Antihypertensive efficacy and safety of the angiotensin receptor blocker azilsartan in elderly patients with hypertension.

OBJECTIVES: The number of elderly patients with hypertension has been steadily increasing. However, there are limited data on the safety and efficacy of the new angiotensin type 1 receptor blocker (ARB) azilsartan in elderly patients with hypertension. We investigated the clinical efficacy and safety of azilsartan in this population. METHODS: The study population comprised 56 ambulatory patients with essential hypertension. We evaluated the reduction in blood pressure and safety after 12 weeks of treatment with azilsartan in 29 hypertensive patients ≥65 years of age (aged group) in comparison with the findings in 27 patients <65 years of age (non-aged group). RESULTS: Systolic blood pressure in the aged group declined significantly from 155 ± 18 mmHg at baseline to 138 ± 11 mmHg after 12 weeks of treatment with azilsartan, and that in the non-aged group also declined significantly from 152 ± 20 mmHg at baseline to 142 ± 13 mmHg after 12 weeks of treatment with azilsartan. There were no significant differences in the magnitude of change in blood pressures from pre-treatment to post-treatment with azilsartan between the non-aged and aged groups. There were no changes in clinical laboratory findings, including serum levels of creatinine, potassium, lipids, and other metabolic variables, after 12 weeks of treatment with azilsartan in both groups. CONCLUSIONS: Our findings suggest that azilsartan is effective in lowering blood pressure in elderly patients and may be safe. Therefore, azilsartan could be a valuable option for treating hypertension in elderly and non-elderly patients.

Impact of circulating cathepsin K on the coronary calcification and the clinical outcome in chronic kidney disease patients.

Chronic kidney disease (CKD) is a cause of coronary artery calcification (CAC) and an independent predictor of major adverse cardiac and cerebrovascular events (MACCE). Cathepsin K (CatK) is a lysosomal cysteine protease which affects vascular calcification and glucose metabolism disorder. We investigated the relationships among CatK, CAC, diabetes mellitus (DM) and MACCE in CKD patients. 113 consecutive CKD patients were enrolled. Their CAC was evaluated by computed tomography. Their plasma CatK level was measured by ELISA. They were divided into two groups by CatK levels and followed up for up to 3 years. The impact of CatK was analyzed in all participants, diabetic patients and non-diabetic patients. Kaplan-Meier analysis demonstrated a significant higher incidence of MACCE in the high CatK group (P = 0.028). The CatK level was significantly higher in patients with MACCE compared to that in patients without MACCE (P = 0.034). Cox's model revealed the higher plasma CatK and BNP level as independent predictors of MACCE (P = 0.043 and P < 0.01, respectively). Only in non-diabetic patients, there was a significant correlation between CatK and CAC score, and high CatK group had a significant higher level of LDL-C and LDL-C/HDL-C ratio (P < 0.05 and P < 0.001, respectively) than low CatK group. And these lipid disorders were independent predictors of CatK elevation. In CKD patients, our results indicated an impact of higher CatK level on their MACCE. The significant association among the CatK level, CAC and MACCE was found in non-diabetic CKD patients.

Prescription patterns of oral anticoagulants for patients with non-valvular atrial fibrillation: experience at a Japanese single institution.

New oral anticoagulants (NOACs) are now clinically available. However, few studies have demonstrated which patients with non-valvular atrial fibrillation (NVAF) actually receive NOACs in a clinical setting. We analyzed 182 NVAF patients who received oral anticoagulants. Clinical backgrounds and the risk of stroke, systemic embolism, and bleeding associated with oral anticoagulants were investigated. Seventy-three (40 %) patients were treated with NOACs and 109 (60 %) patients were treated with warfarin. A significantly lower mean number of bleeding risk factors was observed among the patients treated with NOACs than among those treated with warfarin (P = 0.010). Of the bleeding risk factors, NOACs were significantly less frequently prescribed in patients with a bleeding history and elderly subjects (>65 years) than in those who received warfarin (P < 0.001 and P = 0.029). A multivariate logistic regression analysis revealed that CHF and bleeding history were independently and significantly associated with the administration of NOACs (P = 0.047 and P = 0.003). The rate of a history of intracranial hemorrhage was comparable between the patients treated with NOACs and those treated with warfarin (P = 1.000). Significantly lower rates of a history of gastrointestinal and other minor bleeding were observed in the patients who received NOACs versus those who received warfarin (P = 0.001 and P = 0.026). NOACs were less frequently prescribed in patients with a history of bleeding, especially those with a history of gastrointestinal bleeding in a clinical setting.

