the Department of Cardio-Nephrology, Azienda Ospedaliera Universitaria San Martino, Genoa, Italy.
Abstract
Increased arterial stiffness has been shown to predict cardiovascular mortality in patients with primary hypertension. Asymptomatic organ damage is known to precede cardiovascular events. We investigated the relationship between a recently proposed index of stiffness derived from ambulatory blood pressure (BP) and target organ damage in 188 untreated patients with primary hypertension. Ambulatory arterial stiffness index was defined as 1 minus the regression slope of diastolic over systolic BP readings obtained from 24-hour recordings. Albuminuria was measured as the albumin:creatinine ratio, left ventricular mass index was assessed by echocardiography, and carotid abnormalities were evaluated by ultrasonography. The prevalence of microalbuminuria, left ventricular hypertrophy (LVH), and carotid abnormalities was 12%, 38%, and 19%, respectively. Ambulatory arterial stiffness index was positively related to age, triglycerides, office and 24-hour systolic BP, 24-hour pulse pressure, urinary albumin excretion, and carotid intima-media thickness. Patients with microalbuminuria, carotid abnormalities, or LVH showed higher ambulatory arterial stiffness index as compared with those without it. After adjusting for confounding factors, each SD increase in ambulatory arterial stiffness index entails an &2 times higher risk of microalbuminuria, carotid abnormalities, and LVH and doubles the risk of the occurrence of 1 sign of organ damage. Ambulatory arterial stiffness index is associated with organ damage in patients with primary hypertension. These data strengthen the role of this index as a marker of risk and help to explain the high cardiovascular mortality reported in patients with high ambulatory arterial stiffness index.
Key Words: blood pressure monitoring albuminuria hypertrophy hypertension, essential carotid arteries
Introduction
Large-artery stiffness has proved to be an independent predictor of adverse cardiovascular outcome in the general population, as well as in patients with primary hypertension, diabetes, or end-stage renal disease.1–4 However, the widespread measurement of vascular compliance in clinical practice has been limited by the need for dedicated equipment and trained personnel.
A new, easy-to-obtain index, which is derived from ambulatory blood pressure (BP) recordings, has been proposed recently as an indicator of arterial stiffness.5,6 Ambulatory arterial stiffness index (AASI) has been shown to strongly correlate with classic measures of arterial stiffness, such as pulse wave velocity and augmentation index, and to provide prognostic information on cardiovascular mortality.5,6
The occurrence of major cardiovascular events is usually the result of long-term exposure to hypertension and other risk factors and is often preceded by the development of asymptomatic functional and structural abnormalities.7 This so-called target organ damage (TOD) phase is potentially reversible and, in turn, represents a strong independent predictor of unfavorable outcome. Thus, an association between increased AASI and organ damage might help explain the pathophysiological processes underlying the occurrence of cardiovascular complications in patients with high AASI. This study was, therefore, initiated to investigate the relationship between AASI and microalbuminuria, left ventricular hypertrophy (LVH), and carotid atherosclerosis in a large group of never previously treated patients with primary hypertension.
Methods
Patients
Between January 2003 and January 2006, all of the untreated patients with primary hypertension attending the outpatient clinic of our institution were asked to participate in this study, which was part of a larger trial (Microalbuminuria: A Genoa Investigation on Complications [MAGIC]) approved by the ethics committee of our department.8 The study adhered to the principles of the Declaration of Helsinki and Title 45, US Code of Federal Regulations, Part 46, Protection of Human Subjects, Revised November 13, 2001, effective December 13, 2001. All of the procedures followed were in accordance with institutional guidelines. Inclusion criteria included office BP 140 mmHg systolic or 90 mmHg diastolic on 2 visits and absence of secondary causes of hypertension, whereas exclusion criteria were previous cardiovascular and life-threatening disease, any condition preventing technical quality of ambulatory BP monitoring, such as atrial fibrillation, and other major dysrhythmias. Altogether, 196 patients (all white Europeans) from among a total of 245 hypertensive patients seen at our clinic within the above-mentioned time range fulfilled the inclusion criteria. After written informed consent had been obtained, all of the patients underwent the following procedures: (1) office BP measurement; (2) 24-hour ambulatory BP monitoring; (3) standard questionnaire to assess history and lifestyle habits; (4) blood and urine sampling; (5) standard 12-lead ECG; (6) echocardiogram; and (7) carotid ultrasonography (US).
Of the included patients, 188 completed the study and had good technical quality 24-hour ambulatory BP monitoring and ultrasonographic examinations. Of the participating patients, 164 (87%) had never been treated for hypertension, whereas 24 (13%) had received antihypertensive treatment in the past, albeit intermittently and not during the 6 months before the study. Smoking status was defined as current use.
