Aortic Augmentation Index is Independently Associated With N-Terminal Pro B-type Natriuretic Peptide in Patients With Peripheral Arterial Disease

Abstract

Objectives:

To investigate the relationship of aortic augmentation index (AIx) with N-terminal pro B-type natriuretic peptide (NTproBNP) plasma levels in patients with peripheral arterial disease (PAD) with normal left ventricular (LV) function.

Methods:

Totally, 31 patients (23 males, mean age 65 ± 7.4) with a confirmed diagnosis of PAD of the lower limbs (ankle–brachial pressure index [ABPI] <0.90 in at least 1 leg) were enrolled in this study. All patients underwent pulse wave analysis by applanation tonometry of the radial artery using the SphygmoCor system and had a measurement of plasma NTproBNP levels.

Results:

Patients had a mean resting ABPI of 0.62 ± 0.19 and a mean AIx 32.6% ± 6.9. Median (interquartile range) NTproBNP plasma level was 75 (44-210) pg/mL. In a univariate analysis which included age, brachial systolic blood pressure (BSBP), brachial diastolic blood pressure (BDBP), ejection duration index (ED%), heart rate (HR), and NTproBNP, aortic AIx was significantly associated (Spearman rho) with NTproBNP, HR, and ED% (r = .49, P = .006; r = −.72, P = .000, and r = −.42, P = .02, respectively). Multivariate linear regression analysis showed that AIx was associated with NTproBNP (β = 0.38, P = .02) independent of gender, HR, ED%, and use of β-blockers. N-terminal pro B-type natriuretic peptide explained 8% of the variance in aortic AIx, whereas HR explained 15% of the variance.

Conclusion:

In patients with PAD with normal LV systolic function, AIx is independently associated with NTproBNP. Structural changes in the myocardium might occur due to increased LV afterload as a result of increased wave reflections and arterial stiffness due to atherosclerosis leading to an increase in NTproBNP plasma levels.

Keywords

augmentation index N-terminal pro B-type natriuretic peptide peripheral arterial disease

Introduction

Augmentation index (AIx) is a measure of the effect of wave reflection on the second systolic peak and represents the measure of additional load on the left ventricle (LV) as a result of wave reflections.¹ The AIx is primarily a measure of wave reflections; however, due to its correlation with pulse wave velocity, it has been considered as a measure of arterial stiffness too.² It is calculated from the blood pressure (BP) waveform as the augmentation pressure divided by pulse pressure. It has been shown that AIx is an independent predictor of cardiovascular events in patients with end-stage renal disease³ and in patients after percutaneous coronary intervention.⁴

On the other hand, the amino-terminal fragment of B-type natriuretic peptide prohormone (NTproBNP) is a marker of cardiac function and is increased in symptomatic and asymptomatic heart disease.^5,6 N-terminal pro B-type natriuretic peptide has been shown to be a robust and independent predictor of all-cause mortality in patients with symptomatic peripheral arterial disease (PAD) or intermittent claudication (IC) and is considered a valuable tool for risk stratification in this patients’ cohort.⁷ Although NTproBNP is a surrogate marker of left ventricular systolic dysfunction (LVSD) and is increased in patients with heart failure, some studies have shown that NTproBNP plasma levels are increased in patients with atherosclerosis irrespective of LVSD.^6,8 Therefore, finding potential causes that may contribute to increased NTproBNP levels in patients with atherosclerosis and understanding the mechanism behind this increase could be essential to decrease the associated high cardiovascular morbidity and mortality.

The relationship between AIx and B-type natriuretic peptide (BNP) was studied in patients with atrial fibrillation (AF)⁹ and in patients with hypertension¹⁰ ; however, to date there are no studies in the literature, which reported on the association of these 2 surrogate markers in patients with atherosclerosis. The objective of this study, therefore, was to investigate the association of aortic AIx measured by applanation tonometry of the radial artery with plasma levels of NTproBNP in patients with IC not known to have heart failure and to study the mechanism behind this association.

