Research Article For reprint orders, please contact: [email protected]

Cardiotrophin-1 is associated with increased risk of arterial stiffness

Aim: Cardiotrophin-1 null mice presented decreased arterial stiffness. The aim of this study is to investigate the relationship between cardiotrophin-1 and arterial stiffness, assessed by brachial-ankle pulse-wave velocity (baPWV). Methods: We enrolled 300 subjects, 200 with baPWV >1400 and 100 with baPWV ≤1400 cm/s. Results: Cardiotrophin-1 levels were significantly higher in subjects with baPWV >1400 than those with baPWV ≤1400 cm/s. The multivariate logistic regression analysis showed that age, prehypertension, hypertension and cardiotrophin-1 were independently associated with baPWV >1400 cm/s after adjusting for gender, obesity, diabetes, homeostasis model assessment-insulin resistance, total cholesterol, high-density lipoprotein cholesterol, triglyceride, high-sensitivity C-reactive protein, creatinine, smoking and habitual exercise. Conclusion: Cardiotrophin-1 is positively related to baPWV independent of traditional cardiometabolic risk factors for arterial stiffness. Keywords:  arterial stiffness • brachial-ankle pulse-wave velocity • cardiotrophin-1

Cardiotrophin-1, a member of the IL-6 superfamily, binds to the glycoprotein 130/ leukemia inhibitory factor receptor complex [1] , and induces hypertrophy and prolongs survival of cardiomyocytes through the activation of both MAPK and Janus kinase-signal transducer and activator of transcription signaling pathways [2] . Previous studies have shown that cardiotrophin-1 concentrations are increased in individuals with hypertension [3–5] , hypertensive patients with left ventricular hypertrophy (LVH) [3] and heart failure [5,6] . These evidences suggest that cardiotrophin-1 may serve as a biomarker of LVH and heart failure in hypertensive patients [7] . In addition, cardiotrophin-1 might play a role in the arterial wall remodeling in hypertension [8,9] . Arterial stiffness is recognized as a surrogate marker for cardiovascular disease, and has independent predictive value for all-cause and cardiovascular mortalities [10] . Previous studies have shown a strong association of arterial stiffness with age and cardiovascular risk factors, such as hypertension, diabetes,

10.2217/BMM.14.87 © 2015 Future Medicine Ltd

obesity, hyperlipidemia, smoking, metabolic syndrome [10] and insulin resistance [11] . Out of the available noninvasive methods to assess arterial stiffness, carotid-femoral pulse-wave velocity (cfPWV) is the gold-standard measurement and is well validated as a strong predictor of adverse cardiovascular outcome [12] . However, a high level of skill and the exposure of the inguinal region are required for its measurement, therefore the application of cfPWV is mostly limited to research purpose [13] . Instead, the measurement of brachialankle pulse-wave velocity (baPWV) only involves wrapping a pressure cuff around each of the four extremities, and is simple to use in clinical practice [14] . Recently, one animal study showed that cardiotrophin-1 null mice lacking cardiotrophin-1 presented higher distensibility for a given blood pressure and decreased arterial stiffness [15] , suggesting cardiotrophin-1 may be a major regulator of arterial stiffness. However, the association between cardiotrophin-1 and arterial stiffness in human has not been explored. Thus, the aim of this

Biomark. Med. (2015) 9(2), 123–130

Hao-Chang Hung1,2, Feng-Hwa Lu3,4, Horng-Yih Ou1,4, Hung-Tsung Wu5, Jin-Shang Wu3,4, Yi-Ching Yang3,4 & Chih-Jen Chang*,3,4 Division of Endocrinology & Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan 2 The Institute of Basic Medical Sciences of National Cheng Kung University, Tainan, Taiwan 3 Department of Family Medicine, National Cheng Kung University Hospital, Tainan, Taiwan 4 College of Medicine, National Cheng Kung University, Tainan, Taiwan 5 Research Center of Herbal Medicine, New Drugs, & Nutritional Supplements, National Cheng Kung University, Tainan, Taiwan *Author for correspondence: changcj.ncku@ gmail.com 1

part of

ISSN 1752-0363

123

Research Article  Hung, Lu, Ou et al. study was to investigate the relationship between cardiotrophin-1 and arterial stiffness, by baPWV, in a Chinese population. Methods Study population

