBC age was significantly shorter in the haemodialysis group than in the peritoneal dialysis group (47.7 days vs. 59.8 days, p r = 0.54), ferritin level (r = 0.47), and haptoglobin level (r = 0.39) but inversely related with reticulocyte (r = − 0.36), weekly doses of erythropoiesis-stimulating agents (ESAs; r = − 0.62), erythropoietin resistance index (r = − 0.64), and intradialytic ultrafiltration rate (r = − 0.32). Conclusions Shortened RBC age was observed in patients who were receiving maintenance haemodialysis and was associated with iron deficiency, greater haptoglobin consumption, higher ESA requirements, and poor erythropoietin responsiveness, as well as with greater intradialytic fluid extraction.

Background: Cause of anaemia in end-stage renal disease is not only due to relative deficiency in erythropoietin production, but also to the complex clinical conditions. We sought to investigate the underlying mechanisms of anaemia in patients with end-stage renal disease undergoing maintenance dialysis by measuring erythrocyte creatine.Methods: In a cross-sectional study, we evaluated 69 patients with end-stage renal disease receiving haemodialysis (n = 55) or peritoneal dialysis (n = 14). Erythrocyte creatine, a quantitative marker of mean red blood cell (RBC) age, was measured.Results: Mean RBC age was significantly shorter in haemodialysis patients than in those with peritoneal dialysis (47.7 days vs. 59.8 days, pConclusions: Shortened RBC age was observed in patients receiving maintenance haemodialysis. Shortened RBC age was associated with iron deficiency, greater haptoglobin consumption, higher ESA requirements, and poor erythropoietin responsiveness as well as greater intradialytic fluid extraction.

Objectives and background Although tissue protrusion (TP) between the stent struts after stent implantation has been implicate as a potential factor of stent failure, the incidence, natural history, and predictive factor of TP after stent implantation remains unclear. This prospective study evaluated the fate of TP after drug-eluting stent (DES) deployment using optical coherence tomography (OCT). Method and result This study analyzed TP for 42 lesions after DES in which three serial OCTs, including preprocedure, postprocedure, and 1-month after the procedure were performed. TP was classified into the five groups: (a) persistent, (b) progressive, (c) healed, (d) regressive, and (e) late-acquired. Immediately after the procedure, 100 TPs in 37 lesions (88%) were identified. Of those, 53 (53%) were persistent, 3 (3%) were progressive, 20 (20%) were healed, and 24 (24%) were regressed at 1-month follow-up. Seven TPs in five patients (13%) were observed only at 1-month follow-up (late-acquired). Conclusion In lesions with late-acquired TP, calcified nodule was identified as an underlying plaque morphology on preprocedural OCT. A serial OCT analysis found TP occurred not only immediately after DES implantation, but also 1-month after DES implantation.

IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methodsWe registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.ResultsOf the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.ConclusionsAlogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

Background: Haemolysis due to mechanical stress on red blood cells (RBCs) during extracorporeal circulation has been reported in patients receiving haemodialysis. However, little is known about the incidence of, and the mechanisms underlying haemolysis in patients receiving maintenance haemodialysis. We sought to investigate the incidence and underlying mechanisms of haemolysis in patients with end-stage renal disease undergoing maintenance dialysis by measuring erythrocyte creatine.Method: In a cross-sectional study, we evaluated 69 patients with end-stage renal disease receiving haemodialysis (n = 55) or peritoneal dialysis (n = 14). Erythrocyte creatine, a quantitative marker of mean RBC age, was measured with other haemolytic markers including haptoglobin, reticulocyte count and lactate dehydrogenase.Results: RBC age was significantly shorter [47.7 (43.2–52.8) days vs. 59.8 (56.0–66.2) days, pConclusions: Haemolysis exists in patients receiving maintenance haemodialysis, especially in those with greater intradialytic fluid extraction.

Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) are reported to prevent cardiovascular events by a mechanism possibly including diuresis and sodium excretion. In this respect, diuresis-induced compensatory upregulation of the renin-angiotensin-aldosterone (RAA) system should be clarified and we performed a randomized controlled trial using dapagliflozin, an SGLT2I. Hypertensive diabetic patients taking angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers were randomly assigned to a dapagliflozin group (DAPA) or a control group (CTRL) with the difference in the changes in plasma renin activity (PRA) after 24 weeks of the treatment as the primary outcome. PRA, plasma aldosterone concentration (PAC), age, sex, BMI, blood pressure, pulse rate, eGFRcys, and HbA1c were not different between the groups at baseline. After 24 weeks, the changes in the PRA from the baseline of the DAPA (n = 44) and CTRL (n = 39) groups were 6.30 ± 15.55 and 1.42 ± 11.43 ng/mL/h, respectively (p = 0.11) although the power of detection was too small. However, post hoc nonparametric analyses revealed that there was a definite increase in the PRA and PAC in the DAPA group (p < 0.0001 and p = 0.00025, respectively) but not in the CTRL group. The PRA in the DAPA group after 24 weeks treatment was significantly elevated compared to the CTRL group (p = 0.013) but not for the PAC. Accordingly, it would be suggested that dapagliflozin may not induce a profound increase, if any, in PAC after 24 weeks of treatment in hypertensive type 2 diabetic patients under RAA suppression.

