Impaired endothelial function in hypertensive patients with target organ damage

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Abstract

To evaluate the correlation between endothelial dysfunction and multiple target organ damage (TOD), we measured endothelial function using high-resolution ultrasonography in hypertensive patients with or without TOD. Two hundred and eighty patients with hypertension were divided into four groups as follows: no TOD (Group I, n=61); 1 TOD (Group II, n=113); 2 TOD (Group III, n=59); and 3 TOD (Group IV, n=47). Endothelial function was assessed by endothelium-dependent flow-mediated dilatation (FMD) and -independent vasodilation (after sublingual administration of nitroglycerin) of the brachial artery using high-resolution vascular ultrasound. We also assessed the intima–media thickness (IMT) of the common carotid, carotid to femoral pulse wave velocity (cf-PWV) and left ventricular mass index (LVMI). FMD was inversely associated with the number of affected organs. FMD was lower in the patient groups with 3 TOD (Group IV: 6.85±4.70% vs Group II: 10.00±6.15%, P<0.01), 2 TOD (Group III: 7.37±5.02% vs Group II, P<0.01) and 1 TOD as compared with patients with no TOD (Group I: 11.88±7.11% vs Group II, P<0.05). In univariate correlation analysis, there was a significant relationship between FMD and IMT, serum creatinine, LVMI and cf-PWV. In stepwise multivariate regression analysis, FMD still correlated with waist size (β=−0.283, P<0.01), age (β=−0.231, P<0.05) and IMT (β=−0.197, P=0.05). These findings suggested that reduced FMD was associated with the number of TOD and may be considered an indicator for evaluating TOD.

Introduction

Target organ damage (TOD) has been shown to have an adverse prognostic significance that is independent of blood pressure (BP) and traditional risk factors in hypertensive patients.1, 2, 3, 4 Subclinical signs of TOD, such as left ventricular hypertrophy (LVH), carotid wall thickening and/or plaque build-up, alteration of arterial stiffness, microalbuminuria (MA) and a slight increase in serum creatinine, have been included in the list of hypertensive TOD by the 2007 European Society of Hypertension/European Society of Cardiology guidelines for the management of arterial hypertension.5

Flow-mediated dilatation (FMD) of the brachial artery is a marker of endothelial function and can be measured during reactive hyperaemia using high-resolution ultrasound.6 FMD occurs mainly as the result of endothelial release of nitric oxide and correlates with coronary endothelial function.7 Impairment of FMD is also associated with hypertension.8, 9, 10 Consequently, antihypertensive treatment improves endothelial function.11, 12

Little is known about the clinical correlation of endothelial function and multiple TOD in essential hypertension. In this study, we evaluated whether FMD could be an indicator for multiple organ damage in essential hypertensive patients.

Materials and methods

Study population

Two hundred and eighty patients with hypertension (162 men, 118 women), ranging from 22 to 83 years of age (mean: 59±10), were recruited from the outpatient clinic of Ruijin Hospital Shanghai, PR China. Exclusion criteria included ischaemic stroke, cerebral haemorrhage, transient ischaemic attack, myocardial infarction, angina, coronary revascularization, heart failure, diabetic nephropathy, renal impairment (serum creatinine M>133, W>124 mmol l−1), peripheral artery disease and tumour.

Participants underwent physical examination and blood tests to assess cardiovascular risk factors including age, gender, waist, waist–hip ratio, C-reactive protein, body mass index (BMI), smoking, the history of hypertension, systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP), plasma fasting glucose, serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, serum creatinine, urinary albumin–creatinine ratio (UACR) and intima–media thickness (IMT) of the common carotid.

Definition of TOD

According to the 2007 European Society of Hypertension/European Society of Cardiology guidelines for the management of arterial hypertension, TOD is defined as the presence of MA (UACR22 (M); or 31 (W) mg per g creatinine), a slight increase in plasma creatinine (M: 115–133 mmol l−1; W: 107–124 mmol l−1), arterial stiffness (carotid–femoral pulse wave velocity, cf-PWV>12 m s−1), evidence of LVH under echocardiography and vascular alterations as evidenced by vascular ultrasound. In particular, LVH was defined as a left ventricular mass index (LVMI)125 g m−2 in men and 110 g m−2 in women. The presence of 1 carotid atherosclerotic plaques or diffuse IM thickening was taken as evidence of vascular alterations. A plaque was defined as a focal thickening >1.3 mm in any segment of the carotid arteries. Diffuse IM thickening was diagnosed when common carotid IMT exceeded 0.9 mm.