The study was approved by the Institutional Review Board of the National Cheng Kung University Hospital, and all eligible subjects gave written informed consent before participation. From June 2007 to July 2009, all subjects who had been admitted for a physical checkup at the Preventive Health Center of National Cheng Kung University Hospital were screened. All healthy subjects who did not have a medical history of diabetes received a standard 75 g oral glucose tolerance test after a 12-h overnight fast, a normal diet for 3 days before the test and abstention from smoking for more than 24 h. None of the women were pregnant when tested. The study subjects were selected from our previous study [16] . Briefly, we selected 360 subjects following this algorithm: the study subjects were classified into four groups, normal glucose tolerance, impaired fasting glucose, impaired glucose tolerance and newly diagnosed diabetes, in the order of their admission to the study. Each consecutive index diabetic subject was matched to the first subject of the same gender in the other three groups from the list who had the same age. If an exact age match could not be found, then the first subject closest to the age of the index subject (within ±1 year) was picked. Subjects with incomplete data or without medical residual sample were excluded. Finally, 300 subjects were entered for final analysis. After an overnight 12-h fast, all subjects received a blood test, including routine biochemistry, hemogram, fasting plasma glucose (FPG), total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL), hemoglobin A1c (A1C), insulin and cardiotrophin-1. Wearing light indoor clothes, each subject’s body height (to the nearest 0.1 cm) and weight (to the nearest 0.1 kg) were measured. Body mass index (BMI; in kg/m2) was calculated as weight (in kilograms) divided by height (in meters) squared. Obesity was defined as a BMI ≥27, according to the recommendations of the Department of Health in Taiwan. For blood pressure measurement, subjects were resting in a supine position in a quiet ambience, and measurements were obtained in a fasting state between 0800 and 1000 h. Two blood pressure readings, separated by intervals of at least 5 min, were taken with an appropriate-sized cuff wrapped around the right upper arm using a DINAMAP vital sign monitor (model 1846SX; Critikon, Inc., CA, USA). Subjects with a systolic blood pressure (SBP) more than or equal to 140 mmHg or diastolic blood pressure (DBP) more than or equal to 90 mmHg

124

Biomark. Med. (2015) 9(2)

were defined as having hypertension. Prehypertension was defined for those with SBP 120–139 mmHg and/ or DBP 80–89 mmHg. Habitual exercise was defined as exercise three or more times per week when the subjects engaged in activities sufficient to work up a sweat. Smoking habit was classified into smokers (defined as at least one pack/month for the previous 6 months) and nonsmokers. Brachial-ankle pulse wave velocity (baPWV) was measured by using a noninvasive vascular screening device (BP-203RPE II; Colin Medical Technology, Komaki, Japan) with four pneumatic pressure cuffs that simultaneously measured BP and pulse waves in bilateral brachial tibial arteries after 5 min of bed rest. The baPWV was calculated as the distance traveled by the pulse wave divided by the time taken to travel the distance. Mean baPWV was used for final analysis because of a significant positive correlation between left and right baPWV (r = 0.968, p < 0.001). The measurement of baPWV was performed by a single well-trained technician. The Pearson’s correlation coefficients of intraobserver reproducibility was r = 0.87, and the CV was 10.0%. An increased baPWV (>1400 cm/s) is useful to discriminate patients with either stroke or coronary heart disease independent from conventional atherosclerotic risk factors [17] . Blood glucose was measured by a hexokinase method (Roche Diagnostic GmbH, Mannheim, Germany). Diabetes was diagnosed according to the recommendations of the American Diabetes Association as FPG ≥7.0 mmol/l or 2-h postload glucose ≥11.1 mmol/l. Serum insulin (Mercodia AB, Uppsala, Sweden) was measured by ELISA. Insulin resistance was defined by the homeostasis model assessmentinsulin resistance (HOMA-IR) index as (fasting insulin [μU/ml] × fasting plasma glucose [mM])/22.5. High-sensitive C-reactive protein (hsCRP) was measured using a highly sensitive ELISA kit (intra-assay CV of 2.9%, interassay CV 4.7%; Immunology Consultants Laboratory, OR, USA). The determination of serum cardiotrophin-1 was carried out using human cardiotrophin-1 ELISA kits (intra-assay CV 1400 cm/s. The independent variables age, gender, cardiotrophin-1, smoking habit, habitual exercise, SBP or prehypertension and hypertension, BMI, FPG or diabetes, total cholesterol or hypercholesterolemia, triglyceride or hypertriglyceridemia, HDL or low HDL, HOMA-IR, hsCRP and creatinine. A p value less than 0.05 was considered statistically significant. Results A total of 300 subjects, 200 (66.7%) with baPWV >1400 and 100 (33.3%) with baPWV≤1400 cm/s, were enrolled. The comparisons of clinical characteristics between the two groups were shown in Table 1. Subjects with baPWV >1400 cm/s were older and had significantly higher SBP, DBP and HOMA-IR levels, and higher prevalence of hypertension and diabetes than those with baPWV ≤1400 cm/s. In addition, cardiotrophin-1 level was significantly higher in subjects with baPWV >1400 cm/s than those with baPWV

