Inflammation does not influence arterial stiffness and pulse ... - Nature

Journal of Human Hypertension (2013) 27, 629–634 & 2013 Macmillan Publishers Limited All rights reserved 0950-9240/13 www.nature.com/jhh

ORIGINAL ARTICLE

Inflammation does not influence arterial stiffness and pulse-wave velocity in patients with coronary artery disease AD Blann, N Kuzniatsova and GYH Lip Vascular function is an important pathophysiological factor in cardiovascular disease, and is influenced by many factors, one of the principles being hypertension. Developing evidence suggests that inflammation may be another risk factor. Vascular function and blood pressure haemodynamics can be assessed by arterial stiffness, pulse pressure and plasma markers. Testing the hypothesis of a relationship between inflammatory markers, hypertension and vascular function, we recruited 222 stable coronary artery disease outpatients, assessing inflammation with levels of high sensitivity CRP and interleukin-6 (IL-6), vascular function/ arterial stiffness by pulse-wave velocity (PWV), augementation (SphygmoCor system Artcor, Sidney, Australia), aortic and brachial artery pulse pressure, Von Willebrand factor (vWf) and soluble E-selectin (both enzyme-linked immunosorbent assay). In multivariate regression analysis, PWVs, augmentation indices and pulse pressures were linked with age, blood pressure and (some) with heart rate (all Po0.01), while vWf was associated with age (P ¼ 0.01). We conclude that, in patients with stable coronary artery disease, arterial stiffness and pulse pressure are related strongly and independently with age, blood pressure and heart rate, and that any effect of inflammation is minimal. Journal of Human Hypertension (2013) 27, 629–634; doi:10.1038/jhh.2013.17; published online 28 March 2013 Keywords: coronary artery disease; inflammation; CRP; pulse-wave velocity; vascular function; interleukin-6

INTRODUCTION The importance of good vascular function and blood pressure control in minimising the development and progression of cardiovascular disease is established.1,2 Among the methods of assessing vascular function are arterial stiffness,3,4 and levels of specific plasma markers of the endothelium such as Von Willebrand factor (VWf) and soluble E-selectin.5–7 While the four major risk factors for the development of atherosclerosis (hypertension, diabetes, smoking, dyslipidaemia) have dominated the pathophysiology of the disease for decades, and continue to do so, another risk factor may be inflammation.8,9 Evidence in favour of this includes high levels of inflammatory plasma markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) in hypertension and in atherosclerosis.10–14 The link between generalised inflammation and clinical disease such as hypertension and stroke, may be that increased cytokine activity causes adverse activation or damage to the endothelium, and changes in VWf and soluble E-selectin may reflect this.5–7,14–16 There is considerable data on the relationships between large artery vascular function and inflammation in apparently healthy community-living subjects,17–22 in essential hypertension23,24 and in diabetes.25 However, the inter-relationships between vascular function (as defined by factors such as hypertension, pulse pressures and arterial stiffness) and inflammation in patients with clear stable coronary artery disease are relatively unexplored. The present study was designed to test the hypothesis that in patients with existing coronary artery disease there is a relationship between arterial vascular function, hypertension and inflammation. As it is evident that atherosclerosis is a complex multi-factorial condition, we compared inflammatory and vascular

markers with the standard modifiable (smoking, dyslipidaemia, diabetes, body mass index) and non-modifiable (age, sex) risk factors for this disease. We tested our hypothesis in stable outpatients attending a cardiology clinic using two different approaches: arterial stiffness and pulse pressures of large arteries and levels of plasma markers—VWf and soluble E-selectin. Subjects We recruited 222 patients with proven coronary artery disease. No patient with myocardial infarction or an invasive procedure was within 3 months of their index event. Medical histroy, clinical, demographic and prescription drugs are listed in Table 1. Exclusion criteria were current use of oral or parenteral anticoagulation or other anti-platelet drugs (except aspirin) or clopidogrel, other non-steroidal anti-inflammatory drugs, bleeding abnormalities and/or significant hepatic, neoplastic, renal, connective tissue disease or inflammatory disease. The project had the approval of the Local Research Ethics Committee and written informed consent was obtained from each subject. Laboratory Arterial stiffness was used to assess physiological vascular function, which to some extent depends on endothelial function and smooth muscle tone (predominantly in the muscular conduit arteries). Haemodynamic assessment was commenced after 5 min of rest in the supine position.3,26 After blood pressure measurement, the SphygmoCor tonometer (SphygmoCor System Artcor, Sidney, Australia) was placed over the right carotid, radial and femoral arteries and measures collected over three cycles. The

