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Endothelial dysfunction in hypertensive patients and in normotensive offspring of subjects with essential hypertension
  1. Department of Angiology
  2. University Medical Centre
  3. Riharjeva 24
  4. 1000-Ljubljana, Slovenia
  1. Dr Žižek: jelka.kos{at}

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Essential arterial hypertension (EH) is an important risk factor for atherosclerosis. There is growing evidence that endothelial dysfunction is the earliest event in atherogenesis and also precedes morphological changes of the arterial wall in hypertensive patients.1 One of the most widely recognised methods of determining the endothelial function is the dilation capability of arteries. Risk factors of atherosclerosis, including EH, probably decrease the production and increase the consumption of nitric oxide which plays a central role in the vasodilation.

Studies where venous occlusion plethysmography was used for measurement of changes in the blood flow demonstrated that patients with EH showed impaired endothelium dependent vasodilation of peripheral resistance arteries. On the other hand, there is only little evidence, albeit controversial, of the dilation capability of systemic conduit arteries in EH patients.2-4

The aim of the present study was to evaluate non-invasively whether flow-mediated dilation (FMD) of the brachial artery is also impaired, in spite of treatment in patients with EH, and to find whether these abnormalities precede clinical manifestations of elevated blood pressure and can therefore be detected in the normotensive offspring of subjects with EH (hypertensive familial trait (FT)).

The study encompassed four groups involving a total of 172 subjects. In the first group there were 46 patients (35 men and 11 women, mean age 49 years) with the EH documented for at least two years. Only hypertonics with well documented elevated blood pressure (⩾ 145/95 mm Hg in a sitting position in at least three different measurements before starting treatment) were included. The hypertensive subjects took their medication (either long acting calcium channel antagonists or angiotensin converting enzyme (ACE) inhibitors) 6–8 hours before haemodynamic measurements were performed. The second group of 44 healthy normotensive subjects (32 men and 12 women), matched with the patients in age and sex, served as controls. The third group comprised 41 subjects (23 men and 18 women, mean age 25 years), with a family history of essential hypertension in their first degree relatives (parents or siblings, or both). In the fourth control group there were 41 volunteers age and sex matched with FT subjects, and without a family history of hypertension. Both groups of young volunteers had recorded normal blood pressure at least three times in the year preceding the investigation. Information on blood pressure was obtained from family doctors and their medical records.

The dilation capability of the brachial artery was studied by high resolution ultrasound. The method of haemodynamic measurements was described elsewhere.1 The relative flow increase during reactive hyperaemia was calculated as the maximum flow divided by the flow during rest. The FMD response was expressed as a change in the end diastolic diameter of the brachial artery during reactive hyperaemia compared to the baseline measurement, and used as a measure of endothelium dependent vasodilation. Endothelium independent vasodilation of the brachial artery was studied by way of the sublingual application of 0.5 mg glyceryl trinitrate (GTN).

The patients with EH had significantly higher systolic and diastolic blood pressure than the controls (140.76 (11.74) mm Hgv 122.52 (8.11) mm Hg, p < 0.00005) and a higher body mass index in comparison to the control group (28.60 (3.61) kg/m2 v 25.05 (2.59) kg/m2, p < 0.00005). Systolic and diastolic blood pressure, although in the normal range, was higher in the FT group than in the controls (121.95 (9.54) mm Hgv 114.88 (9.39) mm Hg, p = 0.001; 80.24 (6.22) mm Hg v 75.49 (5.57) mm Hg, p = 0.0005 respectively). Subjects with a family history of hypertension also had a higher body mass index than healthy controls (24.33 (3.72) kg/m2 v 21.81 (2.45) kg/m2, p = 0.0006).

The mean resting diameter of the brachial artery in EH patients and in subjects with FT was comparable to the control groups (4.5 (0.87) mm v 4.2 (0.68) mm, p = 0.085; 3.7 mm (0.69) v 3.6 (0.52) mm, p = 0.211, respectively). The mean hyperaemic flow increase observed after cuff deflation was lower in EH patients than in the control group (380 (128)% v 476 (180)%, p = 0.005), while mean flow increase during reactive hyperaemia was comparable between the FT group and the controls (476 (129)%v 444 (140)%, p = 0.099).

FMD in hypertonics was significantly less than in controls (fig 1), and GTN induced dilation as well (12.1 (4.3)% v16.1 (4.6)%, p = 0.00007). FMD in hypertensive patients was also impaired when corrected for the GTN response (2.9 (3.0)%v 7.7 (2.4)%, p < 0.00005). In subjects with FT, FMD was also decreased in comparison to controls (fig 1); in contrast to hypertonics, the GTN induced dilation was comparable between the groups of young volunteers (14.0 (5.3)%v 15.7 (5.2)%).

