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Impaired high-density lipoprotein (HDL) function is a risk factor for cardiac mortality. We aimed to investigate the association between oxidized HDL (oxHDL) and pericoronary adipose tissue (PCAT) attenuation, a novel imaging biomarker of pericoronary inflammation, by using coronary computed tomography angiography (CTA).A total of 287 outpatients with suspected coronary artery disease who had undergone both oxHDL measurement and coronary CTA were examined. PCAT attenuation values were assessed at the proximal 10-50 mm segments of the right coronary artery on coronary CTA. The presence of significant stenosis (luminal narrowing of50 %) and high-risk plaque characteristics were also evaluated. Patients were then classified into tertiles according to their oxHDL level: low (n = 95), moderate (n = 96), and high (n = 96) groups.PCAT attenuation in the high oxHDL group was significantly higher than that in other groups after adjusting for age and apolipoprotein-A-I. Multivariate linear regression analysis revealed that oxHDL was significantly associated with PCAT attenuation in the right coronary artery (β = 3.832, p 0.001), whereas HDL cholesterol was not. Furthermore, subgroup analyses demonstrated that the association between oxHDL and PCAT attenuation remained significant in older patients (β = 6.367, p 0.001) and in those with hypertension (β = 4.922, p 0.011), dyslipidemia (β = 3.264, p = 0.010), diabetes mellitus (β = 4.284, p = 0.015), and significant stenosis (β = 3.075, p = 0.021).High oxHDL levels were significantly associated with increased pericoronary inflammation, as assessed using coronary CTA. Our results may explain the association between impaired HDL function and the development of coronary atherosclerosis.

Pulmonary injury is a major complication of balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension (CTEPH). Lung injury after BPA can be exacerbated by a high mean pulmonary arterial pressure (PAP). Although oxygen inhalation is expected to lower mean PAP in patients with CTEPH, no relevant investigation has been conducted.Consecutive patients with CTEPH who underwent BPA were enrolled in this study. We evaluated the hemodynamics using right heart catheterization while breathing ambient air and with administration of 5 L/min oxygen for 10 min.This study included 52 consecutive patients with CTEPH, of whom 23 (44%) were treated with specific pulmonary vasodilators. Exposure to oxygen was well tolerated. Oxygen administration significantly decreased mean PAP by 3.8 ± 3.2 mmHg (p0.001) and pulmonary vascular resistance by 0.8 ± 1.8 Wood units (p0.001). Moreover, the ratio of pulmonary vascular resistance to systemic vascular resistance was significantly reduced by 13.5% (p0.001). Multivariate regression analysis identified baseline mean PAP (β = -0.427, p = 0.006) as the only significant predictor of decreased mean PAP under oxygen administration. No significant difference in oxygen effect on mean PAP was found between patients with and without vasodilators.In patients with CTEPH, 5 L/min supplemental oxygen inhalation could decrease mean PAP significantly by selective pulmonary artery dilatation, regardless of the usage of vasodilators, and thus could be helpful to maximize the safety of BPA.UMIN Clinical Trials Registry (No.: UMIN000026882); URL: https://www.umin.ac.jp/ctr/index.htm.

Arterial stiffness increases with age, as well as in various pathological states, including obesity, diabetes mellitus, smoking, and dyslipidemia, and it has important consequences for cardiovascular health. Arterial stiffness plays a central role in hemodynamic dysfunction characterized by excess pulsatility; specifically, it leads to heart failure, cerebrovascular disease, and renal failure. Among measures of arterial stiffness, carotid-femoral pulse wave velocity is considered as the reference standard; however, it has not been incorporated into routine clinical practice. Cardio-ankle vascular index (CAVI), which is a marker of arterial stiffness measured from the origin of the aorta to the ankle, was developed in 2004. CAVI is based on stiffness parameter β, which is theoretically independent of blood pressure at the time of measurement. CAVI applies stiffness parameter β to arterial segments between the heart and ankle. The measurement of CAVI is simple and well-standardized, and its reproducibility and accuracy are acceptable. Several studies have demonstrated that CAVI is high in patients with various atherosclerotic risk factors, and treatment of cardiovascular risk factors and lifestyle modifications improve CAVI. Several prospective studies have investigated the association between CAVI and future cardiovascular events in the general population and in patients with cardiovascular risk factors. A cut-off value of 9.0 is proposed for predicting patients at a high risk of cardiovascular events. From this review, it is clear that CAVI may be useful in the prevention of cardiovascular disease.

Noninvasive assessment of stenotic lesions in patients with complex adult congenital heart disease (ACHD) is challenging due to its complex morphology. The simultaneous two-screen display of multidetector-computed tomography (MDCT) and real-time echogram (STDME) technology can display a virtual multi-planar reconstruction from MDCT corresponding to the same cross-sectional image from transthoracic echocardiography (TTE). We investigated the usefulness of the STDME technology for stenosis severity assessment in complex ACHD patients.Twenty-four complex ACHD patients with stenotic lesions were enrolled in this study. All patients underwent TTE and the STDME technology within a week after MDCT. Peak velocity and pressure gradient (PG) across the stenotic site were measured using continuous wave Doppler. Cardiac catheterization was performed in 17 patients.Nine out of the twenty-four patients had undergone repair with a conduit. Peak velocity and PG from the STDME technology were higher than those from TTE (peak velocity: 3.1 ± 1.1 vs. 2.8 ± 1.0 m/s; peak PG: 43 ± 28 vs. 34 ± 21 mmHg; both p0.01). Peak PG from the STDME technology showed significant correlations with those from catheterization in patients with a conduit (n=7) and those without a conduit (n=10) (r = 0.795 and 0.880, respectively; both p0.05), while peak PG from TTE was correlated with catheterization measurements only in patients without a conduit (r = 0.850, p0.05).The STDME technology enables more accurate assessment of conduit stenosis severity than does TTE in complex ACHD patients.

