Abstract

Using 24-h ambulatory blood pressure (BP) monitoring and digitized M-mode echocardiography, we evaluated whether microalbuminuria is related to preclinical left ventricular (LV) diastolic dysfunction in hypertensive patients. We selected 87 never-treated hypertensive patients (mean 24-h BP > 140 and/or > 90 mm Hg); albuminuria was evaluated as mean value of 24-h urinary albumin excretion (UAE) from two 24-h urine collections. Microalbuminuria was found in 28 patients, classified as MA+ (UAE 30 to 300 mg/24 h); 59 patients had normal UAE (< 30 mg/24 h) and were classified as MA−. The MA+ and MA− groups did not differ with regard to age, sex, body mass index, or 24-h heart rate, whereas 24-h, daytime, and nighttime systolic and diastolic BP were significantly higher in MA+ than in MA−. The LV mass index was greater in MA+, as was the prevalence of LV hypertrophy; peak shortening rate of LV diameter, index of systolic function, was normal in all, but was lower in MA+. Peak lengthening rate of LV diameter and peak thinning rate of posterior wall, indices of diastolic function, were lower in MA+ and the prevalence of diastolic dysfunction was higher in MA+. UAE was inversely correlated with both indices of LV diastolic function, also after correction for age, 24-h heart rate, 24-h BP, and LV mass. In conclusion, in never-treated hypertensive patients, microalbuminuria is not only associated with greater myocardial mass, but is also related with preclinical impairment of LV diastolic function. This relation, independent from increased BP or LV mass, strengthens the role of microalbuminuria as an early and reliable marker of preclinical cardiac involvement. Am J Hypertens 2001;14:644–648 © 2001 American Journal of Hypertension, Ltd.

Microalbuminuria, which is frequently found in patients with essential hypertenion, is an independent predictor not only of renal damage, but also of higher cardiovascular risk.1–4 Increased urinary albumin excretion (UAE) has been found to correlate with left ventricular (LV) mass and to be associated with a greater prevalence of myocardial hypertrophy.5,,,,10 Moreover, one recent study showed a preclinical impairment of LV systolic function in hypertensive patients with microalbuminuria as compared to patients without microalbuminuria.10 It is known that systolic dysfunction usually occurs late in the clinical history of hypertensive cardiopathy, whereas the first functional change is a progressive impairment of diastolic function.11–13 This impairment is significantly influenced by LV mass and is greater in patients with more severe LV hypertrophy.11,13,15 However myocardial hypertrophy and diastolic impairment are not always linked. In fact, a clear dissociation of these phenomena has been demonstrated, for instance, in spontaneously hypertensive rats with use of therapeutic intervention that normalized myocardial fibrosis and therefore LV stiffness, without affecting myocardial hypertrophy.16 Moreover, diastolic dysfunction has been described in hypertensive patients with normal LV mass, often preceding the development of a detectable myocardial hypertrophy.17

Therefore, we considered it of interest to evaluate, in never treated hypertensive patients, if microalbuminuria is related to preclinical LV diastolic dysfunction, taking also into account the possible influence of LV mass on the relationship.

Methods

Patients

We enrolled in our study hypertensive patients who had never been treated with antihypertensive drugs. Other criteria of selection were as follows: LV M-mode echocardiogram of good quality; no clinical, electrocardiographic or echocardiographic evidence of heart failure, myocardial infarction, angina pectoris, or congenital or valvular heart disease; normal urinalysis and creatinine clearance > 80 mL/min/1.73 m2; no systemic diseases (such as diabetes mellitus or connective tissue disorders) that per se could induce changes in LV structure and function. Arterial blood pressure (BP) was evaluated on the basis of at least three measurements by sphygmomanometer, which were taken on different days. We selected subjects with BP > 160 and/or 95 mm Hg. Subsequently, each patient underwent a 24-h noninvasive ambulatory BP monitoring, and patients with a mean 24-h BP > 140 and/or 90 mm Hg were enrolled in the study. Following these criteria, we selected 87 hypertensive patients (55 men, 32 women, mean age 41 ± 6 years, mean body mass index [BMI] 25.5 ± 3.6. kg/m2).

The study protocol was approved by the Ethical Committee of the Department of Clinical and Biological Sciences, and all the subjects gave their informed consent.

Protocol

All patients, after a clinical work-up to rule out secondary hypertension, underwent urinary albumin excretion measurements, 24-h ambulatory BP monitoring, and LV echocardiographic examination.

Urinary albumin excretion

Each patient collected 24-h urine twice, 1 week apart, for determination of UAE; the patients had been instructed to maintain their usual diet and to avoid sustained physical activity during the 2 days of urine collection. Urinary albumin concentration was measured by an immunonephelometric method (microAlbumin Beckman, Galway, Ireland); the intra- and interassay variabilities of the method were < 5% and < 7%, respectively. For each patient the UAE was considered the mean of values obtained from the two separate 24-h urine collections. If the difference between values obtained from the two samples was >25% of the higher value, a third sample was requested. Microalbuminuria was defined as UAE between 30 and 300 mg/24 h for the average of the two urine collections.

