Aortic Augmentation Index is not a Useful Index of Cardiovascular Risk in Type 2 Diabetes

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ORIGINAL ARTICLE

Aortic Augmentation Index is not a Useful Index of Cardiovascular Risk

in Type 2 Diabetes

Mei-Yeh Wang

1

, Nei-Chung Chang

2

, Ju-Chi Liu

3

, Pei-Shan Tsai

4,5,6 * 1_{Department of Nursing, Cardinal Tien College of Healthcare and Management, Hsin Dien, New Taipei City, Taiwan} 2_{Cardiology Section, Department of Medicine, Taipei Medical University and Hospital, Taipei, Taiwan}

3_{Division of Cardiovascular Medicine, Taipei Medical University Shuang-Ho Hospital, Jhonghe, New Taipei City, Taiwan} 4_{Graduate Institute of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan}

5_{Department of Nursing, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan} 6_{Sleep Science Center, Taipei Medical University Hospital, Taipei, Taiwan}

a r t i c l e i n f o

Article history: Received: Aug 20, 2010 Revised: Nov 3, 2010 Accepted: Dec 6, 2010 KEY WORDS: augmentation index; nocturnal BP reduction; Type 2 diabetes

Background: Impairment of arterial properties has been suggested as a pathological link between dia-betes and adverse cardiovascular (CV) events. Accumulating evidence has supported a role for reduced nocturnal blood pressure (BP) reduction in predicting CV risk. In light of the clinical importance of CV risk in diabetic patients, the question of whether normotensive Type 2 diabetic patients have increased CV risk as determined by augmentation index (AI) value deserves further attention. The association between AI value and the magnitude of nocturnal BP reduction is also of interest.

Purpose: This study aimed to compare AI between normotensive Type 2 diabetic patients and mildly hypertensive patients. The association between AI and the magnitude of nocturnal BP reduction in Type 2 diabetic patients was also examined.

Methods: A total of 113 participants were included in this study. AI was derived by pulse wave analysis using radial applanation tonometry coupled with the generalized transfer function. Ambulatory BP measurements were performed over a 24-hour period.

Results: There was no signiﬁcant difference in AI between the diabetic patients and the mildly hyper-tensive patients after adjustment of age and body height. On the other hand, the diabetic patients exhibited a signiﬁcantly lesser degree of nocturnal BP reduction than the mildly hypertensive patients even after adjusting conventional CV risk. AI was not correlated to the magnitude of nocturnal BP reduction in the diabetic patients.

Conclusions: The diabetic patients did not have higher AI than mild hypertensive patients, whereas the diabetic patients had signiﬁcant blunted nocturnal BP reduction than the mildly hypertensive patients. The utility of AI as a maker for CV risk in normotensive Type 2 diabetic patients remained to be determined.

1. Introduction

Individuals with diabetes mellitus have been shown to have an increased risk of cardiovascular (CV) disease.1,2Impairment of arterial properties has been suggested as a pathological link between dia-betes and the risk of CV disease and/or target organ damage. In patients with Type 2 diabetes, arterial stiffness as determined by pulse wave velocity (PWV), was an independent predictor of CV mortality3and was independently associated with albumin-creati-nine ratio,4an index of renal hypertensive target organ damage.

The principal function of the arterial system is to deliver an adequate supply of blood to the tissues and organs. In performing this conduit function, the arteries transform the pulsatile flow generated by ventricular contraction and pressure in arteries into a steadyflow and pressure in peripheral tissues. The viscoelastic properties of the arterial wall described in terms of distensibility and stiffness determine an artery’s ability to perform this cushion function.5,6 Aortic distensibility is the reciprocal value of aortic stiffness. Various measures of arterial distensibility and arterial stiffness have been proposed as CV risk markers. Augmentation index (AI) analyzed based on the measure of wave reflection in the aorta is one of the most commonly used surrogate indices of aortic distensibility.6A higher AI represented decreased arterial disten-sibility. Using noninvasive radial applanation tonometry combined * Corresponding author. Graduate Institute of Nursing, College of Nursing, Taipei

Medical University, 250 Wu Hsing St, Taipei 110, Taiwan. E-mail:ptsai@tmu.edu.tw(P.-S. Tsai).

