Eitaro Kodani

Relation of Smoking Status to Serum Levels of N-Terminal Pro-Brain Natriuretic Peptide in Middle-Aged Men Without Overt Cardiovascular Disease

Cigarette smoking impairs arterial function and promotes atherosclerosis. However, whether smoking status is associated with cardiac overload has not yet been fully examined, particularly from an epidemiologic viewpoint. The present study examined the relation of smoking status to serum levels of N-terminal pro-brain natriuretic peptide (NT-pro-BNP), a marker of cardiac overload, in middle-aged men without overt cardiovascular disease. Serum NT-pro-BNP levels were measured in a work-site based population of 969 men (mean age 44 ± 6 years) who did not have any history or presence of cardiovascular disease. Smoking status was evaluated by self-reported questionnaire. Four hundred fifty-nine, 222, and 288 subjects were never, former, and current smokers, respectively. NT-pro-BNP levels were significantly higher in current smokers (21.7 ± 2.3 pg/ml) than in never smokers (17.9 ± 2.1 pg/ml, p <0.001). This significant difference was maintained even after adjusting for age, obesity, heart rate, hypertension, dyslipidemia, impaired fasting glucose/diabetes mellitus, left ventricular hypertrophy, estimated glomerular filtration rate, high-sensitivity C-reactive protein, alcohol consumption, and regular exercise. Current smokers had an increased odds ratio (3.04, 95% confidence interval 1.64 to 5.61, p <0.001) for elevated NT-pro-BNP (>54.5 pg/ml) compared to never smokers, even after adjusting for the studied variables. In contrast, former smokers did not show a significantly increased odds ratio for elevated NT-pro-BNP. NT-pro-BNP levels showed a weak, but significant negative correlation with duration of smoking cessation (partial r = -0.15, p = 0.034) in former smokers. In conclusion, these results suggest that cigarette smoking increases cardiac overload, whereas smoking cessation ameliorates these conditions.

Use of Warfarin in Elderly Patients With Non-Valvular Atrial Fibrillation – Subanalysis of the J-RHYTHM Registry –

BACKGROUND To clarify the effects of warfarin therapy in very old patients with non-valvular atrial fibrillation (NVAF), a post-hoc analysis was performed using the data of the J-RHYTHM Registry. METHODSANDRESULTS A consecutive series of AF outpatients was enrolled from 158 institutions. Of 7,937 patients, 7,406 with NVAF (men, 70.8%; 69.8±10.0 years) were followed for 2 years or until an event occurred. Patients were divided into 3 age groups (<70, 70-84, and ≥85 years) and 5 subgroups according to international normalized ratio (INR; <1.6, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0). Prevalence of female sex, permanent AF, hypertension, coronary artery disease, heart failure, and history of ischemic stroke/transient ischemic attack was higher in the older groups. In the oldest group, 79.7% of patients received warfarin and their time in therapeutic range, using the Japanese target INR of 1.6-2.6, was 67.1%. Rate of thromboembolic events was lower in the age groups <70 and 70-84 years (P=0.027 and P<0.001, respectively) for patients receiving warfarin compared with those who were not. In the oldest group, the rate of thromboembolism plus major hemorrhage was lower at INR 1.6-2.59. CONCLUSIONS Warfarin could have beneficial effects even in very old NVAF patients if INR is kept between 1.6 and 2.59.

Beneficial Effect of Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Nonvalvular Atrial Fibrillation – Results of the J-RHYTHM Registry 2 –