Background: Recently, drug-eluting stents have been widely adopted rather than bare-metal stents in patients on chronic hemodialysis (HD) based on the extrapolation of data from patients on non-HD. However, whether DES implantation is associated with a reduced rate of in-stent restenosis (ISR) is unclear. We investigated the incidence of ISR and its predictors in patients on HD after drug-eluting stent implantation.Methods and Results: We analyzed 194 consecutive patients (331 lesions) on HD who underwent follow-up angiography after drug-eluting stent implantation. ISR was observed in 74 lesions (22.4%). Angiographically, the relative incidence of AHA/ACC type C lesion was increased (47% vs. 32%; P=0.043), the minimal lumen diameter (MLD) before DES implantation was smaller (0.82±0.49 vs. 0.97±0.45mm; PConclusion: ISR was observed in 74 lesions (22.4%). A small MLD, long LL and the use of rotational atherectomy were independent predictors of ISR after drug-eluting stent implantation in patients on HD. There was no significant difference in ISR rate between the first- and the second-generation drug-eluting stents.

Funding Acknowledgements None Background Recent studies have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors have a favorable effect on cardiovascular events in diabetic patients. However, the underlying mechanism associated with favorable outcome has not been clearly identified. Purpose The purpose of this study was to investigate the effect of tofogliflozin, SGLT2 inhibitor, on systolic and diastolic cardiac function in patients with type 2 diabetes mellitus (T2DM). Methods We enrolled 26 consecutive T2DM out-patients on glucose-lowering drugs who initiated tofogliflozin and underwent echocardiogram before and ≥ 6 months after tofogliflozin administration. During this period, we also enrolled 162 T2DM out-patients taking other glucose-lowering drugs as a control group. Propensity score analysis was performed to match the patient characteristics. As a result, 40 patients (tofogliflozin group: 20 patients and control group: 20 patients) were finally used for analysis. Left ventricular systolic function was assessed by measuring 2D-echocardiographic left ventricular ejection fraction (LVEF) and diastolic cardiac function by pulsed wave Doppler derived early diastolic velocity (E/e’). Results There were no significant differences in patient characteristics and echocardiographic parameters at baseline. Follow-up E/e’ was significantly improved in tofogliflozin compared to control (11.7 ± 3.5 vs. 14.4 ± 4.5, p = 0.037). Moreover, the change in LVEF from baseline to follow up was 5.8± 7.2% in tofogliflozin group and 1.2 ± 6.9% in control group; difference significant: p = 0.047. Conclusions In addition to conventional oral glucose-lowering drugs, additional tofogliflozin administration had a favorable effect on left ventricular systolic and diastolic function in patients with T2DM.

The drug-coated balloon (DCB) angioplasty is considered a standard therapeutic option for in-stent restenosis. In the present case, we observed high-intensity spots on optical coherence tomography (OCT) and bright spots on coronary angioplasty (CAS) immediately after DCB angioplasty. The superficial high-intensity area on OCT presumably corresponded with the bright spots on CAS. The high-intensity superficial regions were thought to represent an iopromide/paclitaxel mixture. The present serial observation demonstrated that the eluted drugs remained for at least 2 months but disappeared within 6 months. At the site where we observed the drugs, neointimal growth was successfully inhibited and stabilized at the 6-month follow-up. The association of eluted drugs after DCB angioplasty with consequent neointimal growth is of scientific interest. Further prospective imaging studies with a large sample size are warranted to clarify this association.

Inconsistent results have been reported concerning the effect of tolvaptan treatment on long-term prognostic outcomes in patients with acute decompensated heart failure (ADHF) and data are limited on prognostic factors affecting this patient population. We investigated prognostic factors influencing long-term clinical outcomes in patients with ADHF treated with tolvaptan in a real-world setting. A total of 263 consecutive patients hospitalized for ADHF and treated with tolvaptan were retrospectively enrolled. The patients were stratified into those who developed the combined event of cardiac death or rehospitalization for worsening heart failure within 1 year (n = 108) and those who were free of this combined event within 1 year (n = 155). Adjusted multivariate Cox proportional hazards model revealed that change in serum sodium level between pre-treatment and 24 h after tolvaptan administration [hazard ratio (HR) 0.913, 95% confidence interval (CI) 0.841–0.989, p = 0.025] and the time taken for tolvaptan initiation from admission (HR 1.043, 95% CI 1.009–1.074, p = 0.015) were independent predictors of combined event occurrence within 1 year. Moreover, change in serum sodium level > 1 mEq/L between pre-treatment and 24 h after administration and initiation of tolvaptan

