Yoshio Iwashima

Hypoadiponectinemia is an independent risk factor for hypertension

Adiponectin is one of the key molecules in the metabolic syndrome, and its concentration is decreased in obesity, type-2 diabetes, and coronary artery disease. Genetic investigation has revealed that 2 polymorphisms (I164T and G276T) are related to adiponectin concentration and diabetes. To examine whether adiponectin affects hypertension genetically or biologically, we performed a case-control study. A total of 446 diagnosed cases of hypertension (HT) in men and 312 normotensive (NT) men were enrolled in this study. Plasma adiponectin concentration was measured using an enzyme-linked immunosorbent assay system. Single nucleotide polymorphisms were determined by TaqMan polymerase chain reaction method. After adjustment for confounding factors, adiponectin concentration was significantly lower in HT (HT: 5.2±0.2 μg/mL; NT: 6.1±0.2 μg/mL; P <0.001). Furthermore, multiple regression analysis indicated that hypoadiponectinemia was an independent risk factor for hypertension (P <0.001). Blood pressure was inversely associated with adiponectin concentration in normotensives regardless of insulin resistance. In subjects carrying the TC genotype of the I164T polymorphism, adiponectin concentration was significantly lower (TC: 2.6±0.9 μg/mL; TT: 5.5±0.1 μg/mL; P <0.01), and most of them had hypertension. In contrast, the G276T polymorphism was not associated with adiponectin concentration or hypertension. In conclusion, hypoadiponectinemia is a marker for predisposition to hypertension in men.

Association of Hypoadiponectinemia With Smoking Habit in Men

Adiponectin is emerging as an important molecule in obesity, the metabolic syndrome, and cardiovascular disease. On the other hand, smoking habit is well known to be related to cardiovascular disease and hypertension. To examine the association between adiponectin concentration and smoking habit, we performed an epidemiological survey and an acute exposure test in humans and an experiment in adipocytes to elucidate the mechanism underlying the association between adiponectin and smoking. In the epidemiological study, we enrolled a total of 331 male subjects to examine chronic smoking exposure. Plasma adiponectin was significantly lower (P=0.01) in current smokers (5.3±0.3 &mgr;g/mL) than in never-smokers (6.5±0.4 &mgr;g/mL). A significant association between smoking and low adiponectin level was also confirmed in multiple regression analysis including age, body mass index, hypertension, diabetes, hyperlipidemia, and creatinine clearance (never-smokers 6.5±0.4 &mgr;g/mL; past smokers 5.6±0.3 &mgr;g/mL; current smokers 5.2±0.4 &mgr;g/mL; F=4.52; P=0.01). To examine the acute effect of smoking on adiponectin concentration for 12 hours, we measured plasma adiponectin level in 5 male never-smokers before smoking and 3, 6, and 12 hours after smoking, with the result that adiponectin showed a significant decrease after smoking (12 hours; −14.5±0.6%; P<0.01). In cultured mouse 3T3-L1 adipocytes, H2O2 and nicotine reduced the mRNA expression and secretion of adiponectin in a dose-dependent manner. Smoking habit is associated with adiponectin concentration in men, and its suppressive effect is mediated in part through direct inhibition of smoking on adiponectin expression in adipocytes.

Uric Acid, Left Ventricular Mass Index, and Risk of Cardiovascular Disease in Essential Hypertension

Elevated serum uric acid (UA) is frequently encountered in individuals with hypertension, but whether the relationship between UA and cardiovascular events is circumstantial or causal remains to be answered. We examined the association between serum UA and left ventricular mass index (LVMI) and investigated prospectively whether the combination of UA and LVMI can predict the incidence of cardiovascular disease (CVD) in asymptomatic subjects with essential hypertension. A total of 619 subjects (mean age, 61 years; 52% female) free of prior CVD were included in this study. A significant association between UA and LVMI was also confirmed in multiple regression analysis (male: F=4.29, P<0.04; female: F=4.24, P<0.05). During follow-up (mean, 34 months), 28 subjects (14 female) developed CVD including myocardial infarction, angina pectoris, congestive heart failure, cerebral infarction, and transient cerebral ischemia. Sex-specific median values were used to separate the higher group from the lower group of UA and LVMI. Kaplan–Meier curves showed a significantly poorer survival rate in the group with higher UA and LVMI (LVMI, male: >126.9, female: >112.0 g/m2; UA, male: >374.7, female: >303.3 &mgr;mol/L; log-rank &khgr;2=13.18; P<0.01). Multivariate Cox regression analysis showed that the combination of higher UA and LVMI was an independent predictor for CVD events (hazard ratio, 2.38; P<0.03). Our findings demonstrate that UA is independently associated with LVMI and suggest that the combination of hyperuricemia combined with left ventricular hypertrophy is an independent and powerful predictor for CVD. The association between UA and CVD events may be introduced in part because of a direct association of UA with LVMI.