BACKGROUND The J-RHYTHM Registry 2 was a multicenter, prospective observational study that extended the follow-up period of the J-RHYTHM Registry in order to investigate long-term outcomes and effects of non-vitamin K antagonist oral anticoagulants (NOACs) in Japanese patients with atrial fibrillation (AF). METHODSANDRESULTS Among 6,616 patients with nonvalvular AF (NVAF) (men 71.0%, 69.7±9.9 years, CHADS2score 1.7±1.2), event rates were compared among patients receiving warfarin (n=3,964), NOACs (n=923), and no anticoagulation therapy (No-OAC, n=753) at the end of follow-up, except for 976 patients lacking anticoagulant data. During the 5-year follow-up period, thromboembolism occurred in 196 (4.9%), 19 (2.1%), and 45 (6.0%) patients, respectively; major hemorrhage in 233 (5.9%), 22 (2.4%), and 36 (4.8%); all-cause death in 230 (5.8%), 13 (1.4%), and 105 (13.9%), (P<0.001 for each). After adjusting for the components of the CHA2DS2-VASc score and antiplatelet drug use, the odds ratio (OR) in the Warfarin group was significantly lower for all-cause death compared with that in the No-OAC group (OR 0.30, 95% confidence interval [CI] 0.23-0.39, P<0.001), whereas ORs in the NOACs group were significantly lower for all events (OR 0.42, 95% CI 0.24-0.74, P=0.003 for thromboembolism; OR 0.53, 95% CI 0.31-0.93, P=0.027 for major hemorrhage; and OR 0.10, 95% CI 0.06-0.18, P<0.001 for all-cause death, respectively). CONCLUSIONS NOACs could be beneficial for reducing event rates of all types in Japanese NVAF patients.

Target Intensity of Anticoagulation With Warfarin in Japanese Patients With Valvular Atrial Fibrillation : Subanalysis of the J-RHYTHM Registry

BACKGROUND Warfarin is widely used for prevention of thromboembolism in patients with valvular atrial fibrillation (AF), and an international normalized ratio (INR) of prothrombin time between 2.0 and 3.0 is recommended. Optimal intensity of anticoagulation with warfarin in Japanese patients with valvular AF, however, has not been clarified thoroughly as yet. METHODS AND RESULTS We evaluated the status of anti-thrombotic therapy and incidence rates of events in 410 patients with mitral stenosis and/or mechanical valve replacement (valvular AF) among 7,816 patients with AF followed in the J-RHYTHM Registry. Patients were divided into 5 groups based on INR (<1.6, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0) at the time of event or at the end of follow-up in order to determine the target INR for patients with valvular AF. Warfarin was prescribed in 407 (99.3%) of valvular AF patients. During a 2-year follow-up period, thromboembolism and major hemorrhage occurred in 12 (2.9%) and in 15 (3.7%) patients, respectively. Among patients receiving warfarin, 2-year incidence rates of thromboembolism were 10.3%, 1.6%, 0.6%, 3.0%, and 0.0% (P=0.003 for trend), and those of major hemorrhage were 1.5%, 1.6%, 3.2%, 6.1%, and 21.1% (P<0.001 for trend), respectively. CONCLUSIONS I NR between 1.6 and 2.6 could be optimal to prevent thromboembolism without increasing major hemorrhage in Japanese patients with valvular AF. INR 2.6-2.99 would also be effective, but is associated with a modestly increased risk of major hemorrhage.

Dyslipidemia and the Risk of Developing Hypertension in a Working‐Age Male Population

Background Hypertension is one of the main comorbidities associated with dyslipidemia. This study aimed to examine the extent to which dyslipidemia increases the risk of developing hypertension in a Japanese working‐age male population. Methods and Results We analyzed data from 14 215 nonhypertensive male workers (age 38±9 years) who underwent annual medical checkups. Subjects were followed up for a median of 4 years to determine new‐onset hypertension, defined as blood pressure (BP) ≥140/90 mm Hg or use of antihypertensive medication. The associations between serum lipid levels and development of hypertension were examined. During the follow‐up period, 1483 subjects developed hypertension. After adjusting for age, body mass index, impaired fasting glucose/diabetes, baseline BP category, alcohol intake, smoking, exercise, and parental history of hypertension, subjects with a total cholesterol (TC) level ≥222 mg/dL were at a significantly increased risk of developing hypertension (hazard ratio: 1.28; 95% CI: 1.06–1.56) compared to subjects with a TC level ≤167 mg/dL. Similar results were observed for subjects with high low‐density lipoprotein cholesterol (LDLC) and non‐high‐density lipoprotein cholesterol (HDLC) levels. A U‐shaped relationship was found between HDLC level and risk of hypertension; compared to the third quintile, the multiadjusted hazard ratio was 1.22 (95% CI: 1.03–1.43) in the lowest quintile and 1.34 (95% CI: 1.12–1.60) in the highest quintile. Conclusions Elevated serum levels of TC, LDLC, and non‐HDLC were associated with an increased risk of hypertension in working‐age Japanese men. For HDLC, risk of hypertension was increased at both low and high levels.

