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A 59-year-old man with a high level of antinuclear antibody received nivolumab and ipilimumab plus che-motherapy for lung cancer. Two weeks after the second course, he was admitted with a fever and severe fa-tigue. Laboratory studies showed elevated markers of myocardial damage, and a myocardial biopsy showed inflammatory cell infiltration, damaged myocardial fibers. Myocarditis was diagnosed as an immune-related adverse event (irAE), and high-dose corticosteroids were initiated. However, his cardiac function rapidly worsened, and he died on the fifth day after admission. There is no established treatment strategy for fulmi-nant myocarditis as an irAE, and the further exploration of viable treatment strategies is required.

Aims: Pericoronary adipose tissue (PCAT) attenuation on coronary computed tomography angiography (CTA) is a noninvasive biomarker for pericoronary inflammation and is associated with cardiac mortality. We aimed to investigate the association between PCAT attenuation and endothelial dysfunction assessed using flow-mediated dilation (FMD). Methods: A total of 119 outpatients who underwent both coronary CTA and FMD measurements were examined. PCAT attenuation values were assessed at the proximal 40-mm segments of all three major coronary arteries on coronary CTA. Endothelial function was assessed using FMD. Patients were then classified into two groups: those with endothelial dysfunction (FMD ＜4%, n=44) and those without endothelial dysfunction (FMD ≥ 4%, n=75). Results: In all three coronary arteries, PCAT attenuation was significantly higher in patients with endothelial dysfunction than in those without endothelial dysfunction. Multivariate logistic regression analysis revealed that PCAT attenuation in the right coronary artery (odds ratio [OR]=1.543; 95% confidence interval [CI]=1.004–2.369, p=0.048) and left anterior descending artery (OR=1.525, 95% CI=1.004–2.369, p=0.049) was an independent predictor of endothelial dysfunction. Subgroup analysis of patients with adverse CTA findings (significant stenosis and/or high-risk plaque) and those with coronary artery calcium score ＞100 showed that high PCAT attenuation in all three coronary arteries was a significant predictor of endothelial dysfunction. Conclusion: High PCAT attenuation was significantly associated with FMD-assessed endothelial dysfunction in patients with suspected coronary artery disease. Our results suggest that endothelial dysfunction is one of the pathophysiological mechanisms linking pericoronary inflammation to cardiac mortality.

Catheter ablation (CA) of ventricular tachycardia (VT) after repair of congenital heart disease may be difficult because of complex anatomy and sometimes unmappable VT. Here, we report a 41-year-old woman with successful CA of unmappable VT in a patient with complete transposition of the great arteries after Rastelli repair. Clinical VT was induced by programmed electrical stimulation, when the mapping catheter was placed at the high anterior right ventricular outflow tract (RVOT). During VT, the local potential at the high anterior RVOT under the right ventricle (RV) – pulmonary artery (PA) conduit was equal to that at the timing of onset of QRS. The VT was unmappable because the hemodynamics deteriorated. Pace mapping was also tried at the aortic cusp and the left ventricular outflow tract (LVOT). Fractionated potential during sinus rhythm was observed at the noncoronary cusp, and the paced QRS morphology at this site was similar to that of the clinical VT, with a delay of 55 ms from pacing to the onset of QRS. However, mapping at the LVOT was impossible due to the difficulty of catheter manipulation. Radiofrequency energy was successfully applied at the noncoronary cusp and the high anterior RVOT under the RV-PA conduit.

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.

Background Although isolated cardiac sarcoidosis (CS) is not uncommon, little is known about the prognosis. We aimed to clarify clinical features and clinical outcomes in patients with isolated CS. Methods Two-hundred eighty-six patients with suspected CS were enrolled. Systemic CS (SCS) was diagnosed by histological or clinical confirmation of sarcoidosis according to the guidelines. Isolated CS was diagnosed by histological or clinical confirmation in the heart alone. The endpoint was cardiac death, hospitalization for heart failure, or fatal ventricular arrhythmia. Results Twenty-one patients were diagnosed with isolated CS, and 63 were diagnosed with SCS. The frequencies of diagnostic criteria, such as high-grade atrioventricular block or fatal ventricular arrhythmia, basal thinning of the ventricular septum, left ventricular contractile dysfunction, positive myocardial uptake of gallium-67 citrate scintigraphy or fluorine-18 fluorodeoxyglucose positron emission tomography, and delayed contrast enhancement of cardiac magnetic resonance, were higher or equivalent in patients with isolated CS, compared to those with SCS. Over a median follow-up of 31 months (range: 1–175 months), cardiac death, hospitalization for heart failure, or fatal ventricular arrhythmia occurred in 14 (67%) patients with isolated CS, 24 (38%) patients with SCS, and 63 (31%) patients without CS. The rate of cardiac events was higher in patients with isolated CS (log-rank test, p = 0.01). Cox proportional hazard analysis showed that isolated CS, age, and New York Heart Association functional class were independently associated with cardiac events. Conclusions Patients with isolated CS have clinical features compatible with SCS, and have cardiac events at a higher rate.