Chronic kidney disease as an independent risk factor for new-onset atrial fibrillation in hypertensive patients.

Objective Chronic kidney disease (CKD) has recently been recognized to be a powerful predictor of cardiovascular morbidity and mortality. Atrial fibrillation (AF), which is a common arrhythmia in hypertensives, is associated with increased risks of cardiovascular events and death. However, the association between CKD and the onset of AF has not been fully elucidated. The present study assessed the hypothesis that CKD may influence the onset of AF in hypertensives. Methods A total of 1118 hypertensive patients (mean age, 63 years) without previous paroxysmal AF, heart failure, myocardial infarction, or valvular disease were enrolled. CKD was defined as decreased glomerular filtration rate (<60 ml/min per 1.73 m2) and/or the presence of proteinuria (≥1+). Results During follow-up periods (mean, 4.5 years), 57 cases of new-onset AF were found (1.1% per year). Kaplan–Meier curves revealed that the cumulative AF event-free rate was decreased in the CKD group (log-rank test P < 0.001). By univariate Cox regression analysis, age, smoking, left atrial dimension, left ventricular mass index, and the presence of CKD were significantly associated with the occurrence of AF. Among these possible predictors, CKD (hazard ratio 2.18, P = 0.009) was an independent determinant for the onset of AF in multivariate analysis. Advanced stages of CKD (stages 4 and 5) were strongly related to the increased occurrence of AF. Conclusion The present study demonstrated that the complication of CKD, especially progressed renal dysfunction, was a powerful predictor of new-onset AF in hypertensive patients, independently of left ventricular hypertrophy and left atrial dilatation.

Renal Resistive Index and Cardiovascular and Renal Outcomes in Essential Hypertension

Increased renal restive index (RI) measured using Doppler ultrasonography has been shown to correlate with the degree of renal impairment in hypertensive patients. We investigated the prognostic role of RI in cardiovascular and renal outcomes. A total of 426 essential hypertensive subjects (mean age, 63 years; 50% female) with no previous cardiovascular disease were included in this study. Renal segmental arterial RI was measured by duplex Doppler ultrasonography. During follow-up (mean, 3.1 years), 57 participants developed the primary composite end points including cardiovascular and renal outcomes. In multivariate Cox regression analysis, RI was an independent predictor of worse outcome in total subjects (hazard ratio, 1.71 for 1 SD increase), as well as in patients with estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m2 (hazard ratio, 2.11 for 1 SD increase; P<0.01, respectively). When divided into 4 groups based on the respective sex-specific median levels of RI in the eGFR ≥60 and eGFR <60 mL/min per 1.73 m2 groups, the group with eGFR <60 and high RI (male ≥0.73, female ≥0.72) had a significantly poorer event-free survival rate (&khgr;2=126.4; P<0.01), and the adjusted hazard ratio by multivariate Cox regression analysis was 9.58 (95% CI, 3.26–32.89; P<0.01). In conclusion, impairment of renal hemodynamics evaluated by increased RI is associated with an increased risk of primary composite end points, and the combination of high RI and low eGFR is a powerful predictor of these diseases in essential hypertension. In hypertensive patients with chronic kidney disease, RI evaluation may complement predictors of cardiovascular and renal outcomes.