Methods

This study was conducted in accordance with Helsinki declaration and the international conference for harmonization and good clinical practice (ICH/GCP) guidelines. Following approval from the local research ethics committee and the hospital research and development department, patients diagnosed with symptomatic lower limb arterial disease or IC were prospectively recruited from a vascular consultant-led outpatient clinic of a university teaching hospital over a 10-month period from February 2011. All recruited patients underwent initial assessments that included a thorough clinical history and examination and establishing current smoking status.

Inclusion Criteria

Patients were included in this study if they had unilateral or bilateral IC and an ankle–brachial pressure index (ABPI) <0.9, with no evidence of heart failure from history, clinical examination, and previous echocardiograms. Moreover, patients’ plasma level of NTproBNP must be <300 pg/mL to be eligible for inclusion in the study.¹¹

Hemodynamic Measurements

Heart rate (HR), brachial systolic blood pressure (BSBP), and brachial diastolic blood pressure (BDBP) were measured using an automated oscillometric device (Welch Allyn, Arden, North Carolina,), after resting for 5 minutes in a sitting position. This device has been validated in terms of BP measurement in several previous studies.^12
–14 All patients underwent ABPI measurement of each leg (ABPI of the most symptomatic leg was recorded) using a highly sensitive 8-MHz Doppler probe (Parks Medical Electronics, Inc, Aloha, Oregon).

Pulse wave analysis

The SphygmoCor device (Model SCOR-Pvx, software version 8; AtCor Medical Pty. Ltd., Sydney, Australia) was used for pulse wave analysis (PWA). A handheld high-fidelity tonometer (Miller tonometer, Houston, Texas,) was used for applanation tonometry of the right radial artery. The SphygmoCor device generated an average radial pulse wave contour after a 10-second recording period. This was then converted to a central pulse wave using a general transfer function available within the SphygmoCor device.^15,16 Both AIx and ejection duration index (ED%) were then derived from PWA.

Laboratory Measurements

Blood samples were obtained for a serum lipid profile including total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) which was analyzed using an enzymatic method. In terms of NTproBNP measurement, blood samples were taken in EDTA Vacutainers and centrifuged at 4°C. The resultant plasma was analyzed using an Elecsys 2010 analyzer (Roche diagnostics). For the purpose of diagnosing heart failure, patients with NTproBNP plasma levels <300 pg/mL were unlikely to have heart failure and patients with levels > 500 pg/mL were very likely to have heart failure.¹¹

Statistical Analysis

A Statistical Package for the Social Sciences Program (SPSS) version 18 for Windows (SPSS Inc, Chicago, Illinois) was used for statistical analysis. Continuous variables were expressed as mean ± standard deviation (SD) for parametric variables and median (interquartile range [IQR]) for nonparametric variables. Correlations between AIx and different clinical variables were studied with Spearman rank correlation coefficient (Spearman rho) as NTproBNP showed a skewed distribution. Factors which were significant in univariate analysis (P < .05) were included in a multivariate linear regression to further explore the relationship between AIx and NTproBNP. A P value of less than .05 was considered to be statistically significant. All tests were 2-tailed.

Results

Patients’ characteristics are summarized in Table 1. Overall, 31 patients (23 [74%] males) were recruited and completed the study. Median (IQR) NTproBNP plasma level was 75 (44-210) pg/mL, and all patients were not known to have heart failure at the time of recruitment. Patients had a mean ± SD resting ABPI of 0.62 ± 0.19 and a mean AIx of 32.6% ± 6.9. Table 2 illustrates the relationship between AIx and different clinical variables using Spearman rank correlation. The AIx showed a significant moderate positive correlation with NTproBNP (Figure 1), a significant strong negative correlation with HR (Figure 2), and a significant moderate negative correlation with ED% (Figure 3). However, there was no significant correlation between AIx and age, BSBP, and BDBP. Factors which showed significant association with AIx (P < .05) in the univariate analysis were entered into a multivariate regression analysis (Table 2) to further explore the relationship between AIx and NTproBNP. Additionally, gender and use of β-blockers were also included in the multivariate analysis as these 2 variables can affect AIx measurements.^17,18 In the multivariate analysis, AIx was associated with HR and NTproBNP independent of gender, ED%, and use of β-blockers. Furthermore, NTproBNP explained 8% of the variance in aortic AIx in the model, whereas HR explained 15% of the variance.

