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.

Non-Invasive Central Venous Pressure Measurement Using Enclosed-Zone Central Venous Pressure (ezCVPTM).

BACKGROUND: Central venous pressure (CVP) is measured to assess intravascular fluid status. Although the clinical gold standard for evaluating CVP is invasive measurement using catheterization, the use of catheterization is limited in a clinical setting because of its invasiveness. We developed novel non-invasive technique, enclosed-zone (ezCVPTM) measurement for estimating CVP. The purpose of this study was to assess the feasibility of ezCVP and the relationship between ezCVP and CVP measured by a catheter.Methods and Results:We conducted 291 measurements in 97 patients. Linear regression analysis revealed that ezCVP was significantly correlated with CVP (r=0.65, P<0.0001). The Bland-Altman analysis showed that ezCVP had an underestimation bias of -2.5 mmHg with 95% limits of agreement of -14.1 mmHg and 9.6 mmHg for CVP (P<0.0001). The areas under the curves of receiver operating curve with ezCVP to detect the CVP ≥12 cmH2O (8.8 mmHg) and CVP >10 mmHg were 0.81 or 0.88, respectively. The sensitivity, specificity and positive likelihood ratio of ezCVP for the CVP ≥8.8 mmHg and CVP >10 mmHg were 0.59, 0.96 and 14.8 with a cut-off value of 11.9 and 0.79, 0.97 and 26.3 with a cut-off value of 12.7. CONCLUSIONS: These findings suggest that ezCVP measurement is feasible and useful for assessing CVP.

Target of Triglycerides as Residual Risk for Cardiovascular Events in Patients With Coronary Artery Disease　- Post Hoc Analysis of the FMD-J Study A.

BACKGROUND: Circulating triglyceride (TG) levels are a current focus as a residual risk for cardiovascular (CV) events. We evaluated the relationship between circulating TG levels and future CV events in patients with coronary artery disease (CAD) who were treated with conventional therapy. Methods and Results: We analyzed data for 652 patients who were enrolled in the FMD-J Study A. We investigated the associations between serum TG levels and first major CV events (death from CV cause, nonfatal acute coronary syndrome (ACS), nonfatal stroke, and CAD) for a 3-year follow-up period. Patients were divided into 4 groups based on serum TG level: low-normal (<100 mg/dL), high-normal (100-149 mg/dL), borderline hypertriglyceridemia (150-199 mg/dL), and moderate hypertriglyceridemia (≥200 mg/dL). During a median follow-up period of 46.6 months, 14 patients died (9 from CV causes), 16 had nonfatal ACS, 6 had nonfatal stroke, and 54 had CAD. The Kaplan-Meier curves for first major CV event among the 4 groups were significantly different (P=0.04). After adjustment for various confounders, serum TG level ≥100 mg/dL were significantly associated with an increased risk of first major CV events compared with serum TG level <100 mg/dL. CONCLUSIONS: Serum TG level may be a surrogate marker for predicting CV events in patients with CAD.

Real-life experience of a stent-less revascularization strategy using a combination of excimer laser and drug-coated balloon for patients with acute coronary syndrome.

OBJECTIVES: We aimed to test a novel stent-less revascularization strategy using a combination of excimer laser coronary angioplasty (ELCA) and drug-coated balloon (DCB) for patients with acute coronary syndrome (ACS). BACKGROUND: Percutaneous coronary intervention with drug eluting stents is a standard invasive treatment for ACS. Some unsolved issues however remain, such as stent thrombosis and bleeding risks associated with dual antiplatelet therapy. METHODS: Consecutive ACS patients were planned to receive either a DCB application following ELCA without a stent implantation or conventional revascularization with a coronary stent. The endpoints were (i) major cardiac adverse events (MACEs), defined as the composite of cardiac death, myocardial infarctions, and target lesion revascularization; (ii) target vessel revascularization (TVR); and (iii) angiographic outcome. RESULTS: Since a greater than expected number of patients allocated to the stent-less treatment arm eventually received a bailout stenting, the following 3 as-treated groups were compared; DCB with ELCA group (N = 60), Stent with ELCA group (N = 23), and Stent without ELCA group (N = 85). During a mean follow-up period of 420 ± 137 days, and with angiographic 6- and 12-month-follow-up rates of 96.7%, 87%, and 81.2%, and 50%, 65.2%, and 45.9%, respectively, the MACE rate did not differ across the groups (10%, 4.3%, and 3.5%; P = 0.22) while an incidence of TVR was more common (15%, 0, and 4.7%; P = 0.02) and the diameter stenosis at 6-months of follow-up was greater (25.7 ± 18.2, 14.9 ± 13.1 and 16.2 ± 15.4%; P = 0.002) in the DCB with ELCA group. CONCLUSIONS: The stent-less revascularization strategy with DCB and ELCA was associated with a higher occurrence of restenosis in ACS patients.