Numerous basic studies have shown a relationship between interleukin-6 (IL-6) and the development or severity of myocarditis. However, there has been no study in which the effect of IL-6 levels in patients with myocarditis was evaluated.We enrolled control patients (n = 12) and consecutive patients with acute myocarditis (n = 13), including lymphocytic, eosinophilic, and giant cell myocarditis, and investigated the pathological and clinical effects of IL-6 on human myocarditis.The serum IL-6 level in patients with myocarditis (16.7 [9.9, 103.8] pg/mL) was significantly higher than that in the control patients (1.4 [1.0, 1.9] pg/mL) (P0.001). Immunohistochemical analysis showed that IL-6 was expressed in infiltrating inflammatory cells of endomyocardial biopsy samples from all patients with myocarditis. Moreover, the log-transformed value of serum IL-6 level showed significant positive correlations with serum creatine kinase (CK) level, CK-MB level, peak CK level, peak CK-MB level and C-reactive protein level (all P ≤ 0.005) and a negative correlation with the left ventricular (LV) ejection fraction (p = 0.014). We divided the patients with myocarditis into a low IL-6 group (9.9 [4.5, 14.2] pg/dL, n = 7) and a high IL-6 group (108.9 [51.1, 130.9] pg/dL, n = 6). The degree of infiltration of IL-6-expressing inflammatory cells in myocardial samples obtained from patients in the high IL-6 group was significantly more severe than that in samples obtained from patients in the low IL-6 group. Furthermore, patients in the high IL-6 group significantly more frequently received catecholamine therapy (P = 0.005), venoarterial extracorporeal membrane oxygenation (P = 0.029), and artificial respirator support (P = 0.021) in the acute phase of myocarditis.The results suggest that there is a strong impact of IL-6 on cardiac injury and dysfunction in patients with myocarditis.

No established methodology exists for diagnosis of aortic stenosis (AS) using focused cardiac ultrasound (FOCUS). We evaluated the diagnostic accuracy of our developed visual AS score for screening AS in an emergency department.Seventy-two emergency outpatients with suspected cardiovascular disease were studied. Emergency physicians assessed the visual AS score in addition to conducting the standard FOCUS, and then the aortic valve area index (AVAI) was measured by expert sonographers in the echocardiography laboratory. AVAI values0.85 cmSeventeen (24%) patients had moderate or severe AS. Visual AS scores assessed by emergency physicians and by expert sonographers showed excellent agreement (κ = 0.93), and a strong association was noted between the visual AS score assessed by emergency physicians and the AVAI assessed by expert sonographers (R = -0.71, p0.0001). A visual AS score ≥3 assessed by emergency physicians had a sensitivity of 82%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 95% for diagnosing moderate or severe AS. The prevalence of new-onset AS-related events during hospitalization was higher in patients with visual AS score ≥3 assessed by emergency physicians than in the remaining patients [7 (50%) vs. 2 (3%), p0.0001].The visual AS score is a useful AS screening tool for emergency physicians who are not expert cardiologists.

Exercise therapy following endovascular treatment (EVT) is important for patients with peripheral artery disease (PAD); however, continuous exercise therapy is difficult to be performed in clinical practice. This study aimed to investigate the association between the implementation of home-based exercise using pedometers after EVT and 1-year clinical outcomes.This multicenter observational prospective cohort registry included patients with PAD complaining of intermittent claudication who underwent EVT for aortoiliac and/or femoropopliteal artery lesions between January 2016 and March 2019. Patients were instructed to perform home-based exercises using a specific pedometer after EVT. The study population was divided into good and poor recording groups according to the frequency of the pedometer measurements. The good recording group was defined as those who completed ≥50 % of the prescribed daily pedometer recording during the follow-up period. The poor recording group was defined as those with an inability to use a pedometer and/or who completed50 % of the prescribed daily pedometer recordings. The primary outcome was 1-year major adverse events (MAE), defined as a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, target vessel revascularization, and major amputation of the target limb.The mean age was 74.4 years; 78 % were male. A total of 623 lesions were analyzed (58.7 % aortoiliac, 41.3 % femoropopliteal). At 1 year, a lower cumulative incidence of MAE was observed in the good recording group compared to that in the poor recording group [10/233 (4.3 %) vs. 35/267 (13.7 %) patients, respectively; p 0.001]. Multivariate Cox regression analysis showed that patients in the good recording group had a lower hazard ratio for 1-year MAE (0.33; 95 % confidence interval, 0.16-0.68; p = 0.004) than that in the poor recording group.Good self-recording of pedometer measurements was associated with favorable prognosis in patients with PAD following EVT.

Background: Right ventricular (RV) function is important for outcomes in pulmonary hypertension. Evaluation of RV myocardial characteristics is useful to assess the disease severity. Shear wave elastography (SWE) provides information of shear wave (SW) elasticity, which is related to tissue hardness, and SW dispersion slope, which reflects tissue viscosity. This study aimed to test the hypothesis that SW elasticity is increased and SW dispersion slope is decreased in the right ventricle of monocrotaline (MCT)-induced pulmonary hypertension rats. Methods: Rats were divided into MCT-induced pulmonary hypertension group (n = 10) and control group (n = 10). SW elasticity and SW dispersion slope were measured on excised hearts. Myocardial fibrosis was evaluated histologically. Results: RV hypertrophy was observed in the MCT group. SW elasticity of right ventricle was higher in the MCT group than in the control group (3.5 ± 0.9 kPa vs. 2.5 ± 0.4 kPa, p < 0.01). SW dispersion slope of right ventricle was lower in the MCT group than in the control group (5.3 ± 1.7 m/s/kHz vs. 7.7 ± 1.5 m/s/kHz, p < 0.01). The fibrosis area of right ventricle was increased in MCT group compared with control group (18 ± 5% vs. 8 ± 3%, p < 0.01), and was positively related to SW elasticity and negatively related to SW dispersion slope. Conclusions: Higher SW elasticity and lower SW dispersion slope were observed in the fibrotic myocardium of right ventricle in MCT-induced pulmonary hypertension rats. SWE may have the potential to evaluate RV function by assessing myocardial characteristics.