Table 1.

Summary of Patients’ Characteristics

Characteristics
Age, years	65 ± 7.4^a
Height, cm	168 ± 7.7^a
Weight, kg	80.6 ± 13.6^a
BMI, kg/m²	28.4 ± 4^a
Total cholesterol, mmol/L	4.5 ± 1^a
Triglycerides, mmol/L	1.7 ± 0.9^a
LDL-C, mmol/L	2.5 ± 0.9^a
HDL-C, mmol/L	1.2 ± 0.46^a
Total cholesterol/HDL-C	4 ± 1.4^a
HR, bpm	68.7 ± 9.6^a
BSBP, mm Hg	138 (130-157)^b
BDBP, mm Hg	80 (74-83)^b
MAP, mm Hg	98.6 (94-107)^b
Pulse pressure, mm Hg	60 (50-77)^b
ED%	35 ± 3.5^a
Current smokers, %	50
Diabetes, (%)	10
Medications
Aspirin, %	83
Statins, %	80
Calcium channel blockers, %	43
β-blockers, %	13

Abbreviations: BMI, body mass index; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; HR, heart rate; BSBP, brachial systolic blood pressure; BDBP, brachial diastolic blood pressure; MAP, mean arterial pressure; ED%, ejection duration index; IQR, interquartile range; SD, standard deviation.

^a Mean ± SD.

^b Median (IQR).

Table 2.

Relationship of Aortic Augmentation Index With Different Clinical Variables in a Univariate and Multivariate Analysis^a

	Univariate		Multivariate
Clinical Variable	r	P	Beta	P
Dependent variable: AIx
Age	.2	.28
Gender	–	–	0.05	.74
BMI	.2	.28	–	–
Height	−.26	.17	–	–
NTproBNP	.49	.006^b	0.37	.04^b
HR	−.72	.001^b	−0.70	.006^b
ED%	−.42	.02^b	0.11	.65
BSBP	.06	.73	–	–
BDBP	−.12	.5	–	–
β-blockers	–	–	−0.002	.99

Abbreviations: BMI, body mass index; NTproBNP, N-terminal pro B-type natriuretic peptide; HR, heart rate; ED%, ejection duration index; BSBP, brachial systolic blood pressure; BDBP, brachial diastolic blood pressure.

^a R ² = .59; F value = 6.98; Root mean square (RMS) = 12.9.

^b Significant (P < .05).

On the other hand, in addition to a significant moderate correlation with AIx, NTproBNP plasma levels significantly correlated with BSBP (r = .39, P = .02). However, there was no association between NTproBNP levels and age (r = .13, P = .48) or ED% (r = .07, P = .71) or HR (r = −.15, P = .42) or BDBP (r = .006, P = .97).

Discussion

This is the first study in the medical literature to show an association between AIx and NTproBNP in patients with PAD not known to have heart failure. Previous studies have shown an association between AIx and BNP levels in patients with AF⁹ and hypertension.¹⁰ Kaji et al⁹ showed that AIx was independently associated with BNP plasma levels in 92 patients with paroxysmal AF in comparison to the 90 age- and gender-matched individuals. Sakuragi et al¹⁰ also showed an independent association between BNP plasma levels and AIx in 60 treated hypertensive patients not known to have heart failure. In the latter study,¹⁰ there were more LV hypertrophy and diastolic dysfunction in patients with increased radial AIx.