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.

Transvenous lead extraction (TLE) is necessary because of system infection, lead malfunction, or system upgrade. Patients with severe left ventricular dysfunction (SLVD) undergoing TLE may be at a higher risk because hemodynamic parameters may change unfavorably during or after TLE; however, this has not yet been clarified.The purpose of this study was to examine whether patients with SLVD undergoing TLE have higher mortality.All patients who underwent TLE were stratified as follows: patients with ejection fraction ≤ 35% (SLVD group) and those with ejection fraction35% (non-SLVD group).We assessed the data of 200 patients [SLVD group, 36 (18%); non-SLVD group, 164 (82%)]). Brain natriuretic peptide level and cardiac resynchronization therapy rate were higher in the SLVD group than in the non-SLVD group. There were no significant between-group differences in major complications and clinical success rates. Patients with SLVD were more likely to require additional hemodynamic support, such as catecholamine infusion, temporary atrium-ventricle sequential pacing, and temporary cardiac resynchronization therapy pacing (27.8% vs 1.2%; P.001). The survival rate was not significantly different between the groups at 30 days and 1 year after TLE (SLVD vs non-SLVD: 30 days: 97.2% vs 99.4%; P = .215; 1 year: 80.6% vs 91.5%; P = .053). Multivariate Cox regression analysis revealed log brain natriuretic peptide and serum hemoglobin levels as predictors for 1-year mortality.The prognosis after TLE was comparable between patients with and without SLVD. However, additional hemodynamic support was often necessary for patients with SLVD.

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.

Aims Liver dysfunction is important for prognosis in heart failure (HF). Shear wave elastography (SWE), which is a novel ultrasound technique for charactering tissues, has been used in liver diseases. However, clinical implication of SWE, including dispersion slope, remains unknown in heart diseases. This study aimed to evaluate the efficacy of SWE assessing liver function in the severity of HF. Methods and results We enrolled 316 consecutive patients with or suspected heart diseases, who were classified according to the American College of Cardiology Foundation/American Heart Association stage of HF, including 37 with Stage A, 139 with Stage B, 114 with Stage C, and 26 with Stage D, and 45 normal subjects. Elasticity and dispersion slope of shear wave were assessed according to the HF stage. Elasticity and dispersion slope were not elevated in normal subjects and patients with Stage A. Elasticity was slightly increased from Stage A to Stage C and was remarkably elevated in Stage D (normal: 5.2 ± 1.1 kPa, Stage A: 5.4 ± 1.2 kPa, Stage B: 6.4 ± 1.8 kPa, Stage C: 7.8 ± 3.5 kPa, and Stage D: 17.7 ± 12.7 kPa), whereas dispersion slope was gradually increased from Stage A to Stage D (normal: 9.7 ± 1.7m/s/kHz, Stage A: 10.4 ± 1.6m/s/kHz, Stage B: 11.7 ± 2.4m/s/kHz, Stage C: 13.2 ± 3.4m/s/kHz, and Stage D: 17.6 ± 5.6 m/s/kHz). In the early HF stage, dispersion slope was elevated. In the advanced HF stage, both elasticity and dispersion slope were elevated. Liver function test abnormalities were observed only from Stage C or Stage D. Conclusions Dispersion slope could detect early liver damage, and the combination of elasticity and dispersion slope could clarify the progression of liver dysfunction in HF. SWE may be valuable to manage therapeutic strategies in patients with HF.

Surgical restoration of subvalvular geometry is very important to prevent recurrence of ischemic/functional mitral regurgitation. We evaluated an approach to the radical repair of left ventricular (LV) remodeling for three different cases with responsible coronary lesions. Leaflet tethering was corrected by tugging of the papillary-ventricular complex, which consists of the base of papillary muscles and posterior LV wall. The main lesion of the postinfarction scar was concomitantly excluded. Restoration of LV remodeling diminished mitral regurgitation with minimal leaflet tethering and improved systolic LV function. This technique may be an aggressive and encouraged approach for patients with ischemic/functional mitral regurgitation.

