exercise blood pressure and endothelial dysfunction in hypertension

Exercise blood pressure and endothelial dysfunctionin hypertension

N. Tzemos, P. O. Lim, T. M. MacDonald

Introduction

Impairment in vascular endothelial nitric oxide (NO)

bioactivity or endothelial dysfunction is encountered

in many cardiovascular diseases, including hyperten-

sion (1). There are now prognostic data suggesting

that endothelial dysfunction that was demonstrated

in the coronary arteries relates to future cardiac

events (2). Importantly, abnormal endothelium-

dependent vasodilatation may be present in the coro-

nary vasculature of hypertensives, despite normal

coronary angiograms (3). These findings have practi-

cal and prognostic implications as cardiac events are

common in hypertensives and may be predicted by

the presence or persistence of endothelial dysfunction

despite treatment (4,5).

There is no simple method of assessing the endo-

thelial function, and current techniques are either

invasive, costly or complicated making them unsuit-

able for routine clinical application. We hypothes-

ised that an exaggerated blood pressure (BP)

response to exercise might be an easily measured,

non-invasive surrogate marker of endothelial dys-

function, as it is known to be associated with

impaired peripheral vasodilatory response to exer-

cise (6). Furthermore, an exaggerated rise in systolic

SUMMARY

Background: Hypertensive patients with persistent endothelial dysfunction have

adverse cardiovascular prognosis. However, current methods aimed to assess

endothelial dysfunction in those patients who possess clinical applicability. We

hypothesised that such individuals could potentially be identified by an exagger-

ated systolic blood pressure (BP) response to a submaximal exercise.

Methods: We studied 22 male patients with essential hypertension who were

categorised into two age-matched groups depending on their exercise systolic

BP (ExSBP) rise during the 3-min exercise step test; the exaggerated ExSBP

group [hyper-responders (‡ 40 mmHg)] and the low ExSBP responder group

[hypo-responders (£ 20 mmHg)]. Eleven healthy volunteers matched for age

were used as control. Clinic and daytime ambulatory BP were assessed after

14 days of anti-hypertensive treatment withdrawal, which were not significantly

different between groups. Vascular reactivity in response to intra-arterial infu-

sions of acetylcholine, NG-monomethyl-l-arginine (l-NMMA) and sodium

nitroprusside was assessed using forearm venous occlusion plethysmography.

Results: The hyper-responder group had significantly less forearm vasodilatation

to acetylcholine compared with the hypo-responder group [percentage change

in the forearm blood flow 125 (17) vs. 260 (28), mean (SEM); p < 0.001].

Similarly, the vasoconstrictive response to l-NMMA was significantly impaired in

the hyper-responder group in comparison to the hypo-responder group [)30 (2)

vs. )45 (4); p < 0.05]. In contrast, the vascular response to sodium nitroprus-

side was not different between groups suggesting preserved endothelial-indepen-

dent vasodilatation. Conclusions: Despite similar ambulatory and office BP, the

exaggerated ExSBP group had significantly worse endothelial function compared

with the low ExSBP responder group. This simple and non-invasive test may be

useful in routine clinical practice to aid risk stratification in hypertensive

patients.

What’s knownImpairment in endothelial nitric oxide (NO) release

or endothelial dysfunction is encountered in many

cardiovascular diseases including hypertension.

Coronary endothelial dysfunction is known to

predict future cardiovascular events and it has been

reported that abnormal endothelium-dependent

vasodilation can be demonstrated in the coronary

circulation in hypertensives despite normal coronary

angiograms. These findings have practical and

prognostic implications as cardiovascular events are

a common mode of death in hypertensives and

these may be predicted by the presence of

endothelial dysfunction. However, there is no

simple method of assessing the endothelial function

and current techniques are either invasive, costly or

complicated making them unsuitable for routine

clinical application.

What’s newUsing a simple 3-minute exercise step test we have

shown that treated hypertensive patients with an

exaggerated exercise blood pressure response had

significantly worse endothelial function compared to

those with normal blood pressure exercise response.

