Association between Familial Hypercholesterolemia and Serum Levels of Cholesterol Synthesis and Absorption Markers: The CACHE Study FH Analysis.

AIM: Serum levels of cholesterol absorption and synthesis markers are known to be associated with cardiovascular risk. Familial hypercholesterolemia (FH) is a well-known inherited disorder presenting elevated low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels and premature coronary disease. In this study, we aim to examine the differences in terms of serum markers of cholesterol metabolism between FH and non-FH individuals and to examine their associations with serum lipid levels. METHODS: In this study, we utilized data on serum markers of cholesterol metabolism, namely, lathosterol (Latho, synthesis marker), campesterol (Campe, absorption marker), and sitosterol (Sito, absorption marker) measured by gas chromatography of the CACHE consortium, which comprised of 13 research groups in Japan. Clinical data were compiled using REDCap system. Among the 2944 individuals in the CACHE population, we selected individuals without lipid-lowering medications and hemodialysis patients for this CACHE study FH analysis. Multivariable adjustment was performed to assess the associations. RESULTS: In this study, we analyzed data from 51 FH patients and 1924 non-FH individuals. After adjustment for possible confounders, the FH group was shown to have significantly higher Campe and Sito concentrations and insignificantly higher Latho concentrations than the non-FH group. These marker concentrations showed nonlinear associations with TC in the FH group. Campe/Latho and Sito/Latho ratios were significantly higher in the FH group than in the non-FH group. CONCLUSION: FH group had significantly elevated serum Campe and Sito concentrations and insignificantly elevated Latho concentrations; thus, intestinal cholesterol absorption relative to hepatic cholesterol synthesis was suggested to be elevated in patients with FH. Serum Latho, Campe, and Sito concentrations showed nonlinear associations with TC in the FH group.

Comparison of Cryoballoon and Contact Force-Sensing Radiofrequency Ablation for Persistent Atrial Fibrillation in Clinical Practice.

BACKGROUND: Outcomes of cryoballoon ablation for persistent atrial fibrillation (AF) are unclear, especially in Japanese patients, so the effectiveness and safety of cryoballoon ablation in clinical practice were retrospectively compared with those of contact force-sensing radiofrequency (CFRF) ablation including the high-power protocol.Methods and Results:Consecutive patients with persistent AF were reviewed, and 253 and 265 patients who underwent cryoballoon and CFRF ablation, respectively, were enrolled. The primary endpoint was atrial arrhythmia recurrence. The secondary endpoints were periprocedural complications and repeat ablation. The rate of additional left atrial (LA) ablation after pulmonary vein isolation (PVI) was similar between groups (68.8% cryoballoon vs. 74.0% CFRF, P=0.19). Freedom from atrial arrhythmia recurrence was comparable between groups over a follow-up of 25.5±12.5 months (72.3% cryoballoon vs. 69.8% CFRF; adjusted hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.59-1.21, P=0.36). Outcomes were similar in the subgroups of PVI alone and PVI plus additional LA ablation. LA posterior wall isolation, absence of defragmentation, and low creatine clearance, but not catheter selection, were associated with the primary endpoint. Periprocedural complications (adjusted HR 0.73, 95% CI 0.34-1.54, P=0.41) and repeat ablation (adjusted HR 1.11, 95% CI 0.71-1.74, P=0.64) were similar for both procedures. CONCLUSIONS: Cryoballoon ablation for persistent AF in Japanese clinical practice had acceptable outcomes comparable to those of advanced CFRF ablation.

Radiation effects on atherosclerosis in atomic bomb survivors: a cross-sectional study using structural equation modeling.