Clinical Characteristics and Long-Term Outcomes of Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) has various morphological and clinical features. A decade has passed since the previous survey of the epidemiological and clinical characteristics of Japanese HCM patients. The Aichi Hypertrophic Cardiomyopathy (AHC) Registry is based on a prospective multicenter observational study of HCM patients. The clinical characteristics of 42 ambulant HCM patients followed up for up to 5 years were investigated. The primary endpoint was major adverse cardiac events (MACE), defined as death, non-fatal stroke, admission due to congestive heart failure (CHF), or episodes of sustained ventricular tachycardia/fibrillation. The MACE-free survival during the 5-year follow-up period was 76% according to Kaplan-Meier analysis. HCM-related death occurred in 3 (7%) patients and SCD occurred in 2 (5%) patients. Additionally, 3 (7%) patients were admitted to the hospital due to CHF. Meanwhile, sustained VT was detected in one (2%) of the patients who received ICD implantation and subsequently terminated with antitachycardia pacing using an ICD. The patients with HCM exhibiting left ventricular outflow obstruction (HOCM) had a slightly lower MACE-free survival rate than those with neither HOCM nor dilated-HCM (dHCM) (71% versus 81%, log-rank P = 0.581). Furthermore, the patients with dHCM demonstrated a significantly lower MACE-free survival rate than those with neither HOCM nor dHCM (33% versus 81%, log-rank P = 0.029). In the AHC Registry targeting current Japanese HCM patients, we demonstrated that many HCM patients continue to suffer from MACE despite the development of various treatments for HCM.

Takotsubo cardiomyopathy with involvement of delayed-onset rhabdomyolysis and acute kidney injury after rosuvastatin treatment.

Takotsubo cardiomyopathy is a disorder characterized by left ventricular apical ballooning with preceding emotional and/or physical stressors. This condition is also an important differential diagnosis of acute coronary syndrome. We herein describe a case of Takotsubo cardiomyopathy, a significant clinical phenomenon, triggered by delayed-onset rhabdomyolysis following the administration of long-term statin treatment, without any preceding stressors or changes in the patient's medical condition, in association with complaints of non-specific muscle-related symptoms. Although an electrocardiogram showed remarkable ST-segment elevation, a careful reading of the electrocardiogram findings revealed the features of Takotsubo cardiomyopathy. Withdrawing the statin therapy improved the patient's cardiac function.

Impact of cigarette smoking on coronary plaque composition.

OBJECTIVES: Cigarette smoking is associated with atherosclerosis and is an important risk factor for cardiovascular disease. We evaluated the impact of cigarette smoking on coronary plaque composition using integrated backscatter intravascular ultrasound (IB-IVUS). METHODS: A total of 143 consecutive patients undergoing percutaneous coronary intervention were enrolled. A history of illness, as well as smoking habits, was obtained by interview. Participants were asked to report whether they were current smokers, had quit smoking, or had never smoked. According to interview results, patients were divided into the following three groups: current, former, and never smokers. Conventional and IB-IVUS tissue characterization analyses were carried out. Three-dimensional analyses were carried out to determine plaque volume and the volume of each plaque component (lipid, fibrous, and calcified). RESULTS: IB-IVUS analysis indicated that the patients in the current smoker group had significantly increased percent lipid volume and significantly decreased percent fibrous volume (P=0.01 and 0.03). Logistic regression analysis showed that the current smoking state (odds ratio 3.51, 95% confidence interval 1.02-12.10, P=0.04) was independently associated with the presence of lipid-rich plaques, which was defined as the upper 75th percentile of the study population. CONCLUSION: Smoking is independently associated with lipid-rich plaques, contributing to the increasing risk for plaque vulnerability.