Cardiac resynchronization therapy for patients with cardiac sarcoidosis.

Aims: Sarcoidosis with cardiac involvement is a rare pathological condition, and therefore cardiac resynchronization therapy (CRT) for patients with cardiac sarcoidosis is even further rare. We aimed to clarify the clinical features of patients with cardiac sarcoidosis who received CRT. Methods and results: We retrospectively reviewed the clinical data on CRT at three cardiovascular centres to detect cardiac sarcoidosis patients. We identified 18 (8.9%) patients with cardiac sarcoidosis who met the inclusion criteria out of 202 with systolic heart failure who received CRT based on the guidelines. The majority of the patients were female [15 (83.3%)] and underwent an upgrade from a pacemaker or implantable cardioverter defibrillator [13 (72.2%)]. We found 1 (5.6%) cardiovascular death during the follow-up period (mean ± SD, 4.7 ± 3.0 years). Seven (38.9%) patients had a composite outcome of cardiovascular death or hospitalization from worsening heart failure within 5 years after the CRT. Twelve (66.7%) patients had a history of sustained ventricular arrhythmias or those occurring after the CRT. Among the overall patients, no significant improvement was found in either the end-systolic volume or left ventricular ejection fraction (LVEF) 6 months after the CRT. A worsening LVEF was, however, more likely to be seen in 5 (27.8%) patients with ventricular arrhythmias after the CRT than in those without (P = 0.04). An improved clinical composite score was seen in 10 (55.6%) patients. Conclusions: Cardiac sarcoidosis patients receiving CRT may have poor LV reverse remodelling and a high incidence of ventricular arrhythmias.

Who is the operator, that is the question: a multicentre study of catheter ablation of atrial fibrillation.

AIMS: A worldwide survey reported that the success rate of atrial fibrillation (AF) ablation was higher in high-volume centers compared with low-volume centers. We tested whether the procedure volume of each operator was associated with the outcome of AF ablation in high-volume centres. METHODS AND RESULTS: We studied 471 patients with paroxysmal AF who underwent pulmonary vein (PV) isolation for the first time in three cardiovascular centers where the annual AF ablation volume was >100 procedures. We classified a total of 10 primary operators according to their operation volume on the basis of ACC/AHA/ACP CLINICAL COMPETENCE STATEMENT; high-volume operator (≥50 cases/year, N = 3) or low-volume operator (<50 cases/year, N = 7). The patients included were dichotomized according to the annual operation volume of their attending physician. The endpoints were the freedom from AF recurrence 1 year after the ablation, major complications including thromboembolisms, massive bleeding or death, and the procedural duration. RESULTS: A complete isolation of the four PVs was achieved in 99.1%. The freedom from AF recurrence was more common in patients treated by high-volume operators than those treated by low-volume operators (165/216 [76.4%] vs. 160/255 [62.8%]; P = 0.001). A high-volume operator was the only independent predictor of the freedom from AF recurrence (hazard ratio 1.73, 95% confidence interval 1.23-2.48; P = 0.002). The patients treated by high-volume operators were less likely to have major complications (1.4% vs. 7.8%; P = 0.001), and had a shorter procedural duration (139.9 ± 25.3 vs. 149.3 ± 27.1 min; P = 0.03). CONCLUSIONS: Operator proficiency may predict the outcome after AF ablation even in high-volume centres.

Role of galactolipid biosynthesis in coordinated development of photosynthetic complexes and thylakoid membranes during chloroplast biogenesis in Arabidopsis.