Past reports indicated that total-body irradiation at low to moderate doses could be responsible for cardiovascular disease risks, but the mechanism remains unclear. The purpose of this study was to investigate the association between radiation exposure and atherosclerosis, an underlying pathology of cardiovascular diseases, in the Japanese atomic bomb survivors. We performed a cross-sectional study measuring 14 clinical-physiological atherosclerosis indicators during clinical exams from 2010 to 2014 in 3274 participants of the Adult Health Study cohort. Multivariable analyses were performed by using a structural equation model with latent factors representing underlying atherosclerotic pathologies: (1) arterial stiffness, (2) calcification, and (3) plaque　as measured with indicators chosen a priori on the basis of clinical-physiological knowledge. Radiation was linearly associated with calcification (standardized coefficient per Gy 0.15, 95 % confidence interval: CI [0.070, 0.23]) and plaque (0.11, 95 % CI [0.029, 0.20]), small associations that were comparable to about 2 years of aging per Gy of radiation exposure, but not with arterial stiffness (0.036, 95 % CI [- 0.025, 0.095]). The model fitted better and had narrower confidence intervals than separate ordinary regression models explaining individual indicators independently. The associations were less evident when the dose range was restricted to a maximum of 2 or 1 Gy. By combining individual clinical-physiological indicators that are correlated because of common, underlying atherosclerotic pathologies, we found a small, but significant association of radiation with atherosclerosis.

Smoking status and endothelial function in Japanese men.

It is established that smoking is a major risk factor of atherosclerosis. Endothelial dysfunction occurs in the initial step in the pathogenesis of atherosclerosis and plays a critical role in the development of atherosclerosis. The purpose of this study was to evaluate the association between smoking status and endothelial function in detail in men. We measured flow-mediated vasodilation (FMD) in 2209 Japanese men including 1181 men who had never smoked and 1028 current smokers. All of the participants were divided into five groups by smoking pack-years: never smoker group (= 0), light smoker group (> 0 to 10), moderate smoker group (> 10 to 20), heavy smoker group (> 20 to 30) and excessive smoker group (> 30). FMD significantly decreased in relation to pack-years (6.6 ± 3.4% in the never smoker group, 6.8 ± 3.0% in the light smoker group, 6.5 ± 2.9% in the moderate smoker group, 5.9 ± 2.9% in the heavy smoker group, and 4.9 ± 2.7% in the excessive smoker group; P < 0.001). After adjustment for age (≥ 65 years), body mass index, systolic blood pressure, low-density lipoprotein cholesterol, glucose, and year of recruitment, FMD was significantly smaller in the excessive smoker group than in the never smoker group as a reference group (OR 1.95, 95% CI 1.42 to 2.67; P < 0.001). These findings suggest that FMD decreases with an increase in the number of cigarettes smoked and that excessive smoking is associated with endothelial dysfunction. Cigarette smoking is harmful to vascular function in men who are heavy smokers.

Relationship between interleukin-1ß gene expression in epicardial adipose tissue and coronary atherosclerosis based on computed tomographic analysis.

BACKGROUND: Anti-inflammatory therapy targeting interleukin (IL)-1ß reduced cardiovascular events in a randomized trial. We evaluated the relationship between IL-1ß mRNA expression in epicardial adipose tissue (EAT) and clinically-assessed coronary atherosclerosis on computed tomography (CT). METHODS: We studied 45 patients before cardiac surgery (coronary artery bypass grafting [CABG], n â€‹= â€‹18; non-CABG, n â€‹= â€‹27). EAT volume, the coronary calcium score (CCS), and the presence of non- and/or partially-calcified coronary plaques (NCPs) and high-risk coronary plaques (HRPs; minimum CT density <30 Hounsfield units and vascular remodeling index >1.1) on CT angiography were assessed. EAT samples were obtained during cardiac surgery. IL-1ß mRNA expression in EAT was measured using quantitative real-time PCR and normalized to that of ß-actin in each patient. RESULTS: There was no difference in IL-1ß mRNA levels between patients who were scheduled for CABG and non-CABG surgery or among subgroups based on the CCS. However, patients with NCPs (median [interquartile range], 4.1[2.0-11.6]E-4 versus 1.8[0.6-4.5]E-4, p â€‹= â€‹0.024) and HRP (7.6[3.0-20.4]E-4 versus 1.9[0.7-4.3]E-4, p â€‹= â€‹0.0023) had higher IL-1ß mRNA levels than those without these plaques. On multivariate analysis adjusted for age, sex, coronary risk factors, statin therapy, CCS, and EAT volume, the presence of HRPs was significantly correlated with elevated IL-1ß mRNA levels in EAT (ߠ​= â€‹0.39, p â€‹= â€‹0.047). CONCLUSION: Our data suggest a contribution of EAT to coronary atherosclerosis through molecular behavior, such as IL-1ß gene expression, which may be a new therapeutic target.