Association of Renal Resistive Index With Target Organ Damage in Essential Hypertension

BACKGROUND The renal resistive index (RI) measured using Doppler ultrasonography has been used as a diagnostic tool in the daily work-up of kidney diseases. A better understanding of its relationship with preclinical organ damage may help in determining overall cardiovascular risk in hypertensive patients. METHODS We evaluated the association between RI and the presence and degree of target organ damage (TOD) in 288 (130 male) essential hypertensive patients. RI, carotid intima-media thickness (IMT), and left ventricular (LV) mass index were assessed by ultrasound scan. Albuminuria was measured as the albumin-to-creatinine ratio (ACR) in three consecutive first morning urine samples. RESULTS In univariate analysis, patients with TOD showed significantly higher RI as compared with those without TOD (presence vs. absence of carotid wall thickening, LV hypertrophy, and albuminuria, P < 0.01, respectively). The severity of each TOD increased progressively from the lower to the upper RI tertile. Multiple logistic regression analysis found that each standard deviation increase in RI gave a 47% higher odds of having LV hypertrophy, and a 70% higher odds of having albuminuria (P < 0.05, respectively). The occurrence of at least two signs of TOD also significantly increased in parallel with elevation of RI (odds ratio (OR): 1.89 for 1 s.d. increase, P < 0.01). CONCLUSIONS These results suggest that increased RI may be a marker of subclinical TOD in patients with essential hypertension.

Plasma adrenomedullin as an independent predictor of future cardiovascular events in high-risk patients: Comparison with C-reactive protein and adiponectin

This study investigated the predictive power of plasma adrenomedullin (AM) for future cardiovascular (CV) events. In 121 patients with multiple CV risk factors and/or disease, plasma concentrations of AM, high sensitive C-reactive protein (hs-CRP), and adiponectin were measured. During follow-up periods (mean, 3.5 years) after the baseline assessment, 28 patients newly experienced CV events such as stroke/transient ischemic attack, acute coronary syndrome, and congestive heart failure. The plasma level of AM, but not hs-CRP or adiponectin, was significantly higher in patients who had CV events than in event-free subjects. When the patients were divided into three groups by tertiles of basal levels of AM (<10.1, 10.1-13.1, and > or =13.1 fmol/mL), cumulative event-free rates by the Kaplan-Meier method were decreased according to the increase in basal AM levels (83.2%, 68.6%, and 52.8% in the lowest, middle, and highest tertiles of AM, respectively; log-rank test, P=0.033). By univariate Cox regression analysis, previous coronary artery disease, creatinine clearance, and plasma AM and hs-CRP levels were significantly associated with CV events during follow-up. Among these possible predictors, high plasma AM (P=0.004) and low creatinine clearance (P=0.043) were independent determinants for morbidity in multivariate analysis. These findings indicate that plasma AM is a powerful independent predictor of future CV events in high-risk patients, suggesting its predictive value is superior to that of hs-CRP or adiponectin.

Autonomic function in hypertensive patients with neurovascular compression of the ventrolateral medulla oblongata

OBJECTIVE To study whether abnormalities of autonomic function exist in patients with essential hypertension and neurovascular compression (NVC) of the medulla oblongata. SUBJECTS AND METHODS We studied 25 untreated patients with essential hypertension (13 men and 12 women, 27-74 years old). High-resolution magnetic resonance imaging and magnetic resonance angiography were used to detect NVC. Twenty-four-hour ambulatory monitoring of blood pressure and electrocardiogram were performed, and the power spectrum of heart rate variability was analyzed. On a separate day, various autonomic activity tests, including mental stress, hand grip, cold pressor, and Valsalva maneuver were performed. Baroreflex sensitivity was calculated from changes of blood pressure and R-R interval during phenylephrine infusion. A clonidine suppression test was also performed, with measurement of plasma catecholamine levels. RESULTS Fourteen of 25 patients (56%) had NVC (C group), and 11 patients did not have NVC (NC group). There were no significant differences in age, sex, family history, or duration of hypertension between the C and NC groups. Average 24-h systolic blood pressure was similar between the two groups, although 24-h diastolic blood pressure was higher in the C group than the NC group. Daytime, night-time, and 24-h heart rate was significantly higher in the C group than in the NC group. Night-time low frequency/high frequency ratio was slightly higher in the C group. Plasma norepinephrine levels were significantly higher (467 +/- 217 versus 299 +/- 122 pg/ml), and baroflex sensitivity was slightly lower in the C group than in the NC group. Responses of blood pressure and heart rate to mental stress, cold pressor, hand grip, Valsalva maneuver, phenylephrine infusion, and clonidine tests were not significantly different between the two groups. CONCLUSIONS NVC of the medulla oblongata was frequently found in patients with essential hypertension. Patients with NVC appeared to have enhanced sympathetic nervous activity compared with those without the compression.