Background The receptor for advanced glycation end products (RAGE), a transmembrane receptor belonging to the immunoglobulin superfamily, is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with pulmonary arterial hypertension (PAH) and is implicated in the etiology of PAH. Recently, we reported that RAGE-aptamer, a short and single-stranded DNA directed against RAGE, inhibited an inappropriate increase in cultured PASMCs in PAH. The aim of this study was to determine the efficacy of RAGE-aptamer in monocrotaline-induced PAH in rats. Methods and Results Rats were assigned to either an untreated control group, a group that received continuous subcutaneous administration of RAGE-aptamer immediately after monocrotaline injection, or a group that received control-aptamer immediately after monocrotaline injection. All rats survived 21 days after injection of monocrotaline and control-aptamer or RAGE-aptamer. Injection of monocrotaline with continuous subcutaneous delivery of control-aptamer resulted in higher right ventricular systolic pressure compared with controls. This increase was attenuated by continuous subcutaneous delivery of RAGE-aptamer. The proportion of small pulmonary arteries with full muscularization was greater in the monocrotaline and control-aptamer group than in the control group. Continuous subcutaneous delivery of RAGE-aptamer significantly reduced the percentage of small pulmonary arteries with full muscularization. Conclusions Continuous subcutaneous delivery of RAGE-aptamer suppresses development of monocrotaline-induced PAH in rats. Inhibition of RAGE ameliorates muscularization of small pulmonary arteries. Treatment with RAGE-aptamer might be a new therapeutic option for PAH.

Previous studies demonstrated that the incidence of atrial fibrillation (AF) was significantly increased when patients aged ≥40 years had surgical atrial septal defect (ASD) closure (sASD). However, limited information is available on such findings in transcatheter ASD closure (tASD). The purpose of this study was to investigate the incidence of newly developed AF after tASD in patients aged ≥40 years in whom preoperative AF or atrial flutter (AFL) had not been detected and to compare with the incidence after sASD.The medical records of patients aged ≥40 years without a history of AF or AFL who underwent tASD (n = 281) or sASD (n = 24) were reviewed. Patients who had catheter ablation before the ASD closure were excluded. Patients with a patent foramen ovale were also excluded. The incidence of newly developed AF after ASD closure and the risk factors for that were evaluated statistically.Eleven patients had newly developed AF (5 in tASD and 6 in sASD) postoperatively including 6 persistent AF (3 each after tASD and sASD). The cumulative incidence of newly developed AF was 0.7% in tASD and 16.7% in sASD, and 2.7% and 20.8% at 1 and 5 years, respectively (p 0.001). ASD diameter ≥30 mm and sASD were potential risk factors for newly developed AF after ASD closure and postoperative persistent AF.In patients aged ≥40 years without a history of AF or AFL, the incidence of newly developed AF after tASD closure was lower than that after sASD. A large ASD more than 30 mm diameter was a potential risk factor for development of AF even if it is closed by transcatheter procedure. Further long-term evaluation after tASD is required to clarify preventive benefit for new onset AF in adult ASD population.

Background: With the rapidly aging population in Japan, the number of patients hospitalized for acute decompensated heart failure (ADHF) is increasing. Mitoyo General Hospital created an innovative clinical pathway (CP) for promoting early discharge in patients with ADHF. Major points of the CP were as follows: using tolvaptan as a standard therapy, completing the acute therapies within three days, and starting cardiac rehabilitation from the second day after admission. Methods: We collected data for patients with ADHF who were admitted to our hospital before introduction of the CP (non-CP group) (April 2014-July 2015) and after introduction of the CP (CP group) (August 2015-July 2019). We investigated the impact of the CP on the length of hospital stay (LOHS) and readmission after discharge. Results: After screening, 593 patients were enrolled in this study. After performing propensity score matching, 129 patients in the non-CP group and 129 patients in the CP group were analyzed. LOHS of patients in the CP group was significantly shorter than that of patients in the non-CP group [20 (14-28) days vs 12 (8-21) days] (p < 0.001) without an increase in mortality during hospitalization or an increase in the rate of readmission due to ADHF within 30 days. Use of the CP was an independent negative factor contributing to LOHS for patients with ADHF, even after adjustment of other factors including the use of tolvaptan (p < 0.001). The CP significantly decreased the proportion of patients readmitted to hospitals due to ADHF within 6 months [n = 32 (27%) vs n = 18 ( 15%), p = 0.026] and 1 year [n = 40 (34%) vs n = 23 ( 19%), p = 0.009] after discharge compared to the proportion in the non-CP group. Conclusions: The CP significantly reduced the LOHS of patients without increasing the in-hospital mortality and it also reduced the risk of readmission in the mid-term and long-term. (c) 2021 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Malondialdehyde-modified low-density lipoprotein (MDA-LDL) is a predictive marker of cardiovascular events in patients with stable angina pectoris. However, little is known about this marker in patients with acute coronary syndrome (ACS). We investigated the prognostic relevance of MDA-LDL to cardiovascular outcomes in patients with ACS.A total of 370 consecutive patients with ACS who underwent primary percutaneous coronary intervention (PCI) were enrolled from October 2009 to September 2014 at Mitoyo General Hospital. Serum MDA-LDL levels were measured at admission. The patients were divided into three tertile groups according to serum MDA-LDL levels. The primary outcomes were cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, revascularization, and heart failure requiring hospital admission.MDA-LDL levels in patients with acute myocardial infarction were significantly greater than those in patients with unstable angina pectoris (mean±standard deviation: 133±48U/L vs. 157±69U/L, p=0.001). During follow-up [472 (195-920) days], 82 (22%) events occurred. Kaplan-Meier analysis showed that patients in the highest MDA-LDL tertile had the worst prognosis (log-rank, p0.001). Cox regression analysis showed that serum MDA-LDL levels were an independent predictor of cardiovascular events after PCI in patients with ACS, even after adjustment for age, sex, body mass index, conventional cardiovascular risk factors, other lipid biomarkers, statin use on admission, cardiac biomarkers, and presence or absence of multivessel disease (hazard ratio: 1.80 per 1 standard deviation U/L increase, 95% confidence interval: 1.07-3.16, p=0.027).Serum MDA-LDL levels on admission are a significant prognostic marker in patients with ACS who undergo successful PCI.