Effects of polyunsaturated fatty acids on periprocedural myocardial infarction after elective percutaneous coronary intervention.

AIMS: The aim of this study was to address the association of lipid profiles with periprocedural myocardial infarction (pMI) after elective percutaneous coronary intervention (PCI). METHODS AND RESULTS: Of the 302 consecutive patients who received elective PCI at the Chubu Rosai Hospital, Nagoya, Japan between June 2009 and December 2010, data from 231 native coronary lesions were analysed. Various biomarkers including serum troponin T (TnT), eicosapentaenoic acid (EPA), arachidonic acid (AA), and low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol were measured at baseline and at 18 hrs after PCI. pMI was defined as a post-procedural increase of TnT >3 times above the upper normal limit. Patients with pMI had significantly lower EPA/AA (0.25 [0.19-0.28] vs. 0.45 [0.21-0.62], p<0.001) and higher LDL/HDL cholesterol (3.00±1.05 vs. 2.36±0.90, p=0.008) than patients without pMI. On multivariate logistic analysis, EPA/AA per 0.1 increase (hazard ratio [HR] 0.62, 95% CI: 0.43-0.88, p=0.007), LDL/HDL (HR 1.92, 95% CI: 1.15-3.19, p=0.012), stented length (HR 1.40, 95% CI: 1.07-1.83, p=0.015), and the presence of unstable angina pectoris (UAP) (HR 8.89, 95% CI: 2.83-27.9, p<0.001) were significantly and independently associated with the incidence of pMI. CONCLUSIONS: EPA/AA and LDL/HDL were significantly associated with pMI after PCI, creating the possibility of a new therapeutic target of pMI.

Plasma indoxyl sulfate and estimated glomerular filtration rate.

BACKGROUND: Indoxyl sulfate (IS), a uremic toxin, has cardiovascular as well as uremic toxicity. We evaluated the prognostic value of blood IS level for long-term outcome. METHODS AND RESULTS: This study followed 311 patients with coronary artery disease. Plasma IS level and estimated glomerular filtration rate (eGFR) were determined. The endpoint was a major adverse cardiac event (MACE). Median follow-up was 759 days. IS was significantly higher in patients with MACE than in those without (P<0.001). Patients were divided according to quartiles (Q) of plasma IS level (Q1, Q2, Q3, and Q4). On Kaplan-Meier analysis a significantly lower MACE-free rate was obtained for Q4 compared with the other quartiles (P<0.001). In patients with eGFR ≥90, 89-60, 59-30, 29-15, and <15 ml·min(-1)·1.73 m(-2), the percentage of patients in Q4 was 0%, 13%, 29%, 100%, and 100%, respectively. In patients with eGFR 89-60 ml·min(-1)·1.73 m(-2), there was no significant difference in MACE-free rate between Q4 and the other quartiles; in patients with eGFR 59-30 ml·min(-1)·1.73 m(-2), a significantly lower MACE-free rate was obtained for Q4 compared with the other quartiles (P=0.832 and P=0.015, respectively). CONCLUSIONS: Plasma IS level is a significant predictor of MACE, especially in patients with eGFR 59-30 ml·min(-1)·1.73 m(-2).

Recovery of flow-mediated vasodilatation after repetitive measurements is involved in early vascular impairment: comparison with indices of vascular tone.

