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

1177 Hypertens Res Vol.30 (2007) No.12 p.1177-1185 Original Article C-Reactive Protein, Left Ventricular Mass Index, and Risk of Cardiovascular Disease in Essential Hypertension Yoshio IWASHIMA1), Takeshi HORIO2), Kei KAMIDE2), Hiromi RAKUGI1), Toshio OGIHARA1), and Yuhei KAWANO2) 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. ( Hypertens Res 2007; 30: 1177–1185) Key Words: C-reactive protein, hypertrophy, cardiovascular disease, echocardiography, follow-up study Introduction Hypertension is a central risk factor for cardiovascular disease (CVD), and the cardiovascular prognosis in patients with hypertension depends not only on the level of blood pressure (BP), but also on the presence of associated risk factors. Inflammatory processes are now recognized to play a fundamental role in atherogenesis (1). In addition, basic and clini- cal data suggest the possible involvement of inflammation in the genesis of hypertension and that hypertension in turn induces a proinflammatory response (2–4). C-reactive protein (CRP), a marker of the reactant plasma protein component of the inflammatory response, has been found to be a robust predictor of the development of CVD in several large epidemiological studies (5–10). The guidelines from the European Society of Hypertension and the European Society of Cardiology (ESH-ESC) (11), and the Centers for Disease Control From the 1)Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Japan; and 2)Division of Hypertension and Nephrology, Department of Medicine, National Cardiovascular Center, Suita, Japan. Address for Reprints: Takeshi Horio, M.D., Ph.D., Division of Hypertension and Nephrology, Department of Medicine, National Cardiovascular Center, 5–7–1, Fujishirodai, Suita 565–8565, Japan. E-mail: Received April 25, 2007; Accepted in revised form July 8, 2007. 1178 Hypertens Res Vol. 30, No. 12 (2007) and Prevention/American Heart Association (CDC/AHA) (12) also stress the importance of measuring CRP in primary prevention. On the other hand, an elevated CRP level is affected by or linked to hypertension and many metabolic factors such as insulin resistance (13, 14), all of which are also associated with left ventricular hypertrophy (LVH). Previous reports have examined the association between CRP and left ventricular (LV) mass, but the results obtained are controversial (15–19). Thus, the clinical importance of CRP in LVH has not been fully elucidated. In this study, we investigated the potential interrelationships between CRP and LV mass index (LVMI) in patients with essential hypertension by using the clinical cut-off levels of CRP. We further sought to evaluate the interrelationships between CRP, LVMI, and incidence of CVD in asymptomatic hypertensive patients. In addition, we attempted to determine whether CRP might provide useful prognostic information to enhance that by provided by LVH. Methods Study Subjects From March 1997 to March 2004, a total of 629 essential hypertensive patients who had good-quality echocardiographic recordings were consecutively enrolled in this study and monitored for 31.6 ± 0.8 months. All subjects were selected from patients who were admitted and underwent medical investigation including a general check-up at the National Cardiovascular Center in Osaka, Japan. Hypertension was defined as systolic BP (SBP) ≥ 140 mmHg and/or diastolic BP (DBP) ≥ 90 mmHg on repeated measurements, or receipt of antihypertensive treatment. Diabetes mellitus was defined according to the American Diabetes Association criteria (20). Smoking status was determined by interview, and defined as currently smoking or not. Ischemic heart disease was defined as a 75% or greater organic stenosis of at least one major coronary artery as confirmed by coronary angiography, or a history of myocardial infarction or percutaneous transluminal coronary angioplasty. Exclusion criteria included ischemic heart disease, acute coronary syndrome, congestive heart failure (CHF) (New York Heart Association [NYHA] class II or greater), old cerebral infarction, history of transient ischemic attack, secondary hypertension, receipt of hormone replacement therapy and/or an anti-inflammatory drug (aspirin or nonsteroidal anti-inflammatory drug [NSAID]), chronic infection, and cancer. Participants with moderate or severe aortic or mitral regurgitation or a heart rate > 100 bpm were also excluded. All procedures in the present study were carried out in accordance with institutional and national ethical guidelines for human studies. All subjects enrolled in this study were Japanese, and all gave informed consent to participate in this study. Baseline Clinical Characteristics After fasting overnight, BP was measured with an appropriate arm cuff and a mercury column sphygmomanometer on the left arm after a resting period of at least 10 min in the supine position. After BP measurement, venous blood sampling was performed in all subjects. Height and body weight were measured, and body mass index was calculated. The following parameters were also determined: total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-chol), and CRP levels. High-sensitivity CRP was measured by a validated (...truncated)