DUNDEE STEP TEST: A NOVEL NON-INVASIVE METHOD OF ASSESSING ENDOTHELIAL FUNCTION IN MAN

SMJ 2002; 47(1): 3-6

Since the seminal work of Furchgott and Zawadski1 our knowledge of the functions of the vascular endothelium has enjoyed an exponential growth over the last two decades. Hence, whilst 20 years ago we erroneously thought of the vascular endothelium as an inert anatomical shelter, now we have acknowledged its rediscovery as an autonomous organ with anti-atherogenic and anti-proliferative properties.2 Additionally, we have learned that a dysfunctional endothelium. can not only act as a promoter of atherosclerosis3 but can also predict adverse outcomes in cardiovascular disease. Despite the fact that endothelial function assessment could potentially become an important target in cardiovascular primary and secondary prevention, its clinical use has been greatly limited by its cumbersome technical assessment.4 In this brief review we describe and report a new, non-invasive, simple and potentially useful method in assessing endothelial function in man.

A functionally integral endothelium. releases nitric oxide (NO), a water and lipid soluble gas, which diffuses to the underlying smooth muscle cells and mediates vasodilation and growth regulation.5 Nitric oxide is synthesised from L-arginine via a constitutive enzyme called nitric oxide synthase (eNOS).6 There is a continuous release of NO (basal NO release) constantly stimulated by vascular shear stress (mechanical forces) on endothelial cells, conferring permanent tonic vasodilation.7 Inhibition of this basal release in humans produces vascular smooth muscle hypertrophy, high peripheral vascular resistance and sustained hypertension.8

NO is also released "on demand" (stimulated NO release) by endogenous substances such as acetylcholine, bradykinin, and substance P acting on specific endothelial cell receptors. Part of NO synthesised is released into the lumen where it interacts with circulating platelets promoting anti-aggregant and anti-adhesive activity.9

Of particular interest is that endothelial dysfunction has been a finding associated with most of the known cardiovascular risk factors such as hypertension, diabetes (both type I, II), cigarette smoking, family history, premature cardiovascular disease and hyperhomocysteinernia.10 Importantly, there is recent evidence to suggest that in vascular diseases such as hypertension and coronary artery disease, the presence of endothelial dysfunction strongly predict future cardiac events.11,12

Despite being the standard for guiding the treatment of hypertension the resting ‘office’ BP may not be the best measure of cardiac risk.13,14 For example, it correlates poorly with LVH, an important cardiac prognostic factor.13,14,15,18 Gottdiener and colleagues have found a significant relationship between maximal exercise SBP (>210mmHg) and LVH in normotensive volunteers.16 Similarly, Mahoney and colleagues have shown in 274 children aged 6-15 years that the exercise diastolic BP and the rise in systolic BP (ASBP) correlated better with LVH than resting BP measures.17 These findings were intriguing. However, there are alternative ways of assessing the BP; such as ambulatory BP, home BP and exercise BP that in separate studies appear to correlate better with LVH than the office BP.13

There has been considerable controversy about the type of exercise used to assess exercise blood pressure. Submaximal exercise has several advantages as it is less effort dependent and perhaps reflects daily life activities more closely than maximal exercise.19,20

This ExSBP correlates well with that obtained during bicycle ergometry at the same workload of about five METs.21 The low exercise intensity of this step test is similar to that used in large outcome trials and mimics the activities of daily living which to a large extent account for BP variability.22 The exercise test can be completed by most subjects irrespective of cardiovascular fitness. Hence, the Dundee step test can practically be implemented into an ambulatory clinic setting.

In a recent study from our centre, the ExSBP obtained using the Dundee step test was a better measure than resting BP in deciding whether sustained hypertension was present.23 Using a definition of mean daytime ambulatory BP >140/90 mmHg as indicative of sustained hypertension, the positive predictive value of a Clinic resting diastolic BP >90 mmHg and resting systolic BP>140 mmHg for sustained hypertension were 64% and 67%, respectively in 191 consecutive hypertension clinic referrals. In comparison, an ExSBP >180 mmHg had a positive predictive value of 76%, and this rose to 93% if an ExSBP >210 mmHg threshold was used.

Another study examined clinic BP control and ExSBP. It seems probable that treated hypertensives with an uncontrolled ExSBP are at higher risk of cardiovascular disease or premature death compared with subjects whose ESBP is controlled.24 In order to determine whether or not this is the case, a step test sub-study of the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) is being carried out.24

Aside from LVH, ExSBP is also an independent predictor of another important prognostic marker, the maximum heart-rate-corrected QT interval (QTcmax).25 This relationship was uncovered in a relatively small study involving only 29 untreated hypertensives free from ischaemic heart disease with a mean age of 51 years.

The skeletal muscle constitutes approximately 40% of the total body mass and at rest receives approximately 15-20% of cardiac output.26 During exercise, this rises to 80-90% in addition to increased peripheral 02 extraction.26 Dynamic exercise has a significant impact on muscular vascular bed homeostasis via an poorly understood phenomenon known as exercise hyperaemia, which is a net result of interlinkage between neural, metabolic, and hydrostatic processes.27

In the resting state shear stress causes a continuous (tonic) NO release modulating the peripheral vascular tone in favour of a vasodilated state.28 Normally, the peripheral vascular resistance falls during exercise due to peripheral vasodilatation. This is partly attributable to an enhanced NO release during exercise via vascular wall shear stress.29 Endo and colleagues have reported that the role of NO is minimal in hyperaemic vasodilation induced by static handgrip. They suggested that metabolic factors are probably more important.30 Others however have found a significant contribution of NO in hyperaemic vasodilation.31

Recently Gilligan and colleagues have shown that basal NO release, as assessed pharmacologically by L-NMMA (a specific antagonist of nitric oxide synthase), is partly responsible for the increased flow after isometric exercise (handgrip).29 Although, there is conflicting evidence regarding the role of NO in exercise vasodilation in health, we hypothesised that reduced NO bioactivity or endothelial dysfunction might limit exercise peripheral vasodilatation that normally buffers against an exaggerated rise in ExSBP. Consequently it followed that an exaggerated blood pressure response to exercise might be an easily measured, non-invasive surrogate marker of endothelial dysfunction since it is known to be associated with impaired peripheral vasodilatory response to exercise.14,24 Furthermore, an exaggerated rise in systolic BP during exercise is itself a potent predictor of cardiac mortality.14

We therefore investigated 22 male patients with essential hypertension and without other risk factors, which were subsequently divided in hyper-responder (ExSBP >200mmHg) and normoresponders (ExSBP <l80mmHg) according to their exercise systolic BP response.32 We found that the hyperesponder group had significantly impaired forearm NO bioactivity or endothelial dysfunction compared to normoresponders.32 (Fig. 1)

This finding might have important implications since there is recent evidence to suggest that the forearm vascular endothelial dysfunction is a potent predictor of cardiac outcome in hypertension.11 This is not surprising since there is a close correlation between the vascular function of the forearm vessels and that of the coronary circulation.33

Importantly, abnormal endothelium-dependent vasodilation has been demonstrated in the coronary arteries of hypertensives despite normal coronary angiograms.34 These findings have practical and prognostic implications since cardiovascular events are a common mode of death in hypertensives and these may be predicted by the presence of forearm vascular constriction.

References

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