BACKGROUND We previously identified circulating mesoangioblasts (cMABs), a subset of mesenchymal stem cells that express cardiac mesodermal markers, in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). We also found that hepatocyte growth factor (HGF) is upregulated during cardiac surgery with CPB in humans, and induces MAB-like cell mobilization in rodents. These results strongly suggest that heparin induced MAB mobilization via HGF upregulation. Here, we tested this hypothesis in patients undergoing cardiac surgery or cardiac catheterization. We also examined whether human cMABs are derived from the heart.Methods and Results:Plasma HGF levels were determined by ELISA. Mononuclear cells isolated from blood samples were cultured on fibronectin-coated dishes, and outgrowing cMAB colonies were counted. We first confirmed that HGF upregulation and cMAB mobilization were observed before the start of CPB, excluding the possibility that CPB is the primary inducer of cMAB mobilization. We then examined patients undergoing cardiac catheterization and found that heparin significantly increased plasma HGF levels and the number of cMAB colonies in a dose-dependent manner. The results of simultaneous blood sampling from the aortic sinus, coronary sinus, and right atrium were consistent with the notion that human cMABs are derived from the heart. CONCLUSIONS Human cMABs are mobilized by heparin injection during cardiac surgery or cardiac catheterization, presumably via HGF upregulation.

A 60-year-old man with a history of hypertension, type 2 diabetes, and reflux esophagitis was admitted to our hospital with hemoptysis, dyspnea, and leg edema. We diagnosed him with adult IgA vasculitis based on the presence of purpura, elevated serum IgA fibronectin complexes, pathophysiological findings, a skin biopsy showing leukocytoclastic vasculitis, and immunofluorescence studies demonstrating granular IgA and C3 deposits in the blood vessel wall. He showed concurrent cardiopulmonary involvement without involvement of the gastrointestinal system and kidneys, which are commonly affected in IgA vasculitis patients. Following treatment with prednisolone, the patient recovered with improvement in cardiopulmonary manifestations.

A 75-year-old woman who had previously been diagnosed with Bland-White-Garland syndrome was admitted to our hospital for acute decompensated heart failure (ADHF). Following her recovery from ADHF, pharmacologic stress myocardial scintigraphy revealed myocardial ischemia in the basal anterior area of the left ventricle. Moreover, myocardial scintigraphy showed the improvement of the myocardial ischemia after 6 months of nicorandil administration.

Arterial stiffness is an important risk factor for cardiovascular disease (CVD) in patients with end-stage renal failure. However, little is known about the factors that contribute to arterial rigidity in peritoneal dialysis (PD) patients. The aim of this study was to define the pattern and determinants of the longitudinal change in arterial stiffness after PD initiation.Arterial stiffening was estimated for 46 PD patients by using brachial-ankle pulse wave velocity (baPWV) and carotid intima-media thickness (cIMT). The cross-sectional relationship between the arterial markers and their clinical determinants was studied. The longitudinal effects of blood pressure (BP), body fluid status, and glucose were studied over the two years after initiating PD.Multivariate analysis showed that higher baPWV was associated positively with urinary protein excretion (P < 0.001), systolic BP (P = 0.001), and hemoglobin A1c (P = 0.003). In contrast, increased cIMT correlated with smoking (P = 0.004) and hypoalbuminemia (P = 0.04), suggesting that endothelial dysfunction is implicated in the atherogenic process. Neither cIMT nor baPWV correlated significantly with other PD-related covariates of volume overload, peritoneal solute transport, kidney function, and C-reactive protein. Longitudinal observation demonstrated that BP had a greater influence on baPWV changes than hyperglycemia or fluid status.Our study indicates that 1) baPWV represent an arterial marker that integrates multifactorial interaction between modifiable variables including BP and plasma glucose; and 2) intervention aimed at controlling BP as well as nutritional conditions (glucose and albumin) may reduce CVD risk in PD patients.

A 50-year-old woman diagnosed with vasospastic angina presented to our hospital with repeated typical chest pain. The patient experienced cardiac arrest 14 years previously because of the vasospasm ([Figure 1A][1]). Although the patient was prescribed multiple medications for more than 10 years

A 73-year-old woman with dyslipidemia and diabetes underwent percutaneous coronary intervention in the right coronary artery due to stable angina. Tandem lesions were treated with 2 sirolimus-eluting stents (ULTIMASTER, Terumo, Tokyo, Japan) separately ([Figure 1A][1]). After implantation of a 2.5