It is possible that this blunted vasodilatory response

to exercise was secondary to severely impaired NO

bioactivity in those patients. If is that the case, then

this simple 3-minute exercise (Dundee step test)

could be a useful surrogate marker of endothelial

dysfunction thus making it attractive for introduction

in clinical practice.

Division of Medicine &

Therapeutics, Hypertension

Research Centre, Ninewells

Hospital & Medical School,

University of Dundee, Dundee,

UK

Correspondence to:

Dr Nikolaos Tzemos,

Division of Medicine &

Therapeutics, Hypertension

Research Centre, Ninewells

Hospital and Medical School,

University of Dundee, Dundee

DD1 9SY, UK

Tel.: + 44 1382 633854

Fax: + 44 1382 425513

Email: [email protected]

Disclosures

None.

OR IG INAL PAPER

ª 2009 The AuthorsJournal compilation ª 2009 Blackwell Publishing Ltd Int J Clin Pract, February 2009, 63, 2, 202–206

202 doi: 10.1111/j.1742-1241.2008.01922.x

BP during exercise is in itself a potent predictor of

cardiac mortality (7).

Materials and methods

A total of 100 patients with longstanding hyperten-

sion that had been treated (daytime ambulatory

blood pressure > 135 ⁄ 85 mmHg, whilst off treat-

ment) were initially screened for this study from

those referred to the Tayside specialist hypertension

clinic. Subjects were then selected for the study

depending on their systolic BP response to exercise.

The aim was to select two groups of subjects in the

extremes of exercise systolic BP (ExSBP) responses.

Thus, we chose subjects with £ 20 mmHg rise in

ExSBP and peak ExSBP of < 200 mmHg, as hypo-

responders. Subjects with a ‡ 40 mmHg rise in

ExSBP and peak ExSBP of > 200 mmHg were classi-

fied as hyper-responders. We excluded subjects

whose ExSBP rose between 20 and 40 mmHg. After

excluding patients with a history of coronary artery

disease, diabetes, hyperlipidaemia (total cholesterol

> 5.6 mmol ⁄ l), renal impairment or other vascular

diseases, we finally studied 22 male hypertensive sub-

jects. Also, secondary causes of hypertension were

excluded by careful scrutiny of history, physical

examination, biochemical and imaging studies wher-

ever clinically indicated. All subjects were non-smok-

ers and in addition, no subject was taking any drugs

known to affect the vascular endothelium. Impor-

tantly, none of the patients was currently an athlete

or engaged in any athletic competition. We have

excluded female patients from this study because of

the confounding effects of oestrogens on the endo-

thelial function before menopause. Finally, 11 nor-

motensive healthy volunteers were also recruited as

control comparison group from advertisement within

our institution. Written informed consent was

obtained from each study patient and this study has

the approval of the Tayside committee on Research

Medical Ethics.

Each patient underwent ambulatory BP monitoring

after anti-hypertensive therapy had been discontinued

for at least 14 days. ExSBP was then assessed at the

beginning of each study visit using the Dundee step

test (7) (Figure 1). Briefly, this was a submaximal

lightweight exercise step test using a step with a

height of 17.5 cm and a stepping rate of 92 per min-

ute set using a metronome. ExSBP was measured after

3 min of exercise using a validated automated exercise

BP monitor (Tango; SunTech Medical Instruments,

Morrisville, NC, USA). We have chosen the Dundee

step test as method of exercise because it assesses sub-

maximal exercise, which might be of advantage to

maximal exercise as it is not effort-related and thus

relatively independent of physical fitness and more

importantly it reflects daily life activities (7).

Brachial artery endothelial function was then

assessed using forearm strain gauge venous occlusion

plethysmography (8). Patients were studied in a

fasted state and in a temperature-controlled room

(24 ± 0.5 �C) as previously described (9). Briefly, fol-

lowing supine rest of 30 min, incremental brachial

intra-arterial infusions lasting 5 min each of acetyl-

choline (25, 50 and 100 nmol ⁄ min) and sodium

nitroprusside [SNP (4.2, 12.6 and 37.8 nmol ⁄ min)]

were used to assess the endothelial-dependent (NO

related) and -independent vasodilatation respectively.

