European Heart Journal Advance Access originally published online on April 19, 2007
European Heart Journal 2007 28(9):1162-1169; doi:10.1093/eurheartj/ehm089
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Low-grade inflammation and hypoadiponectinaemia have an additive detrimental effect on aortic stiffness in essential hypertensive patients
1 Department of Cardiology, Hippokration Hospital, Athens, Greece
2 First Cardiology Clinic, University of Athens, Hippokration Hospital, Athens, Greece
Received 12 October 2006; revised 9 March 2007; accepted 15 March 2007; online publish-ahead-of-print 19 April 2007.
* Corresponding author: 43, Agias Marinas Street, 15127 Melissia, Athens, Greece. Tel: +30 210 7704802; fax: +30 210 7704802. E-mail address: ktsioufis{at}hippocratio.gr
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Abstract |
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Aims: In this study, we investigated the combined effect of increased high-sensitivity C-reactive protein (hs-C-reactive protein) and hypoadiponectinaemia on aortic stiffness in essential hypertensive subjects.
Methods and results: A total of 267 untreated patients with stage I–II essential hypertension underwent ambulatory BP and carotid–femoral pulse wave velocity (c–f PWV) evaluation. The distributions of hs-C-reactive protein and adiponectin were split by the median (1.3 mg/L and 7.8 µg/mL, respectively) and accordingly subjects were stratified into those with high and low values. Patients with high (n = 134) compared with those with low hs-C-reactive protein (n = 133) values exhibited greater c–f PWV levels (by 0.8 m/s, P < 0.0001), whereas patients with low (n = 133) compared with those with high (n = 134) adiponectin levels had higher c–f PWV (by 0.9 m/s, P < 0.0001). Stepwise regression analysis revealed that age, 24 h systolic BP, hs-C-reactive protein and adiponectin were independent predictors of arterial stiffness. In patients with low hs-C-reactive protein, hypoadiponectinaemia (n = 46) compared with high adiponectin (n = 87) was accompanied by increased c–f PWV (by 0.8 m/s, P < 0.0001). Similarly in patients with high hs-C-reactive protein, hypoadiponectinaemia (n = 84) compared with high adiponectin (n = 50) was related to heightened c–f PWV (by 0.7 m/s, P = 0.008).
Conclusion: In essential hypertension, pronounced low-grade inflammation in conjunction with hypoadiponectinaemia exerts an additive detrimental effect on aortic stiffness, accelerating the vascular ageing process.
Key Words: High-sensitivity C-reactive protein • Adiponectin • Aortic stiffness • Hypertension
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Introduction |
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Mounting evidence suggests that diverse inflammatory and adipose tissue associated pro-atherogenic mechanisms play a fundamental role in the pathogenesis of diffuse vascular damage.1–3 Increased levels of high-sensitivity C-reactive protein (hs-C-reactive protein), the most established downstream marker of inflammation, characterize hypertensive subjects,4 and contribute to target organ damage.5,6 Moreover, adiponectin, an adipocyte-derived plasma protein that is found decreased in the hypertensive state,6,7 acts as an endogenous antiatherogenic factor and it is associated with increased cardiovascular risk.3,8
Aortic stiffness, measured by carotid–femoral pulse wave velocity (c–f PWV), constitutes a hallmark of the aging process9 and an independent predictor of adverse cardiovascular events in hypertensives.10 A broad gamut of metabolic factors and vasoactive regulators has been associated with c–f PWV9,11 and there is an increasing interest in the determination of the impact of subclinical inflammation12–14 and adiponectin15,16 on arterial stiffening processes. Regarding the latter, the data are scarce in the setting of essential hypertension14–16 and studies have not been focused on ambulatory blood pressure (BP) measurements that provide a more efficient reflection of the haemodynamic load imposed on the vasculature than office BP.17
On this basis, we sought to examine whether the combination of hypoadiponectinaemia with increased hs-C-reactive protein levels could have an additive detrimental effect on aortic stiffness, as assessed by c–f PWV, in non-diabetic essential hypertensive subjects.