In repetitive measurements of flow-mediated dilatation (FMD), the duration of the interval between measurements remains controversial. In this pilot study, we conducted three sequential measurements of low-flow-mediated constriction (L-FMC), FMD and flow-mediated total dilation (FMTD; L-FMC+ FMD) at baseline and intervals of 15 and 60 min in 30 healthy males. FMD15, L-FMC15, and FMTD15 were significantly lower than the respective first measurements, but all indices showed full recovery at 60 min in all subjects. The baseline diameter was slightly increased at 15 min and restored at 60 min, but the maximum diameter, and the baseline and reactive flow velocity unchanged. We examined the relationship between recovery rate of FMTD at 15 min (FMTD-R) and cardio-ankle vascular index (CAVI). Univariate analysis showed moderate correlation between FMTD-R, and CAVI and L-FMC0. Patients were divided according to FMTD-R value; the low-FMTD-R group [below the median value (-26.2%)] included a significantly higher proportion of smokers and higher CAVI values than the high-FMTD-R group. The reproducibility of FMTD and FMTD-R was evaluated in another group of 25 healthy subjects. The range of variation across measurements was 1.1% for FMTD and 4.6% for FMTD-R; with intraclass correlation coefficients of 0.93 and 0.95, respectively. The present study demonstrated blunted recovery of FMD within 15 min, suggesting the need for selection of a more adequate interval between measurements to avoid underestimation of FMD in subsequent measurements. The findings demonstrated the reproducibility of FMTD-R and FMTD measurements, and that FMTD-R might be involved in arterial stiffness and early vascular impairment in the healthy subjects.

Relation of omega-3 fatty acid and C-reactive protein to peripheral artery disease in patients with coronary artery disease.

Eicosapentaenoic acid (EPA), a member of the omega-3 polyunsaturated fatty acid family, prevents cardiovascular disease. C-reactive protein (CRP) is a marker of inflammation, which promotes atherosclerosis. The aim of this study was to investigate the relationship among EPA, CRP, and the prevalence of peripheral artery disease (PAD), which is a manifestation of systemic atherosclerosis. A cross-sectional study was performed on 238 patients with coronary artery disease (CAD). Blood EPA and CRP levels and ankle-brachial pressure indices were measured. Cut-off values for plasma EPA levels and serum CRP levels were determined using receiver operating characteristic (ROC) analysis. Patients with ABIs ≤0.9 were defined as having PAD. EPA levels were significantly lower and CRP levels were significantly higher in patients with PAD than in those without [48 (26-77) vs. 58 (41-83) µg/ml, p = 0.026 and 3.3 (0.64-14.0) vs. 0.70 (0.32, 2.4) mg/l, p = 0.004]. Multivariate analysis for PAD revealed that high CRP levels and low EPA levels were significant and independent predictors of PAD [odds ratio 3.1 (95 % CI 1.4-6.9), p = 0.006 and odds ratio 4.9 (95 % CI 1.5-9.7), p = 0.004]. Furthermore, to predict PAD, adding high CRP levels and low EPA levels to the established risk factors significantly improved the area under the ROC curves, from 0.66 to 0.78, of the PAD prediction model (p = 0.004). A significant relationship among EPA, CRP, and PAD was confirmed in patients with CAD.

Prognostic impact of lipid contents on the target lesion in patients with drug eluting stent implantation.

We sought to determine the morphologic predictors of major adverse cardiac events (MACEs) after successful percutaneous coronary intervention (PCI) with drug-eluting stents (DES), using integrated backscatter intravascular ultrasound (IB-IVUS). Conventional IVUS and IB-IVUS were performed in 260 consecutive patients who underwent PCI with DES. Three-dimensional analyses were performed to determine plaque volume and the volume of each plaque component (lipid, fibrous, and calcification). Patients were divided into two groups according to the median lipid volume (LV) in the target lesion. MACEs were defined as death, nonfatal myocardial infarction, and any repeat revascularization. The median follow-up interval was 1285 days. MACEs were observed in 64 patients (24.6 %). Patients having a larger LV compared with their counterparts had worse long-term clinical outcomes regarding mortality (3.8 vs. 0 %, P = 0.02) and MACEs (31.5 vs. 17.7 %, P = 0.008) by log-rank test. After adjustment for confounders, large LV (odds ratio 1.95, 95 % confidence interval 1.14-3.33, P = 0.02) was significantly and independently associated with MACEs. The assessment of coronary plaque characteristics in the target lesion may be useful to predict long-term outcome following successful coronary intervention.