Background : Multiple spikes within the QRS complex, known as fragmented QRS (fQRS), are associated with the occurrences of ventricular arrhythmic events (VAEs) in patients with Brugada syndrome and hypertrophic cardiomyopathy. However, the association between fQRS and occurrence of VAEs in patients with cardiac sarcoidosis (CS) has not been elucidated. Methods : We evaluated the associations between fQRS and cardiac events including VAEs [non-sustained ventricular tachycardia (NSVT), sustained ventricular tachycardia (VT), and ventricular fibrillation (VF)], hospitalization for heart failure, and all-cause death in 68 patients with CS (30 patients with fQRS vs. 38 patients without fQRS) over a 5-year period. Results : Cardiac events occurred in 22 patients with fQRS and 18 patients without fQRS (73% vs. 47%, p=0.009). Of the cardiac events that occurred in CS patients, VAEs occurred more frequently in patients with fQRS than in patients without fQRS (VAEs: 70% vs. 45%, p=0.017; NSVT: 70% vs. 45%, p=0.010; VT: 43% vs. 18%, p=0.011, and VF: 6.7% vs. 2.6%, p=0.34), whereas there was no significant difference in hospitalization for heart failure or all-cause death between patients with and those without fQRS (hospitalization for heart failure: 6.7% vs. 5.3%, p=0.75; all-cause death: 6.7% vs. 5.3%, p=0.64). Multivariate analysis showed that fQRS in the baseline electrocardiogram was independently associated with VAEs (hazard ratio: 2.21, 95% confidence interval: 1.15–4.25, p=0.017). Conclusion : fQRS is a predictor of VAEs in patients with CS.

Background Perioperative atrial fibrillation (POAF) after non-cardiac surgery is a risk factor for cardiovascular events including stroke and death. The aim of this subanalysis of the MAMACARI study, a multicenter randomized control study on the effectiveness of a bisoprolol transdermal patch for prevention of perioperative myocardial injury in high-risk patients undergoing non-cardiac surgery, was to identify the predictors of POAF after non-cardiac surgery in high-risk patients and to determine changes in blood pressure and heart rate during bisoprolol patch administration in the perioperative period. Methods and Results Patients aged over 60 years with hypertension and a high revised cardiac risk index (≥2) who were scheduled to undergo non-cardiac surgery were randomly assigned to a bisoprolol patch group (n = 120) or a control group (n = 120). We divided the patients into two groups: patients with POAF (POAF group; n = 16) and patients without POAF (non-POAF group; n = 206). Multivariate analysis showed that bisoprolol patch therapy (OR: 0.30, 95% CI: 0.092–0.978) and surgery time of 250 min or more (OR: 4.99, 95% CI: 1.37–18.2) were independently associated with POAF. Although systolic blood pressure did not differ significantly between the two groups throughout the perioperative period, treatment with a bisoprolol patch significantly reduced heart rate throughout the perioperative period compared with that in the control group. Conclusions Low dose of a bisoprolol patch in the perioperative period was effective for prevention of POAF after non-cardiac surgery in high-risk patients, while long surgery time was an independent risk factor for POAF. It is expected that low dose of a bisoprolol patch can prevent POAF without causing hypotension.

Background Cardiovascular events in patients with atrial fibrillation (AF) can be lowered by catheter ablation. We hypothesized the underlying mechanism was improvement in renal and endothelial function corresponding to AF burden, and investigated whether restoration of sinus rhythm (SR) after ablation affected these functions according to AF type. Methods and Results We prospectively measured estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and reactive hyperemia index (RHI) in 358 consecutive patients with AF before and 6 and 12 months after the ablation. For each AF type [paroxysmal AF (PAF), n = 229, and persistent AF (PeAF), n = 129], we evaluated changes in these markers and influence of chronic kidney disease (CKD). The eGFR and natural logarithm-transformed (ln) UACR improved at 6 months in the PeAF group (68.7 ± 18.7–71.8 ± 18.9 mL/min/1.73 m2, p = 0.003 and 3.1±1.6 to 2.8±1.5, p Conclusions SR restoration after ablation was associated with an improved eGFR and UACR in PeAF patients, but not PAF patients. In PeAF patients with CKD, an improved endothelial function after ablation was associated with an improved renal function.

Treatment goals in pulmonary arterial hypertension (PAH) include improved quality of life and exercise capacity as well as improved life prognosis. In our experience, only remarkable reductions in pulmonary arterial pressure (PAP) improve long-term survival. Lowering PAP could contribute to reverse remodeling by reducing hemodynamic stress. Proper and prompt use of PAH-specific drugs lowers PAP in patients with PAH. Upfront combination therapy with different PAH-specific drugs and quickly establishing high-dose epoprostenol lowers PAP sufficiently to improve prognosis in patients with PAH. PAH is often a comorbidity with other diseases including congenital heart defect, connective tissue diseases, and pulmonary arterial aneurysm. It is essential in these conditions to lower PAP to allow the next treatment strategy. In this report, we review modern treatments to lower PAP in patients with PAH.

This study aimed to investigate the mechanisms of acute changes in functional mitral regurgitation (FMR) by preload alterations.Twenty-two consecutive patients with left ventricular ejection fraction40% and at least mild FMR underwent transthoracic echocardiography. Passive leg lifting and sublingual administration of nitroglycerin were performed to alter preload. Mitral regurgitant volume (MRV) was assessed using the Doppler method.MRV changed in parallel with preload alterations. MRV correlated better with tenting height (TH) than with mitral annular area (MAA) at baseline, whereas the difference in the correlate coefficients was not statistically significant (R=0.69 and R=0.40, respectively; p=0.19). On the other hand, changes in MRV between each sequential stage correlated better with those in MAA than with those in TH (R=0.68 and R=0.44, respectively; p=0.043). Multiple regression analysis revealed that baseline TH was the independent determinant of baseline MRV (R=0.69, p=0.0004), whereas changes in MAA with preload alteration were the independent determinant of the changes in MRV (R=0.68, p0.0001). Changes in left atrial (LA) volume were the independent determinant of the changes in MAA (R=0.30, p=0.0063).Acute changes in FMR with preload alterations resulted from the transverse changes in MAA rather than the longitudinal changes in tethering-tenting of mitral geometry, and mitral annular deformation was determined by changes in LA volume. Preload reduction might help heart failure treatment through the reduction in FMR resulting from the decrease in LA and mitral annular size.