The number of patients with adult congenital heart disease (ACHD) has been dramatically increasing and adults with congenital heart disease now outnumber children with congenital heart disease. However, patients with ACHD are still at increased risk of morbidity and mortality due to residua and sequelae. Although echocardiography is an indispensable imaging modality in the comprehensive assessment of ACHD, accurate echocardiographic assessment of ACHD is challenging especially for physicians or sonographers who are not familiar with ACHD because of its complex morphology, physiology, and hemodynamics. A recently developed fusion imaging technology can provide synchronized display of real-time echocardiographic images and multiplanar reconstruction images of computed tomography or magnetic resonance imaging corresponding to the image plane of real-time echocardiography. We have reported the clinical utility of this fusion imaging technology for the precise evaluation of complex ACHD. On the other hand, conventional echocardiographic technology also plays an important role in assessing unique ACHD pathophysiology. For example, restrictive right ventricular physiology is a common finding after tetralogy of Fallot or pulmonary stenosis repair and can be evaluated by conventional pulsed-wave Doppler. In this review, we discuss the clinical usefulness of modern and conventional echocardiographic technologies for the evaluation of ACHD by presenting a case series.

BACKGROUND In the Prospective Comparison of angiotensin receptor neprilysin inhibitor (ARNI) With ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) study, treatment with sacubitril/valsartan reduced the primary outcome of cardiovascular (CV) death and heart failure (HF) hospitalization compared with enalapril in patients with chronic HF and reduced ejection fraction (HFrEF). A prospective randomized trial was conducted to assess the efficacy and safety of sacubitril/valsartan in Japanese HFrEF patients.Methods and Results:In the Prospective comparison of ARNI with ACEi to determine the noveL beneficiaL trEatment vaLue in Japanese Heart Failure patients (PARALLEL-HF) study, 225 Japanese HFrEF patients (New York Heart Association [NYHA] class II-IV, left ventricular ejection fraction [LVEF] ≤35%) were randomized (1 : 1) to receive sacubitril/valsartan 200 mg bid or enalapril 10 mg bid. Over a median follow up of 33.9 months, no significant between-group difference was observed for the primary composite outcome of CV death and HF hospitalization (HR 1.09; 95% CI 0.65-1.82; P=0.6260). Early and sustained reductions in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline were observed with sacubitril/valsartan compared with enalapril (between-group difference: Week 2: 25.7%, P

It is important to determine the functional changes of organs that occur as a result of aging, the understanding of which may lead to the maintenance of a healthy life. Glucose metabolism in healthy bodies is one of the potential markers used to evaluate the changes of organ function. Thus, information about normal organ glucose metabolism may help to understand the functional changes of organs. [18F]-Fluoro-2-deoxy-2-d-glucose (18F-FDG), a glucose analog, has been used to measure glucose metabolism in various fields, such as basic medical research and drug discovery. However, glucose metabolism changes in aged animals have not yet been fully clarified. The aim of this study is to evaluate changes in glucose metabolism in organs and brain regions by measuring 18F-FDG accumulation and 18F-FDG autoradiography with insulin loading in aged and young wild-type mice. In the untreated groups, the levels of 18F-FDG accumulation in the blood, plasma, muscle, lungs, spleen, pancreas, testes, stomach, small intestine, kidneys, liver, brain, and brain regions, namely, the cortex, striatum, thalamus, and hippocampus, were all significantly higher in the aged mice. The treated group showed lower 18F-FDG accumulation levels in the pancreas and kidneys, as well as in the cortex, striatum, thalamus, and hippocampus in the aged mice than the untreated groups, whereas higher 18F-FDG accumulation levels were observed in those in the young mice. These results demonstrate that insulin loading decreases effect on 18F-FDG accumulation levels in some organs of the aged mice. Therefore, aging can increase insulin resistance and lead to systemic glucose metabolism dysfunction.