Oscillometric measurement of brachial artery cross-sectional area and its relationship with cardiovascular risk factors and arterial stiffness in a middle-aged male population

An enlarged arterial diameter is associated with an increased risk for cardiovascular disease. This study examined the relationship of noninvasively measured brachial artery cross-sectional area with cardiovascular risk factors and arterial stiffness in a middle-aged male population. Absolute volumetric changes of the brachial artery were measured with a newly developed oscillometric method during a general health examination in 387 men (mean age: 38±9 years) without known cardiovascular disease. Based on the measurement, the estimated area (eA) of the brachial artery at end-diastole was obtained. Brachial artery volume elastic modulus (VE) and brachial–ankle pulse wave velocity (baPWV) were simultaneously measured as indices of arterial stiffness by the same device. The relationships of eA with cardiovascular risk factors, including age, obesity, hypertension, dyslipidemia, impaired fasting glucose/diabetes mellitus (IFG/DM), hyperuricemia, smoking and their associated continuous variables, as well as VE and baPWV, were examined. Overall, the mean eA was 12.9±2.9 mm2. The eA was significantly higher in subjects with obesity, hypertension or IFG/DM than in those without each of these risk factors. In a multiple linear regression analysis, body mass index (β=0.31, P<0.001), age (β=0.25, P<0.001), systolic blood pressure (β=0.16, P=0.004) and pulse rate (β=−0.13, P=0.005) were independent determinants of eA. In contrast, neither VE nor baPWV were selected as independent determinants of eA. In conclusion, enlarged brachial artery cross-sectional area was significantly associated with cardiovascular risk factors such as age, body mass index and systolic blood pressure, but it was not associated with increased arterial stiffness.

Utility of rapid D-dimer measurement for screening of acute cardiovascular disease in the emergency setting

BACKGROUND Rapid and accurate methods for screening are necessary for the diagnosis of acute cardiovascular diseases (ACVD), including acute coronary syndrome (ACS), pulmonary thromboembolism, and acute aortic dissection. In this study, the utility of rapid D-dimer measurement for the screening of ACVD was evaluated. METHODS AND RESULTS Consecutive 279 emergent patients in whom ACVD was suspected or not ruled out were enrolled. The median D-dimer concentration of ACVD group (1.10 μg/ml) was significantly higher than that in the non-ACVD group (0.69 μg/ml, p<0.05). Sensitivity, specificity, positive predictive value, and negative predictive value of D-dimer (with cut-off level of 0.75 μg/ml) for the discrimination of ACVD from non-ACVD was 75%, 55%, 38%, and 85%, respectively. In ACVD group, the level of D-dimer in the large vessel disease subgroup was significantly higher than that in the ACS subgroup (6.99 μg/ml and 0.89 μg/ml, respectively; p<0.05). The well-balanced cut-off point for discriminating the two subgroups was D-dimer level of 5.0 μg/ml. D-dimer (with cut-off level of 0.75 μg/ml) showed significantly higher positive test rate for the detection of ACS in very early phase (within 2 h from the onset) compared with troponin T (p<0.05). CONCLUSIONS Rapid measurement of D-dimer is useful for the screening of ACVD in the emergency setting.

Secondary Prevention of Stroke with Warfarin in Patients with Nonvalvular Atrial Fibrillation: Subanalysis of the J-RHYTHM Registry