University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK. Correspondence: Dr AD Blann, University of Birmingham Centre for Cardiovascular Sciences, Department of Medicine, City Hospital, Dudley Road, Birmingham B18 7QH, UK. Email: [email protected] Received 19 October 2012; revised 28 December 2012; accepted 11 February 2013; published online 28 March 2013

Arterial stiffness and PWV in patients with coronary artery disease AD Blann et al

630 Table 1. Clinical, demographic, pharmaceutical and laboratory details of the 222 participants Demographics Age (years) Sex (n, male/female) Smoking (n, not current) Body mass index (kg m 2) Laboratory Haemoglobin A1c (%) Total cholesterol (mmol l 1) Triglycerides (mmol l 1) High-density lipoprotein cholesterol (mmol l 1) Prescribed drugs Aspirin Statin ACEI/ARB b-Blocker Calcium channel blocker Nitrate Clopidogrel Diuretic Nicorandil Omega-3 fatty acid Medical history Myocardial infarction (n ¼ 193) Coronary artery bypass grafting (n ¼ 52) Stenosis proven by percutaneous coronary intervention (n ¼ 108) Diabetes (n ¼ 41) Stroke (n ¼ 15) Peripheral artery disease (n ¼ 29) Angina (n ¼ 108)

63.3 (10.1) 181/41 154/68 27.4 (3.9) 6.6 (1.3) 4.0 (1.0) 1.3 (1.0–1.9) 1.3 (0.4) 99.1% 94.1% 81.5% 72.5% 28.4% 20.3% 15.4% 11.3% 7.2% 6.7% 86.9% 23.4% 48.6% 18.5% 6.7% 13.1% 48.6%

Abbreviations: ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blockers. Data are provided as absolute number (%) of persons, mean (s.d.) or median (interquartile range).

distance of the radial and femoral analyses from the carotid was taken as from the supra-sternal notch to the position of the probe on the particular artery. The software then analysed the pulse wave using a validated generalised transfer function. Established17,18,22,23,26–28 indices of vascular function and haemodynamics were generated: (i) augmentation blood pressure (the measure of contribution that the wave reflection makes to the central aortic pressure, and it is obtained by measuring the reflected wave coming from the periphery to the centre) expressed as mm Hg; (ii) the augmentation index (calculated as augmentation blood pressure divided by pulse pressure 100 to give a percentage); (iii) the augmentation index corrected for heart rate and adjusted to a standard rate of 75 beats per minute; (iv) carotid to radial pulse-wave velocity (PWV) (m s 1); (v) carotid to femoral PWV; (vi) aortic pulse pressure and (vii) brachial artery pulse pressure, the latter two indices being the difference between systolic and diastolic blood pressures at each site28 (Table 2). Plasma markers Von Willebrand factor, soluble E-selectin, IL-6 and high-sensitivity CRP were measured by commercial immunoassay (for example, Dako, Copenhagen, Denmark and R&D Systems, Abingdon, UK). Intra-assay coefficients of variation (CVs) were o5%, inter-assay CVs were o10%. Power calculation and analysis We planned a multivariate analysis of 16 factors (age, sex, smoking, IL-6, CRP, diabetes, body mass index, systolic and diastolic blood pressure, history of hypertension/intake of antihypertensive medication, diabetes, heart rate, total Journal of Human Hypertension (2013) 629 – 634

Table 2.