Chronic renal disease (CKD) is a determinant of coronary artery calcification (CAC), which is a predictor of cardiovascular events. However, in a population without CKD, the association between CAC and renal function is unclear. CAC is affected by sex. This study aimed to determine whether serum cystatin C, a sensitive marker of kidney function, or sex differences are associated with CAC in patients without CKD.We evaluated 456 consecutive patients (61±13 years, 42% women) without CKD and evidence of coronary artery disease. The CAC (Agatston) score was examined by multidetector computed tomography.When patients were categorized into three CAC groups based on the Agatston score, mild (10), moderate (11-399), and severe (≥400) in each sex, serum cystatin C levels gradually increased by severity of CAC in women, but not men. Receiver operating characteristic curve analysis showed that, in women, a cut-off value of 0.97mg/l for cystatin C discriminated patients with severe CAC with a sensitivity of 71% and specificity of 77% (area under the curve, 0.74; 95% CI: 0.62-0.86; p0.01). Multivariate logistic analysis showed that serum cystatin C was not associated with severe CAC in all patients and men, but this association was observed in women (OR: 7.80 for cystatin C≥0.97mg/l, 95% CI: 1.76-34.6, p0.01).Higher serum cystatin C levels are associated with greater CAC in women without CKD. Measurement of cystatin C may be useful for identifying women who are at high risk for cardiovascular disease.

Background Ambulatory measurement of intrathoracic impedance (ITI) with an implanted device has potential to assess fluid accumulation in patients with heart failure (HF), but it has failed to reduce HF-related hospitalization because of a high false-positive rate. Objective We aimed to examine whether a modified algorithm (OptiVol 2.0) could reduce false-positive HF events documented in our multicenter trial (MOMOTARO). Methods The MOMOTARO trial assessed the potential that fluid index could predict fluid accumulation and therefore HF. The MOMOTARO trial assessed whether HF events could be detected based on fluid accumulation as assessed by fluid index. We re-analyzed raw data of ITI trends of the threshold-crossing events with the modified algorithm. Results The study consisted of 195 patients who had been implanted with a high-energy device. During a mean follow-up period of 658 ± 165 days, there were 154 primary HF events detected by the previous algorithm (OptiVol 1.0). With the previous algorithm, there was no significant difference in log concentration of brain natriuretic peptide (BNP) between baseline and alert ( p = 0.21). Among 150 alerts of the previous algorithm, only 37 reached the threshold by the modified algorithm, and log BNP was significantly higher in these 37 events compared with the baseline value (2.40 ± 0.46 vs. 2.27 ± 0.52, p Conclusion Our simulation study demonstrates that fluid index calculated with the modified algorithm reduces the number of false-positive threshold-crossing HF events and is promising for accurate diagnosis of fluid accumulation in patients.

Background Intravenous epoprostenol is an effective treatment for idiopathic and heritable pulmonary arterial hypertension. We aimed to clarify factors that determine the survival of patients with severe pulmonary hypertension who received epoprostenol treatment. Methods This is a retrospective observational study consisting of 46 patients with idiopathic and heritable pulmonary arterial hypertension in World Health Organization (WHO) functional class III or IV and undergoing intravenous epoprostenol treatment. We compared the following factors between survivors and non-survivors: clinical characteristics, exercise capacity, hemodynamics, interval between diagnosis and treatment initiation, concomitant pulmonary arterial hypertension-targeted drugs, maximum dose of epoprostenol, and the speed of up-titration. We defined a rapid increase group as those receiving epoprostenol ≥20 ng/kg/min at 3 months and ≥45 ng/kg/min at 1 year of treatment. Results Thirty-two patients (70%) survived and 14 patients died during an average follow-up period of 2100 days. Mean pulmonary artery pressure, concomitant pulmonary arterial hypertension-targeted drugs, and the maximum epoprostenol dose were comparable between the two subsets of patients. WHO functional class III was more common than class IV, and the 6-min walking distance was longer in the survivor than the non-survivor group. The survivors typically showed a rapid increase in epoprostenol dose during the first year of treatment. This rapid increase group was associated with a continuous reduction in mean pulmonary artery pressure during the follow-up period, whereas the slow increase group showed no reduction in mean pulmonary artery pressure after 6 months of treatment. The 9.5-year survival rate was also significantly better in the rapid increase group compared with the slow increase group (100% vs. 64%, p = 0.022). Conclusions In idiopathic and heritable pulmonary arterial hypertension patients, a rapid increase in epoprostenol dose soon after the initiation of treatment seems to be important to achieve a continuous reduction in mean pulmonary artery pressure and to improve survival.

Heart failure remains the leading cause of death worldwide, and is a burgeoning problem in public health due to the limited capacity of postnatal hearts to self-renew. The pathophysiological changes in injured hearts can sometimes be manifested as scar formation or myocardial degradation, rather than supplemental muscle regeneration to replenish lost tissue during the healing processes. Stem cell therapies have been investigated as a possible treatment approach for children and adults with potentially fatal cardiovascular disease that does not respond to current medical therapies. Although the heart is one of the least regenerative organs in mammals, discoveries made during the past few decades have improved our understanding of cardiac development and resident stem/progenitor pools, which may be lineage-restricted subpopulations during the post-neonatal stage of cardiac morphogenesis. Recently, investigation has specifically focused on factors that activate either endogenous progenitor cells or preexisting cardiomyocytes, to regenerate cardiovascular cells and replace the damaged heart tissues. The discovery of induced pluripotent stem cells has advanced our technological capability to direct cardiac reprogramming by essential factors that are crucial for heart field completion in each stage. Cardiac tissue engineering technology has recently shown progress in generating myocardial tissue on human native cardiac extracellular matrix scaffolds. This review summarizes recent advances in the field of cardiac cell therapies with an emphasis on cellular mechanisms, such as bone marrow stem cells and cardiac progenitor cells, which show the high potential for success in preclinical and clinical meta-analysis studies. Expanding our current understanding of mechanisms of self-renewal in the neonatal mammalian heart may lead to the development of novel cardiovascular regenerative medicines for pediatric heart diseases.