Aims Fibrosis‐4 index (FIB‐4 index), calculated by age, aspartate aminotransferase, alanine aminotransferase, and platelet count, is a simple marker to evaluate liver fibrosis and is associated with right‐sided heart failure. However, the clinical relevance of FIB‐4 in patients with heart failure with preserved ejection fraction (HFpEF) remains unclear. We investigated the prognostic implication of the FIB‐4 index regarding right ventricular dysfunction in patients with HFpEF. Methods and results This prospective study included 116 consecutive HFpEF patients (mean age 79 years, 43% male) hospitalized with acute decompensated heart failure. We evaluated the association of the FIB‐4 index with right ventricular function determined by tricuspid annular plane systolic excursion (TAPSE) and tricuspid lateral annular systolic velocity (S′) before discharge. Cox regression analysis was performed to evaluate the association between the FIB‐4 index and major adverse cardiovascular events (MACE) defined as the composite of cardiovascular death, readmission for heart failure, nonfatal myocardial infarction, and nonfatal stroke. FIB‐4 index before discharge was significantly lower than that at admission (2.62 [1.92–3.46] and 3.03 [2.05–4.67], median [interquartile range], P

Pulmonary vein (PV) isolation using balloon ablation was developed as a technique for patients with paroxysmal atrial fibrillation (PAF). While most studies examined cryoballoon ablation (CBA), there have also been many reports on hot balloon ablation (HBA). We aimed to evaluate the clinical characteristics and outcomes between HBA and CBA. In a total of 103 consecutive patients with PAF who underwent catheter ablation, 60 propensity score–matched (30 CBA and 30 HBA) patients were enrolled. The procedural differences and clinical outcomes between the two groups were analyzed. The requirement for additional touch-up ablation was more frequent in the left superior pulmonary vein (LSP) in the HBA group than in the CBA group. Pre-procedural computed tomography (CT) images showed that a thicker left pulmonary vein ridge and larger cross-sectional area of the LSPV were significantly associated with residual PV potentials after HBA. However, post-procedural CT images showed that PV stenosis (> 25%) was higher in the HBA group (33%) than in the CBA group (0%). PV stenosis after HBA was observed most frequently in the right superior PV (50%). The atrial fibrillation/atrial tachycardia–free survival rate during follow-up (365 ± 102 days) was similar between the two groups (CBA vs. HBA, 83% vs. 90%). Although both balloon modalities can relieve atrial arrhythmia after the procedure, careful attention is required during HBA procedures, especially for the right superior PV, to avoid PV stenosis.

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.

Oxidized high-density lipoprotein (oxHDL), unlike native HDL, is characterized by reduced cholesterol efflux capability and anti-inflammatory properties. The ratio of oxHDL to apolipoprotein A-I (oxHDL/apoAI) is a possible marker of dysfunctional HDL. The aim of this study was to evaluate the association between oxHDL/apoAI and coronary plaque characteristics that increase the likelihood of cardiovascular events as determined by coronary computed tomography (CT) angiography.A total of 297 patients (mean age; 67 years, men; 63%) who underwent coronary CT angiography for suspected stable coronary artery disease (CAD) were included. High-risk plaques (HRP) were defined by three characteristics: positive remodeling; low-density plaques; and spotty calcification. Significant stenosis was defined as a luminal narrowing of70%. Serum concentrations of oxHDL were measured using an enzyme-linked immunosorbent assay.Patients with higher oxHDL/ApoAI showed significantly greater prevalence of HRP (p = 0.03) and significant stenosis (p 0.01) compared with patients with low oxHDL/ ApoAI. The multivariate logistic analysis demonstrated that oxHDL/ApoAI significantly associated with the presence of HRP and significant coronary stenosis (p = 0.01 and 0.01). In the follow-up study including 243 patients for a median period of 1.8 years, univariate cox regression analysis showed that oxHDL/ApoAI, HRP and significant stenosis were significant predictors of cardiovascular events.A high oxHDL/apoAI was associated with the presence of HRP and significant stenosis determined by coronary CT angiography, which can lead to cardiovascular events in patients with suspected stable CAD.

A 52-year-old man with consciousness disorder following a 2-day history of general fatigue, diarrhea, vomiting and excessive thirst was admitted to our hospital. Severe hyperglycemia (1,739 mg/dL) with a slightly elevated HbA1c level (6.9%), ketonuria and low C-peptide level (0.07 ng/mL) confirmed the diagnosis of fulminant type 1 diabetes mellitus (FT1DM). Following sudden unexplained cardiogenic shock shortly after the initiation of insulin therapy with no evidence of myocardial ischemia assessed by coronary angiography, the patient was supported with percutaneous venoarterial extracorporeal membrane oxygenation. Electron microscopic analysis of the myocardium revealed massive lipid droplets without the infiltration of inflammatory cells. His left ventricular function began to recover during the following days and returned to a normal level on day 14. Currently, the impact of FT1DM on intramyocardial lipid deposition is poorly understood. However, this case suggests that even short-term exposure to high concentrations of glucose can be responsible for lipotoxicity followed by severe cardiac dysfunction.