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Methods |
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Study participants
The study population consisted of 455 consecutive subjects with untreated newly diagnosed (within the last 2 years) stage I–II essential hypertension who referred or self-referred to our outpatient hypertension unit within a period of 24 months (between 9 February 2004 and 27 February 2006).18 Diagnosis of hypertension was based on three outpatient measures of BP > 140/90 mmHg and confirmed by daytime ambulatory BP > 135/85 mmHg. All subjects underwent the usual clinical and laboratory work-up in order to rule out secondary forms of hypertension.18
Exclusion criteria included atherosclerotic cardiovascular and valvular disease, and any other clinically significant concurrent systemic disease. We also excluded subjects with diabetes mellitus (fasting glucose > 125 mg/dL) or impaired glucose tolerance, familial dyslipidaemia, atrial fibrillation, or impulse conduction abnormalities. Moreover, none of the participants had any history or clinical/laboratory evidence of recent infection, inflammation, or underwent any medical treatment (including lipid-lowering and hormone replacement therapy) 1 month prior to entry in the study.
On this basis, 3 patients were excluded due to secondary hypertension, 73 due to disturbed glucose metabolism, 51 due to dyslipidaemia, 6 due to significant concurrent systemic disease, 23 due to evident atherosclerotic/valvular heart disease, 4 due to atrial fibrillation, 11 because of clinical/laboratory sign of recent infection, and 8 due to medical treatment, whereas 5 patients although eligible for participation did not complete the procedures and 4 refused to give informed consent. Finally, 267 essential hypertensives fulfilling the inclusion criteria were selected for participation and completed the study. The patients were studied supine, having fasted and abstained from smoking, alcohol, and caffeinated beverages in the 12 h before the study. The study protocol included ambulatory BP monitoring, assessment of aortic stiffness, echocardiographic examination, anthropometric and metabolic determinations, as well as hs-C-reactive protein and adiponectin levels estimation. The study protocol complies with the Declaration of Helsinki, was approved by our institutional Ethics Committee and all participants gave written informed consent.
Office and ambulatory blood pressure measurement
Office BP measurement was performed at three different visits in our outpatient clinic, according to the recent guidelines.18 Ambulatory BP was recorded over a working day (Monday through Friday) using the automatic Spacelabs units 90207 (Redmond, WA, USA). The procedure has been described in detail.19 In brief, the cuff was fixed to the non-dominant arm and the device was set to obtain automatic heart rate and BP readings at 15 min intervals during the daytime and at 30 min intervals during the nighttime. In keeping with current practice, daytime and nighttime were defined using short fixed-clock time intervals, which ranged from 10.00 am to 8.00 pm and from midnight to 6.00 am, respectively. Twenty-four-hour systolic and diastolic BP values were the mean of the overall 24 h recordings after artifact editing.
Cardiac ultrasonography
The echocardiographic studies were performed by an experienced senior echocardiographer who was blind to the clinical status of the examined subject, according to the recommendations of the American Society of Echocadiography.20
Assessment of aortic stiffness
Carotid–femoral PWV measurements were performed by two trained clinicians who were familiar with the technique, in a controlled room temperature with constant noise and light intensity, by using a validated non-invasive automatic device (Complior SP; Artech Medical, Pantin, France).21,22 The latter allows online pulse wave recording and automatic calculation of c–f PW, an established index of aortic stiffness, by measuring the time delay between the rapid upstroke of the carotid and femoral artery pulse waves. In brief, all subjects rested for 15–20 min while pulse pressure and BP were measured at the brachial artery using an automatic oscillometric device (Dinamap XL; Johnson & Johnson Inc., Raritan, NJ, USA). Measurements of c–f PWV were performed while the patient was in the supine position with a slight extension of the head and the right lower limb in external rotation. Two different pulse-wave tracings were recorded simultaneously at two sites (at the base of the neck for common carotid artery and over the right femoral artery) with two pressure-sensitive transducers. The distance for the calculation of c–f PWV was estimated from superficial measurement of the distance between the aforementioned two transducers. In each patient, five consecutive measurements of c–f PWV were performed and the mean c–f PWV was obtained.