Noradrenaline (60, 120 and 240 nmol ⁄ l) was used as

control vasoconstrictor (endothelium-independent

vasoconstrictor) and NG-monomethyl-l-arginine

[l-NMMA (1, 2 and 4 lmol ⁄ min)] as a competitive

antagonist of endothelial NO synthase, was used to

assess basal NO release. An identical protocol of drug

infusion order was kept for all study visits and

patients were unaware of the substance infused. Fore-

arm blood flow (FBF per ml ⁄ 100 ml forearm volume)

was expressed as percentage change in FBF from base-

line immediately preceding each drug infusion (DFBF

%). BP and heart rate were non-invasively (OMRON,

HEM-705CP, Matsusaka, Japan) recorded in the

non-infused (control) arm before each infusion.

Figure 1 Demonstration of submaximal exercise blood

pressure assessment using the Dundee step test

Exercise blood pressure and endothelium 203


Because BP and baseline forearm flows did not vary

significantly during visits, the FBF ratio between

infused and control arm in response to drugs was

expressed as percentage of the ratio measured during

the control period [DFBF % (mean ± SEM)].

Laboratory testingBlood sampling for all biochemical parameters took

place at the end of each visit with the subjects in

fasted state. All samples were assayed on the day of

collection using indirect ion-selective electrodes for

sodium, potassium and spectrophotometry for the

rest of biochemical parameters. All parameters were

measured through standard autoanalyser technology

in our routine hospital clinical chemistry service

operating with quality control standards (± 2.5%

interassay coefficient of variation).

StatisticsClinical characteristics between clinic visits were

compared by paired t-test whilst FBF measurements

for individual treatments were compared using two-

way ANOVA and the Bonferroni method for calcu-

lating 95% confidence intervals correcting for treat-

ment periods. Wilcoxon rank-sum test was used

when variables were not normally distributed.

p < 0.05 was considered significant.

ReproducibilityA total of 15 subjects (seven controls, eight hyperten-

sives) were re-studied after 4 days of the initial test

and exercise step tests were repeated. Intra-observer

variability was expressed as mean percentage error as

calculated by the following formula: standard devia-

tion of the difference between two measurements

·100% ⁄ mean of the two measurements. The intra-

subject correlation of variation was 6% with a mean

difference of 10.6 (SD) mmHg.

Experimental results

We studied 11 hyper-responders and 11 hypo-

responders among hypertensive patients (Table 1).

Eleven normotensive (daytime systolic and diastolic

BP 116 ± 3 and 74 mmHg respectively) male healthy

volunteers matched for age (mean age 50 ± 8 years)

were used as control comparison group. All groups

were comparable for age body mass index and forearm

circumference ⁄ length (Table 2). There were no signifi-

cant differences between the hypertensive groups with

regard to fasting cholesterol, triglycerides levels and

electrolytes (Table 1). Despite the very different

ExSBP, hyper-responders and hypo-responders had

similar office and daytime ambulatory BP (Table 2).

Hypertensive patients had, independently of their

ExSBP response, evidence of impaired NO bioactivity

compared with healthy volunteers (Figure 2). Acetyl-

choline and l-NMMA forearm vascular responses

(both endothelial-dependent) were significantly

blunted in hypertensive patients. In turn, the vascular

responses to SNP and noradrenaline (endothelial-

independent) were no different confirming the pres-

ence of endothelial dysfunction (Figure 2).