A B S T R A C T Background: Earlobe creases (ELC) are frequently observed in patients with atherosclerosis. Atherosclerosis is considered to be a systemic vascular inflammatory disease, and oxidative stress is known to be a contributor to vascular inflammation. It is well known that inflammatory biomarkers [high-sensitivity C-reactive protein (hs-CRP), pentraxin3 (PTX3)] and oxidative stress markers [malondialdehyde lowdensity lipoprotein (MDA-LDL)] are associated with atherosclerotic changes. This study was designed to test the hypothesis that biomarkers of inflammation and oxidative stress are increased in patients with ELC. Methods: A total of 223 consecutive patients with atherosclerotic risk factors were enrolled and divided into two groups. One group consisted of patients with ELC (ELC group, n = 134) and the other was without ELC (non-ELC group, n = 89). Medical information and biomarker levels related to atherosclerosis were acquired from these patients. Results: The male ratio, prevalence of hypertension, diabetes mellitus, and MDA-LDL, hs-CRP, and PTX3 levels were found to be higher in the ELC group, compared with the non-ELC group. A multiple logistic regression analysis showed that PTX3 levels, rather than hs-CRP, constituted the strongest predictive factor for the appearance of ELC. Conclusions: Vascular inflammation and oxidative stress are associated with the presence of ELC.

The presence of coronary artery calcification (CAC) and its severity predict future cardiovascular events and is used for risk stratification. However, the association of CAC with heart failure (HF) in patients without a history of coronary artery disease (CAD) remains unclear. This study aimed to determine the correlations of CAC with N-terminal pro-B-type natriuretic peptide (NT-proBNP) and HF events in patients without a history of CAD or HF.From June 2010 to June 2013, a total of 487 patients without a history of CAD and HF were enrolled. All of the patients underwent plane multi-detector computed tomography. They were divided into four categories according to CAC scores: ≤10, 11-100, 101-400, and ≥401.The proportion of patients with high NT-proBNP levels increased with CAC categories (p0.0001). The CAC score was associated with NT-proBNP levels ≥400pg/ml, with an odds ratio of 2.901 (95% confidence interval: 1.368-6.151, p=0.0055) for CAC scores ≥401 compared with CAC scores of 0-10 after adjustment for confounding factors. During the follow-up period of 497±315 days, nine patients were admitted for HF. Kaplan-Meier analysis showed that patients with CAC scores ≥401 had a lower rate of freedom from admission for HF with cumulative incidences of 0.4%, 1%, 2%, and 8% for CAC scores of 0-10, 11-100, 101-400, and ≥401, respectively (p0.0001). Increasing CAC scores were associated with an increase in incidence of admission for HF, with a hazard ratio of 10.371 for CAC scores ≥401 (95% CI: 1.062-101.309, p=0.0443) compared with CAC scores of 0-10 after adjustment for risk factors.Severe CAC is an independent determinant of high NT-proBNP levels and a predictor of admission for HF in a population without a history of CAD or HF.

High platelet reactivity before percutaneous coronary intervention (PCI) reportedly increases the risk of PCI-related myocardial infarction (PMI) following elective PCI. We conducted a pilot study to evaluate changes in platelet reactivity during PCI and their association with the incidence of PMI.In total, 133 consecutive patients undergoing elective PCI after pretreatment with dual antiplatelet therapy for at least 7 days were prospectively enrolled. Platelet reactivity was measured by the VerifyNowPlatelet reactivity significantly increased from 177.3 ± 53.4 P2Y12 reaction units (PRU) before PCI to 203.4 ± 52.8 PRU immediately after PCI (p 0.001). Absolute changes in platelet reactivity were significantly greater in patients with than without PMI (32.4 ± 29.0 vs. 21.2 ± 24.8 PRU, respectively; p = 0.021). In the multivariable logistic regression analysis, the absolute change in PRU was an independent predictor of the incidence of PMI. Receiver operating characteristic curve analysis of the change in PRU during PCI for discriminating PMI showed a sensitivity, specificity, and the cut-off value of 46%, 76%, and 37 PRU, respectively (area under the curve = 0.607, p = 0.0235). When the patients were divided into two groups, namely a greater (change in PRU ≥ 37) and smaller (change in PRU 37) increase group, the incidence rate of PMI was significantly higher in the greater than smaller increase group (59.1% vs. 34.8%, respectively; p = 0.008). Additional exploratory analyses by intracoronary imaging demonstrated that the proximal reference lumen area in the greater increase group was significantly smaller than that in the smaller increase group (6.5 ± 2.4 vs. 7.7 ± 3.1 mmAn increase in platelet reactivity after elective PCI is possibly associated with PMI. This finding should be validated by a larger-scale study.

Background Recent clinical trials have demonstrated the efficacy of short-term treatment with tolvaptan, an oral vasopressin V2 receptor antagonist, in patients with heart failure. However, the response to tolvaptan varies among patients. The aim of this study was to determine factors associated with response to tolvaptan in patients with acute decompensated heart failure (ADHF). Methods The Tolvaptan Registry, a prospective, observational, multicenter cohort study performed in Japan, aims to determine factors affecting the responsiveness of tolvaptan in patients with ADHF. We enrolled ADHF patients treated with tolvaptan and they were divided into two groups: responders and non-responders. Responders were defined as subjects who met all of the following three conditions: (1) increasing urine volume during a 24-hour period after the start of tolvaptan treatment; (2) improvement in New York Heart Association functional class; and (3) decrease in cardiothoracic ratio assessed by chest X-ray on day 3 of tolvaptan administration. Results Among the 114 patients, treatment with tolvaptan improved three conditions of heart failure in more than half of all the cohorts (71 patients, 62%). As for baseline characteristics, estimated glomerular filtration rate, urine osmolality, and kidney size were significantly greater in responders than in non-responders. Multivariate logistic analysis revealed that kidney size was independently associated with responders (odds ratio: 1.083, p = 0.001, 95% confidence interval 1.031–1.137). Conclusions The main clinical characteristic of responders to treatment with tolvaptan is that kidney size is preserved.