Laboratory measurements
Venous blood sampling was performed from the anticubital fossa between 8:00 am and 9:00 am for the estimation of lipid levels, fasting glucose, haemoglobin A(1c), creatinine, hs-C-reactive protein, and adiponectin concentrations. Levels of hs-C-reactive protein were assessed using validated high-sensitivity assay (Dade Behring CardioPhase* hsCRP Assay, Marburg, Germany) with intra-assay and inter-assay coefficient of variation of 3.4 and 2.1%, respectively, and a minimal detectable concentration of 0.175 mg/L. Adiponectin was evaluated by a sandwich ELISA system (adiponectin ELISA kit, BioVendor, Heidelberg, Germany) with intra-assay and inter-assay coefficient of variation of 4.5 and 4.1%, respectively, and a minimal detectable concentration of 0.2 µg/mL.
Statistical analysis
STATA statistical software, (Version 9.0, Stata Corporation, TX, USA), was used for statistical analyses. All continuous variables are presented as means and standard deviations if their distribution was normal. The Shapiro–Wilk statistic was used in order to test for any deviation from normality. If any variable had a skewed distribution, descriptive statistics include medians and interquartile ranges. The categorical variables are described with absolute and relative (percentages) frequencies. The distributions of hs-C-reactive protein and adiponectin were split by the median (1.3 and 7.8 µg/mL, respectively) and high and low values were defined accordingly for each marker. Significant differences between the study subgroups were determined using the Student independent-samples t-test after checking for equality of variances using the Levene's test and analysis of variance (ANOVA). Analysis of covariance was performed in order to detect significant differences in c–f PWV between study subgroups after adjustment for established confounders. The potential association between categorical variables was tested with the Pearson's 
2 statistic. In order to adjust for the inflation of type I error due to the high amount of multiple comparisons, we used the Bonferroni correction. Since there were four study groups, six pairwise comparisons were possible and the differences were considered significant if the P-value was less than 0.008. Because of the skewed distribution, hs-C-reactive protein, and adiponectin values were logarithmically (log10) transformed prior to statistical testing. Moreover, before entering the multiple regression models, the independent variables of log hs-C-reactive protein and log adiponectin have been centred (i.e. subtracting the mean score from each data-point) and a new term has been created that is the interaction between the aforementioned centred variables. The mean values that were used for the calculation of centred log hs-C-reactive protein were 0.159, 0.177, and 0.118 for the total population, males, and females, respectively, while the mean values used for the estimation of centred log adiponectin were 0.908, 0.855, and 1.013 for the total population, males, and females, respectively. Forward stepwise linear multiple regression models were used to examine the independent significant predictors of c–f PWV. The candidate explanatory (independent) variables for entering the multiple regression model were age, sex, smoking status, body mass index, waist-to-hip ratio, 24 h systolic BP, 24 h diastolic BP, 24 h heart rate, glucose, HbA1c, triglycerides, HDL, and LDL-cholesterol, centred log hs-C-reactive protein, centred log adiponectin, and the centred log hs-C-reactive protein x centred log adiponectin interaction term. In order to validate our multiple linear regression models, we tested the normality and heteroscedasticity of the residuals produced. Any potential multicollinearity between the explanatory variables was tested by calculating the variance inflation factor (VIF) and tolerance (1/VIF). No multicollinearity was found since tolerance values were higher than 0.1. Our multiple regression model had the highest adjusted R2 value of all other models, explaining the variability of our dependent variable the best way possible. Statistical significance was set at P < 0.05 for two-sided tests during linear regression modelling. The power analysis showed that a number of at least 265 subjects is adequate to detect two-sided mean differences of >0.5 between subgroups and the investigated biochemical variables and could achieve statistical power >0.90 at the 5% probability level (P-value).