Clinical implications of 18F-sodium fluoride uptake in subclinical aortic valve calcification: Its relation to coronary atherosclerosis and its predictive value.

BACKGROUND: Uptake of 18F-sodium fluoride (18F-NaF) on positron emission tomography (PET) reflects active calcification. Application of this technique in the early phase of aortic valve calcification (AVC) is of clinical interest. We investigated clinical implications of 18F-NaF uptake in subclinical AVC evaluated simultaneously with coronary atherosclerosis, and the utility of 18F-NaF uptake in predicting AVC progression. METHODS: We studied 25 patients with subclinical AVC and coronary plaques detected on computed tomography (CT) who underwent 18F-NaF PET/CT. AVC score, volume, mean density, and the presence of high-risk coronary plaque were evaluated on CT in each patient. Focal 18F-NaF uptake in AVC and in coronary plaques was quantified with the maximum tissue-to-background ratio (TBRmax). RESULTS: There were positive correlations between AVC TBRmax (A-TBRmax) and AVC parameters on CT. The 14 patients with high-risk coronary plaque had significantly higher A-TBRmax than those without such plaque (1.60 ± 0.18 vs 1.42 ± 0.13, respectively; P = 0.012). A-TBRmax positively correlated with maximum TBRmax of coronary plaque per patient (r = 0.55, P = 0.0043). In the 11 patients who underwent follow-up CT scan, A-TBRmax positively correlated with subsequent increase in AVC score (r = 0.74, P = 0.0091). CONCLUSION: Our 18F-NaF PET- and CT-based data indicate relationships between calcification activity in subclinical AVC and characteristics of coronary atherosclerosis. 18F-NaF PET may provide new information regarding molecular conditions and future progression of subclinical AVC.

A Comparison of Adrenalectomy and Eplerenone on Vascular Function in Patients with Aldosterone-producing Adenoma.

CONTEXT: It remains unclear whether adrenalectomy has more beneficial effects than treatment with a mineralocorticoid receptor antagonist on vascular function in patients with aldosterone-producing adenoma (APA). OBJECTIVE: The aim of this study was to compare the effects of adrenalectomy and treatment with eplerenone on vascular function in patients with APA. DESIGN, SETTING, AND PATIENTS: Flow-mediated vasodilation (FMD), as an index of endothelium-dependent vasodilation, and nitroglycerine-induced vasodilation (NID), as an index of endothelium-independent vasodilation, were measured to assess vascular function before and after a 3-month treatment with eplerenone and at 3 months after adrenalectomy in 23 patients with APA. RESULTS: Flow-mediated vasodilation and NID after adrenalectomy were significantly higher than those before treatment with eplerenone (5.4 ± 2.6% vs 2.7 ± 1.9% and 14.8 ± 4.7% vs 9.6 ± 4.6%, P < 0.01, respectively) and those after treatment with eplerenone (5.4 ± 2.6% vs 3.1 ± 2.3% and 14.8 ± 4.7% vs 11.0 ± 5.3%, P < 0.01 and P = 0.03, respectively), while treatment with eplerenone did not alter FMD and NID compared with those before treatment with eplerenone. After adrenalectomy, the increase in FMD and NID were significantly correlated with a decrease in plasma aldosterone concentration and a decrease in the aldosterone-renin ratio. There were no significant relationships between FMD and changes in other parameters or between NID and changes in other parameters. CONCLUSIONS: Adrenalectomy, but not treatment with eplerenone, improved vascular function in patients with APA. Adrenalectomy may be more effective than treatment with eplerenone for reducing the incidence of future cardiovascular events in patients with APA. Clinical Trial Information: URL for the clinical trial: http://UMIN; Registration Number for the clinical trial: UMIN000003409.

Effects of aging on coronary flow reserve in patients with no evidence of myocardial perfusion abnormality.