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.

Graphical abstract, Highlights • Identification of high-risk PFO associated with stroke is important. • Low-angle PFO is reported to be one of the high-risk PFO morphologies. • Low-angle PFO can allow venous blood to flow directly from the IVC to the LA. • The case showed direct blood flow from the IVC to LA through the low-angle PFO.

A subgroup of right bundle branch block (RBBB) patients may exhibit a significant left ventricular (LV) activation delay. We evaluated echocardiography in a non-ischemic heart failure patient whose QRS morphology changed from left bundle branch block (LBBB) to atypical RBBB. The septum to posterior wall motion delay (SPWMD) measured using the M-mode was 196 ms while the patient presented with LBBB but decreased to 32 ms after the morphology changed to RBBB. These changes were also associated with delayed appearance of the septal displacement peak. Speckle tracking longitudinal strain was evaluated using three standard apical views after the morphology changed to RBBB. The LV contraction initially appeared in the basal inferior wall and there was delayed anterior wall contraction. The LV contraction pattern in our patient changed when the QRS morphology changed to atypical RBBB. A specific LV contraction sequence observed in atypical RBBB may reflect a significant LV activation delay between the inferior and anterior wall.

Background The incidence of ventricular tachycardia (VT) in patients following Fontan operation is reported as 3.5%. Furthermore, in patients with repaired double outlet right ventricle (DORV), scar-related VT and outflow tract VT have been reported; however, Purkinje-related VT has not previously been reported. In this report, we present the case of idiopathic left VT (ILVT) in a patient with DORV who underwent Fontan operation. Case summary A 31-year-old man was diagnosed as having DORV with complete atrioventricular defect at birth. When he was 17 years old, he underwent surgical repair, including extracardiac Fontan operation and common atrioventricular valve replacement. Five years later, VT was detected. Since some medications were ineffective in suppressing VT, he was referred to our hospital for definitive treatment. Ventricular tachycardia was induced by atrial and ventricular programmed electrical stimulations. The mechanism of the VT was determined to be re-entry. The earliest activation site was located at the mid-inferior septum of the hypoplastic left ventricle, in which Purkinje potentials were observed before the local ventricular electrogram. Radiofrequency catheter ablation (RFCA) was performed at this site to eliminate VT. Discussion Most VTs originate from surgical scars in patients with congenital heart disease. Catheter ablation was feasible in scar-related VT. To the best of our knowledge, this is the first report of ILVT treated successfully with RFCA in a DORV patient who had undergone Fontan operation.

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.

Objectives The absence of bleeding on probing (BOP) is a good predictor of disease stability. This study investigated whether detection of hemoglobin (Hb) in gingival crevicular fluid (GCF) indicates minute signs of periodontal disease, even in BOP (−) cases. Materials and methods GCF was collected from gingival sulci of 152 sound maxillary and mandibular teeth from 76 patients who had entered supportive periodontal therapy (SPT) using the split-mouth design. As clinical parameters, plaque index, GCF amount, gingival index, probing depth (PD), clinical attachment level, BOP, and alveolar bone resorption ratio were then recorded. As biochemical parameters, Hb amount, alkaline phosphatase (ALP) activity, and protein amount in GCF were measured. Periodontal conditions of diseased sites (PD ≥ 4 mm, BOP (+)) and healthy sites (PD ≤ 4 mm, BOP (−)) were further classified into two groups using the Hb cutoff value determined by PD and BOP and analyzed. Results Despite being healthy, ALP activity and protein amount in sulci of the group with Hb level greater than the cutoff value were significantly higher than those in the group with Hb level less than the cutoff value (P Conclusions This study indicates that Hb examination is a promising candidate marker of pre-symptomatic periodontal disease because Hb presence in GCF suggests slight tissue damage, even in healthy sites defined as BOP (−). Clinical relevance Hb examination of GCF is a powerful diagnostic tool for pre-symptomatic diagnosis of periodontal disease.