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Results |
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On the basis of the median hs-C-reactive protein (1.3 mg/L) our population was divided into subjects with high (n = 134) and low (n = 133) hs-C-reactive protein values. Patients with high compared with those with low hs-C-reactive protein values exhibited greater c–f PWV levels (8.2 ± 1.3 vs. 7.4 ± 1.1 m/s, P < 0.0001). Similarly our population was divided according to the median adiponectin (7.8 µg/mL) into those with high (n = 133) and low (n = 134) adiponectin values. Patients with low compared with those with high adiponectin levels had higher c–f PWV (8.3 ± 1.3 vs. 7.4 ± 0.9 m/s, P < 0.0001). Accounting for age, sex, smoking status, body mass index, waist-to-hip ratio, ambulatory BP, glucose, HbA1c, and lipid levels did not abolish the significant difference in c–f PWV between the aforementioned groups (P < 0.005 for both cases).
In the entire study population, c–f PWV was positively related to age (r = 0.356, P < 0.0001), waist-to-hip ratio (r = 0.216, P < 0.0001), 24 h systolic BP (r = 0.231, P < 0.0001), left ventricular mass index (r = 0.126, P = 0.043), log hs-C-reactive protein (r = 0.339, P < 0.0001; Figure 1 upper panel), while it was negatively associated with log adiponectin (r = –0.255, P < 0.0001, Figure 1 lower panel). Regarding hs-C-reactive protein, it was related to age (r = 0.145, P = 0.018), body mass index (r = 0.286, P < 0.0001), 24 h systolic BP (r = 0.213, P = 0.001), 24 h heart rate (r = 0.179, P = 0.005), triglycerides (r = 0.222, P < 0.0001) and it was negatively correlated with high-density lipoprotein cholesterol (r = –0.167, P = 0.009) and log adiponectin (r = –0.290, P < 0.0001). Regarding the association of hs-C-reactive protein with adiponectin, it was significant in both male and female patients (r = –0.206, P = 0.006 and r = –0.436, P < 0.0001, respectively). Moreover, log adiponectin was negatively associated with male sex (r = –0.333, P < 0.0001), body mass index (r = –0.183, P = 0.003), waist-to-hip ratio (r = –0.287, P < 0.0001), 24 h systolic BP (r = –0.236, P < 0.0001), 24 h heart rate (r = –0.176, P = 0.004), and positively related to high-density lipoprotein cholesterol (r = 0.152, P = 0.17). Moreover, when we split the population according to sex, the relationships of c–f PWV with log hs-C-reactive protein (r = 0.375, P < 0.0001 for males and r = 0.228, P = 0.031 for females) and log adiponectin (r = –0.227, P = 0.002 for males and r = –0.250, P = 0.017 for females) remained statistically significant. By multiple regression models, using c–f PWV as the dependent variable and age, male sex, smoking status, body mass index, waist-to-hip ratio, 24 h systolic BP, 24 h diastolic BP, 24 h heart rate, glucose, HbA1c, triglycerides, HDL and LDL-cholesterol, log hs-C-reactive protein, log adiponectin and the interaction of hs-C-reactive protein with adiponectin as the independent variables, it was revealed that age, 24 h systolic BP, log hs-C-reactive protein, log adiponectin, and the interaction of hs-C-reactive protein with adiponectin were independent predictors of the c–f PWV in the total population as well as in males, whereas age was the only predictor of stiffness in females (Table 1).