In this study, we have shown that there is an association between aortic AIx and NTproBNP plasma levels in patients with PAD who are free from heart failure independent of gender, age, HR, ED%, and use of β-blockers. These covariates which were included in the multivariate analysis were found to have a relationship with AIx and cardiac function. For instance, age has been implemented as a possible factor affecting AIx values as arteries become less elastic and stiffer as they age, resulting in an increase in AIx, brachial BP, and mean arterial pressure.¹⁹ On the other hand, it has been reported that AIx was higher in women than in men over the age of 55 years, in a cohort of 458 patients.¹⁸ Furthermore, it is well known that AIx is affected by changes in HR. This was demonstrated in patients with normal LV function who underwent diagnostic cardiac catheterization.²⁰ The right atrium was paced to increase HR which caused a decrease in the AIx by 5.6% for each 10 beats/min increase in HR. Ejection duration represents the duration of LV systolic ejection in milliseconds. The ratio between the duration of LV systolic ejection and the total duration of the cardiac cycle is ED%. The latter can serve as a useful marker of cardiac function as it has been shown that ED% is elevated in patients with LVSD²¹ and was associated with AIx in the univariate analysis. Another confounding factor that can affect AIx is the use of β-blockers. These drugs have the ability to reduce HR and to prolong the ventricular ejection time, leading to a delay in the peak of the forward wave causing an increase in AIx compared to other agents. Another factor that has been suggested in explaining the increase in AIx by some B-blockers such as atenolol is their inability to reduce the wall/lumen ratio of muscular arteries and arterioles responsible for producing wave reflections (reflection sites) that are located at the origin of resistant arterioles.¹⁷ However, other β-blockers such as dilevalol have vasodilating properties leading to a decrease in AIx.²²

B-type natriuretic peptide and its N-terminal counterpart, NTproBNP, are secreted mainly from the ventricular heart muscle. B-type natriuretic peptide causes natriuresis, diuresis, and smooth muscle relaxation, while NTproBNP is biologically inactive.¹¹ It has been found that NTproBNP is more stable and more likely to reflect the actual concentration of the circulating peptide than BNP which varies with exercise and in myocardial ischemia.¹¹ Both peptides have shown to have prognostic value in symptomatic and asymptomatic heart failure.²³ However, patients with atherosclerosis with no evidence of LVSD were shown to have increased plasma levels of BNP,^6,8 indicating increased cardiovascular morbidity and mortality; therefore, understanding and finding possible causes for increased plasma levels of BNP in this cohort of patients is of paramount importance. Otsuka et al²⁴ reported that patients with increased cardiovascular risk have higher values of aortic AIx. This was evident in our patient’s cohort with a mean AIx of 32.6 ± 6.9% (range 15%-44%). The mechanism behind the increase in NTproBNP levels in patients with PAD can be explained by the increased aortic AIx which reflects an increase in wave reflections and LV afterload as a result. The increase in LV afterload will cause structural changes in the myocardium which could lead to LV hypertrophy and systolic dysfunction in the long term, leading to increased cardiovascular morbidity and mortality.

To conclude, although this study included a relatively small number of patients, it has shed a light on the mechanism behind the increase in NTproBNP levels in patients with PAD and its association with increased wave reflections. Despite the recent advancements in PAD risk stratification and management, the associated morbidity and mortality due to cardiovascular events remain high. Therefore, the identification of new risk factors and targeting them with new treatments is crucial. Increased arterial stiffness and wave reflections in patients with PAD could be targeted by these future treatments, thus decreasing the associated cardiac damage that might occur as a result.

Footnotes

Acknowledgments

We are grateful for the Welsh Heart Research Institute for providing training on using the SphygmoCor. We are also grateful to Professor J. R.Cockcroft for facilitating the training on the device.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded internally.

References

Davies

Struthers

. Pulse wave analysis and pulse wave velocity: a critical review of their strengths and weaknesses. J Hypertens. 2003;21(3):463–472.

Yasmin

Brown MJ.

Similarities and differences between augmentation index and pulse wave velocity in the assessment of arterial stiffness. QJM. 1999;92(10):595–600.

London

Blacher

Pannier

Guerin

Marchais

Safar

. Arterial wave reflections and survival in end-stage renal failure. Hypertension. 2001;38(3):434–438.

Weber

Auer

O'Rourke

. Arterial stiffness, wave reflections, and the risk of coronary artery disease. Circulation. 2004;109(2):184–189.

McDonagh

Robb

Murdoch

. Biochemical detection of left-ventricular systolic dysfunction. Lancet. 1998;351(9095):9–13.