However, although both hypertensive groups had

a dose-response increase in FBF, the hyper-responder

group had significantly less dose-dependent increase

in forearm vasodilatation in response to acetylcholine

thus, less endothelium-dependent vasodilatation (Fig-

ure 2). The vasoconstrictive response to l-NMMA

was also significantly impaired in the hyper-respond-

ers while this response was near normal in the hypo-

responders. Hence, both stimulated and basal NO

Table 1 Clinical and biochemical parameters of the study population

Parameter

Hyper-responders

(n = 11)

Hypo-responders

(n = 11) p-value

Age, years 51 ± 9 49 ± 10 0.2

Body mass index, Kg ⁄ m2 28 ± 1 29 ± 1 0.4

Past anti-hypertensive therapy

(number ⁄ medication)

1A ⁄ 7B ⁄ 2C ⁄ 5D 11B ⁄ 6D ns

Serum potassium, mmol ⁄ l 4 ± 0.3 4 ± 0.2 0.8

Serum creatinine, mmol ⁄ l 97 ± 9 96 ± 8 0.4

Fasting serum cholesterol, mmol ⁄ l 5.3 ± 0.6 5.5 ± 0.2 0.3

Fasting serum HDL, mmol ⁄ l 1.4 ± 0.2 1.3 ± 0.3 0.4

Fasting serum LDL, mmol ⁄ l 3.4 ± 0.8 3.3 ± 0.9 0.3

Fasting serum triglycerides, mmol ⁄ l 2.3 ± 0.9 2.1 ± 1 0.4

Fasting plasma glucose, mmol ⁄ l 5.5 ± 0.8 5.9 ± 0.5 0.8

A, angiotensin-converting enzyme inhibitor; B, b-blocker; C, calcium channel blocker; D, diuretic.

204 Exercise blood pressure and endothelium


release were significantly impaired in the hyper-

responder group suggesting a significant impairment

of the vascular l-arginine-NO pathway. In contrast,

the vasodilatory response to SNP (NO-independent

response) was not different between groups indicat-

ing that the brachial arteries in these two groups

were functionally, rather than structurally different

and that vascular smooth muscle was able to dilate

equally in both groups (Figure 2).

Table 2 Hemodynamic parameters of the study population

Parameter

Hyper-responders

(n = 11)

Hypo-responders

(n = 11) p-value

Ambulatory daytime systolic blood pressure, mmHg (median ⁄ range) 147 ± 10 (146 ⁄ 34) 149 ± 13 (148 ⁄ 40) 0.8

Ambulatory daytime diastolic blood pressure, mmHg (median ⁄ range) 98 ± 9 (93 ⁄ 17) 100 ± 11 (101 ⁄ 34) 0.2

Office systolic blood pressure, mmHg (median ⁄ range) 165 ± 11 (162 ⁄ 40) 160 ± 12 (160 ⁄ 41) 0.4

Office diastolic blood pressure, mmHg (median ⁄ range) 102 ± 7 (102 ⁄ 20) 103 ± 10 (100 ⁄ 106) 0.8

Exercise systolic blood pressure, mmHg (median ⁄ range) 211 ± 18 (210 ⁄ 68) 179 ± 26 (184 ⁄ 90) 0.001

Change in systolic blood pressure, mmHg (median ⁄ range) 48 ± 12 (53 ⁄ 40) 18 ± 19 (18 ⁄ 29) 0.001

Rest heart rate, beats ⁄ min 73 ± 13 (73 ⁄ 42) 74 ± 9 (73 ⁄ 34) 0.5

Exercise heart rate, beats ⁄ min (median ⁄ range) 118 ± 13 (120 ⁄ 39) 110 ± 14 (111 ⁄ 49) 0.3

Absolute baseline FBF per ml ⁄ 100 ml forearm volume 3.2 ± 0.8 3.5 ± 1.9 0.6

Forearm circumference ⁄ length, cm 28 ± 2 ⁄ 29 ± 1 28 ± 1 ⁄ 28 ± 2 0.6 ⁄ 0.4

Change in systolic blood pressure indicates difference of systolic blood pressure between rest and exercise. Data are expressed as

mean (SD) except for FBF expressed as mean (SEM). Median and range values are also reported for those parameters not normally

distributed. FBF, forearm blood flow.