BP Measurement
Office BP was measured by a trained nurse, with the patient in the sitting position after a 5-minute rest, with a mercury sphygmomanometer using an appropriate-sized cuff. The systolic (SBP) and diastolic (DBP) BPs were read to the nearest 2 mmHg. Disappearance of Korotkoff’s sounds (phase V) was the criterion for DBP. The mean of 3 consecutive readings was used in the statistical analysis.
Twenty-four hour ambulatory BP monitoring was carried out on the nondominant arm using an oscillometric device (Spacelabs 90207; SpaceLabs Inc). The device was set to obtain BP readings every 15 minutes during the daytime (7 AM to 11 PM) and every 30 minutes during the nighttime (11 PM to 7 AM).
Ambulatory Arterial Stiffness Index
AASI was calculated as 1 minus the regression slope of DBP plotted against SBP obtained from individual 24-hour BP monitoring.5 The slope was not forced through the origin.
Target Organ Damage
Albuminuria
The presence of microalbuminuria was evaluated in each patient by measuring the albumin:creatinine ratio (ACR) on 3 nonconsecutive first morning samples. Urine albumin concentration was measured by a commercially available radioimmunoassay kit (Immunotech, Pantec). Microalbuminuria was defined as ACR 2.5 mg/mmol in men and ACR 3.5 mg/mmol in women.9
Echocardiography
All of the echocardiographic studies were performed using an Acuson Sequoia C-256 ultrasound machine. The overall, monodimensional left ventricular measurements and the bidimensional (apical 4- and 2-chamber) views were obtained according to the recommendations of the American Society of Echocardiography.10 All of the tracings were obtained and read by a single observer blinded to the clinical characteristics of the patients under observation. The presence of LVH was defined as left ventricular mass index (LVMI) >49.2 g/m2.7 in men and >46.7 g/m2.7 in women.11
Common Carotid US Scan
Carotid arteries were investigated in the longitudinal and the transverse projections by high-resolution, real-time US using a 10-MHz in-line duplex Diasonic Spectra System.12 The intima-media thickness (IMT) of both carotid arteries was always measured on the common carotid artery outside the plaque, if any was present. Carotid plaque was defined as IMT >1.3 mm. Each measurement was calculated by taking the average of 3 readings. Carotid abnormalities were diagnosed when there was 1 carotid plaque or when there was diffuse common carotid artery thickening defined as an average IMT 0.9 mm.9
Statistical Analysis
All of the data are expressed as arithmetic mean±SD or median (interquartile range) for skewed variables. Relations among variables were assessed by using linear regression analysis, the Pearson correlation coefficient (r) for normally distributed variables, and by the nonparametric Spearman’s correlation coefficients () for skewed variables. Principal component analysis was used to construct a composite, continuous variable, including urinary albumin excretion, carotid IMT, and left ventricular mass. Principal component analysis is a mathematical technique that transforms a set of correlated risk factors to a linear combination of variables that accounts for the maximum proportion of the total variance in the data. Standardized scoring coefficients are estimated and used to compute the principal component score for each patient. This component score is then used as the dependent variable in multiple regression analysis.
ANOVA was used to analyze data from patients with or without end-organ damage. Relative risk and 95% CIs were calculated by exponentiation of logistic regression coefficients. To assess the influence of various BP components on the presence of TOD, multiple and logistic regression analyses were performed on the basis of 2 models: model 1, which included systolic BP, and model 2, which included mean BP and pulse pressure.
All of the statistical analyses were performed with the use of Statview for Windows (SAS Institute Inc, version 5.0.1). A value of P<0.05 was considered statistically significant.
Results
The main clinical characteristics of the study patients (123 men and 65 women) are reported in Table 1. The overall prevalence of microalbuminuria, LVH, and carotid abnormalities was 12%, 38%, and 19%, respectively.
Univariate analysis showed that AASI was positively related to age (r=0.153; P=0.0358), triglycerides (=0.178; P=0.0186), and SBP (both office, r=0.169; P=0.0208 and 24-hour, r=0.216; P=0.0029), as well as 24-hour pulse pressure (r=0.216; P=0.0029). Moreover, AASI was positively related to early signs of TOD, such as urinary albumin excretion (=0.234; P=0.0019) and carotid IMT (r=0.196; P=0.0159), whereas the correlation between AASI and LVMI, even in the presence of a positive linear trend, did not reach statistical significance (Figure 1).