Background Management of adult congenital heart disease (ACHD) patients requires understanding of its complex morphology and functional features. An innovative imaging technique has been developed to display a virtual multi-planar reconstruction obtained from contrast-enhanced multidetector-computed tomography (MDCT) corresponding to the same cross-sectional image from transthoracic echocardiography (TTE). The aim of this study is to assess the usefulness of this imaging technology in ACHD patients. Methods This study consisted of 46 consecutive patients (30 women; mean age, 52 ± 18 years old) with ACHD who had undergone contrast MDCT. All patients underwent TTE within a week of MDCT. An experienced sonographer who did not know the results of MDCT conducted a diagnosis using TTE and, then, using the new imaging technology. We studied whether this imaging technology provided additional or unexpected findings or makes more accurate diagnosis. Results In this imaging technology, MDCT cross-section provides higher-resolution image to the deep compared to corresponding TTE image. Depending on the MDCT section which can be arbitrarily set under the echo guide, we can diagnose unexpected or incremental lesions or more accurately assess the severity of the lesion in 27 patients (59%) compared to TTE study alone. This imaging technology was useful in the following situations: 1. For anatomical guidance for Doppler flow assessment. 2. Assessment of morphology of obstruction in outflow tracts or conduit. 3. To clarify the etiology of unordinary severe valvular disease. 4. Assessment of the patient with diseased prosthetic valves. Conclusions This integrated imaging technology provides incremental role over TTE in complex anatomy, and allows functional information in ACHD patients.

Background Antithrombotic therapy with oral anticoagulants (OAC) in patients with atrial fibrillation (AF) after stent implantation, where dual antiplatelet therapy (DAPT) is also recommended, is not established. Antithrombotic therapies prescribed vary widely among cardiologists and may change year by year, according to the accumulation of new evidence. Methods A questionnaire-based survey concerning the antithrombotic therapy prescribed for OAC-treated AF patients who underwent stent implantation was conducted from 2014 to 2016. The survey was completed by the Fellows of the Japanese College of Cardiology (FJCC). Results The questionnaire was sent to 1023 fellows in 2014, a total of 1057 fellows in 2015, and 1073 fellows in 2016; 268 (26%), 418 (40%), and 416 (39%) answers were obtained, respectively. The duration of DAPT did not change in patients with bare metal stents; however, it tended to become shorter with the use of the drug-eluting stent (DES). Significant shortening of DAPT duration was observed with DES for stable coronary artery disease from 2015 to 2016. A similar tendency was observed for acute coronary syndrome (ACS); however, this was not significant between 2015 and 2016. A shorter duration of DAPT is preferred by electrophysiologists rather than by interventionalists and general cardiologists. OAC monotherapy is not popular one year after stent implantation, although the prevalence of its use increased year by year. Aspirin and thienopyridines are used equally as a single antiplatelet in DAPT, and clopidogrel is also a popular agent. The prevalence of direct OAC use increased year by year. Conclusions The questionnaire showed variation in antithrombotic therapy used for OAC-treated AF patients after stenting, and how it changes year by year. Although the duration of DAPT tended to shorten, variations are still observed, i.e. the selection of a single antiplatelet or OAC.

Background Pulmonary artery (PA) dilatation is usually observed in patients with pulmonary hypertension (PH), but a PA aneurysm (PA diameter > 40 mm) is rare. The difference between characteristics of patients with and those without progression of PA diameter remains poorly understood. We assessed the changes in PA diameter in patients with PH coexisting with and without a PA aneurysm. Methods We investigated the changes in PA diameter by multi-detector computed tomography performed twice with an interval of more than one year in 44 patients with PH. Seventeen patients had a PA aneurysm and 27 patients did not have a PA aneurysm at baseline. Results The median follow-up period was 3.6 years. All patients received medical or invasive treatment for PH. At baseline, main PA diameters were 52 ± 15 mm in patients with a PA aneurysm and 33 ± 3 mm in patients without a PA aneurysm. Mean PA pressure was higher in patients with a PA aneurysm than in those without a PA aneurysm (61 ± 15 mmHg vs. 51 ± 16 mmHg, p = 0.04). At follow-up, mean PA pressure significantly decreased in both patients with a PA aneurysm (44 ± 11 mmHg) and patients without a PA aneurysm (41 ± 18 mmHg). Main PA diameter significantly increased in patients with a PA aneurysm (65 ± 28 mm, change ratio: 23.3%), while it did not increase in patients without a PA aneurysm (32 ± 3 mm, change ratio: −3.1%). Conclusions PA dilatation progressed in patients with a PA aneurysm despite treatment of PH. The progression of PA dilatation is independent of reduction of PA pressure by PH treatment.

Background The prognosis of heart failure patients with reduced ejection fraction (HFrEF) in Japan remains poor, although there is growing evidence for increasing use of evidence-based pharmacotherapies in Japanese real-world HF registries. Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor shown to reduce mortality and morbidity in the recently completed largest outcome trial in patients with HFrEF (PARADIGM-HF trial). The prospectively designed phase III PARALLEL-HF (Prospective comparison of ARNI with ACE inhibitor to determine the noveL beneficiaL trEatment vaLue in Japanese Heart Failure patients) study aims to assess the clinical efficacy and safety of LCZ696 in Japanese HFrEF patients, and show similar improvements in clinical outcomes as the PARADIGM-HF study enabling the registration of LCZ696 in Japan. Methods and design This is a multicenter, randomized, double-blind, parallel-group, active controlled study of 220 Japanese HFrEF patients. Eligibility criteria include a diagnosis of chronic HF (New York Heart Association Class II-IV) and reduced ejection fraction (left ventricular ejection fraction ≤35%) and increased plasma concentrations of natriuretic peptides [N-terminal pro B-type natriuretic peptide (NT-proBNP) ≥600 pg/mL, or NT-proBNP ≥400 pg/mL for those who had a hospitalization for HF within the last 12 months] at the screening visit. The study consists of three phases: (i) screening, (ii) single-blind active LCZ696 run-in, and (iii) double-blind randomized treatment. Patients tolerating LCZ696 50 mg bid during the treatment run-in are randomized (1:1) to receive LCZ696 100 mg bid or enalapril 5 mg bid for 4 weeks followed by up-titration to target doses of LCZ696 200 mg bid or enalapril 10 mg bid in a double-blind manner. The primary outcome is the composite of cardiovascular death or HF hospitalization and the study is an event-driven trial. Conclusions The design of the PARALLEL-HF study is aligned with the PARADIGM-HF study and aims to assess the efficacy and safety of LCZ696 in Japanese HFrEF patients.

