Elevation of urine albumin to creatinine ratio (UACR) as a sensitive marker for microalbuminuria is associated with increased heart diseases risk.1–3 Like other risk factors for coronary artery disease such as advanced age, diabetes mellitus, and systolic hypertension, microalbuminuria has been associated with atherosclerotic risk factors,4,5 and is thought to reflect microvascular damage in the glomeruli and in the systemic vasculature6 with increasing risk of lipid insudation and development of atherosclerosis.7 However, albuminuria, reflecting systemic microvascular damage, and left ventricular (LV) geometric abnormalities have been shown to predict increased cardiovascular morbidity and mortality.8 Jensen and colleagues9,10 demonstrated that an increased UACR was a risk factor for arteriosclerosis in patients with hypertension and in healthy subjects because they had an increased transcapillary albumin escape rate.11
Albuminuria-related cardiovascular risk is potentially extended to patients with hypertension and LV hypertrophy (LVH). Some studies reported that patients with microalbuminuria, particularly hypertensive groups, have a higher prevalence of LVH,12 which might also contribute to the increased cardiovascular mortality observed in patients with a high UACR that can be independent of age, systolic blood pressure, diabetes, and race;8 however, other studies could not prove this relationship.13
This study was undertaken to determine whether high UACR is associated with LVH and systolic and diastolic LV dysfunction, independently of established cardiovascular risk factors, in an essential hypertensive population free of evident renal failure.
Patients and Methods
The study population consisted of 125 consecutive patients with primary uncomplicated hypertension admitted to clinical hypertension in Isfahan Cardiovascular Research Center. Systolic and diastolic blood pressure measurements were taken twice at an interval of one minute using the same instrument. Patients were excluded for the following reasons—the echocardiographic image was of poor acoustic quality, any regional wall motion abnormalities, any valvular heart disease, pericardial disease, cardiomyopathy based on the echocardiographic findings, creatinine level >1.5 mg/dl in males and >1.4 mg/dL for females, hemoglobin <13 mg/dl in men and <12 mg/dl in women, clinical history of angina or congestive heart failure, known coronary artery disease, incomplete clinical data, unwillingness to participate or inability to participate for logistic reasons.
The Ethical Committee of Isfahan University of Medical Sciences approved the study and consent was obtained from all participants. Study information was gathered from interviews conducted by a trained physician during the first day of admission. Data were collected using a self-administered questionnaire and included demographic characteristics, medical history, oral medications, and duration of diagnosed hypertension.
Venous blood samples were obtained immediately at presentation at the supine position to measure lipid profile and fasting blood sugar. Urine albumin concentration was determined by standard methods using a turbidimetric method (Hitachi 717 Analyzer) on a single urine specimen taken on the morning of the echocardiography. Both serum and urine creatinine were analyzed using the Jaffe reaction without deproteinizing and then quantified by a photometric method (Hitachi 717 Analyzer). The urine albumin concentration, expressed as a ratio to the urinary creatinine concentration (UACR), was used as a measure of glomerular vascular permeability to allow for urine dilution. We defined microalbuminuria as UACR ≥3.5 mg/mmol.
Two-dimensional echocardiography was performed for each participant by a single cardiologist with a commercially available machine with a 1–5 MHz transducer. The LV parameters were measured according to the guidelines of the American Society of Echocardiography. LVH was defined as a LV mass index >100 g/m2 of body surface area in women and >130 g/m2 in men. Doppler echocardiography was also performed and early (E) and late (A) diastolic peak velocities, deceleration time, and early to late diastolic peak velocity (E/A) ratio were determined. Early mitral annulus velocity (E') was measured at the septal portion of the mitral annulus in an apical four-chamber view using a tissue Doppler technique.
Data are presented as mean ± SD for continuous variables and percentages for categorical variables. Comparisons of categorical variables across the groups were performed using an overall chi-square test or Fisher's exact test if required. Comparisons of continuous variables were performed using an independent t test. Descriptive statistics, including sensitivity and specificity of UACR, in determining the presence or exclusion of significant acute coronary syndrome were calculated.
Receiver operator characteristic (ROC) curves were constructed to investigate the diagnostic power of the variable. The cut-off score was estimated for prediction of LVH by the ROC curve analysis (the empirical point that maximizes sensitivity and specificity of the UACR level for predicting LVH). p Values of 0.05 or less were considered statistically significant. All the statistical analyses were performed using SPSS version 13 (SPSS Inc., Chicago, IL) and the STATA statistical package (version 10.0; College Station, TX).