Multiple regression analysis showed that AASI was independently associated with urinary albumin excretion and carotid IMT (Table 2). Moreover, by means of principal components analysis, a single, composite variable simultaneously including all 3 of these signs of TOD was found. The component accounted for 48% of the variance in the measured variables. The scoring coefficients of the individual variables were as follows: urinary albumin excretion, 0.511; carotid IMT, 0.391; and LVMI, 0.533. Multiple regression analysis showed that AASI was independently associated with the TOD principal component (Table 2).
Furthermore, patients with microalbuminuria, carotid abnormalities, or LVH had significantly higher values of AASI as compared with those without it (Figure 2). The independent relationship of AASI to the presence of early organ damage was confirmed by results of multiple logistic regression analysis (Table 3). In fact, after adjusting for several potentially confounding factors, each SD increase in AASI (ie, 0.17) entailed an &2 times higher risk of microalbuminuria, carotid abnormalities, and LVH.
The association between AASI and subclinical organ damage was even more apparent when the simultaneous occurrence of various signs of TOD was taken into consideration. In fact, the subgroup of patients having microalbuminuria, LVH, and carotid abnormalities showed higher AASI as compared with those with lesser degrees of target organ involvement (Figure 3). Moreover, the occurrence of 1 sign of TOD doubles for each SD increase in AASI (Table 4).
Discussion
The present study provides the first systematic evaluation of the relationship between AASI and TOD in a group of untreated patients with primary hypertension. Our results indicate that arterial stiffening is associated with the presence of microalbuminuria, LVH, and carotid atherosclerosis (Figure 2) and that each SD increment in AASI doubles the risk of having signs of subclinical organ damage (Table 4). Furthermore, the association between ambulatory stiffness and organ damage seems to be graded and linear, because patients with more severe organ involvement are characterized by higher AASI (Figure 3).
Arterial stiffness is an established, independent predictor of cardiovascular mortality in patients with primary hypertension, as well in those with end-stage renal disease.2,3 Its prognostic value has been shown to extend even beyond classic cardiovascular risk factors. In fact, Boutouyrie et al13 reported recently that in a cohort of 1045 hypertensive patients, pulse wave velocity remained an independent predictor of cardiovascular events after adjustment for coronary risk score as assessed by the Framingham algorithm. Evaluation of arterial compliance, however, remains a cumbersome, time-consuming procedure, which requires specific technical equipment and cannot be easily performed in daily clinical practice.
Very recently, AASI, a new index of vascular stiffness, which can be obtained easily from ambulatory BP recordings, has been shown to provide prognostic information on cardiovascular mortality.6 The development of subclinical cardiovascular damage, that is, microalbuminuria, carotid atherosclerosis, and/or LVH, is also known to precede and predict the acute onset of major events and has proved to be a powerful independent predictor of cardiovascular prognosis.7 Thus, our results indicating a strong relationship between AASI and the presence and degree of organ damage may help clarify the pathogenetic mechanisms leading to the high rate of cardiovascular mortality that is observed in patients with high AASI.
Arterial stiffening is deemed to reflect widespread atherosclerosis, and the correlation we found between AASI and age is in keeping with this notion.1 Although our study cannot establish a causal relationship between the observed findings because of its cross-sectional design, it does support the view that hypertensive TOD is a multifactorial process resulting from the interaction of both hemodynamic (eg, BP load) and atherosclerotic factors. Furthermore, our results indicate that AASI has an additional predictive value for identifying TOD above and beyond classic cardiovascular risk factors. In fact, the results of multiple and logistic regression analysis showed that the association between AASI and signs of TOD remained significant even after adjusting for several potential confounders and well-known determinants of cardiovascular damage, such as age, body mass index, lipid profile, duration of hypertension, and BP levels.
The relationship among various 24-hour BP components, TOD, and AASI is intriguing and deserves some comments. In fact, whereas both mean BP and pulse pressure are considered promoters of hypertensive end-organ damage14 and correlated with urinary albumin excretion, IMT, and left ventricular mass in our study (data not shown), their association with cardiovascular abnormalities loses strength in multivariate logistic regression analysis after adjusting for AASI. In conclusion, this study provides the first evidence that AASI is associated with signs of subclinical TOD in patients with primary hypertension and that it maintains its role regardless of classic cardiovascular risk factors.
Perspectives
Other than integrating previous data showing that AASI is a strong predictor of cardiovascular mortality, our results could have practical, useful implications in risk assessment strategies. In fact, they support the role of the AASI as an indicator of generalized atherosclerosis and one that may be useful in clinical practice to assess a patient’s global risk status.
Acknowledgments
We thank Massimo Del Sette, MD, and Gian Paolo Bezante, MD, for performing cardiovascular ultrasound scans.
Disclosures
None.
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