Haemodynamics, inflammation and vascular function

Haemodynamics Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (cycles/min) Aortic pulse pressure (mm Hg) Brachial pulse pressure (mm Hg) Inflammation IL-6 (pg ml 1) High-sensitivity CRP (g l 1)

135 75 65 46.7 59.4

(20) (11) (12) (15.2) (16.5)

3.1 (1.1–12.6) 1.2 (0.7–2.3)

Vascular function Von Willebrand factor (IU dl 1) Soluble E-selectin (ng ml 1) Augmentation (mm Hg) Augmentation index (%) Augmentation index (corrected) (%) PWV (radial) (m s 1) PWV (femoral) (m s 1)

95 45 13.0 29.5 23.0 7.8 9.5

(23) (25–64.5) (9.0–18.7) (22.0–36.0) (15.3–28.0) (1.1) (2.6)

Abbreviations: CRP, C-reactive protein; IL-6, interleukin-6; PWV, pulse-wave velocity. Data are provided as absolute number (%) of persons, mean (s.d.) or median (inter-quartile range).

cholesterol, triglycerides, high-density lipoprotein-cholesterol and HbA1c) that we believed may have an impact on the vascular indices. According to Altman,29 the sample size should exceed the number of variables by a factor of 10, prompting an initial sample size of 160. However, as some of our variables (such as systolic and diastolic blood pressures) and some indices (such as the augmentation indices) clearly inter-relate mathematically and/or physiologically, we aimed to recruit up to 40% more subjects to allow for possible error. The final sample size provides the power at 1 b ¼ 0.85 and a o0.05 for a two-sided correlation coefficient of 0.20.30 Data distributed normally are presented as mean and s.d.; data distributed non-normally are presented as median and inter-quartile range. Continuous data with a Spearman rank correlation 40.15, and categorical indices with a Pp0.025 were entered into a multivariate regression analysis. Po0.05 was considered significant, and all analyses were performed on Minitab release 16 (Minitab Inc., State College, PA, USA).

RESULTS Clinical, laboratory and demographic data are shown in Tables 1 and 2. Univariate relationships between the vascular indices and 11 risk factors with a continuous variation are shown in Tables 3 and 4: many being very highly significant (for example, r40.4, Po0.001). Carotid-femoral PWV correlated with age, systolic blood pressure, heart rate and HbA1c; carotid-radial PWV correlated with diastolic blood pressure; vWf correlated with age and soluble E-selectin correlated with triglycerides and with HbA1c (Table 3). Data on the augmentation indices and pulse pressures are shown in Table 4. All indices increased with age and systolic blood pressure, while several correlated with diastolic blood pressure and heart rate. Total cholesterol correlated with the augmentation index after correcting for heart rate, and the uncorrected augmentation index correlated with HbA1c. There were no significant correlations between IL-6 and hsCRP and any other research index. Relationships between the vascular indices and three risk factors with a categorical variation are shown in Table 5. The most striking difference was soluble E-selectin in diabetes (reflecting its correlation with HbA1c in Table 3). Similarly, the small effect of diabetes on carotid-femoral PWV reflected the correlation of the latter with HbA1c. Corrected augmentation index varied according & 2013 Macmillan Publishers Limited


631 Table 3. Correlation analysis between risk factors with a continuous variation and plasma markers and PWV indices Risk factor

Soluble E-selectin

PWV radial

PWV femoral

vWf

Age

0.038 0.577

0.050 0.469

0.452 o0.001

0.222 0.001

Body mass index

0.153 0.023

0.016 0.811

0.020 0.779

0.026 0.705

Systolic BP

0.175 0.009

0.148 0.030

0.372 o0.001

0.050 0.456

Diastolic BP

0.031 0.651

0.360 o0.001

0.164 0.019

0.144 0.032

Heart rate

0.099 0.144

0.105 0.123

0.201 0.004

0.081 0.228

Total cholesterol

0.119 0.089

0.059 0.409

0.005 0.940

0.029 0.678

Triglycerides

0.243 0.001

0.180 0.012

0.099 0.183

0.005 0.943

0.077 0.291

0.049 0.504

0.034 0.655

0.070 0.334

HbA1c

0.218 0.014

0.156 0.164

0.238 0.036

0.095 0.391

IL-6

0.186 0.007

0.046 0.520

0.093 0.202

0.039 0.582

hsCRP

0.124 0.069

0.023 0.744

0.098 0.170

0.164 0.016

HDL cholesterol

Abbreviations: BP, blood pressure; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin-6; PWV, pulse-wave velocity; vWf, Von Willebrand factor. Upper figure: Spearman correlation coefficient, lower figure: P-value.