BACKGROUND Prior ischemic stroke or transient ischemic attack (TIA) is a high risk for thromboembolism in patients with nonvalvular atrial fibrillation (NVAF). To clarify rates of thromboembolic and hemorrhagic events, and target intensities of warfarin for secondary prevention, a subanalysis was performed using data from the J-RHYTHM Registry. METHODS Of 7937 outpatients with atrial fibrillation, 7406 with NVAF (men 70.8%, 69.8 ± 10.0 years) were followed for 2 years or until an event occurred. Event rates and effect of warfarin were compared between patients with (secondary prevention) and without (primary prevention) prior stroke/TIA. RESULTS Prevalence of male sex, diabetes mellitus, and mean age were higher in the secondary prevention group, showing a higher CHADS2 (congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and history of stroke or TIA) score than the primary prevention group (3.5 ± 1.0 versus 1.4 ± 1.0, P < .001). In the secondary prevention group, 93.4% of patients received warfarin and their time in therapeutic range was 62.8%. During follow-up, thromboembolism occurred more frequently in the secondary than in the primary prevention group (2.8% versus 1.5%, P = .004), especially in patients without warfarin. Major hemorrhage also occurred more frequently in the secondary prevention group (3.0% versus 1.7%, P = .006). Compared with patients not taking warfarin, combined rates of both events were lower at an international normalized ratio (INR) of 1.6-2.59 in patients taking warfarin in the secondary as well as in the primary prevention groups. CONCLUSIONS Both thromboembolism and major hemorrhage occurred more frequently in NVAF patients with prior ischemic stroke/TIA. Target INR should be 1.6-2.59 for secondary as well as primary prevention of thromboembolism in Japanese NVAF patients.

Development of a risk prediction model for incident hypertension in a working-age Japanese male population

The aim of this study was to develop a risk prediction model for incident hypertension in a Japanese male population. Study participants included 15 025 nonhypertensive Japanese male workers (mean age, 38.8±8.9 years) who underwent an annual medical checkup at a company. The participants were followed-up for a median of 4.0 years to determine new-onset hypertension, defined as a systolic blood pressure (BP) ⩾140 mm Hg, a diastolic BP ⩾90 mm Hg, or the initiation of antihypertensive medication. Participants were divided into the following two cohorts for subsequent analyses: the derivation cohort (n=12 020, 80% of the study population) and the validation cohort (n=3005, the remaining 20% of the study population). In the derivation cohort, a multivariate Cox proportional hazards model demonstrated that age, body mass index, systolic and diastolic BP, current smoking status, excessive alcohol intake and parental history of hypertension were independent predictors of incident hypertension. Using these variables, a risk prediction model was constructed to estimate the 4-year risk of incident hypertension. In the validation cohort, the risk prediction model demonstrated high discrimination ability and acceptable calibration, with a C-statistic of 0.861 (95% confidence interval 0.844, 0.877) and a modified Hosmer–Lemeshow χ2 statistic of 15.2 (P=0.085). A risk score sheet was constructed to enable the simple calculation of the approximate 4-year probability of incident hypertension. In conclusion, a practical risk prediction model for incident hypertension was successfully developed in a working-age Japanese male population.

Effect of insulin resistance associated with compensatory hyperinsulinemia on the long-term prognosis in patients with vasospastic angina.

BACKGROUND Insulin resistance associated with compensatory hyperinsulinemia plays a significant role in the pathogenesis of cardiovascular diseases, including vasospastic angina (VSA). However, the effects of insulin resistance associated with hyperinsulinemia on the long-term prognosis in patients with VSA remain unclear. METHODS A total of 265 selected patients with VSA and 56 control subjects with atypical chest pain were enrolled in the present study. Patients with VSA had a positive acetylcholine (ACh) provocation test with normal coronary angiograms, and control subjects had a negative ACh test and normal coronary angiograms. A 75-g oral glucose tolerance test was performed, and the plasma glucose and immunoreactive insulin (IRI) levels were measured before, and 30 min and 120 min (IRI 120) after the 75-g glucose load. RESULTS During the median follow-up period of 90.0 months, thirty-one patients developed cardiac events, including 6 sudden cardiac deaths and 25 readmissions for acute coronary syndrome. Cardiac events occurred in 38.9% of the patients with an IRI 120 ≥ 80 μU/ml and only 1.6% of the patients with an IRI 120<80 μU/ml (log rank 77.220, p<0.001). A multivariate analysis showed that an IRI 120 ≥ 80 μU/ml (hazard ratio 27.49, 95% confidence interval: 4.66-162.10, p<0.001) was an independent predictor of cardiac events. CONCLUSIONS These data indicate that insulin resistance associated with compensatory hyperinsulinemia increases the risk of cardiac events in VSA patients.