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with the generalized transfer function, the aortic pressure wave can be synthesized and AI can be calculated as the ratio of augmented pressure to pulse pressure.5Unlike measurements of aortic PWV, measurements of AI using applanation tonometry are easy to perform and require minimum training.7 High levels of both within- and between-observer repeatability of AI measurements using applanation tonometry was demonstrated in patients with CV risk factors.8The signiﬁcant association between higher AI and increased CV risk has been demonstrated in earlier studies. Patients with cardiomyopathy had higher AI value than healthy control individuals.9AI value was positively correlated to increased CV risk scores in patients with coronary and atherosclerotic disease.10In patients with coronary heart disease (CHD), AI was an independent determinant of ischemic threshold.11_{In addition, AI independently} predicted myocardial infraction, clinical restenosis, and death of patients undergoing percutaneous coronary intervention in a 2-year prospective study.12

It has been established that elevated blood pressure (BP) accelerates vascular and cardiac abnormalities in diabetes.13,14For example, diabetic patients with hypertension have higher PWV than patients with diabetes alone.15 However, in a group of normotensive Type 2 diabetic patients without a history of CHD, pulsatile changes in the aortic diameter was smaller than the healthy control individuals but no different from nondiabetic patients with CHD examined by Doppler tissue imaging,16 sug-gesting that impaired arterial function may occur in diabetic patients even in the absence of hypertension and CHD. Given that excessive CV risk may be linked to impaired arterial function, further investigation is warranted to determine whether Type 2 diabetic patients with normal BP have impaired arterial properties as determined by AI value. The question of whether Type 2 diabetic patients with normal BP would have higher AI than mildly hyper-tensive patients is also of interest.

Mounting evidence has suggested a significant impact of blun-ted nocturnal BP reduction (i.e., nondipping) on poor CV prognosis and severe target organ damage.14,17e19 Compared with diabetic patients with normal nocturnal BP reduction, diabetic patients with blunted nocturnal BP reduction were associated with marked endothelial dysfunction20and increased macrovascular complica-tions (i.e., symptoms of angina pectoris and history of myocardial infarction).21In addition, a significant association between AI value and abnormal diurnal BP dipping was observed in hypertensive patients.22_{However, studies that speci}_{fically examine the} associa-tion between diurnal BP variaassocia-tion and AI in normotensive Type 2 diabetic patients have been lacking. Given the close association between the nondipping pattern and poor CV prognosis and that between impaired arterial function and poor CV prognosis in dia-betic patients, it is speculated that the degree of AI is associated with the magnitude of nocturnal BP reduction in diabetic patients. The aim of the present study was to examine whether Type 2 diabetic patients with normal BP, when compared with patients with essential mild hypertension, have higher AI. The association between AI value and the magnitude of nocturnal BP reduction in Type 2 diabetic patients was also examined.

2. Methods 2.1. Participants

Data analyzed in this study were part of two larger studies. One study examined the efﬁcacy of real-time BP biofeedback for indi-viduals with prehypertension or Stage 1 hypertension according to the classiﬁcation of BP outlined by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.23The other study examined

manifestation of the subclinical indicators of CV risks for normo-tensive patients with CV risk. The diagnosis of Type 2 diabetes was based on the criteria of the American Diabetes Association. In both studies, participants were referrals from the outpatient depart-ments of cardiology, endocrinology and metabolism, and family medicine. Patients who had a history of established CV disease, neurological disease, renal disease, and cancer were excluded. All participants were free from antihypertensive medications. The research protocol was approved by the Institutional Review Boards at all participating institutions and all participants gave informed consent.

2.2. Measurements

2.2.1. Ambulatory BP measurements

Ambulatory BP (ABP) measurement was performed over a 24-hour period using an automatic BP recorder (Model 90217; SpaceLabs Inc., Redmond, WA, USA). The monitor was programmed to take BP measurements every 30 minutes during the day and evening (6

AM_e10PM) and every 60 minutes during the night (10PM_e6AM) for a 24-hour period. Participants were given a diary and were instructed to record the time they went to sleep and the time they woke up to identify the individuals’ boundaries between periods of sleep and wake time. ABP recordings with at least 75% satisfactory readings out of the maximum number of possible readings (40 readings) over the 24-hour period were included in the analysis. Nocturnal systolic blood pressure reduction was calculated as mean daytime SBP minus mean nighttime SBP. Nocturnal SBP dipping ratio was calculated as the ratio of nocturnal SBP reduction to mean daytime SBP. Participants whose SBP dipping ratio was 10% or greater were deﬁned as dippers.