Assessment of brachial artery endothelial function

Arterial endothelial function of the brachial artery was assessed non-invasively by means of ultrasound examination, as reported earlier.13 High-resolution echocardiography Doppler ultrasound (HD11EX ultrasound; Philips Medical Systems, Andover, MA, USA) with a broad-band linear array transducer (multiple frequency: 4–12 MHz) was used to measure the flow velocity and diameter of the right brachial arteries. The right brachial artery, proximal to the antecubital fossa, was imaged longitudinally using the linear-array transducer. FMD was assessed by measuring the brachial artery diameter at baseline and during reactive hyperaemia. Reactive hyperaemia was induced by deflating a cuff previously inflated to at least 50 mm Hg above systolic pressure for 5 min in the upper arm. Arterial flow velocity was measured at baseline and during reactive hyperaemia using pulsed-wave Doppler. After 15 min, the endothelium-independent response was assessed by the change in artery diameter at 3 min after a 400 μg dose of sublingual glyceryl trinitrate. All scans were recorded by a computer for analysis. The parameters were measured for three consecutive cardiac cycles with the top of the R wave on the electrocardiogram and the average was taken.

Measurement of arterial stiffness

Pulse wave velocity was measured automatically with a Complior SP (Artech-Medical co., Paris, France) device according to the methods described earlier.14 Briefly, cf-PWV was calculated from measurements of the pulse transit time between the two recording sites, namely the femoral and common carotid arteries. During preprocessing analysis, the gain of each waveform was adjusted to generate a signal of equal magnitude for the two waveforms.

Statistical analysis

Data are presented as mean±s.d. unless otherwise stated. Within the patient group, Pearson correlation analysis was used to identify possible relationships between FMD and cardiovascular risk factors. A stepwise multiple linear regression analysis was used to identify significant determinants of FMD and TOD. One-way analysis of variance was used to compare FMD among the four groups of patients with different numbers of TOD. Statistical significance was defined as P<0.05. All statistical analyses were performed using SPSS Version 11.5 (SPSS Inc.).

Results

Patient population

Of the 280 patients, 58% were men and 42% were women, with respective mean ages of 59±10 years and 60±8 years; 9.3% had DM, 86% had a family history of hypertension and 32% were smokers; 61 patients had no TOD, 113 had damage in one target organ, 59 had two target organs damaged and 47 had 3 target organs damaged. Patients in the hypertensive population were using oral antihypertensive agents, including angiotensin-converting enzyme inhibitors (n=81), angiotensin II receptor blockers (n=69), calcium antagonists (n=156), β-blockers (n=54) and diuretics (n=23). As the study subjects were using antihypertensive medications that may have affected our FMD results, we analysed the drug ratio in different groups and found there were no significant differences of the proportion of antihypertensive medications in different groups according to the report by Wolff et al.15 (Table 1). Otherwise, drug administration was suspended at least 24 h before the measurement of FMD.

Table 1 Characteristics of the study population

Correlation of FMD with cardiovascular risk factors

Univariate analysis identified a relationship between FMD and age (r=−0.235, P<0.001), BMI (r=−0.227, P<0.001), waist size (r=−0.244, P<0.001), waist–hip ratio (r=−0.200, P=0.001), high-density lipoprotein cholesterol (r=0.186, P=0.002), SBP (r=−0.125, P=0.036), PP (r=−0.187, P=0.002) and the course of hypertension (r=−0.202, P=0.001). However, there was no relationship between FMD and hypersensitive C-reactive protein, DBP, blood-fasting glucose, postprandial glucose, total cholesterol, triglyceride or low-density lipoprotein cholesterol (Table 2).