The galactolipids monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG) are the predominant lipids in thylakoid membranes and indispensable for photosynthesis. Among the three isoforms that catalyze MGDG synthesis in Arabidopsis thaliana, MGD1 is responsible for most galactolipid synthesis in chloroplasts, whereas MGD2 and MGD3 are required for DGDG accumulation during phosphate (Pi) starvation. A null mutant of Arabidopsis MGD1 (mgd1-2), which lacks both galactolipids and shows a severe defect in chloroplast biogenesis under nutrient-sufficient conditions, accumulated large amounts of DGDG, with a strong induction of MGD2/3 expression, during Pi starvation. In plastids of Pi-starved mgd1-2 leaves, biogenesis of thylakoid-like internal membranes, occasionally associated with invagination of the inner envelope, was observed, together with chlorophyll accumulation. Moreover, the mutant accumulated photosynthetic membrane proteins upon Pi starvation, indicating a compensation for MGD1 deficiency by Pi stress-induced galactolipid biosynthesis. However, photosynthetic activity in the mutant was still abolished, and light-harvesting/photosystem core complexes were improperly formed, suggesting a requirement for MGDG for proper assembly of these complexes. During Pi starvation, distribution of plastid nucleoids changed concomitantly with internal membrane biogenesis in the mgd1-2 mutant. Moreover, the reduced expression of nuclear- and plastid-encoded photosynthetic genes observed in the mgd1-2 mutant under Pi-sufficient conditions was restored after Pi starvation. In contrast, Pi starvation had no such positive effects in mutants lacking chlorophyll biosynthesis. These observations demonstrate that galactolipid biosynthesis and subsequent membrane biogenesis inside the plastid strongly influence nucleoid distribution and the expression of both plastid- and nuclear-encoded photosynthetic genes, independently of photosynthesis.

Photoelectron imaging of size-selected metal cluster anions in a quasi-continuous mode.

We present a novel high-repetition-rate photoelectron imaging (PEI) apparatus for exploring electronic structures of metal cluster anions. A continuous beam of mass-selected metal cluster anions, generated by a magnetron-sputtering cluster-ion source coupled with a quadrupole mass filter, is chopped into sub-megahertz ion bunches using a high-voltage pulser. The quasi-continuous anion beam is introduced into a PEI spectrometer, where the anions are photodetached using a 404 nm (3.07 eV) continuous-wave laser diode. As a demonstration, we acquire photoelectron images for size-selected Ag cluster anions, AgN - (N = 3, 7, 14), and show that each image can be obtained in a short accumulation time (50 s) with a kinetic energy resolution (ΔE/E) of 4% at E = 1.77 eV. The quasi-continuous PEI technique enables high-count-rate, space-charge-free acquisition of photoelectron spectra and angular distributions not only from size-selected metal cluster anions but also from anions prepared by other continuous ion sources, such as electrospray ionization.

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.

Association of Body Mass Index with Endothelial Function in Asian Men.

BACKGROUND: The association of body weight with cardiovascular events is still controversial. We evaluated the relationship between body mass index (BMI) and endothelial function. METHODS: We measured flow-mediated vasodilation (FMD) and BMI in 7682 men. All participants were divided into four groups by BMI: underweight (<18.5 kg/m2), normal weight (18.5 to 24.9 kg/m2), overweight (25.0 to 29.9 kg/m2), and obesity (≥30.0 kg/m2). RESULTS: Multiple logistic regression analysis revealed that overweight (OR: 1.30, 95% CI: 1.14-1.47; P < 0.001) and obesity (OR: 1.40, 95% CI: 1.09-1.80; P = 0.009) were associated with an increased risk of a low quartile of FMD. In 5571 younger adults (<60 years), overweight (OR: 1.34, 95% CI: 1.16-1.55; P < 0.001) and obesity (OR: 1.37, 95% CI: 1.04-1.81; P = 0.03) were associated with an increased risk of a low quartile of FMD, and underweight (OR: 0.56, 95% CI: 0.35-0.89; P = 0.01) was associated with a reduced risk of a low quartile of FMD. In 2111 older adults (≥60 years), underweight (OR: 2.16, 95% CI: 1.22-3.80; P = 0.008) was associated with an increased risk of a low quartile of FMD, and overweight and obesity were not associated with a risk of a low quartile of FMD. CONCLUSIONS: In Asian men, endothelial function was impaired in the overweight and obesity groups compared with that in the normal weight group. The risk for endothelial dysfunction was higher in obese younger adults than in obese older adults. The association of BMI with endothelial function may be different in young and elderly men. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.umin.ac.jp (University Hospital Medical Information Network Clinical Trials Registry) (UMIN000012952).