2.2.2. Augmentation index

AI is calculated as the ratio of augmented pressure to pulse pressure and expressed as a percentage. Augmentation pressure is deﬁned as the difference between the early and late systolic shoulders of central aortic pressure waveforms. Radial applanation tonometer (Millar Pressure Tonometer, Millar Instruments Inc., Houston, Texas, USA) was used to acquire the aortic pressure waveform noninvasively using the generalized transfer function (SphygmoCor Vx system, AtCor Medical, New South Wales, Australia). Adjusted values of AI with heart rate at 75 beats/min were used in the data analysis. The AI was measured twice and the mean value was used for analysis. The higher value of AI indicates smaller distensibility in the aorta.

2.3. Statistics

Data were analyzed using statistical analysis software, SPSS (version 14.0; SPSS Inc., Chicago, IL, USA). Descriptive statistics were performed to describe the demographic data and the summary measures for the data. The difference between two groups was analyzed by unpaired Student’s t test,

c

2_{test, or Fisher}

exact probability test. Person’s correlation was computed to quantify the relationship between variables. A p value less that 0.05 was considered statistically signi_ﬁcant.

3. Results

A total of 77 individuals with Type 2 diabetes and 36 individuals with mild hypertension participated in this study. Participants in the diabetic group were signiﬁcantly older and shorter in height than the mildly hypertensive group. There was no difference in gender between the diabetic group and the hypertensive group. Other conventional CV risk factors (i.e., exercise habit and body

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mass index) were not statistically different between groups with the exception of smoking habit in which the percentage of smokers was signiﬁcantly higher in the diabetic group. Biodemographic and lifestyle data of the study participants were summarized inTable 1. In the whole sample, AI was signiﬁcantly higher in female than in male (p< 0.001). The older the individual, the greater the value of AI was (r¼ 0.58, p < 0.001). As expected, height was negatively correlated to AI (r¼ 0.54, p < 0.001). In the diabetic group, AI was correlated to neither HbA1C value nor the duration of illness.

Moreover, none of the ABP measurement parameters was signi ﬁ-cantly related to AI (data are not shown). There was no association between AI value and the magnitude of nocturnal BP reduction (p¼ 0.53).

There was a trend showing that the diabetic patients had higher mean values of AI than the hypertensive patients (24.5 10.5 vs. 21.2 12.1, respectively). However, after adjusting for age and body height, there was no significant difference in AI between the dia-betic group and the mildly hypertensive group (p¼ 0.14). Inter-estingly, the diabetic group exhibited a significantly lesser degree of nocturnal BP reduction both in the absolute and in the percentage differences as compared with the mildly hypertensive group. The significant difference remained even after adjusting for conven-tional CV risk, including age, gender, and smoking (p¼ 0.01;

Table 2). In addition, the percentage of dippers in the diabetic group was signiﬁcantly lower than that in the mildly hypertensive group (p¼ 0.003;Table 2).

4. Discussion

Findings from this study revealed that there was no difference in AI between the diabetic group and the mildly hypertensive group after adjusting for age and body height. AI value was also not correlated to the magnitude of nocturnal BP reduction in the dia-betic group. On the other hand, a blunted nocturnal BP reduction was observed in the diabetic group as compared with the mildly hypertensive group. A signiﬁcant association between blunted nocturnal BP reduction and marked CV risk has been consistently demonstrated in Type 2 diabetic patients.20,21Theﬁnding that the diabetic group had decreased nocturnal BP reduction thus indicates that the diabetic group might have increased CV risk than the

mildly hypertensive group, although AI failed to correlate to nocturnal BP reduction, an indicator of increased CV risk in the diabetic group. Given that impaired arterial function has been suggested as a pathological link between diabetes and adverse CV events, the validity of AI as a surrogate measure of impaired arterial function and/or the utility of AI as a maker for CV risk in normo-tensive Type 2 diabetic patients is questionable and remains to be determined.