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Given the significant interaction of adiponectin with hs-C-reactive protein on c–f PWV values as indicated by our multiple regression model in the entire population, we classified patients with low hs-C-reactive protein levels into two subgroups with high (n = 87) and low (n = 46) adiponectin and patients with high hs-C-reactive protein into two other subgroups with high (n = 50) and low (n = 84) adiponectin (Tables 2 and 3). The demographic and laboratory parameters of these four groups are presented in Table 2, while the office/ambulatory BP and arterial stiffness data are reported in Table 3. Patients with low hs-C-reactive protein and low adiponectin levels compared with those with low hs-C-reactive protein and high adiponectin, exhibited higher c–f PWV (by 0.8 m/s, P < 0.0001), whereas no difference was observed among groups in left ventricular mass index (112 ± 15 vs. 107 ± 17 g/m2, P = 0.173) and in relative wall thickness (0.41 ± 0.08 vs. 0.41 ± 0.07, P = 0.89). Focusing on patients with high hs-C-reactive protein levels, those with low adiponectin compared with those with high adiponectin exhibited higher c–f PWV (by 0.7 m/s, P = 0.004) (Table 3), whereas there was no difference among the study subgroups regarding left ventricular mass index (111 ± 15 vs. 109 ± 12 g/m2, P = 0.266) and relative wall thickness (0.42 ± 0.06 vs. 0.43 ± 0.09, P = 0.585). Furthermore, patients with low hs-C-reactive protein/low adiponectin when compared with those with high hs-C-reactive protein/high adiponectin did not differ regarding c–f PWV (P = 0.874). The significant interaction between high hs-C-reactive protein and hypoadiponectinaemia on c–f PWV is additionally reflected by the finding that the subgroup of high hs-C-reactive protein/low adiponectin exhibited the higher c–f PWV levels compared with the subgroups of high hs-C-reactive protein/high adiponectin, low hs-C-reactive protein/low adiponectin, and low hs-C-reactive protein/high adiponectin (overall P < 0.0001) (Figure 2). Analysis of covariance revealed that the aforementioned differences among the study subgroups remained statistically significant even after adjusting for age, sex, smoking status, body mass index, waist-to-hip ratio, ambulatory BP, glucose, HbA1c, and lipid levels (P < 0.0001 for all).
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Discussion |
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The novel finding of the present study is that pronounced inflammatory activation in conjunction with hypoadiponectinaemia has a deleterious and most importantly additive effect on large artery stiffness in essential hypertension. This acceleration of vascular ageing caused by the interaction of hs-C-reactive protein with adiponectin is independent of demographic, haemodynamic, and metabolic confounders. Additionally, when increased hs-C-reactive protein is not accompanied by decreased adiponectin and vice-versa, arterial elasticity is deteriorated but in an inferior degree compared with that observed when both hs-C-reactive protein and adiponectin-associated stiffening pathways are activated.
Despite some inconsistencies, most studies support a correlation of hs-C-reactive protein with measures of arterial stiffness, in healthy subjects,12 patients with inflammatory diseases13 and essential hypertension.14 Similarly, adiponectin has been linked to aortic stiffening in diabetic and hypertensive patients.15,16,23 In both sexes, hs-C-reactive protein and adiponectin were interrelated, extending in this sense previous findings.14,16 However, hs-C-reactive protein and adiponectin were independent predictors of c–f PWV and exhibited an interaction on arterial stiffness only in males. This discrepancy suggests activation of distinct stiffening and atherosclerotic processes in the two genders and warrants further investigation. Furthermore, although age was the most important determinant of stiffness, there was no difference in age among the study groups and adjustment for the latter did not affect the interaction of inflammatory activation and hypoadiponectinaemia on stiffness.
One of the critical points of our study is that the estimation of the haemodynamic load was performed by means of ambulatory BP. The observed associations of 24 h systolic BP with both hs-C-reactive protein and adiponectin indicate that the imposition of oscillatory and low shear stress on the vascular beds may activate subclinical inflammatory and adiponectin-associated atherogenetic mechanisms.4–6,24 However, it is not yet clear whether higher BP levels cause mechanical changes in endothelial cells, promoting a cascade of mechanisms of inflammation and proatherogenesis or whether it is the other way around or even a bi-directional interrelationship. In our case, one could suggest that the alterations conferred by hs-C-reactive protein and adiponectin on arterial mechanics are beyond BP levels. This is supported by the fact that the differences in c–f PWV between groups remained significant after adjustment for changes in BP and by that 24 h systolic BP was an inferior predictor of stiffness compared with hs-C-reactive protein and adiponectin.