Inconvenient relationship of haemoglobin A1c level with endothelial function in type 2 diabetes in a cross-sectional study.

OBJECTIVE: The aim of this study was to determine the relationship of haemoglobin A1c (HbA1c) level with flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) in patients with type 2 diabetes. DESIGN: Cross-sectional study. SETTING: 22 university hospitals and affiliated clinics in Japan. PARTICIPANTS: 1215 patients with type 2 diabetes including 349 patients not taking antidiabetic drugs. MEASURES: We evaluated FMD and HbA1c level. All patients were divided into four groups based on HbA1c level: <6.5%, 6.5%-6.9%, 7.0%-7.9% and ≥8.0%. RESULTS: An inverted U-shaped pattern of association between HbA1c level and FMD was observed at the peak of HbA1c of about 7%. FMD was significantly smaller in the HbA1c <6.5% group than in the HbA1c 6.5%-6.9% group and HbA1c 7.0%-7.9% group (p<0.001 and p<0.001), and FMD values were similar in the HbA1c <6.5% group and HbA1c ≥8.0% group. There were no significant differences in NID values among the four groups. After adjustments for confounding factors, FMD was significantly smaller in the HbA1c <6.5% group than in the HbA1c 6.5%-6.9% and HbA1c 7.0%-7.9% group (p=0.002 and p=0.04). In patients not taking antidiabetic drugs, FMD was also significantly smaller in the HbA1c <6.5% group than in the HbA1c 6.5%-6.9% group and HbA1c 7.0%-7.9% group (p<0.001 and p=0.02), and there were no significant differences in NID values among the four groups. CONCLUSIONS: These findings suggest that there is an inverted U-shaped pattern of association between FMD and HbA1c and that a low HbA1c level of <6.5% is associated with endothelial dysfunction. TRIAL REGISTRATION NUMBER: UMIN000012950, UMIN000012951, UMIN000012952 and UMIN000003409.

Prolamellar bodies formed by cyanobacterial protochlorophyllide oxidoreductase in Arabidopsis.

In angiosperms, chlorophyll biosynthesis is light dependent. A key factor in this process is protochlorophyllide oxidoreductase (POR), which requires light to catalyze the reduction of protochlorophyllide to chlorophyllide. It is believed that this protein originated from an ancient cyanobacterial enzyme that was introduced into proto-plant cells during the primary symbiosis. Here we report that PORs from the cyanobacteria Gloeobacter violaceus PCC7421 and Synechocystis sp. PCC6803 function in plastids. First, we found that the G. violaceus POR shows a higher affinity to its substrate protochlorophyllide than the Synechocystis POR but a similar affinity to plant PORs. Secondly, the reduced size of prolamellar bodies caused by a knockdown mutation of one of the POR genes, PORA, in Arabidopsis could be complemented by heterologous expression of the cyanobacterial PORs. Photoactive protochlorophyllide in the etioplasts of the complementing lines, however, was retained at a low level as in the parent PORA knockdown mutant, indicating that the observed formation of prolamellar bodies was irrelevant to the assembly of photoactive protochlorophyllide. This work reveals a new view on the formation of prolamellar bodies and provides new clues about the function of POR in the etioplast-chloroplast transition.

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.

Hematocrit, hemoglobin and red blood cells are associated with vascular function and vascular structure in men.

High and low hematocrit (Hct) and hemoglobin (Hb) levels are associated with the risk of cardiovascular disease. The purpose of this study was to determine the relationships of Hct, Hb and red blood cells (RBCs) with vascular function and structure. We measured flow-mediated vasodilation (FMD), nitroglycerin-induced vasodilation (NID), brachial intima media thickness (IMT), and brachial-ankle pulse wave velocity (baPWV) in 807 men. The subjects were divided into six groups according to the levels of Hct, Hb and RBCs. NID was highest in the 46.0-48.9% Hct group among the six groups according to Hct levels. Brachial IMT was lowest in the 46.0-48.9% Hct group among the six groups. There were no significant differences in FMD and baPWV among the six groups. We used 46.0-48.9% Hct as a reference to define the lower tertile. The adjusted odds ratio of being in the low tertile of NID was significantly higher in the < 42.9% and ≥ 49.0% Hct groups. Adjusted odds ratio of being in the low tertile of brachial IMT was significantly lower in the < 39.9% Hct groups. Similar results were obtained for Hb and RBCs. Low and high levels of Hct, Hb and RBCs were associated with vascular smooth muscle dysfunction, and low Hct levels were associated with abnormal vascular structure. Increases in the levels of Hct, Hb and RBCs within normal ranges may have beneficial effects on the vasculature.