future science group

Research Article

≤1400 cm/s (325.7 [566.9] versus 224.1 [397.2] pg/ ml; p = 0.001). The relationship between baPWV >1400 cm/s and clinical variables was examined with multivariate logistic regression analyses. When selecting variables showing univariate association at p < 0.1 in the multivariate regression analysis, which included age, cardiotrophin-1, systolic blood pressure/prehypertension/hypertension and fasting plasma glucose/diabetes, age (OR: 1.055; 95% CI: 1.020–1.091; p = 0.02), cardiotrophin-1 (OR: 2.723; 95% CI: 1.242–5.973; p = 0.012) and systolic blood pressure (OR: 1.068; 95% CI: 1.040–1.097; p < 0.001) were independently associated with baPWV >1400 cm/s. However, variables not included in the above analysis, such as BMI/ obesity, lipid profile and smoking, had been shown to be associated with baPWV according to the results of previous studies [10,17] . Therefore we included BMI/ obesity, lipid profile and smoking as predictor variables, in addition to age, cardiotrophin-1 and systolic blood pressure. The main findings for the association between cardiotrophin-1 and arterial stiffness were similar in both regression models. As shown in Table 2, age, cardiotrophin-1 and SBP (model 1) or prehypertension and hypertension (model 2) were independent predictors of baPWV >1400 cm/s after controlling for gender, BMI or obesity, FPG or diabetes, HOMA-IR, total cholesterol or hypercholesterolemia, triglyceride or hypertriglyceridemia, HDL or low HDL, hsCRP, creatinine, smoking and habitual exercise habit. Discussion To the best of our knowledge, this work is the first study to investigate the association between cardiotrophin-1 and arterial stiffness in human. Our study reports that subjects with elevated baPWV had significantly higher cardiotrophin-1 levels than those without it. In addition, age, cardiotrophin-1, SBP or hypertension and prehypertension were positively associated with arterial stiffness, measured by baPWV, independent of ­traditional cardiometabolic risk factors. Arterial stiffness represents early detectable manifestations of adverse structural and functional changes within the vessels, and greater arterial stiffness is able to predict all-cause and CV mortality [12] . Although the cfPWV (using the carotid-femoral distance) is the gold-standard measurement of PWV, the baPWV (using the distance between brachium and ankle) is significantly correlated with cfPWV (r = 0.76; p < 0.0001) [18] . Furthermore, baPWV is associated with increased risk of total cardiovascular events and allcause mortality in Asian [19] . Apart from the dominant effect of aging, hypertension, obesity, hypercholesterolemia, diabetes and smoking were associated with

www.futuremedicine.com

125

Research Article  Hung, Lu, Ou et al.

Table 1. Comparisons of clinical characteristics between subjects with baPWV ≤1400 and >1400 cm/s.  

baPWV (cm/s)

p-value

 

≤1400

>1400

 

N

100

200



Age (years)

54.3 ± 10.6

63.8 ± 9.8

Cardiotrophin-1 is associated with increased risk of arterial stiffness.

Cardiotrophin-1 null mice presented decreased arterial stiffness. The aim of this study is to investigate the relationship between cardiotrophin-1 and...
1MB Sizes 0 Downloads 24 Views