Interleukin-6 as an independent predictor of future cardiovascular events in high-risk Japanese patients: Comparison with C-reactive protein

Inflammation is associated with the development of atherosclerotic vascular lesions and some inflammatory parameters are used as cardiovascular (CV) risk markers. The present study was designed to assess the predictive power of interleukin (IL)-6 for future CV events. In 121 Japanese patients with multiple CV risk factors and/or disease, serum concentrations of IL-6 and high sensitive C-reactive protein (hs-CRP) were measured. During follow-up periods (mean, 2.9 years) after the baseline assessment, 50 patients newly experienced CV events such as stroke/transient ischemic attack (n=10), heart failure hospitalization (n=6), acute coronary syndrome (n=7), and revascularization for coronary artery disease (n=15) and peripheral arterial disease (n=12). The serum level of IL-6, but not hs-CRP, was significantly higher in patients who had CV events than in event-free subjects (3.9±2.6 and 3.0±2.2 pg/mL, P=0.04). When the patients were divided into three groups by tertiles of basal levels of IL-6 (<1.85, 1.85-3.77, and ≥3.77 pg/mL), cumulative event-free rates by the Kaplan-Meier method were decreased according to the increase in basal IL-6 levels (65%, 50%, and 19% in the lowest, middle, and highest tertiles of IL-6, respectively; log-rank test, P=0.002). By univariate Cox regression analysis, previous CV disease, creatinine clearance, and serum IL-6 levels were significantly associated with CV events during follow-up. Among these possible predictors, the highest tertile of IL-6 was only an independent determinant for the morbidity in the multivariate analysis (hazard ratio 2.80 vs. lowest tertile, P=0.006). These findings indicate that IL-6 is a powerful independent predictor of future CV events in high-risk Japanese patients, suggesting its predictive value is superior to that of hs-CRP.

C-Reactive Protein, Left Ventricular Mass Index, and Risk of Cardiovascular Disease in Essential Hypertension

We examined the association between C-reactive protein (CRP) and left ventricular mass index (LVMI), and investigated prospectively the incidence of cardiovascular disease (CVD) in asymptomatic subjects with essential hypertension. A total of 629 subjects (mean age 62 years, 51% female) free of prior CVD were included in this study. In cross-sectional analysis at baseline, patients were divided into three groups according to serum CRP levels: <1, 1 to 2, and >2 mg/L. In multivariate analysis, LVMI increased in a stepwise fashion with increasing CRP levels in both men (127.2±2.9, 138.7±4.1, 141.8±3.5 g/m2, respectively; F=6.85, p=0.001) and women (119.5±3.6, 129.2±4.9, 130.2±4.8 g/m2; F=4.23, p=0.031). During follow-up (mean 32 months), 52 subjects (19 female) developed CVD. Kaplan-Meier analysis with log-rank tests showed a significantly poorer event-free survival rate in the group with elevated CRP levels (≥1 mg/L) (χ2=8.22, p<0.01) and that with left ventricular hypertrophy (LVH) (χ2=19.91, p<0.01). When participants were divided into four groups on the basis of CRP level (<1 or ≥1 mg/L) and the absence or presence of LVH, the group with LVH/CRP≥1 mg/L showed markedly poorer event-free survival (χ2=28.02, p<0.01), and the adjusted hazard ratio by multivariate Cox regression analysis was 2.65 (95% confidence interval [CI]=1.55–5.46, p<0.01). In the subgroup with LVH (n=362), a significantly lower event-free survival rate of CVD was also observed in the group with CRP≥1 mg/L (hazard ratio [HR] 1.37, 95% CI: 1.02–1.85, p=0.025). Our findings demonstrate that the CRP level is independently associated with LVMI, and suggest that measurement of CRP may provide clinically important prognostic information to supplement LVH.