The score based on the office systolic blood pressure, age, fasting blood glucose level, and estimated glomerular filtration rate (SAGE score) has been proposed as a useful marker to identify elevated values of carotid-femoral pulse wave velocity (PWV). The present cross-sectional study was conducted to examine whether the SAGE score is also a useful marker to identify subjects with elevated brachial-ankle PWV values in Japanese subjects with hypertension. We measured the brachial-ankle PWV and calculated the SAGE score in a total of 1019 employees of a Japanese company with hypertension and 817 subjects with hypertension derived from a multicenter study cohort. The analyses in this study were based on data from these two study groups as well as on a composite population of the two (n = 1836). The receiver operating characteristic curve analysis showed that the area under the curve to identify subjects with brachial-ankle PWV values of ≥1800 cm/s was over 0.70 in each of the three study groups. Even after adjustments, a SAGE score ≥7 had a significant odds ratio for identifying subjects with brachial-ankle PWV values ≥1800 cm/s in the 1836 study subjects from the composite occupational and multicenter study cohort (odds ratio = 2.1, 95% confidence interval = 1.4–3.0, P

BACKGROUND Sarcopenia is characterized by progressive loss of skeletal muscle and has frequently been associated with poor clinical outcomes in patients with advanced heart failure (HF). The urinary creatinine excretion rate (CER) index is an easily measured marker of muscle mass, but its predictive capacity for mortality and cerebrovascular events has not been investigated in patients with a continuous-flow implantable left ventricular assist device (CF-iLVAD).Methods and Results:We retrospectively reviewed 147 patients (mean [±SD] age 43.7±12.5 years, 106 male) who underwent CF-iLVAD implantation between April 2011 and June 2019. CER indices in 24-h urine samples before CF-iLVAD implantation were determined. Over a median follow-up of 2.3 years, there were 10 (6.8%) deaths and 43 (29.3%) cerebrovascular events. Patients were divided into 2 groups (low and high CER index) according to the median CER index in men and women (i.e., 13.71 and 12.06 mg·kg-1·day-1, respectively). Mortality and intracranial hemorrhage rates after CF-iLVAD implantation were significantly higher in the low than high CER index group (mortality 12.3% vs. 1.4% [P

The coronary artery calcium data and reporting system (CAC-DRS) is a novel reporting system based on CAC severity. Lung cancer patients have a high risk of cardiovascular disease (CVD), for which CAC severity may provide additional prognostic information. Using non-gated, non-contrast computed tomography (CT), we evaluated the CAC-DRS for predicting CVD and all-cause death in patients with potentially curable resected lung cancer. We retrospectively studied 309 consecutive patients without a history of CVD (mean age 67.4 ± 8.2 years, 61% male) who underwent curative surgery for non-small-cell lung cancer between May 2012 and March 2019 at the Japanese Red Cross Okayama Hospital. Time to incidence of major adverse cardiac events (MACEs) (non-fatal myocardial infarction, non-fatal stroke and cardiovascular death) and all-cause death was analyzed using Fine and Gray and Cox regression models. The CAC-DRS score was assessed using standard chest CT without electrocardiogram gating. During 52-months’ median follow-up, 43 patients (13.4%) developed incident MACEs or died from any cause; the pathological cancer stages were Ia (n = 20), Ib (n = 8), IIa (n = 2), IIb (n = 2) and IIIa (n = 11). Patients had a graded increase in incidence of MACEs or all-cause death with increasing categories of CAC-DRS. The CAC-DRS score was significantly associated with incident MACEs or all-cause death after adjusting for confounding factors (hazard ratio 1.18; 95% confidence interval 1.10–1.25, p

Introduction Teneligliptin, a dipeptidyl peptidase 4 inhibitor, was approved for the treatment of type 2 diabetes mellitus (T2DM) in Japan in 2012. However, clinical trials of teneligliptin involved limited numbers of elderly patients. Therefore, we investigated the safety and efficacy of teneligliptin in elderly patients with T2DM. Methods This 3-year follow-up RUBY surveillance registered patients with T2DM who started treatment with teneligliptin between May 2013 and February 2015 in Japan. Collected data included demographics, treatments, adverse drug reactions (ADRs), and laboratory variables. Data were analysed for patients in three age subgroups (, Plain Language Summary Teneligliptin is an oral drug taken once daily to manage blood glucose levels in people with type 2 diabetes. A number of studies of teneligliptin have investigated its safety and efficacy, but these studies included limited numbers of elderly people, aged 75 years or older. Following the approval of teneligliptin in Japan, post-marketing surveillance was started to monitor its safety and efficacy when prescribed by doctors to people in actual clinical practice. We analysed data from the surveillance to check if the safety and efficacy of teneligliptin differ in younger and older people separately. We found that there was no clear difference in the number of adverse drug reactions among three age subgroups