Background Intracoronary optical coherence tomography (OCT) is thought to be capable of identifying a vulnerable, rupture-prone plaque based on the presence of a thin-cap fibroatheroma (TCFA). Moreover, recent studies have reported that OCT may be able to identify macrophage infiltration of the fibrous cap, a key characteristic of vulnerable plaque. Purpose This study evaluated the accuracy of OCT image for characterizing TCFA and identifying macrophage infiltration in comparison with histopathology. Methods A total of 924 focal plaques in 206 coronary arteries from 78 autopsy hearts were examined to compare OCT and histological images. By histology, 16 plaques (1.7%) were classified as TCFAsthat contained a large necrotic core covered by a thin (10% by histology. Results With histology as standard, the sensitivity, specificity, and negative-predictive-value of TCFAs were extremely high (more than 90%). However, the positive-predictive-value of TCFAs was only 32%, which indicated a high proportion of false-positives. Most false-positive diagnoses of OCT for TCFAs contained large amounts of foam cell accumulations on luminal surface without necrotic core. Twelve of 16 fibrous-caps were considered as inflamed and the remaining 4 were non-inflamed on histology. However, no significant difference in NSD and signal attenuation ratio were identified between them. There was moderate correlation of the fibrous-cap thickness between OCT and histology (r2 = 0.41 and p Conclusions OCT is a promising intracoronary imaging modality for differentiating tissue characteristics (fibrous, calcified, or lipid-rich plaque) and identifying TCFA. However, it is still challenging to precisely identify inflammation, fibrous-cap thickness, and necrotic core in the native coronary artery. Therefore, careful interpretation is required to assess coronary vulnerable plaque by OCT. Acknowledgement/Funding None

Background Tissue protrusion (TP) between the stent struts after stent implantation has been implicated as a potential factor in the subsequent development of stent thrombosis. However, the incidence, natural history, and predictive factor of TP after stent implantation remains unclear. Purpose To elucidate the fate of TP, we undertook the study assessing TP using short term serial optical coherence tomography (OCT), immediately after deployment of stents and at 1-month follow-up. Methods This was a prospective, single-center study evaluating vascular healing responses with OCT both immediately after and at 1-month after biodegradable-polymer sirolimus-eluting stent (SES) implantation. A total of 18 stable angina patients having OCT-guided PCI with SESs underwent assessment of TP with OCT pre-procedure, post-procedure, and at 1-month follow-up. TP was defined as a tissue prolapse for more than 200 μm between stent struts that directly correlates with the underlying plaque, without abrupt transition and different optical properties. TP was classified into the following 3 groups on the basis of serial assessment: (1) healed, TP present after the procedure but covered by tissue with smooth surface at 1-month follow-up; (2) persistent, TP present both after the procedure and 1-month follow-up; and (3) late-acquired, TP not present at baseline but present at 1-month follow-up. Results Immediately after the procedure, 29 TPs in 13 patients (72%) were identified. Of those, 16 (55%) were healed and 13 (45%) were persistent at 1-month follow-up. Although the size of TP on post-procedural OCT was similar, neointimal area in lesions with healed TP was significantly larger than in lesions with persistent TP due to neointimal proliferation at 1-month follow-up. A synchronous comparison between the post-procedural OCT and the follow-up OCT image showed that 5 TPs were observed only at 1-month follow-up (late-acquired). In lesions with late-acquired TP, calcified nodule or thin-cap fibroatheroma was identified as an underlying plaque morphology on pre-procedural OCT. A representative example is presented in Figure. Incidence of TP and representative case Conclusion Short term serial OCT analysis found that TP can occur not only immediately after SES implantation, but also 1 month after SES implantation. This new concept may provide a new insight into the mechanism of in-stent restenosis and stent thrombosis development after stent implantation. Acknowledgement/Funding None

Background Diastolic wall strain (DWS) has been reported to be associated with left ventricular (LV) stiffness and worse clinical outcomes. We sought to assess the utility of this new index for prediction of prognosis in asymptomatic patients with severe aortic stenosis (AS). Methods Asymptomatic severe AS patients [peak flow velocity (PFV) ≥4.0m/s, mean pressure gradient (mPG) ≥40mmHg, aortic valve area (AVA) ≤1.0cm2, or indexed AVA ≤0.6cm2/m2)] diagnosed between July 2007 and April 2016 were included in this study. Patients with significant mitral valve disease, posterior wall motion abnormality, prior cardiac surgery, hypertrophic cardiomyopathy, and LV ejection fraction Results A total of 184 asymptomatic severe AS, 138 (age 76±9year-old, men 41%, PFV 3.9±1.0m/s, mPG 38±19mmHg, AVA 0.83±0.18cm2, indexed AVA 0.56±0.13cm2/m2) met all study criteria. Of whom, 43 (31%) underwent AVR and 28 (20%) died during a mean follow-up of 25±28months. In a multivariable model after adjusting for clinical and echocardiographic variables, advancing age (per10yrs; HR=2.19, 95% CI=1.19–4.03, P The Kaplan-Meier estimates of survival Conclusion Low-DWS provides prognostic information in patients with asymptomatic severe AS.