Ndrepepa

Braun

Niemoller

. Prognostic value of n-terminal pro-brain natriuretic peptide in patients with chronic stable angina. Circulation. 2005;112(14):2102–2107.

Mueller

Dieplinger

Poelz

Endler

Wagner

Haltmayer

Amino-terminal pro-b-type natriuretic peptide as predictor of mortality in patients with symptomatic peripheral arterial disease: 5-year follow-up data from the linz peripheral arterial disease study. Clin Chem. 2009;55(1):68–77.

Bhalla

Chiang

Epshteyn

. Prognostic role of b-type natriuretic peptide levels in patients with type 2 diabetes mellitus. J Am Coll Cardiol. 2004;44(5):1047–1052.

Kaji

Miyoshi

Doi

. Augmentation index is associated with b-type natriuretic peptide in patients with paroxysmal atrial fibrillation. Hypertens Res. 2009;32(7):611–616.

10.

Sakuragi

Maruo

Taniguchi

. Radial augmentation index associated with increase in b-type natriuretic peptide in patients with hypertension. Int J Cardiol. 2008;130(3):414–419.

11.

Weber

Hamm

. Role of B-type natriuretic peptide (BNP) and NT-proBNP in clinical routine. Heart. 2006;92(6):843–849.

12.

Jones

Taylor

Poston

Shennan

AH.

Validation of the Welch Allyn ‘Vital Signs' oscillometric blood pressure monitor. J Hum Hypertens. 2001;15(3):191–195.

13.

Alpert

BS.

Validation of the Welch Allyn Spot Vital Signs blood pressure device according to the ANSI/AAMI SP10: 2002. Accuracy and cost-efficiency successfully combined. Blood Press Monit. 2007;12(5):345–347.

14.

Davis

Dennis

Railton

. Evaluation of the A&D UA-767 and Welch Allyn Spot Vital Signs noninvasive blood pressure monitors using a blood pressure simulator. J Hum Hypertens. 2005;19(3):197–203.

15.

O’Rourke

Pauca

Jiang

. Pulse wave analysis. Br J Clin Pharmacol. 2001;51(6):507–522.

16.

Pauca

O’Rourke

Kon

. Prospective evaluation of a method for estimating ascending aortic pressure from the radial artery pressure waveform. Hypertension. 2001;38(4):932–937.

17.

Asmar

London

O'Rourke

Safar

. Improvement in blood pressure, arterial stiffness and wave reflections with a very-low-dose perindopril/indapamide combination in hypertensive patient: a comparison with atenolol. Hypertension. 2001;38(4):922–926.

18.

Fantin

Mattocks

Bulpitt

Banya

Rajkumar

. Is augmentation index a good measure of vascular stiffness in the elderly? Age Ageing. 2007;36(1):43–48.

19.

Vaitkevicius

Fleg

Engel

. Effects of age and aerobic capacity on arterial stiffness in healthy adults. Circulation. 1993;88(4 pt 1):1456–1462.

20.

Wilkinson

Mohammad

Tyrrell

. Heart rate dependency of pulse pressure amplification and arterial stiffness. Am J Hypertens. 2002;15(1 pt 1):24–30.

21.

Denardo

Nandyala

Freeman

Pierce

Nichols

. Pulse wave analysis of the aortic pressure waveform in severe left ventricular systolic dysfunction. Circ Heart Fail. 2010;3(1):149–156.

22.

Kelly

Daley

Avolio

O'Rourke

Arterial dilation and reduced wave reflection. Benefit of dilevalol in hypertension. Hypertension. 1989;14(1):14–21.

23.

Mueller

Gegenhuber

Poelz

Haltmayer

. Diagnostic accuracy of B type natriuretic peptide and amino terminal proBNP in the emergency diagnosis of heart failure. Heart. 2005;91(5):606–612.

24.

Otsuka

Kawada

Ibuki

Kusama

Radial arterial wave reflection is associated with the MEGA risk prediction score, an indicator of coronary heart disease risk, in middle-aged men with mild to moderate hypercholesterolemia. J Atheroscler Thromb. 2010;17(7):688–694.