to sex, being higher in women. The brachial artery pulse pressure was lower in men than in women, and was higher in the diabetics. Any effect of drugs on the research indices was assessed for those patients taking clopidogrel (by 15.4%), angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers (by 81.5%), calcium channel blockers (by 28.4%), b-blockers (by 72.5%) and nitrates (by 20.3%) compared with the reciprocal population not taking one of these classes of drugs. The small number of patients taking or not taking aspirin, a statin, or other drugs brought a high possibility of false negatives and so was not attempted. Carotidfemoral PWV was higher in those taking a calcium channel blocker compared with those not taking such a drug (10.4 (2.8) versus 9.1 (2.4) m s 1, respectively, P ¼ 0.003). Similarly, those taking a nitrate had a lower augmentation index that those not taking a nitrate (22.6 (13.4) % versus 30.2 (10.9) %, P ¼ 0.001). Patients taking an angiotensin-converting-enzyme inhibitor or an angiotensin receptor blockers had a higher brachial pulse pressure (61.1 (16.8) mm Hg versus 53.3 (11.7), P ¼ 0.001) and a higher aortic pulse pressure (48.5 (15.3) versus 41.0 (14.4) mm Hg, P ¼ 0.006) compared with those not taking these drugs. Stepwise multivariate analyses were performed to determine which indices had the greatest influence on the variability of the vascular indices. The only index independently related to soluble E-selectin was triglycerides (P ¼ 0.028). Age (P ¼ 0.002) and hsCRP (P ¼ 0.025) were both independent predictors of levels of Von Willebrand factor, accounting for 3.9% and 1.8% (the adjusted r2), respectively, in the variance of this molecule. Factors influencing & 2013 Macmillan Publishers Limited