Diabetes with preserved renal function is an independent risk factor for renal function deterioration after coronary computed tomography angiography.

OBJECTIVES: Diabetes mellitus (DM) and high fasting glucose levels are reportedly risk factors for contrast-induced nephropathy after invasive coronary angiography in patients with renal dysfunction. Cystatin C (CyC) is a sensitive marker for detecting early impairment of renal function. Using CyC, we investigated whether DM would be a risk for worsening renal function after coronary computed tomography angiography (CCTA) in patients with preserved renal function. METHODS: Two hundred twenty-eight patients scheduled for CCTA were enrolled. The serum CyC at preprocedure and 1 day after procedure, urinary microalbumin at preprocedure, and oral fluid volume for 24 hours after procedure were measured. The percentage changes in CyC from preprocedure to 1 day after procedure (%CyC) were also calculated. RESULTS: Ninety-eight patients had DM. The %CyC and urinary microalbumin were significantly greater in DM patients than in non-DM patients. The percentage of patients showing a %CyC of 10% or greater was significantly greater in DM patients than in non-DM patients (27% vs 8%, P < 0.01). Using multivariate regression analysis, oral fluid volume and urinary microalbumin were independent predictors for a %CyC of 10% or greater in DM patients (ß = - 0.428 [P < 0.0001] and ß = 0.464 [P < 0.0001], respectively). CONCLUSIONS: Diabetes mellitus is a risk factor for worsening changes in renal function after CCTA, even in patients with preserved renal function. In particular, elevated microalbuminuria and low oral fluid intake are high-risk factors for renal functional deterioration.

Renal dysfunction and atherosclerosis of the neointima following bare metal stent implantation.

BACKGROUND: Recently, neoatherosclerosis within the neointima after bare metal stent (BMS) implantation, which could cause late restenosis and very late stent thrombosis, has been a cause of concern. Renal dysfunction has been related to late cardiovascular events after coronary intervention. The present study was conducted focusing on the relationship between renal dysfunction and neointimal tissue characteristics with BMS restenosis using integrated backscatter intravascular ultrasound (IB-IVUS). METHODS: We prospectively performed IB-IVUS in 80 consecutive patients requiring target lesion revascularization after BMS implantation; the patients were divided into two groups according to the estimated glomerular filtration [eGFR: ≥60 (n = 49) and <60 ml/min/1.73 m(2) (n = 31)]. RESULTS: Patients with eGFR <60 ml/min/1.73 m(2) had a significantly higher percentage of lipid tissue volume within the neointima and a lower percentage of fibrous tissue volume than those with eGFR ≥60 ml/min/1.73 m(2) (23.2 ± 9.4 vs. 18.0 ± 7.0%, p = 0.005, and 75.3 ± 9.3 vs. 80.4 ± 7.0%, p = 0.007, respectively). Using logistic regression analysis, eGFR <60 ml/min/1.73 m(2) and duration from stent implantation ≥48 months were independent predictors of increased lipid tissue volume within the neointima (odds ratio, 3.93; 95% confidence interval, 1.15-13.46, p = 0.03, and odds ratio, 7.56; 95% confidence interval, 2.02-28.30, p = 0.003, respectively). CONCLUSIONS: Lower eGFR levels were associated with greater lipid tissue volume within the neointima after BMS deployment, suggesting the development of atherosclerosis. Renal dysfunction may affect neointimal tissue characteristics and thus leading to an increased risk of late stent failure.

Long-term outcome of drug-eluting vs. bare-metal stents in patients with acute myocardial infarction. Subgroup analysis of the nagoya acute myocardial infarction study (NAMIS).