Figure 1

Flow mediated dilation (FMD) of brachial artery in patients with essential hypertension (EH), in subjects with hypertensive familial trait (FT), and controls.

In the group of older participants as a whole, the univariate analysis FMD was strongly inversely related to the systolic and diastolic blood pressure (p < 0.00005), to the duration of hypertension (p < 0.00005), the family history of hypertension (p < 0.00005), and the body mass index (p < 0.00005), yet weakly related to the age (p = 0.045). There was also a strong inverse relation observed between the dilation capability (flow and GTN mediated) and the baseline vessel diameter (p < 0.00005). In contrast, hyperaemic flow increase was not a significant predictor of FMD. Variables that were significant in the univariate analysis were included in different multiple regression models. Multivariate analysis with the highest predicting value showed that in patients with EH the FMD was related to the family history of hypertension (partialr = −0.42, p < 0.00005), the systolic blood pressure (partial r = −0.43, p < 0.00005), and the baseline vessel diameter (partialr = −0.27, p = 0.010). The model was significant (p < 0.00005) with a relatively high goodness of fit (R 2 = 0.53). Similar results were obtained when diastolic blood pressure was substituted for the systolic blood pressure.

In both groups of young subjects (FT plus controls), FMD was strongly negatively related to the family history of hypertension (p < 0.00005). FMD was also negatively related to the baseline vessel diameter (p = 0.002). Multivariate regression analyses including the family history of hypertension, the baseline vessel diameter, the body mass index (p < 0.00005), and the systolic blood pressure (p = 0.030), revealed that the family history of hypertension (partial r = −0.42, p = 0.0002) and the baseline vessel diameter (partialr = −0.24, p = 0.048) were the most important determinants of FMD (R 2 = 0.37, p < 0.00005).

The present study demonstrated that, in spite of treatment, hypertonics without cardiovascular events showed decreased FMD of the brachial artery as compared to the normotensive controls. This difference was also preserved after making correction for the GTN response, which could further decrease the vasodilatatory capability of the investigated vessels. The observed difference in FMD between subjects with and without hypertension does not appear to be the consequence of methodologic variation as the intraobserver variability only accounts for 0.9 (1.8)%. Moreover, it was shown that the consequence of differing flow challenges between the groups had no influence on FMD. Only few and conflicting results have been reported in the literature with respect to direct measurements of FMD of conduit arteries. Iiyamaet al 2 and Schmiederet al 3 clearly showed that FMD of the radial artery in untreated hypertonics was blunted during an increased flow provoked by reactive hyperaemia or acetylcholine. On the other hand, Laurent et al 4failed to demonstrate impaired FMD in hypertensive patients. A shorter period of occlusion (2 minutes) of the investigated arm than that in other studies (4–5 minutes), or too small groups may be responsible in the latter study for the inability to demonstrate decreased FMD in hypertonics.

The reduction of FMD in our study was shown to be related to the systolic and diastolic blood pressure. Multivariate analysis confirmed that the systolic and diastolic blood pressure had the strongest independent negative influence on the dilation capability of the brachial artery. Data from experimental studies showed that blood pressure, like any other risk factors of atherosclerosis, caused a decrease in bioavailability of nitric oxide (related to its decreased synthesis and/or release), probably through damage of endothelial cells.

Our study also showed that in normotensive subjects with FT the vasodilator response of the brachial artery was blunted, as compared to the controls, during reactive hyperaemia. In comparison to the controls, our FT subjects showed increased levels of blood pressure, yet these were still in the normal range and they had no other manifestation of hypertensive disease. Previous studies based on plethysmographic investigation showed that normotensive subjects with a family history of EH had higher levels of peripheral resistance than controls, which is probably a consequence of endothelium dysfunction of the small vessels.5 These findings could imply that in subjects with FT a functional abnormality of endothelium may appear early in the life or may even be directly inherited.

Another important finding of our study is the decreased response to GTN in patients with EH compared to the controls, suggesting that hypertension, in addition to endothelial dysfunction, also causes dysfunction of smooth muscle cells. Until now, only a few studies have investigated the effects of hypertension on the functional properties of the smooth muscle cells of conduit arteries. Some investigators reported normal endothelium independent vasodilation of the systemic arteries in hypertensive patients, but Celermajer and colleagues1 demonstrated a blunted response to GTN in subjects with different risk factors of atherosclerosis, as well as in hypertonics. The causes of the conflicting data may be related to the different methods applied, the duration of hypertension, and particularly to the treatment modalities and use of different drugs.

In summary, patients with EH had, in spite of undergoing medication, decreased FMD and, to some extent, also decreased GTN mediated dilation of the brachial artery. These findings indicate that hypertension is related to endothelial and smooth muscle cell dysfunction. Endothelial dysfunction precedes the manifestation of hypertension and is present in the offspring of subjects with EH.