blood vessel indices are shown in Table 6. Only diastolic blood pressure was an independent predictor of carotid-radial PWV, but age, heart rate and systolic blood pressure all independently predicted carotid-femoral PWV, accounting for 33.9% of the its variance. Augmentation, as mm Hg, was independently predicted by systolic blood pressure, heart rate, age and sex so that all four accounted for 46.9% of the variability of this index. Converting augmentation from mm Hg to % found that heart rate, systolic blood pressure, sex and age were independent predictors, together accounting for 27.7% of the variability of this index. This was broadly confirmed in analysing the augmentation index when corrected for heart rate, where age, systolic blood pressure and sex together accounted for 12.9% of the variability. Aortic pulse pressure was linked to systolic blood pressure, age and heart rate, so that all three accounted for 58.9% of the variability of aortic pulse pressure. Brachial pulse pressure was linked to systolic blood pressure and age, and that both indices accounted for 67.9% of the variability of this pulse pressure. DISCUSSION In this study, we show that inflammation, as defined by plasma hsCRP or IL-6, fails to influence the variability of any of the ‘blood vessel’ markers of vascular function. Inflammation also failed to associate with soluble E-selectin, while hsCRP accounted for the variability of 1.8% of levels of Von Willebrand factor. Increased levels of soluble E-selectin are widely believed to reflect inflammation,6 possibly driven by inflammatory cytokines in vitro,31,32 but also in health and clinically-overt disease.33–35 We were therefore surprised to find no major relationship between this molecule and any of the vascular or inflammatory indices, despite a considerable literature. However, most of this literature refers to healthy subjects and those with uncomplicated hypertension,35–37 and not patients (such as ours) with overt coronary artery disease. Similarly, it has been suggested that Von Willebrand factor responds to inflammation, but much of this data arises from tissue culture and patients with marked inflammatory disease.7,38,39 The very weak relationship with hsCRP we have found to some extent supports this view, although the strongest influence on Von Willebrand factor remains ABO blood group.40 We suggest that the complex pathophysiology of coronary artery disease and its treatment renders the interpretation of levels of these plasma molecules very difficult. Similarly, inflammatory indices failed to relate to carotid-femoral PWV, but the latter did instead relate to age, systolic blood pressure and heart rate, which together accounted for over a third of the variability. This pattern was repeated by the blood vessel augmentation pressure data, where almost half of the variability was due to systolic blood pressure, heart rate, age and sex, whereas these risk factors accounted for over a quarter of the variability in augmentation index. These results mirror the strong dependence of PWV on age and blood pressure in a healthy population41 and in a meta-analysis.42 In the latter, age and blood pressure accounted for, on average, 23.5 and 13.5% of the variance in carotid-femoral PWV: in our patients with stable coronary artery disease, these factors were not as strong, accounting for 20.1 and 7.7%, respectively. Perhaps unsurprisingly, systolic blood pressure, age and heart rate accounted for well over half of the variability in aortic and brachial artery pulse pressure. Numerous studies have demonstrated that various risk factors, including hypertension and diabetes, are associated with adverse vascular function.4,14,17,26,43 In a Framingham study26 of over 2000 subjects free of diagnosed coronary artery disease but with some on hypertension treatment (32%) and 8% diabetics, carotidfemoral PWV (but not augmentation index) predicted a direct cardiovascular event, even after adjustment for age, sex and blood Journal of Human Hypertension (2013) 629 – 634


632 Table 4.

Correlation analysis between of risk factors with a continuous variation and factors relation to blood pressure

Risk factor

Augmentation

Augmentation index

Augmentation index corrected

Aortic pulse pressure

Brachial pulse pressure

0.402 o0.001

0.280 o0.001

0.273 o0.001

0.443 o0.001

0.384 o0.001

0.137 0.050

0.084 0.218

0.071 0.296

0.109 0.118

0.054 0.424

0.448 o0.001

0.225 0.001

0.253 o0.001

0.639 o0.001

0.796 o0.001

0.199 0.004

0.206 0.002

0.236 o0.001

0.105 0.130

0.097 0.150

0.432 o0.001

0.413 o0.001

0.030 0.664

0.308 o0.001

0.037 0.582

0.117 0.104

0.186 0.008

0.255 o0.001

0.009 0.897

0.001 0.998

0.052 0.482

0.044 0.538

0.057 0.428

0.091 0.217

0.046 0.519

0.119 0.111

0.151 0.038

0.069 0.345

0.036 0.631

0.025 0.736

HbA1c

0.186 0.108

0.212 0.006

0.024 0.829

0.02 0.867

0.158 0.155

IL-6

0.065 0.369

0.103 0.145

0.061 0.391

0.094 0.194

0.108 0.124

hsCRP

0.021 0.779

0.029 0.675

0.138 0.044

0.021 0.763

0.002 0.995

Age Body mass index Systolic BP Diastolic BP Heart rate Total cholesterol Triglycerides HDL cholesterol

Abbreviations: BP, blood pressure; hsCRP, high-sensitivity C-reactive protein; HDL, high-density lipoprotein; IL-6, interleukin-6. Upper figure: Spearman correlation coefficient, lower figure: P-value.

Table 5.