Coronary flow reserve (CFR) reflects the functional capacity of microcirculation to adapt to blood demand during increased cardiac work. We tested the hypothesis that aging had impacts on coronary flow velocities and CFR in patients with no evidence of myocardial perfusion abnormality on single photon emission computed tomography (SPECT). Seventy-six patients undergoing transthoracic Doppler echocardiography with no evidence of myocardial perfusion abnormality on SPECT were enrolled in this study. CFR was defined as the ratio of hyperemic to resting peak diastolic coronary flow velocity. Patients were divided into the three groups based on age: 17 patients aged less than 70 years (Group I), 38 patients aged 70-79 years (Group II), and 21 patients aged 80 years or more (Group III). Compared with Group I, CFR was significantly lower in Group II (p < 0.01) and Group III (p < 0.01). Multivariate linear regression analysis showed that female (ß = - 0.26, p = 0.03), cigarette smoking (ß = - 0.32, p = 0.004), hemoglobin level (ß = - 0.40, p = 0.001) and LV mass index (ß = 0.24, p = 0.03) were determinants for resting coronary flow velocity. On the other hand, age (ß = -0.30, p = 0.008), hemoglobin level (ß = -0.47, p < 0.001) and LV mass index (ß = 0.24, p = 0.04) were determinants for hyperemic coronary flow velocity. Age was only determinant for CFR (ß = -0.48, p < 0.001). Our data suggested that that aging had a decreased effect on hyperemic coronary flow velocity rather than resting coronary flow velocity, and was further associated with impaired CFR in patients with no evidence of myocardial perfusion abnormality.

Long-Term Clinical Outcomes of Autologous Bone Marrow Mononuclear Cell Implantation in Patients With Severe Thromboangiitis Obliterans.

BACKGROUND: Patients with severe Buerger disease, also known as thromboangiitis obliterans (TAO), are at risk of major limb amputation. It has been shown that autologous bone marrow mononuclear cell (BM-MNC) implantation improves the condition of critical limb ischemia in TAO patients. This study was conducted to further clarify the long-term (>10 years) results of autologous BM-MNC implantation in patients with TAO.Methods and Results:An observational study was conducted of the long-term results of BM-MNC implantation in 47 lower limbs of 27 patients with TAO. The mean (±SD) follow-up period was 12.0±8.6 years. There was no major amputation event up to 10 years of follow-up in patients treated with BM-MNC implantation. The overall amputation-free survival rates were significantly higher in patients who underwent BM-MNC implantation than in internal controls and historical controls. There was no significant difference in amputation-free survival rates between the historical and internal controls. There was also no significant difference in overall survival between patients who underwent BM-MNC implantation and the historical controls. CONCLUSIONS: BM-MNC transplantation successfully prevented major limb amputation over a period of >10 years in patients with severe TAO who had no other therapeutic options.

Successful catheter ablation of persistent atrial fibrillation is associated with improvement in functional tricuspid regurgitation and right heart reverse remodeling.

Atrial fibrillation (AF) is a common disease that changes cardiac morphology, especially in the left atrium (LA). It is now known that certain categories of functional mitral regurgitation (MR) are associated with AF; however, the influence of AF on right cardiac morphology is not fully understood. Our aim in this study was to investigate the association between AF and right cardiac morphology. This was a retrospective cohort study of 86 patients with persistent AF without other cardiac disease who underwent catheter ablation (CA). Seventy-one patients had sustained sinus rhythm (SR) (SR Group) and 15 patients had sustained AF (AF Group) during the study period. We compared the changes in the right cardiac dimensions and tricuspid regurgitation (TR) between the groups 12 months after CA. Patients' baseline echocardiographic assessments revealed that the LA volume index was significantly smaller in the SR group than in the AF group (46.8 ± 11.9 ml/m2 vs 59.3 ± 12.8 ml/m2, respectively; p < 0.01). Comparing baseline data with the 12-month follow-up data, in the SR group, right atrial area (RAA, cm2), tricuspid annular diameter (mm), and tricuspid regurgitant jet area (cm2) were significantly decreased compared with the AF group (19.5 ± 4.5-15.5 ± 3.6 vs 20.7 ± 3.6-19.7 ± 2.3; 30.5 ± 4.9-26.4 ± 3.9 vs 28.7 ± 4.0-28.8 ± 3.1; and 1.4 [interquartile range (IQR) 0.7-2.6]-0.6 [IQR 0.2-1.2] vs 1.2 [IQR 1.1-1.5]-0.9 [IQR 0.4-1.3], respectively). On multivariate analysis, change in RAA correlated with the reduction in tricuspid regurgitant jet area (R = 0.51, p < 0.001). In conclusion, successful CA for persistent AF led to right heart reverse remodeling, and our findings suggested that persistent AF was associated with RAA dilatation and TR.