BACKGROUND: The purpose of the present study was to compare the 5-year clinical outcomes after implantation of drug-eluting stent (DES) and bare-metal stent (BMS) in Japanese patients with acute myocardial infarction (AMI). METHODS AND RESULTS: This study was a subgroup analysis of the Nagoya Acute Myocardial Infarction Study (NAMIS). It included 658 AMI patients, of which 280 were treated with a DES and 378 with a BMS. The major adverse cardiac event (MACE)-free rates during the 5-year follow-up period were similar between the 2 groups (95.7% vs. 96.8%, P=0.482). A significant difference was seen, however, in the target lesion revascularization (TLR) rates (7.9% vs. 17.7%, P<0.0001). Interestingly, there was no significant difference between the 2 groups from year 1 to 5 with regard to late TLR (2.5% vs. 2.1%, P=0.906), despite the markedly lower incidence of TLR within the first year in the DES group compared with the BMS group (5.4% vs. 15.6%, P<0.0001). CONCLUSIONS: In this long-term follow-up analysis of DES compared to BMS in Japanese patients with AMI, there was no significant difference in the incidence of MACE. Although a lower rate of TLR was observed in DES group within the first year, the superiority of DES in relation to the incidence of TLR disappeared after the first year following primary percutaneous coronary intervention.

Impact of angiotensin II receptor blocker therapy (olmesartan or valsartan) on coronary atherosclerotic plaque volume measured by intravascular ultrasound in patients with stable angina pectoris.

Coronary plaques can be reduced by some medications. The aim of this study was to compare the effects of 2 angiotensin II receptor blockers (olmesartan at 20 mg/day or valsartan at 80 mg/day) on coronary plaque by coronary intravascular ultrasound. One hundred hypertensive patients with stable angina pectoris who underwent elective percutaneous coronary intervention were randomly selected to receive 1 of the 2 angiotensin II receptor blockers after coronary intervention. Nontarget coronary lesions with mild to moderate stenosis were measured by volumetric intravascular ultrasound at baseline and after 6 months. After 6 months, both the olmesartan and the valsartan groups showed significant reduction of the examined coronary plaque volume (46.2 ± 24.1 mm³ at baseline vs 41.6 ± 21.1 mm³ at 6 months: 4.7% decrease, p = 0.0002; and 47.2 ± 32.7 mm³ at baseline vs 42.5 ± 30.2 mm³ at 6 months: 4.8% decrease, p = 0.002, respectively). There was no statistically significant difference of plaque regression between the 2 groups (p = 0.96). In conclusion, there was a significant decrease from baseline in the coronary plaque volume in patients with stable angina pectoris who received olmesartan or valsartan for 6 months. In addition, there was no significant difference in the reduction of plaque volume achieved by these 2 medications.

Circulating cathepsin K as a potential novel biomarker of coronary artery disease.

BACKGROUND: Cathepsin K (CatK) is one of the most potent mammalian collagenases involved in atherosclerosis-based vascular disease. We investigated whether circulating CatK is associated with the prevalence of coronary artery disease (CAD). METHODS: Two-hundred fifty-two consecutive subjects were enrolled from among patients who underwent coronary angiography and intravascular ultrasound analyses. One-hundred thirty-two age-matched subjects served as controls. Plasma CatK, intact procollagen type I N-terminal propeptide (I-PINP), and linked carboxy-terminal telopeptide of collagen type I (ICTP) were measured. RESULTS: Patients with CAD had higher CatK levels (44.0 ± 31.2 versus 15.5 ± 8.3 ng/mL, P < 0.001) and ICTP/I-PINP ratios (0.2 ± 0.1 versus 0.04 ± 0.03, P < 0.001) than the controls. Patients with acute coronary syndrome had higher CatK levels than those with stable angina pectoris. Overall, linear regression analysis showed that the CatK levels correlated positively with ICTP/I-PINP ratios (r = 0.41, P < 0.001). Multiple logistic regression analysis showed that CatK levels were independent predictors of CAD (odds ratio, 1.15; 95% CI, 1.07 to 1.23; P < 0.01). Furthermore, CatK levels were also correlated positively with percent plaque volumes and inversely with percent fibrous volumes by intravascular ultrasound. CONCLUSIONS: These data indicated that high levels of CatK are closely linked with the presence of CAD and that CatK serves as a novel biomarker for CAD.