Statin therapy targeting reduction of low-density lipoprotein cholesterol (LDL-C) decreases the risk of coronary heart disease (CHD) and all-cause mortality. However, a substantial number of cases of CHD are not prevented and residual risk factors remain unsettled. A high triglyceride (TG) level is considered to be an important and residual risk factor. Postprandial hyperlipidemia is a condition in which TG-rich chylomicron remnants are increased during the postprandial period and hypertriglycedemia is protracted. Postprandial hyperlipidemia evokes atherogenesis during the postprandial period. Several prospective studies have revealed that nonfasting serum TG levels predict the incidence of CHD. Values of TG, remnant lipoprotein cholesterol, and remnant lipoprotein TG after fat loading were significantly higher in diabetes patients with insulin resistance than in diabetes patients without insulin resistance. Endothelial dysfunction is an initial process of atherogenesis and it contributes to the pathogenesis of CHD. Postprandial hyperlipidemia (postprandial hypertriglyceridemia) is involved in the production of proinflammatory cytokines, recruitment of neutrophils, and generation of oxidative stress, resulting in endothelial dysfunction in healthy subjects, hypertriglyceridemic patients, or type 2 diabetic patients. Effective treatment has not been established till date. Ezetimibe or omega-3 fatty acids significantly decrease postprandial TG elevation and postprandial endothelial dysfunction. Ezetimibe or omega-3 fatty acids added to statin therapy reduce serum TG levels and result in good outcomes in patients with CHD. In conclusion, postprandial hyperlipidemia is an important and residual risk factor especially in patients with insulin resistance syndrome (metabolic syndrome) and diabetes mellitus. Further studies are needed to establish effective treatment.

BackgroundTo evaluate the role of integrated backscatter intravascular ultrasound (IB-IVUS) in assessing the morphology of neointima in bare-metal stent (BMS) and drug-eluting stent (DES) restenosis as compared to the gold-standard, optical coherence tomography (OCT).MethodsA total of 120 cross-sections were evaluated by IB-IVUS and OCT at five cross-sections from 24 patients (24 lesions): at the minimal lumen area (MLA) and at 1 and 2mm proximal and distal to the MLA site in 24 lesions (9 treated with DES and 15 treated with BMS). IB-IVUS and OCT findings were analyzed according to the time at which restenosis was identified (early

SummaryBackgroundLeft ventricular (LV) diastolic dysfunction is related to increased cardiac sympathetic activity. We investigated the effect of cilnidipine, an L/N-type calcium channel blocker, on LV diastolic function and cardiac sympathetic activity in patients with hypertensive heart disease (HHD) using radionuclide myocardial imaging.Methods and resultsThirty-two frame electrocardiography (ECG) -gated 99mTc-sestamibi (MIBI) myocardial single photon emission computed tomography (SPECT), and 123I-metaiodobenzylguanidine (MIBG) imaging were performed before and 6 months after drug administration in 32 outpatients with HHD. Sixteen of the patients were treated with cilnidipine and the other 16 were treated with nifedipine retard. The parameters for assessing LV diastolic function evaluated using ECG-gated 99mTc-MIBI SPECT were peak filling rate (PFR), first-third filling rate (1/3FR), and time to peak filling (TPF). Cardiac sympathetic activity was assessed as early and delayed heart to mediastinum (H/M) ratios and a washout rate (WR), using 123I-MIBG imaging. The PFR and 1/3FR significantly increased after 6 months of treatment with cilnidipine (p

Background Short-duration adaptive servo-ventilation (ASV) therapy can be effective for heart failure (HF) patients. Albuminuria is recognized as a prognostic marker for HF. We investigated whether short-duration and short-term ASV therapy reduced albuminuria in HF patients. Methods and results Twenty-one consecutive HF patients were divided into two groups: those who tolerated ASV therapy (ASV group, n = 14) and those who did not (non-ASV group, n = 7). ASV therapy was administered to enrolled patients for 1 week for 2 h per day (1 h in the morning and 1 h in the afternoon). The urinary albumin to creatinine ratio (UACR), urinary 24 h norepinephrine (NE) excretion, high-sensitivity C-reactive protein (hs-CRP), and plasma brain natriuretic peptide (BNP) levels were measured before and 1 week after ASV therapy. In the ASV group, but not the non-ASV group, the UACR significantly decreased, together with a decrease in urinary NE and hs-CRP levels. There were significant correlations between the changes in UACR and hs-CRP and between the changes in urinary NE and hs-CRP. Multiple linear regression analyses indicated that ASV use was the strongest predictor of decreased UACR. Conclusion Albuminuria, urinary NE, and hs-CRP levels reduced in HF patients who could receive short-duration and short-term ASV therapy. Anti-inflammatory effects of ASV therapy may partly mediate the reduction of albuminuria.

SummaryBackgroundMyocardial fibrosis is the major factor that regulates left ventricular (LV) diastolic function. Pioglitazone, an anti-diabetic drug, is reported to improve the LV diastolic function in diabetic patients, but its influence on myocardial fibrosis has not been clarified. We evaluated the effect of pioglitazone on LV diastolic function and myocardial fibrosis in type 2 diabetic (T2DM) patients.Methods and resultsFifteen T2DM patients were enrolled in the ON group, and the parameters were examined before and after pioglitazone administration (15–30mg/day) for 6 months. Twenty-four T2DM patients were assigned to the OFF group, and the parameters were examined before and 6 months after cessation of pioglitazone. We measured echocardiographic parameters such as early diastolic mitral annular velocity (E′) and plasma concentration of aminoterminal propeptide of procollagen type III (PIIIP), a marker of myocardial fibrosis. In the ON group, pioglitazone significantly increased E′ (6.04±1.70cm/s vs. 6.51±1.64cm/s, p