Relationship between cell number and clinical outcomes of autologous bone-marrow mononuclear cell implantation in critical limb ischemia.

Cell therapy using intramuscular injections of autologous bone-marrow mononuclear cells (BM-MNCs) improves clinical symptoms and can prevent limb amputation in atherosclerotic peripheral arterial disease (PAD) patients with critical limb ischemia (CLI). The purpose of this study was to evaluate the effects of the number of implanted BM-MNCs on clinical outcomes in atherosclerotic PAD patients with CLI who underwent cell therapy. This study was a retrospective observational study with median follow-up period of 13.5 years (range, 6.8-15.5 years) from BM-MNC implantation procedure. The mean number of implanted cells was 1.2 ± 0.7 × 109 per limb. There was no significant difference in number of BM-MNCs implanted between the no major amputation group and major amputation group (1.1 ± 0.7 × 109 vs. 1.5 ± 0.8 × 109 per limb, P = 0.138). There was also no significant difference in number of BM-MNCs implanted between the no death group and death group (1.5 ± 0.9 × 109 vs. 1.8 ± 0.8 × 109 per patient, P = 0.404). Differences in the number of BM-MNCs (mean number, 1.2 ± 0.7 × 109 per limb) for cell therapy did not alter the major amputation-free survival rate or mortality rate in atherosclerotic PAD patients with CLI. A large number of BM-MNCs will not improve limb salvage outcome or mortality.

Upstroke Time Is a Useful Vascular Marker for Detecting Patients With Coronary Artery Disease Among Subjects With Normal Ankle-Brachial Index.

Background Upstroke time is the transit time from the nadir to peak of the waveform of pulse volume recording. The purpose of this study was to determine whether upstroke time at the ankle is a useful vascular marker for detecting patients with advanced atherosclerosis in combination with ankle-brachial index (ABI). Methods and Results We measured upstroke time and ABI in 2313 subjects (mean age, 61.2±15.3 years). The prevalence of coronary artery disease (CAD) was significantly higher in patients with prolonged upstroke time (≥180 ms) than in subjects with normal upstroke time (<180 ms) (29.6% versus 11.8%; P<0.001), with a significant association between prolonged upstroke time and an increased risk of CAD (odds ratio [OR], 1.61; 95% CI, 1.07-2.44; P=0.02). In 1954 subjects with normal ABI (1.00 ≤ ABI ≤ 1.40), the prevalence of CAD was significantly higher in patients with prolonged upstroke time than in subjects with normal upstroke time (29.5% versus 10.6%; P<0.001), with a significant association between prolonged upstroke time and CAD (OR, 2.33; 95% CI, 1.41-3.87; P=0.001), whereas there was no significant association between upstroke time and CAD in subjects with low ABI (<1.00) (OR, 1.24; 95% CI, 0.72-2.16; P=0.44). Conclusions Upstroke time may be a useful vascular marker for detecting patients with CAD, especially in subjects with normal ABI who are usually considered not to have advanced atherosclerosis by ABI measurement alone. More attention should be paid to upstroke time for detecting patients with advanced atherosclerosis. Registration URL: https://www.umin.ac.jp; Unique identifier: UMIN000039512.

Vascular function is further impaired in subjects aged 80 years or older.

The percentage of people aged 80 years or older in Japan has been increasing. The purpose of this study was to investigate the association between vascular functions and aging in the elderly population and to clarify the characteristics of vascular functions in subjects aged 80 years or older. We measured flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID), and brachial-ankle pulse wave velocity (baPWV) in 737 subjects aged 60 years or older who visited the outpatient clinic at Hiroshima University Hospital. FMD and NID were significantly lower in subjects aged 80 years or older than in subjects aged 60-69 years or in subjects aged 70-79 years (1.9 ± 2.0% vs. 2.9 ± 2.6% and 2.7 ± 2.6%, P = 0.008 and P = 0.03, respectively and 8.6 ± 5.1% vs. 12.1 ± 5.6% and 11.2 ± 5.5%, P < 0.001 and P < 0.001, respectively). baPWV was significantly higher in subjects aged 80 years or older than in subjects aged 60-69 years or in subjects aged 70-79 years (1978 ± 452 cm/s vs. 1724 ± 319 cm/s and 1811 ± 318 cm/s, P < 0.001 and P < 0.001, respectively). Age over 80 years was significantly associated with lower FMD (OR, 2.02; 95% CI, 1.19-3.42; P = 0.01), lower NID (OR, 3.62; 95% CI, 2.13-6.17; P < 0.001), and higher baPWV (OR, 3.48; 95% CI, 1.99-6.08; P < 0.001) after adjustment for other cardiovascular risk factors. Vascular functions, including endothelial function, vascular smooth muscle function, and arterial stiffness, were shown to be further impaired in subjects aged 80 years or older, suggesting that vascular functions continue to be impaired throughout life with aging.