400

350

300

250

200

150

Per

cent

age

chan

ge in

FB

FP

erce

ntag

e ch

ange

in F

BF

100

50

0

0

–10

–20

–30

–40

–50

–60

Per

cent

age

chan

ge in

FB

F

0

–10

–20

–30

–40

–50

–60

250

200

150

Per

cent

age

chan

ge in

FB

F

100

50

025 50

*

*

†

†

†

*

*

††

100

1 2 4

4.2 12.6 37.8

60 120 240

Acetylcholine (nmol/min)

L-NMMA (µmol/min)

Sodium nitroprusside (nmol/min)

Norepinephrine (nmol/min)

Figure 2 Percentage changes in forearm flow ratio (infused ⁄ non-infused) from baseline preceding each drug infusion for

three dose levels of acetylcholine, sodium nitroprusside, l-NMMA and noradrenaline. (¤) indicates healthy volunteers (•)

indicates hypo-responders and (n) indicates hyper-responders. *p < 0.05, �p < 0.001

Exercise blood pressure and endothelium 205


Discussion

There are two novel observations in our study. First,

our findings indicate that an exaggerated rise in

ExSBP identifies hypertensives with persistent endo-

thelial function. The ease with which ExSBP can be

obtained using the Dundee step test may make it a

useful non-invasive marker of endothelial dysfunc-

tion in hypertension. Second, the findings also indi-

cate that within hypertensive patients and for the

same level of BP, there is considerable heterogeneity

in endothelial dysfunction severity.

Hypertension is a disease where the systemic arter-

ies are both structurally and functionally abnormal

(10). Indeed, response to the increased arterial pres-

sure the arterial wall undergoes structural changes

such as vascular remodelling and hypertrophy lead-

ing to elevated vascular resistance (11). Apart from

structural changes, the arterial wall also exhibits

functional abnormalities such as impaired NO bioac-

tivity or endothelial dysfunction (1). In the resting

state, shear stress causes a continuous (basal) NO

release modulating the peripheral vascular tone in

favour of a vasodilated state. Normally, the periph-

eral vascular resistance falls during exercise because

of peripheral vasodilatation. This is partly attribut-

able to an enhanced NO release during exercise via

vascular wall shear stress (6). It is likely that endo-

thelial dysfunction limits exercise peripheral vasodila-

tation that normally buffers against an exaggerated

rise in ExSBP. The association between exaggerated

systolic BP and endothelial dysfunction could poten-

tially explain the existing negative relationship found

between exaggerated BP and cardiovascular morbid-

ity and mortality in middle-aged men (12).

This study also shows how variable endothelial

function is in a group of hypertensive patients with

comparable BP control. It suggests that using the

same target treatment in all patients may be inappro-

priate. Perticone et al. have shown that persistence of

endothelial dysfunction despite treatment and reduc-

tion in BP predicted future cardiovascular events (5).

Thus, the 3-min Dundee step test could be a useful

additional test to help identify hypertensive patients

with worse endothelial dysfunction who are likely to

be at higher cardiac risk. Such patients may benefit

from tighter control of their risk factors but this

need to be studied in future research.

Limitations

Our study has certain limitations. We assessed

endothelial function at one point of time and after

anti-hypertensive treatment had been withdrawn. It

would be interesting to perform repeated endothe-

lial function assessments perhaps during medical

therapy to assess whether the observed reduction

in NO bioactivity persists in time. We evaluated

submaximal exercise using a novel step-based exer-

cise test, which differs from the traditional tread-

mill or cycloergometer-based tests employed by

other authors. Despite our test not having been

evaluated, as yet, as extensively as the other exer-

cise tests in long-term prognostic studies, the prac-

ticability of its use appeals for broader clinical use.

Finally, we assessed endothelial vascular responses

in a small and highly selected population. More

scientific work is necessary to evaluate those

responses in a larger population sample with

diverse exercise BP responses.

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Paper received May 2008, accepted September 2008

206 Exercise blood pressure and endothelium


exercise blood pressure and endothelial dysfunction in hypertension

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