Several mechanisms may explain how hs-C-reactive protein and adiponectin contribute to arterial stiffening in hypertension. Circulating inflammatory mediators actively participate in the mechanisms of vascular insult and atheromatous changes,1,2,13,14,25 stiffening the arteries from the early stages of hypertension. Moreover, augmented hs-C-reactive protein in its own turn may decrease the endogenous vasodilator nitric oxide which is an important functional regulator of large artery stiffness in vivo.26 It is also possible that adiponectin interferes with the fundamental determinant of arterial stiffness, the constant elastin, and collagen turnover in the extracellular matrix of the vascular wall,9,13,14,27 which is already impaired by activated inflammatory pathways associated with hs-C-reactive protein. Our findings support the hypothesis that the aforementioned mechanisms are accelerated and exert an additive stiffening effect in the simultaneous presence of increased hs-C-reactive protein and hypoadiponectinaemia. Heart rate influences arterial stiffness,28 however, it seems not to be involved in the interactive effect of hs-C-reactive protein and adiponectin on c–f PWV, because there was no difference in heart rate among the study groups. Similarly, after controlling for smoking status the differences in c–f PWV did not change and this could be due to the age-related effect of smoking on arteries that is more pronounced in younger individuals with lesser vascular disease burden.29 There was also no association of lipid levels, glucose, or haemoglobin A1c with arterial stiffness, possibly reflecting the a priori exclusion of patients with impaired glucose metabolism and hypercholesterolaemia. Nevertheless, it is possible that the exact nature of the deleterious effect of inflammatory activation and hypoadiponectinaemia on aortic stiffness could be attributed to other metabolic, vasoactive, or genetic factors not estimated in this study.
Limitations
The cross-sectional nature of our study limits the ability to infer any temporal and causal relationship of inflammation and hypoadiponectinaemia with arterial stiffening. Another limitation is that we did not estimate wave reflections by augmentation index determination, for a more integrated approach to arterial stiffening.25 The existence of unrecognized stiffening mediators in our setting seems rather possible especially in females and the lack of data on menopausal status further attenuates the study's strength. Owing to the fact that we studied untreated, middle-aged patients who referred to our outpatient hypertension unit, the results could not be directly extendable in other age groups or in patients under antihypertensive treatment in the community. In addition, the exclusion of subjects with impaired fasting glucose makes the findings relevant only to normoglycaemic hypertensives. However, a potential strength of the study is that ambulatory BP measurements were performed, given the insufficient precision of the sphygmomanometer compared with ambulatory monitoring.17
Perspectives
Our data suggest that in hypertensive patients, inflammatory and adiponectin-mediated proatherogenic activation are interrelated and interact leading to a significant increase of arterial stiffness. To what extent the latter is critical regarding outcome should be further evaluated in properly designed longitudinal studies. Moreover, estimation of hs-C-reactive protein and adiponectin could serve as additional tools besides conventional cardiovascular risk factors for global arterial risk assessment. Whether the effect of increased hs-C-reactive protein and low adiponectin are additive in terms of cardiovascular risk in hypertension remains to be determined. On this basis, a unified therapeutic approach that would have anti-stiffening and anti-inflammatory properties might be of clinical importance and improve overall prognosis.23,30–32
In conclusion, hypoadiponectinaemia in conjunction with pronounced low-grade inflammation exerts an additive unfavourable effect on aortic stiffness in the setting of essential hypertension. This finding suggests that co-estimation of hs-C-reactive protein and adiponectin may contribute to a better identification of hypertensives with accelerated vascular ageing and consequently greater risk for cardiovascular events.
Conflict of interest: none declared.
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