Relationship between high-density lipoprotein cholesterol levels and endothelial function in women: a cross-sectional study.

OBJECTIVES: The purpose of this study was to evaluate the relationship between high-density lipoprotein cholesterol (HDL-C) levels and endothelial function in women. DESIGN: Cross-sectional study. SETTING: 22 university hospitals and affiliated clinics in Japan. PARTICIPANTS: 1719 Japanese women aged 17-90 years who were not receiving lipid-lowering therapy. MEASURES: We evaluated flow-mediated vasodilation (FMD) and serum levels of HDL-C. All participants were divided into four groups by HDL-C level: low HDL-C (<40 mg/dL), moderate HDL-C (40-59 mg/dL), high HDL-C (60-79 md/dL) and extremely high HDL-C (≥80 mg/dL). RESULTS: Univariate regression analysis revealed a significant relationship between FMD and HDL-C (r=0.12, p<0.001). FMD values were significantly smaller in the low HDL-C group (5.2%±3.8%) and moderate HDL-C group (5.2%±3.8%) than in the extremely high HDL-C group (6.7%±3.4%) (p=0.024 and p=0.003, respectively), while there was no significant difference in FMD between the high HDL-C group and the extremely high HDL-C group. Multiple logistic regression analysis did not show a significant association between HDL-C levels and FMD. CONCLUSIONS: Endothelial function increased in relation to HDL-C levels. However, there was no association of HDL-C levels with endothelial function after adjustment of traditional cardiovascular risk factors in women. TRIAL REGISTRATION NUMBER: UMIN000012950; Results.

Diagnostic Criteria of Flow-Mediated Vasodilation for Normal Endothelial Function and Nitroglycerin-Induced Vasodilation for Normal Vascular Smooth Muscle Function of the Brachial Artery.

Background Diagnostic criteria of flow-mediated vasodilation (FMD), an index of endothelial function, and nitroglycerin-induced vasodilation (NID), an index of vascular smooth muscle function, of the brachial artery have not been established. The purpose of this study was to propose diagnostic criteria of FMD and NID for normal endothelial function and normal vascular smooth muscle function. Methods and Results We investigated the cutoff values of FMD and NID in subjects with (risk group) and those without cardiovascular risk factors or cardiovascular diseases (no-risk group) in 7277 Japanese subjects (mean age 51.4±10.8 years) from the Flow-Mediated Dilation Japan study and the Flow-Mediated Dilatation Japan Registry study for analysis of the cutoff value of FMD and in 1764 Japanese subjects (62.2±16.1 years) from the registry of Hiroshima University Hospital for analysis of the cutoff value of NID. Receiver-operator characteristic curve analysis of FMD to discriminate subjects in the no-risk group from patients in the risk group showed that the optimal cutoff value of FMD to diagnose subjects in the no-risk group was 7.1%. Receiver-operator characteristic curve analysis of NID to discriminate subjects in the no-risk group from patients in the risk group showed that the optimal cutoff value of NID to diagnose subjects in the no-risk group was 15.6%. Conclusions We propose that the cutoff value for normal endothelial function assessed by FMD of the brachial artery is 7.1% and that the cutoff value for normal vascular smooth muscle function assessed by NID of the brachial artery is 15.6% in Japanese subjects. Clinical Trial Registration www.umin.ac.jp Unique identifiers: UMIN000012950, UMIN000012951, UMIN000012952, and UMIN000003409.

Increased arterial stiffness and cardiovascular risk prediction in controlled hypertensive patients with coronary artery disease: post hoc analysis of FMD-J (Flow-mediated Dilation Japan) Study A.

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.