Aims To establish the indication for programmed ventricular stimulation (PVS) for asymptomatic patients with Brugada syndrome (BrS), we evaluated the prognostic significance of PVS based on abnormal electrocardiogram (ECG) markers. Methods and results One hundred and twenty-five asymptomatic patients with BrS were included. We performed PVS at two sites of the right ventricle with up to three extrastimuli [two pacing cycle lengths and minimum coupling interval (MCI) of 180 ms]. We followed the patients for 133 months and evaluated ventricular fibrillation (VF) events. Fragmented QRS (fQRS) and Tpeak-Tend (Tpe) interval were evaluated as ECG markers for identifying high-risk patients. Fragmented QRS and long Tpe interval (≥100 ms) were observed in 66 and 37 patients, respectively. Ventricular fibrillation was induced by PVS in 60 patients. During follow-up, 10 patients experienced VF events. Fragmented QRS, long Tpe interval, and PVS-induced VF with an MCI of 180 ms or up to two extrastimuli were associated with future VF events (fQRS: P = 0.015, Tpe ≥ 100 ms: P = 0.038, VF induction: P < 0.001). However, PVS-induced VF with an MCI of 200 ms was less specific (P = 0.049). The frequencies of ventricular tachyarrhythmia events during follow-up were 0%/year with no ECG markers and 0.1%/year with no VF induction. The existence of two ECG factors with induced VF was strongly associated with future VF events (event rate: 4.4%/year, P < 0.001), and the existence of one ECG factor with induced VF was also associated (event rate: 1.3%/year, P = 0.011). Conclusion We propose PVS with a strict protocol for asymptomatic patients with fQRS and/or long Tpe interval to identify high-risk patients.

The usefulness of brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, is not fully known for the management of treated hypertensive patients with a history of coronary artery disease (CAD) who have blood pressure less than 130/80 mmHg, a recommended blood pressure target in the updated major hypertension guidelines. We analyzed data for 447 treated hypertensive patients with CAD enrolled in FMD-J Study A for assessment of the predictive value of baPWV for future cardiovascular events. The primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow-up period of 47.6 months, the primary outcome occurred in 64 patients. Blood pressure less than 130/80 mmHg was significantly associated with a lower risk of the composite outcome independent of other cardiovascular risk factors in treated hypertensive patients with CAD (hazard ratio, 0.59; 95% confidence interval (CI), 0.35-0.99; P = 0.04). In treated hypertensive patients with CAD who had blood pressure less than 130/80 mmHg, baPWV above the cutoff value of 1731 cm/s, derived from receiver-operator characteristic curve analysis for the composite outcome was significantly associated with a higher risk of the composite outcome independent of conventional risk factors (hazard ratio, 2.83; 95% CI, 1.02-7.91; P = 0.04). baPWV was an independent predictor of cardiovascular events in treated hypertensive patients with CAD who had blood pressure less than 130/80 mmHg, for whom measurement of baPWV is recommended for cardiovascular risk assessment.

Background Transition to pulmonary arterial hypertension (PAH)-specific drugs is considered in patients with PAH and chronic thromboembolic pulmonary hypertension who do not respond to combination therapy or who experience side effects to the combination drugs. Riociguat directly stimulates soluble guanylate cyclase independently of nitric oxide. Therefore, transition from a phosphodiesterase type 5 inhibitor (PDE5i), which requires nitric oxide to exert its effects, to riociguat might be effective. The length of time of washout periods for transition is important because haemodynamic instability sometimes occurs during these periods or during transition with no washout period. Method We investigated the feasibility of transitioning from a PDE5i to riociguat without washout periods by monitoring haemodynamics under right heart catheterisation in six patients with PAH and one with chronic thromboembolic pulmonary hypertension who had already received dual- or triple-combination therapy. Results Reasons for transition were headache caused by a PDE5i in three patients, and an inadequate response to combination therapy in four. Transition was successful in all patients, with no haemodynamic instability observed. Pulmonary vascular resistance (from 797 ± 241 to 518 ± 230 dyne/s/cm–5) and systemic blood pressure (from 121 ± 13 to 100 ± 15 mmHg) were significantly reduced immediately after transition. There were no significant differences in the tricuspid regurgitation pressure gradient or systemic blood pressure during the post-transition and follow-up periods. Headaches caused by a PDE5i were diminished after transition to riociguat. Conclusions Transition from a PDE5i to riociguat without a washout period is safe. This transition may be a viable option for patients with headaches caused by a PDE5i, or who have an inadequate response to combination therapy that includes a PDE5i.