The role of AI as a significant marker and/or an independent predictor of adverse CV events have been reported in individuals with cardiomypathy,9atherosclerotic disease,10and coronary artery disease.10,11In diabetic patients, however, whether AI is a marker of CV risk has been questioned. For example, AI was not related to PWV in diabetic patients without traditional CV risk factors.24e26In a group of Type 2 diabetics, there was no relationship between AI and left ventricular mass as measured by magnetic resonance imaging.27 In further, AI did not differ between diabetics and nondiabetic controls.24_{A signi}_{ficant difference in PWV but not in AI} was also observed among diabetic patients, patients with impaired glucose tolerance, and normoglycemic patients,25indicating that impaired arterial properties among a spectrum of diabetes may not be stratified by AI. AI is derived based on the aortic pressure wave reflection form, which may be influenced by the combined effect of aortic and peripheral arterial stiffness.28In Type 2 diabetes, both large arteries and small arteries are involved in the prognosis of disordered arterial function. The adipose tissue encapsulating the small conduit arteries may exert a“cushioning effect,” which may alter wave reflection characteristics.29 _{It may be that, in some} manner, the small artery consequences of diabetes are associated with dissipation of the pulse wave, therefore leading to reduced wave re_{flection in diabetic patients.}22 This phenomenon may partially explain the dissociation between PWV and AI in individ-uals with Type 2 diabetes and question the clinical implication of AI as an index of vascular alternation. Although the application of applanation tonometry at the radial artery is technically easy, our results make the clinical usefulness of AI in normotensive Type 2 diabetic patients questionable. Multiple assessments should be performed along the vascular tree based on the underlying processes influencing large arteries and small caliber arteries in Type 2 diabetes. More importantly, diabetes should be treated as a confounding factor in the use of AI as a surrogate of arterial distensibility.

An obvious weakness of the study is that the mildly hyperten-sive group consisted of a small sample size resulting in an imbal-ance between groups. The relatively small sample size may lack the power to detect statistically significant differences between groups. There was some strength in the present study. First, 24-hour BP monitoring was used to confirm the normotensive status of the participants. Second, individuals who were taking antihypertensive medications were excluded from the present study. The perturba-tion influence of BP on arterial stiffness in Type 2 diabetic patients was thus avoided to a lesser extent.

In summary, normotensive Type 2 diabetic patients did not have higher AI than mildly hypertensive patients, whereas normotensive Type 2 diabetic patients had signiﬁcantly blunted nocturnal BP reduction compared with mildly hypertensive patients. In addition, Table 1 Characteristics of the participants

Variables HT (n¼ 36) DM (n¼ 77) p Age (yr) 46.8 10.8 53.3 11.6 0.01 Male gender (%) 72.2 59.7 0.22 Body height (m) 1.7 0.9 1.6 0.8 0.02 Body mass index (kg/m2₎ _24.4_2.9 _25.0_3.1 _0.42

HbA1C (%) d 7.4 2.0 d

AI (%) 21.2 12.1 24.5 10.5 0.14*

Ofﬁce measurements

Systolic blood pressure (mmHg) 142.3 9.7 124.6 12.6 <0.001 Diastolic blood pressure (mmHg) 90.1 8.3 76.4 9.4 <0.001 Mean arterial pressure (mmHg) 107.5 7.5 92.5 9.4 <0.001 Heart rate (bpm) 73.2 11.4 76.7 21.2 0.14 Smoker (%) Yes 5.6 32.9 0.002 No 94.4 67.1 Exercise (%) Yes 47.2 58.4 0.31 No 52.8 41.6

*Adjustment for age and body height.

AI¼ augmentation index; bpm ¼ beats per minute; DM ¼ diabetes mellitus; HT¼ hypertension.

Table 2 Comparison of nocturnal BP dipping pattern between groups Variables HT (n¼ 36) DM (n¼ 77) p SBP decline (mmHg) 18.93 9.37 11.94 12.8 0.01*

SBP dipping ratio (%) 13.16 6.27 9.37 9.51 0.05 Dippers ratio (%) 67.7 38.3 0.003

*Adjustment for age, gender, and smoking.

BP¼ blood pressure; DM ¼ diabetes mellitus; HT ¼ hypertension; SBP ¼ systolic blood pressure.

M.-Y. Wang et al. 72

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the validity of AI to measure arterial function may be limited because of the unique vascular change in Type 2 diabetes. The usefulness of AI as a surrogate of arterial distensibility and/or a maker for CV risk in Type 2 diabetic patients with normal BP is questionable.

Acknowledgments

This study was supported, in part, by grants from National Health Research Institutes, Taiwan (NHRI-EX98-9409SC) and National Science Council, Taiwan (NSC96-2314-B-038-041-MY3).

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