Background Previous histopathological studies have demonstrated that new atherosclerotic formation within the neointima, called neoatherosclerosis, is one of the most important mechanisms leading to both very late in-stent restenosis and stent thrombosis after stent implantation. Therefore, to distinguish lipid-containing atherosclerotic neointima from other tissues using intracoronary imaging modalities is clinically important to prevent late stent failures. Purpose This study evaluated the diagnostic performance of optical coherence tomography (OCT) for the detection of “in-stent fibroatheroma” following stent implantation by comparing cross-sections of the model with the corresponding histological images. Methods Fifty stented coronary arteries from the 31 autopsy hearts were imaged by OCT. Coronary arterial histopathological specimens, all of which included more than 30% of %neointimal hyperplasia, were compared with the corresponding OCT cross-sections. Histological in-stent fibroatheroma was defined as neointima containing large necrotic core and inflammatory cells. OCT-derived in-stent fibroatheroma comprised a low-intensity tissue containing a poorly delineated region with invisible stent strut behind low signal intensity. Results A total of 122 OCT cross-sections were compared with histological images. OCT examination revealed that 24 images (20%) contained low-intensity tissue inside the neointima. Of those, 5 images, in which stent strut behind low signal intensity was invisible, were diagnosed as OCT-derived in-stent fibroatheroma (4%) (Figure A). By histological analysis, only 4 images were classified as in-stent fibroatheroma (3%) (Figure B). With histology as the gold standard, the sensitivity, specificity, positive predictive value, negative predictive value, and overall diagnostic accuracy for OCT-derived in-stent fibroatheroma were 100%, 99%, 80%, 100%, and 99%, respectively. The only histological finding underlying the false-positive-diagnosis of OCT-derived in-stent fibroatheroma was foam cells accumulation without necrotic core on the neointimal surface (Figure C and D). Most tissue that showed low-intensity tissue with visible stent strut by OCT contained proteoglycan matrix and organized thrombus in the absence of an underlying necrotic core. Coregistration of OCT with histology Conclusion This study showed the potential capability of OCT based on the visualization of stent struts behind low-intensity regions for discriminating in-stent fibroatheroma from other neointimal tissues following stent implantation.

Recent studies have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors have a favorable effect on cardiovascular events in diabetic patients. However, the underlying mechanism associated with a favorable outcome has not been clearly identified. The purpose of this study was to investigate the effect of tofogliflozin, SGLT2 inhibitor, on systolic and diastolic cardiac function in patients with type 2 diabetes mellitus (T2DM). We enrolled 26 consecutive T2DM out-patients on glucose-lowering drugs who initiated tofogliflozin and underwent echocardiography before and ≥ 6 months after tofogliflozin administration. During this period, we also enrolled 162 T2DM out-patients taking other glucose-lowering drugs as a control group. Propensity score analysis was performed to match the patient characteristics. As a result, 42 patients (tofogliflozin group 21 patients and control group 21 patients) were finally used for analysis. Left ventricular systolic function was assessed by measuring 2D-echocardiographic left ventricular ejection fraction (LVEF) and diastolic cardiac function by pulsed wave Doppler-derived early diastolic velocity (E/e′). There were no significant differences in patient characteristics and echocardiographic parameters at baseline. The change in LVEF from baseline to follow-up was 5.0 ± 6.9% in the tofogliflozin group and − 0.6 ± 5.5% in the control group; difference significant, p = 0.006. The change in E/e′ was − 1.7 ± 3.4 in the tofogliflozin group and 0.7 ± 4.1 in the control group; difference significant, p = 0.024. In addition to conventional oral glucose-lowering drugs, additional tofogliflozin administration had a favorable effect on left ventricular systolic and diastolic function in patients with T2DM.

This study evaluated whether the influence of lesion length on functional significance is similar between each target artery.In the presence of a similar moderate degree of stenosis, the fractional flow reserve (FFR) in the left anterior descending coronary artery (LAD) is more often0.80 than in the other arteries.A total of 221 lesions with intermediate stenosis on coronary angiography that underwent FFR measurement for the evaluation of myocardial ischemia were enrolled. Quantitative coronary angiographic analysis including percent diameter stenosis and lesion length was performed. The area under the receiver operating characteristics (ROC) curve was estimated for the best cutoff value as a predictor of FFR value of ≤0.80 for each coronary artery.Although lesion length was similar among the lesions with an FFR0.80 at different locations, the mean lesion length was significantly longer for lesions in the right coronary artery (RCA) with an FFR ≤0.80 than for those in the LAD and left circumflex artery (13.4 ± 3.4 vs. 8.6 ± 3.1 vs. 12.0 ± 3.7 mm, p .001). ROC analysis demonstrated that the optimal cutoff value of lesion length for predicting an FFR ≤0.80 was 10.0 mm in the LAD (0.56 area under the curve [AUC], 48% sensitivity, and 76% specificity), whereas 13.1 mm in the RCA (0.84 AUC, 67% sensitivity, and 93% specificity).The impact of lesion length on myocardial ischemia is different for each coronary artery. A longer lesion length is required in the RCA than in the LAD to achieve an FFR ≤0.80.