Background Although transthoracic echocardiography (TTE) may be useful for patent foramen ovale (PFO) screening, the optimal methodologies remain unclear. The aims of this study were to evaluate the efficacy of the abdominal compression Valsalva maneuver and identify the optimal cutoff value of microbubbles in contrast TTE for detecting PFO, compared with transesophageal echocardiography and catheterization as the reference. Methods One hundred thirty-four patients with cryptogenic stroke or migraine who had suspected PFO and underwent TTE and transesophageal echocardiography plus catheterization were enrolled. The sensitivity, specificity, and accuracy of TTE for PFO detection were analyzed according to different provocations (spontaneous Valsalva maneuver, abdominal compression Valsalva maneuver) and different cutoff values of microbubbles for a positive result (at least one microbubble, at least five microbubbles). Results Eighty patients had PFO confirmed by transesophageal echocardiography and catheterization. When the cutoff was at least one microbubble, the sensitivity of TTE in detecting PFO was 93% with the spontaneous Valsalva maneuver and 99% with the abdominal compression Valsalva maneuver. When the cutoff was at least five microbubbles, sensitivity was 85% with the spontaneous Valsalva maneuver and 99% with the abdominal compression Valsalva maneuver. With the abdominal compression Valsalva maneuver, specificity was increased using the cutoff of at least five microbubbles compared with at least one microbubble (89% vs 57%). The abdominal compression Valsalva maneuver with the cutoff of at least 5 microbubbles provided the greatest accuracy of 95%. Conclusions TTE with the abdominal compression Valsalva maneuver had excellent sensitivity. The cutoff of at least five microbubbles increased specificity. Our findings suggest that TTE with these criteria is valuable for PFO diagnosis.

Chronic-active Epstein-Barr virus infection (CAEBV) is a rare disease that can lead to pulmonary arterial hypertension (PAH). However, the treatment for CAEBV-associated PAH has not been established. We discuss a case of improved pulmonary hypertension after chemotherapy in a patient with CAEBV-associated PAH. A 44-year old man was admitted to our hospital because of an abnormal electrocardiogram and liver dysfunction detected by annual medical examination. Echocardiography showed a dilated right ventricle and an estimated right ventricular systolic pressure of 92 mmHg. Right heart catheterization revealed a mean pulmonary arterial pressure of 45 mmHg and pulmonary vascular resistance of 9.8 Wood units. Laboratory examination showed granular lymphocytes and 91% natural killer cells in lymphocyte subsets in peripheral blood. We diagnosed the patient as having CAEBV-associated PAH. After two cycles of chemotherapy without PAH-specific drugs, echocardiography showed improvement in the dilated right ventricle and an estimated right ventricular systolic pressure of 59 mmHg. Right heart catheterization revealed a mean pulmonary arterial pressure of 27 mmHg and pulmonary vascular resistance of 2.4 Wood units. Chemotherapy may improve pulmonary hypertension in patients with CAEBV-associated PAH.

Background: Because transcatheter closure of patent foramen ovale (PFO) has become effective for preventing cryptogenic stroke (CS), it is necessary to determine high-risk PFO associated with CS. This study aimed to clarify the importance of direct right-to-left (RL) shunt through the PFO for identifying high-risk PFO. Methods: We analyzed 137 patients with and without CS who were confirmed to have PFO. The timing of RL shunt through the PFO was evaluated by cardiac cycles after right atrium (RA) opacification on saline contrast transesophageal echocardiography. Direct RL shunt was defined as microbubbles crossing the PFO before and at the same time of RA opacification. Results: Cardiac cycles of microbubbles crossing the PFO were shorter in patients with CS than in those without CS (2.0 ± 2.2 vs. 0.5 ± 1.1, P < .01). Direct RL shunt was more frequently observed in patients with CS than in those without CS (77% vs. 29%, P < .01), with a sensitivity of 79% and a specificity of 71% for the association with CS. Multivariate analysis revealed that direct RL shunt was related to atrial septal aneurysm and low-angle PFO. Regarding functional features of PFO, the detection rate of CS was 50% for large RL shunt alone, and was increased to 83% when direct RL shunt was added. Conclusion: Direct RL shunt was associated with CS and had the incremental value in detecting PFO associated with CS for large RL shunt. The timing of RL shunt can be valuable for identifying high-risk PFO.