Table 2 Correlation of FMD with cardiovascular risk factors

Correlation of FMD with TOD

Univariate analysis confirmed a significant relationship between FMD and IMT (r=−0.257, P<0.001) (Figure 1), LVMI (r=−0.208, P=0.001) (Figure 2), cf-PWV (r=−0.168, P=0.005) (Figure 3) and serum creatinine (r=−0.140, P=0.019) (Figure 4). However, we did not find a correlation between FMD and UACR. A stepwise multiple regression analysis was performed to evaluate the independent determinants of FMD using age, BMI, waist size, waist–hip ratio, smoking, hypertension history, SBP, PP, serum creatinine, UACR, cf-PWV, IMT and LVMI. We found that FMD still correlated with waist (β=−0.283, P<0.01), age (β=−0.231, P<0.05) and IMT (β=−0.197, P=0.05) (Table 3).

Figure 1
figure1

Relationship between FMD and IMT. FMD, flow-mediated dilatation; IMT, intima–media thickness.

Figure 2
figure2

Relationship between FMD and LVMI. FMD, flow-mediated dilatation; LVMI, left ventricular mass index.

Figure 3
figure3

Relationship between FMD and cf-PWV. cf-PWV, carotid to femoral pulse wave velocity; FMD, flow-mediated dilatation.

Figure 4
figure4

Relationship between FMD and serum creatinine. FMD, flow-mediated dilatation.

Table 3 Linear regression analysis of FMD against cardiovascular risk factors and TOD

TOD in hypertensive patients with endothelial dysfunction

The patients were divided into two groups as follows: FMD10% and FMD<10%. Prevalence of IM thickening or plaques and artery stiffness in the FMD<10% groups was higher than that in the FMD10% group (53.15 vs 23.30%, P<0.01; 60.14 vs 45%, P<0.05). In contrast, the prevalence of LVH and MA was not significantly different between the groups (Figure 5).

Figure 5
figure5

Prevalence rates of LVH, IM thickening or plaques, artery stiffness, microalbuminuria (MA) and slight impairment of renal function in patients in the FMD10% and FMD<10% groups. **P<0.01, *P<0.05. IM, intima–media; LVH, left ventricular hypertrophy.

Number of TOD and the severity of FMD and nitroglycerin

Flow-mediated dilatation was significantly reduced as the total number of TOD increased (Figure 6). FMD was lower in the 3 TOD group (Group IV: 6.85±4.70% vs Group II: 10.00±6.15%, P<0.01), the 2 TOD group (Group III: 7.37±5.02% vs Group II, P<0.01) and the 1 TOD group compared with those in the no TOD group (Group II vs Group I: 11.88±7.11%, P<0.05). FMD was higher in the 2 TOD group than in the 3 TOD group, but the difference was not significant (Group III vs Group IV, P=0.65). There were no differences between the no TOD and the 1 TOD groups in respect of nitroglycerin (Group I: 13.20±7.61% vs Group II: 11.01±6.81%, P>0.05). However, nitroglycerin was lower in the 2 TOD group (Group III: 8.57±5.64% vs Group I, P<0.01) and in the 3 TOD group (Group IV: 9.05±6.53% vs Group I, P<0.01) as compared with the no TOD group. Adjusted for age, BMI, waist, waist–hip ratio, SBP, PP and the duration of hypertension, FMD was still lower in the 2 and 3 TOD groups compared with the 1 TOD and no TOD groups. However, there were no differences between all the groups in respect of nitroglycerin.

Figure 6
figure6

The number of target organs damaged and the severity of FMD. FMD was lower in the 3 TOD group (Group IV: 6.85±4.70% vs Group II: 10.00±6.15%, P<0.01), the 2 TOD group (Group III: 7.37±5.02% vs Group II, P<0.01) and the 1 TOD group compared with that in the no TOD group (Group II vs Group I: 11.88±7.11%, P<0.05). FMD, flow-mediated dilatation; TOD, target organ damage.