Background If the threshold at implant of leadless transcatheter pacemakers (LTPs) is less than 2.0 V, pacing thresholds reportedly decrease significantly by 1 month and maintain an optimal value of less than 1.0 V by 6 months. Case summary We report a case series of two patients with unstable pacing thresholds of the LTPs in the subacute phase after implant. The first patient (77-year-old man) was implanted an LTP for sick sinus syndrome. At that time of implant, the pacing threshold was 0.9 V at 0.24 ms. At 1 week and 1 month later, the threshold had increased to more than 2.0 V at 0.24 ms. We investigated the trend data for the week and found variations in the threshold. The second patient (81-year-old man) was implanted an LTP for bradycardia and atrial fibrillation. The pacing threshold at implantation was 0.63 V at 0.24 ms. One week later, the threshold had increased in supine position and decreased in sitting position. The trend data for the week were fluctuating greatly. Discussion The pacing threshold may increase to more than 2.0 V with significant fluctuation on assessment at 1 week and 1 month after implantation in association with changes in body position, even though we confirmed a stable threshold at implant. If an increased threshold is observed, it is necessary to check the trend data and threshold in each body position.

A 22-year-old male was admitted to our hospital with deep vein thrombosis that was complicated by antithrombin deficiency. This deficiency was refractory to anticoagulation therapy. Although catheter-directed thrombolysis could not reperfuse the total occlusion in the left deep vein, a combination of thrombectomy, catheter-directed thrombolysis, and antithrombin concentrate treatment was able to dissolve the clots and ameliorate the blood flow into the left deep vein. Antithrombin concentrate administration would be effective in the treatment of antithrombin deficiency with medical refractory deep vein thrombosis.

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Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by hypertrophy of the myocardium. Some of the patients are diagnosed for HCM during infancy, and the prognosis of infantile HCM is worse than general HCM. Nevertheless, pathophysiology of infantile HCM is less investigated and remains largely unknown. In the present study, we generated induced pluripotent stem cells (iPSCs) from two patients with infantile HCM: one with Noonan syndrome and the other with idiopathic HCM. We found that iPSC-derived cardiomyocytes (iPSC-CMs) from idiopathic HCM patient were significantly larger and showed higher diastolic intracellular calcium concentration compared with the iPSC-CMs from healthy subject. Unlike iPSC-CMs from the adult/adolescent HCM patient, arrhythmia was not observed as a disease-related phenotype in iPSC-CMs from idiopathic infantile HCM patient. Phenotypic screening revealed that Pyr3, a transient receptor potential channel 3 channel inhibitor, decreased both the cell size and diastolic intracellular calcium concentration in iPSC-CMs from both Noonan syndrome and idiopathic infantile HCM patients, suggesting that the target of Pyr3 may play a role in the pathogenesis of infantile HCM, regardless of the etiology. Further research may unveil the possibility of Pyr3 or its derivatives in the treatment of infantile HCM.

Diastolic wall strain (DWS) was reported as a simple and feasible echocardiographic index in assessing left ventricular (LV) diastolic stiffness. We sought to evaluate whether DWS predicts age-related cardiovascular events. Patients referred for transthoracic echocardiogram, those with preserved LV ejection fraction and no clinical heart failure were studied. Cardiovascular events were ascertained using Framingham criteria (myocardial infarction, coronary insufficiency, stroke, transient ischemic attack, congestive heart failure, or cardiovascular death). DWS was calculated with a validated formula. Cox proportional hazards modeling was used to assess the risk of cardiovascular events. Of a total number of 962 patients (mean age 60.9 ± 14.9 years, 48.0% men), 69 (7.2%) developed at least 1 cardiovascular event during a mean follow-up of 43 ± 32 months. After adjusting for cardiovascular comorbidities in a multivariable model, low DWS (≦ 0.33) was a significant independent predictor of cardiovascular events [hazard ratio (HR): 1.87, 95% confidential interval (CI) 1.04–3.36, P = 0.04]. Echocardiographic assessment of DWS may help in identifying the patients at increased risk for future age-related cardiovascular events.

Lysosomal associated membrane protein 2 (LAMP2) is physiologically implicated in autophagy. A genetic LAMP2 defect causes Danon disease, which consists of two major phenotypes of myopathy and cardiomyopathy. In addition, arteriopathy may manifest on rare occasions but the pathological basis remains unknown. We encountered two Danon families that developed small-vessel vasculopathy in the coronary or cerebral arteries. To investigate the underlying mechanisms, we characterized the biological features of LAMP-2–deficient mice and cultured cells. LAMP-2–deficient mice at 9–24 months of age showed medial thickening with luminal stenosis due to proliferation of vascular smooth muscle cells (VSMC) in muscular arteries. Ultrastructural analysis of VSMC revealed various autophagic vacuoles scattered throughout the cytoplasm, suggesting impaired autophagy of long-lived metabolites and degraded organelles (i.e., mitochondria). The VSMC in Lamp2 null mice expressed more vimentin but less α-smooth muscle actin (α-SMA), indicating a switch from contractile to synthetic phenotype. Silencing of LAMP2 in cultured human brain VSMC showed the same phenotypic transition with mitochondrial fragmentation, enhanced mitochondrial respiration, and overproduction of reactive oxygen species (ROS). These findings indicate that LAMP-2 deficiency leads to arterial medial hypertrophy with the phenotypic conversion of VSMC, resulting from age-dependent accumulation of cellular waste generated by aberrant autophagy.