Associations of left ventricular shape with left ventricular volumes and functions assessed by ECG-gated SPECT in patients without significant perfusion abnormality.

Left ventricular (LV) remodeling often results from conditions with an elevated LV hemodynamic load or after myocardial infarction. The present study was undertaken to investigate the associations of LV shape with LV volumes and functions in patients without significant perfusion abnormality. One hundred and sixty-seven patients without significant perfusion abnormality on ECG-gated SPECT were enrolled. LV ejection fraction (LVEF) was obtained for assessing LV systolic function. Peak filling rate (PFR) and one-third mean filling rate (1/3 MFR) were obtained for assessing LV diastolic function. LV shape index (LVSI) was defined as the ratio of the maximum three-dimensional short- and long-axis LV dimension, and varies from 0 (line) to 1 (sphere). There were 125 male and 42 female patients with a mean age of 70 ± 8 years. End-systolic LVSI was 0.49 ± 0.07 (0.34-0.65). End-systolic LVSI was associated with LV end-diastolic volume (r = 0.51, p < 0.001) and LV end-systolic volume (LVESV) (r = 0.64, p < 0.001), and was inversely associated with LVEF (r = - 0.69, p < 0.001), PFR (r = - 0.45, p < 0.001) and 1/3 MFR (r = - 0.26, p = 0.008). End-systolic LVSI was increased with increased LVESV, and was not any more with LVESV of > 40 ml. Multivariate liner regression analysis showed that age (ß = 0.16, p = 0.01), LVESV (ß = 0.20, p = 0.03) and LVEF (ß = - 0.53, p < 0.001) were significantly associated with end-systolic LVSI. Our data suggest that end-systolic LVSI, a measurement of LV shape, has close correlations with LV volumes and functions in patients without significant perfusion abnormality.

Effects of Myocardial Perfusion Defect on the Frontal QRS-T Angle in Anterior Versus Inferior Myocardial Infarction.

Objective The frontal QRS-T angle on a 12-lead electrocardiogram (ECG) has recently become accepted as a variable of ventricular repolarization. We compared the effects of myocardial perfusion defect (MPD) on the frontal QRS-T angle between anterior and inferior myocardial infarction (MI) using single-photon emission computed tomography. Methods The frontal QRS-T angle was defined as the absolute value of the difference between the frontal plane QRS axis and T-wave axis. A QRS-T angle more than 90° was considered abnormal. Patients Forty-two patients with anterior MI and 42 age- and sex-matched patients with inferior MI were enrolled. For controls, 42 age- and sex-matched patients with no MPD were selected. Results The mean frontal QRS-T angles in anterior MI, inferior MI and control subjects were 94.7±46.2°, 26.7±22.1° and 27.0±23.2°, respectively. Compared with controls, the frontal QRS-T angle was larger in anterior MI subjects (p<0.001), and similar in value to that in inferior MI subjects (p=0.69). An abnormal QRS-T angle was frequent in the anterior MI subjects than the inferior MI subjects (55% vs. 2%, p<0.001). In anterior MI subjects, MPD was significantly associated with the T-wave axis (ρ=0.46, p=0.002) and QRS-T angle (ρ=0.47, p=0.002), but was not with the QRS axis (ρ=0.07, p=0.66). In inferior MI subjects, there were no associations between MPD and the ECG variables. Conclusion Our data suggest that the frontal QRS-T angle in inferior MI subjects is not increased as evidently as that in anterior MI subjects.

Percutaneous Coronary Intervention for Interposed Coronary Graft Stenosis after Modified Bentall Procedure in a Teenaged Boy with Takayasu Arteritis.