Discussion

The endothelium is the largest endocrine and paracrine organ in the body. FMD is an appropriate method to assess endothelial function in humans because it is non-invasive and reflects nitric oxide availability. Although the mechanisms of the relationship between hypertension and endothelial dysfunction are unknown, it has been proposed that endothelial dysfunction causes hypertension, which aggravates the impairment of endothelial function.16 In one of the larger studies, Yan et al.17 assessed brachial artery FMD in 1578 middle-aged men without known cardiovascular diseases. Univariate analyses showed that impaired brachial artery FMD was correlated to SBP and DBP. In this study, we found an inverse relationship between FMD and SBP, PP and the duration of hypertension. However, no relationship between FMD and DBP was found, which confirmed with other reports.18

Many studies have investigated the relationship between FMD and cardiovascular risk factors. Benjamin et al.19 investigated 2883 patients and found that FMD was inversely correlated with age, BP, BMI, lipid-lowering therapy and smoking. In their multivariate analysis, FMD was associated with BMI and female sex. Yeboah et al.17assessed 2338 patients and found that FMD was significantly correlated with age, BMI, high-density lipoprotein cholesterol levels, waist–hip ratio, serum cholesterol and the number of cardiovascular risk factors. In this study, we confirmed that the impairment of FMD correlated with age, BMI, waist size, waist–hip ratio and high-density lipoprotein cholesterol. These findings suggested that endothelial dysfunction may be an early stage in the pathogenesis of cardiovascular disease and may be one of its most important risk factors.

Many earlier studies reported the relationship between FMD and single TOD. In this study, we found that FMD in hypertensive patients was inversely related with serum creatinine, cf-PWV, carotid IMT and LVMI, as reported earlier.20, 21, 22 However, we identified no relationship between FMD and UACR. We observed that lower FMD correlated with higher serum creatinine, suggesting that impaired endothelial function may be associated with renal dysfunction in hypertensive patients. Several studies have shown a significant correlation between FMD and carotid IMT,20, 21 a result that is echoed in this study. Other studies reported different results.17, 18 A possible reason for this controversy may be the difference in study populations. Those studies that failed to find a relationship between FMD and IMT featured only healthy subjects. LVH is an important target organ in hypertensive cases. In our study, FMD correlated with LVMI, as reported earlier.22 Malik et al.23 investigated 469 hypertensive individuals and found that a higher log (UACR+0.1) value was associated with lower FMD. However, our study featured 9.3% DM patients, and their UACR was higher than in other hypertensive patients. We believed that this might contribute to our negative result. These findings suggested that FMD was associated with TOD severity. In brief, the severity of TOD was aggravated as FMD was reduced.

This study reported waist size, age and IMT as predictors of FMD reduction, independent of other covariates including BMI, SBP, PP and hypertension history. It should be emphasized that alterations in IMT of carotid arteries are a well-recognized marker of TOD of adverse prognostic significance.2 Our regression model showed that large waist size, old age and IM thickening might predict the presence in hypertensive patients of endothelial dysfunction. In FMD<10% group, the prevalence of IM thickening or plaques was higher than that in the FMD10% group. These findings suggested that IM thickening might partly predict endothelial dysfunction.

This study reported the relationship between the number of TOD and the severity of endothelial dysfunction in hypertensive patients. We found that FMD was inversely associated with the number of TOD at an early stage of TOD in patients with hypertension, and there is significant decrease between no TOD and 1 TOD, 1 TOD and 2 TOD, but at later stages of TOD in patients with hypertension (>2 TOD), there were no differences. On the basis of these results, we suggested that reduced FMD might be an indicator of TOD at an early stage.

In conclusion, this study offered the evidence that reduced FMD might be associated with the number of target organs damaged. As the total number of TOD increased, FMD decreased significantly. FMD may be considered an early indicator for evaluating TOD in hypertensive patients. To confirm this hypothesis, we would recommend a follow-up study that involves a larger patient cohort.

Conflict of interest

The authors declare that they have no competing interests.

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Acknowledgements

This study was supported by National Natural Science Foundation of China (30670832 and 30870941), National Key Project for Basic Research (2004CB518603, 2006CB503804 and 2009CB521905), National High-tech R&D Program (2006AA02Z179) and a grant from the Shanghai Science and Technology Committee (08JC1417400, 08DZ2200400, 08410702400).

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Correspondence to P-J Gao.

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Keywords

  • endothelial dysfunction
  • flow-mediated dilatation
  • target organ damage

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