Aims Type 3 iodothyronine deiodinase (D3), which converts thyroxine (T4) and 3,5,3′-triiodothyronine (T3) to 3,3′,5′-triiodothyronine (rT3) and 3,3′-diiodothyronine (T2), respectively, inactivates thyroid hormones. We investigated the expression and regulation of D3 in human cardiomyocytes which were differentiated from human induced pluripotent stem cells (hiPSCs). Main methods We characterized D3 activity using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. D3, myosine heavy chain α and β (MHCα and β, respectively), sarcoplasmic reticulum calcium ATPase (SERCA), and phospholamban (PLB) mRNA levels were analyzed by quantitative real-time PCR (qPCR) in hiPSC-derived cardiomyocytes (hiPS-CMs). Key findings We identified enzyme activity that catalyzes the conversion of T3 to T2 in both hiPS-CMs and hiPSCs, which showed characteristics compatible with those for D3. D3 mRNA was identified in these cells using qPCR analysis. T3 and hypoxia mimetics such as CoCl2 and DFO, increased the D3 mRNA level in both hiPS-CMs and hiPSCs. Addition of iopanoic acid, a competitive inhibitor of iodothyronine deiodination, in the culture medium of hiPS-CMs, increased the mRNA levels such as MHCα and β, SERCA, and PLB induced by T3. Significants Our findings indicate that D3 is expressed in hiPS-CMs, and may decrease the intracellular T3 concentration, and may decrease the expression of cardiac genes such as MHCα and β, SERCA, and PLB in hiPS-CMs.

We previously reported that the functional deletion of p21, a cyclin-dependent kinase inhibitor, in mice attenuated renal cell senescence in streptozotocin (STZ)-induced type 1 diabetic mice. In the present study, we investigated the effect of iron chelation on renal cell senescence and inflammation in the type 1 diabetic kidney. STZ-treated mice showed increase in iron accumulation, tubular cell senescence and macrophage infiltration at week 28 in the kidney. Administering deferasirox, which removes only dietary iron, significantly attenuated iron accumulation in proximal tubules and the number of infiltrating F4/80-positive cells without effecting blood glucose, hematocrit or hemoglobin levels. In contrast however, deferasirox did not influence renal cell senescence. The lack of p21 decreased the renal tubular iron accumulation and did not change tubular cell senescence. Interestingly, the STZ-treated animals showed an increase in p16, another cyclin-dependent kinase inhibitor. The results suggest that type 1 diabetes increases renal tubular iron accumulation and macrophage infiltration through a p21-dependent mechanism, and that the chelation of dietary iron attenuates these responses.

Visit-to-visit blood pressure variability has been shown to be an independent risk factor for cardiovascular diseases. High visit-to-visit blood pressure variability and endothelial dysfunction are observed in patients with chronic kidney disease. It is therefore assumed that high variability in visit-to-visit blood pressure measurements may be associated with endothelial dysfunction in these patients. The present study investigated the associations between visit-to-visit blood pressure variability and renal and endothelial function in patients with chronic kidney disease. We analyzed 150 consecutive patients with predialysis chronic kidney disease who visited our outpatient clinic from January 2006 to December 2010. The study examined the relationships between variability in visit-to-visit systolic blood pressure levels or mean systolic blood pressure (M SBP) and estimated glomerular filtration rate (eGFR) and flow-mediated dilation, an index of endothelial function. Variability in visit-to-visit systolic blood pressure showed a significant negative association with eGFR, independent of age, hemoglobin A1c, low-density lipoprotein (LDL) cholesterol and uric acid, whereas M SBP did not. Similarly, variability in SBP showed a significant negative association with flow-mediated dilation, independent of age, eGFR, HbA1c, LDL cholesterol and M SBP. These data indicate that variability in visit-to-visit blood pressure measurements is associated with impaired renal and endothelial function in patients with chronic kidney disease. This finding suggests that reducing blood pressure fluctuations might have beneficial effects in patients with chronic kidney disease, although this point needs to be addressed by future studies.