Analysis of risk factors with a categorical distribution

Von Willebrand factor (IU dl 1) Soluble E-selectin (ng ml 1) Augmentation (mm Hg) Augmentation index (%) Augmentation index (%) corrected PWV (radial) (m s 1) PWV (femoral) (m s 1) Aortic pulse pressure (mm Hg) Brachial pulse pressure (mm Hg)

Sex (181 men/41 women)

Smoking (68 yes/154 no)

Diabetes (41 yes/181no)

94 (23) versus 95 (21), P ¼ 0.912 45 (25–65) versus 45 (24–62), P ¼ 0.946 12 (8–18) versus 15 (10–19), P ¼ 0.049 29 (21–35) versus 34 (26–37), P ¼ 0.02 22 (15–28) versus 27 (22–30), P ¼ 0.002 7.8 (1.1) versus 7.5 (1.0), P ¼ 0.087 9.3 (2.6) versus 9.6 (2.5), P ¼ 0.69 45.8 (15.1) versus 50.5 (15.4), P ¼ 0.089 58.5 (15.9) versus 63.5 (18.5), P ¼ 0.021



Abbreviation: PWV, pulse-wave velocity. Data are presented as mean (s.d.) or median (interquartile range), analysed by t-test or Mann–Whitney, respectively.

pressure. More recently, a potential role of inflammation has been promoted,8,9,24 while CRP has emerged as the most accurate plasma marker of this process,11,12,17–23 and may directly promote vascular dysfunction.14,44,45 Despite this we have, in a wellpowered clinical study, been unable to find any evidence that inflammation has any role in large vessel vascular function in coronary artery disease. This may be because the complex nature Journal of Human Hypertension (2013) 629 – 634

of the disease and/or that its treatment(s) include at least one drug with an anti-inflammatory action (that is, aspirin), and it has been suggested that statins have anti-inflammatory activity.46,47 Furthermore, angiotensin-converting-enzyme inhibitors have positive effects on arterial stiffness.48 Indeed, in this study use of calcium channel blockers, nitrates and angiotensin-convertingenzyme inhibitors/angiotensin receptor blockers was associated & 2013 Macmillan Publishers Limited


633 Table 6.

ACKNOWLEDGEMENTS

Multivariate analyses

Dr Kuzniatsova was supported by a Fellowship from the European Cardiology Society.

Vascular index

Independent variable

P-value

r2

Carotid-radial PWV

DBP

o0.001

11.2

Carotid-femoral PWV

Age Heart rate SBP

o0.001 0.003 0.005

19.0 8.4 6.5

Augmentation

SBP Heart rate Age Sex

o0.001 o0.001 o0.001 0.035

20.2 19.6 6.3 0.8

Augmentation index

Heart rate SBP Sex Age

o0.001 o0.001 0.002 0.012

16.7 6.1 3.1 1.9

Augmentation index (corrected)

Age

o0.001

7.0

SBP Sex

0.002 0.013

3.8 2.1

REFERENCES

The authors declare no conflict of interest.

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Journal of Human Hypertension (2013) 629 – 634

Aortic pulse pressure

SBP Age Heart rate

o0.001 o0.001 o0.001

41.2 20.3 9.4

Brachial pulse pressure

SBP Age

o0.001 o0.001

62.8 14.2

Abbreviations: DBP, diastolic blood pressure; PWV, pulse-wave velocity; SBP, systolic blood pressure. Indices listed in order of significance.

with carotid-femoral PWV, the augmentation index, brachial pulse pressure and aortic pulse pressure clearly these drugs were designed to have an effect on blood pressure and heart rate. However, as we lack the power for a more comprehensive analysis to determine any true effect of these agents, we cannot say if these relationships are causal, mathematical or spurious. As our study is limited by its cross-sectional nature, further speculations are restricted and we cannot consider causation. Although inflammation (as quantified by CRP) seems to be related to subclinical cardiovascular disease, including PWV,49 our data denies a role for inflammation in large artery vascular function once coronary artery disease is established. Instead, our data emphasises the need to continue to address high blood pressure and focus on low heart rate in these subjects, especially in the elderly.

What is known about this topic Vascular function is abnormal in hypertension and diabetes and is influenced by age and blood pressure. Inflammation is believed to be a risk factor for coronary artery disease. Inflammation is reputed to influence vascular function. What this study adds In patients with treated, stable coronary artery disease, vascular function seems to be unrelated to inflammation. Vascular function in these patients is strongly influenced by age and blood pressure.

CONFLICT OF INTEREST


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