Results
Descriptive data of the participants are presented in Table 1. The mean age of patients was 53 ± 11 years and 41.7 % were men. UACR was measured in all patients and microalbuminuria was found in seven patients (5.6 %). Mean sitting systolic and diastolic blood pressures at admission were 143.17 ± 18.64 and 88.48 ± 9.37 mmHg and mean body mass index was 29.66 ± 4.54 kg/m2. Mean serum creatinine was 112.47 ± 62.96 mmol/l and mean UACR was 15.58 ± 21.85 mg/mmol. No significant differences were observed between the two groups with and without microalbuminuria in terms of baseline characteristics, oral medications, first measured blood pressures at admission, and serum lipid profile and fasting blood sugar.
Measures of LV structure and systolic and diastolic LV function are summarized in Table 2 and compared across the two groups. UACR was significantly no different in patients with LVH than in patients with normal LV geometry (21.26 ± 31.55 versus 17.80 ± 24.52 mg/mmol, p=0.776). Among LV systolic and diastolic parameters, only E/A ratio was univariately higher in the group without microalbuminuria, however the E/A ratio index was similar between the groups with and without microalbuminuria adjusted for demographics, duration of hypertension, and blood pressures measurements (Table 3). No significant correlation was found between UACR measurement and systolic and diastolic function parameters, including E/A ratio (R=-0.192, p=0.038), E/E’ ratio (R=-0.025, p=0.794), LV ejection fraction (R=0.008, p=0.929), and LV mass (R=-0.132, p=0.154) (Figures 1 and 2).
According to the ROC curve analysis, UACR measurement was not an acceptable indicator of LVH with areas under the ROC curves 0.514 (95 % confidence interval [CI] 0.394–0.634). The optimal cut-off value for UACR for predicting LVH was identified at 9.4, yielding a sensitivity of 51.6 % and a specificity of 48.3 %.
Discussion
This study provided the first assessment of the association between microalbuminuria and LV geometric patterns, and systolic and diastolic LV function in a sample of Iranian patients with essential hypertension without apparent renal failure. The first important finding was that the prevalence of microalbuminuria in patients with primary hypertension was 5.6 %. This proportion is lower than previously reported results; however, the study was conducted when the majority of patients were receiving antihypertensive drug treatment, therefore the results were even more difficult to interpret. In the study by Jalal et al., the prevalence of microalbuminuria in patients with hypertension was found to be 37.5 %.14 In another large clinical trial that involved patients with mild and moderate essential hypertension, a 6.1 % prevalence of microalbuminuria was reported.15 Agewall et al. also reported a prevalence of microalbuminuria of around 23 % in a population of patients with hypertension who were selected as being at high risk for cardiovascular disease.16
Variations in the prevalence of microalbuminuria between 10 % and 40 %17–21 reported in other studies are likely due to differences in the selection criteria, the techniques used for the detection of microalbuminuria, and in some cases, to the small number of patients studied.22 These variations may also be due to differences in age, race, severity of hypertension, and coexistent renal disease in these study populations. In our study, no relationship was found between the indices of LV systolic function and microalbuminuria. This result is similar to the findings of Pontremoli et al., who found no relationship between microalbuminuria and LV relative wall thickness.23 However, this differs slightly from the findings of Wachtell et al., who revealed that microalbuminuria was approximately two- to threefold higher in patients with hypertension with eccentric or concentric LVH, and minimally elevated in the group with concentric LV remodeling compared with patients with normal LV geometry.3 Our study suggested that neither LVH nor concentric LV geometry were associated with high UACR. In addition, our study did not support the efficacy of UACR measurement to stratify risk of LV systolic or diastolic dysfunction in patients with essential hypertension.
Although a weak association was found between microalbuminuria and the E/A ratio index as a LV diastolic filling marker, this association was not multivariately proved when adjusted for gender and age. In fact, based on measuring the partial low sensitivity and specificity of the UACR parameter for predicting LVH, it seems that the presence of microalbuminuria in patients with essential hypertension could not discriminate LVH and normal LV geometry in our population. However, further studies with larger sample sizes are strongly recommended.