Arterial stiffness is an important risk factor for cardiovascular disease (CVD) in patients with end-stage renal failure. However, little is known about the factors that contribute to arterial rigidity in peritoneal dialysis (PD) patients. The aim of this study was to define the pattern and determinants of the longitudinal change in arterial stiffness after PD initiation.Arterial stiffening was estimated for 46 PD patients by using brachial-ankle pulse wave velocity (baPWV) and carotid intima-media thickness (cIMT). The cross-sectional relationship between the arterial markers and their clinical determinants was studied. The longitudinal effects of blood pressure (BP), body fluid status, and glucose were studied over the two years after initiating PD.Multivariate analysis showed that higher baPWV was associated positively with urinary protein excretion (P0.001), systolic BP (P = 0.001), and hemoglobin A1c (P = 0.003). In contrast, increased cIMT correlated with smoking (P = 0.004) and hypoalbuminemia (P = 0.04), suggesting that endothelial dysfunction is implicated in the atherogenic process. Neither cIMT nor baPWV correlated significantly with other PD-related covariates of volume overload, peritoneal solute transport, kidney function, and C-reactive protein. Longitudinal observation demonstrated that BP had a greater influence on baPWV changes than hyperglycemia or fluid status.Our study indicates that 1) baPWV represent an arterial marker that integrates multifactorial interaction between modifiable variables including BP and plasma glucose; and 2) intervention aimed at controlling BP as well as nutritional conditions (glucose and albumin) may reduce CVD risk in PD patients.

The DNA damage response (DDR) plays a pivotal role in maintaining genome integrity. DNA damage and DDR activation are observed in the failing heart, however, the type of DNA damage and its role in the pathogenesis of heart failure remain elusive. Here we show the critical role of DNA single-strand break (SSB) in the pathogenesis of pressure overload-induced heart failure. Accumulation of unrepaired SSB is observed in cardiomyocytes of the failing heart. Unrepaired SSB activates DDR and increases the expression of inflammatory cytokines through NF-κB signalling. Pressure overload-induced heart failure is more severe in the mice lacking XRCC1, an essential protein for SSB repair, which is rescued by blocking DDR activation through genetic deletion of ATM, suggesting the causative role of SSB accumulation and DDR activation in the pathogenesis of heart failure. Prevention of SSB accumulation or persistent DDR activation may become a new therapeutic strategy against heart failure., DNA damage response (DDR) is activated in cardiomyocytes of the failing heart, but the type of DNA damage leading to DDR is unclear. Higo et al. show that in mice heart failure is caused in part by unrepaired DNA single-strand breaks in cardiomyocytes, which activate persistent DDR and trigger an NF-κB-dependent cardiac inflammation.

Microfibrils are exracellular matrix components necessary for elastic fiber assembly and for suspending lenses. We previously reported that latent TGF-β binding protein 2 (LTBP-2), a microfibril-associated protein, is required for forming stable microfibril bundles in ciliary zonules. However, it was not understood why Ltbp2 null mice only showed an eye-specific phenotype, whereas LTBP-2 is abundantly expressed in other tissues containing microfibrils in wild type mice. Here, we show that LTBP-4, another microfibril-associated protein, compensates for the loss of LTBP-2 in microfibril formation. Ltbp2/4S double knockout (DKO) mice showed increased lethality due to emphysema, which was much more severe than that found in Ltbp4S null mice. Elastic fibers in the lungs of Ltbp2/4S DKO mice were severely disorganized and fragmented. Cultured mouse embryonic fibroblasts (MEFs) from Ltbp2/4S DKO embryos developed reduced microfibril meshwork in serum-free conditions, whereas the microfibril formation was restored by the addition of either recombinant LTBP-2 or -4. Finally, ectopic expression of LTBP-4 in the whole body restored ciliary zonule microfibril bundles in the eyes of Ltbp2 null mice. These data suggest that LTBP-2 and -4 have critical overlapping functions in forming the robust structure of microfibrils in vitro and in vivo.

OBJECTIVE Dyslipidemia is a risk factor for not only cardiovascular diseases (CVD), but also chronic kidney disease (CKD). Ezetimibe, a cholesterol absorption inhibitor, lowers cholesterol levels by inhibiting both extrinsic and intrinsic cholesterol absorption via the gastrointestinal duct. However, very few studies have examined its efficacy and safety for patients with dyslipidemia complicated with CKD. METHODS Thirty-seven dyslipidemic patients (low density lipoprotein cholesterol (LDL-C) levels ≥120 mg/dL) complicated with CKD were given ezetimibe (10 mg/day) for twenty-four weeks. The efficacy and safety of the therapy, including the anti-atherosclerotic and renal protective effects, were then examined. RESULTS Significant decreases were observed in the levels of LDL-C (158.9 ± 26.9 mg/dL→123.0 ± 31.8 mg/dL; p

Functional mitral regurgitation (MR) can occur as a result of atrial dilatation in patients with atrial fibrillation (AF), and concomitant MR is associated with worse outcomes. However, risk factor of congestive heart failure (CHF) in AF patients with functional MR has not been determined. In