Anastomotic occlusion of an interposed coronary artery graft after a Bentall procedure is rare and catastrophic. It can lead to myocardial infarction or sudden cardiac death. We found several reports of occlusion and stenosis of a coronary-graft anastomosis, but few describe occlusion of the interposed coronary graft itself, as evaluated with use of intracoronary ultrasonography and computed tomography. We report the case of a 17-year-old boy with Takayasu arteritis who had a myocardial infarction caused by severe ostial stenosis in an interposed left coronary graft. The graft occlusion was confirmed by results of electrocardiography, aortography, and intracoronary ultrasonography. The patient was treated with percutaneous coronary intervention, stenting of the interposed graft, and thrombectomy, but he died of left ventricular dysfunction caused by extensive myocardial infarction. Extrinsic compression may have caused the graft occlusion. When considering emergency percutaneous coronary intervention to interposed coronary artery grafts, operators need to identify the cause of occlusion and decide on the best approach for each patient. Stenting the graft may provide temporary relief. During a hemodynamic crisis, immediately reperfusing the graft is crucial.

Delivery balloon rupture during transcatheter heart valve alignment procedure in extreme descending aorta tortuosity.

A 79-year-old man with a history of partial resection of the lung and the bladder due to cancer, hypertension, dyslipidemia, and heart failure, underwent transcatheter aortic valve replacement with a SAPIEN 3 (S3) valve (Edwards Lifesciences, Irvine, CA, USA). Preprocedural examination showed a bicuspid aortic valve and severe calcification of the leaflets. Computed tomography showed great tortuosity of the descending aorta. A 29-mm S3 valve prosthesis was advanced into the aorta, but a high degree of resistance was encountered in the middle of the descending aorta. The prosthesis was advanced to the level of aortic valve and an attempt was made to deploy the valve. However, the valve balloon did not expand. A balloon rupture was suspected. The balloon catheter was pulled back into the eSheath (Edwards Lifesciences), and the catheter and eSheath were removed together. Rupture of the balloon was confirmed. A new eSheath and prosthesis were prepared, with delivery supported with a Lunderquist guidewire (Cook Medical, Bloomington, IN, USA). The valve alignment procedure was performed in a straighter portion of the descending aorta. The new 29-mm S3 valve was then successfully implanted. .

Elevated Plasma Renin Activity Caused by Accelerated-malignant Hypertension in a Patient with Aldosterone-producing Adenoma Complicated with Renal Insufficiency.

During the malignant phase of hypertension in patients with primary aldosteronism complicated with severe renal failure, the plasma renin activity may markedly increase with a false negative screening result for primary aldosteronism, thus potentially leading to a missed diagnosis of primary aldosteronism. We herein report the case of 37-year-old man who presented with accelerated-malignant hypertension complicated with severe renal insufficiency. The plasma renin activity was markedly increased in the malignant phase of hypertension, which were atypical results for primary aldosteronism. However, a plain abdominal computed tomography scan revealed a left adrenal nodule, which was diagnosed as aldosterone-producing adenoma by adrenal venous sampling.

Review of the Long-term Effects of Autologous Bone-Marrow Mononuclear Cell Implantation on Clinical Outcomes in Patients with Critical Limb Ischemia.

Critical limb ischemia (CLI) is associated with a high risk of limb amputation. It has been shown that cell therapy is safe and has beneficial effects on ischemic clinical symptoms in patients with CLI. The aim of this study was to further investigate the outcomes of intramuscular injection of autologous bone-marrow mononuclear cells (BM-MNCs) in a long-term follow-up period in atherosclerotic peripheral arterial disease (PAD) patients who have no optional therapy. This study was a retrospective and observational study that was carried out to evaluate long-term clinical outcomes in 42 lower limbs of 30 patients with atherosclerotic PAD who underwent BM-MNC implantation. The median follow-up period was 9.25 (range, 6-16) years. The overall amputation-free rates were 73.0% at 5 years after BM-MNC implantation and 70.4% at 10 years in patients with atherosclerotic PAD. The overall amputation-free rates at 5 years and at 10 years after implantation of BM-MNCs were significantly higher in atherosclerotic PAD patients than in internal controls and historical controls. There were no significant differences in amputation rates between the internal control group and historical control group. The rate of overall survival was not significantly different between the BM-MNC implantation group and the historical control group. Implantation of autologous BM-MNCs is feasible for a long-term follow-up period in patients with CLI who have no optional therapy.