Twenty-four-hour ambulatory BP monitoring

Noninvasive ambulatory BP monitoring was performed with a portable automated Takeda TM 2421 (Takeda; Osaka, Japan) and a simultaneous 24-h heart rate monitoring was obtained. The unit was set to take readings every 15 min throughout the 24 h. The following parameters were evaluated: mean 24-hour, daytime (from 7:00 AM to 10:00 PM), and nighttime (from 10:00 PM to 7:00 AM) systolic and diastolic BP and heart rate, and percent nocturnal decrease of systolic and diastolic BP.

Echocardiographic examination

Immediately after the 24-h BP monitoring, each subject underwent an echocardiographic examination using a Hewlett Packard Sonos 1500 with a 2.0/2.5-MHz transducer (Andover, MA). The LV M-mode echocardiograms were recorded under two-dimensional control, at a paper speed of 100 mm/sec, with a simultaneous ECG. The M-mode tracings were blindly evaluated by a single operator who digitized four consecutive cardiac cycles of each echocardiogram, as originally described by Upton and Gibson,18 using a Numonics 2205 graphic tablet (Montgomeryville, PA). Digitized data were processed on an IBM PC, averaging the four cardiac cycles. The following were evaluated: LV end-diastolic diameter, end-diastolic thickness of interventricular septum, and posterior wall, LV mass,19 LV mass index (LV mass/body surface area), peak shortening and peak lengthening rates of LV diameter, and peak thinning rate of LV posterior wall.

Statistical analysis

Data are expressed as mean ± SD. When appropriate, a logarithmic transformation of the data was performed before the analysis. The statistical evaluation of the results was carried out by means of unpaired Student t test; comparisons of proportion between groups were performed using χ2 test. Relationships between variables were assessed using linear regression analysis and Pearson's correlation coefficient. Comparing diastolic indices between normoalbuminuric and microalbuminuric hypertensive patients, we took into account the potential influence of age, heart rate, blood pressure, and LV mass on LV diastolic function by forcing age, 24-h heart rate, 24-h systolic and diastolic BP, and LV mass index as covariates into the model. A P value < .05 was considered statistically significant.

Results

On the basis of UAE we subdivided the 87 patients into two groups: 28 hypertensive patients with microalbuminuria (32%), who were classified as MA+, and 59 hypertensive patients with normal UAE (< 30 mg/24 h), who were classified as MA−. The two groups were comparable with regard to age, sex, BMI, and mean 24-h, daytime, and nighttime heart rates (Table 1). Mean 24-h, daytime, and nighttime values of systolic and diastolic BP were significantly higher in the group with microalbuminuria than in the group with normal UAE; in contrast, mean percent nocturnal decrease of systolic and diastolic BP was similar between the two groups (Table 1), as was the prevalence of nondippers (nocturnal BP fall < 10% of daytime BP): 16 patients with normal UAE (27.1%) and eight patients with microalbuminuria (28.5%) (χ2 test, NS).

Table 1

Demographic data, urinary albumin excretion (UAE), blood pressure, and heart rate (HR) values in hypertensives with (MA+) and without microalbuminuria (MA−)

 MA+ (n = 28) P MA− (n = 59) 
UAE (mg/24 h) 94.7 ± 42.9 <.0001 12.6 ± 9.7 
Age (y) 42 ± 5 NS 41 ± 5 
Sex (men/women) 18/10 NS 37/22 
Body mass index (kg/m225.1 ± 3.7 NS 25.3 ± 3.4 
Systolic BP 24 h (mm Hg) 148 ± 10 .024 142 ± 12 
Diastolic BP 24 h (mm Hg) 94 ± 6 .002 89 ± 7 
Systolic BP day (mm Hg) 153 ± 13 .029 146 ± 14 
Diastolic BP day (mm Hg) 99 ± 8 .004 94 ± 7 
Systolic BP night (mm Hg) 133 ± 13 .029 126 ± 14 
Diastolic BP night (mm Hg) 86 ± 10 .014 81 ± 8 
Systolic BP % night fall 13.4 ± 7.3 NS 13.9 ± 8.5 
Diastolic BP % night fall 13.6 ± 8.2 NS 14.2 ± 7.9 
HR 24 h (beats/min) 72 ± 9 NS 71 ± 10 
HR day (beats/min) 78 ± 8 NS 80 ± 12 
HR night (beats/min) 64 ± 6 NS 62 ± 8 
 MA+ (n = 28) P MA− (n = 59) 
UAE (mg/24 h) 94.7 ± 42.9 <.0001 12.6 ± 9.7 
Age (y) 42 ± 5 NS 41 ± 5 
Sex (men/women) 18/10 NS 37/22 
Body mass index (kg/m225.1 ± 3.7 NS 25.3 ± 3.4 
Systolic BP 24 h (mm Hg) 148 ± 10 .024 142 ± 12 
Diastolic BP 24 h (mm Hg) 94 ± 6 .002 89 ± 7 
Systolic BP day (mm Hg) 153 ± 13 .029 146 ± 14 
Diastolic BP day (mm Hg) 99 ± 8 .004 94 ± 7 
Systolic BP night (mm Hg) 133 ± 13 .029 126 ± 14 
Diastolic BP night (mm Hg) 86 ± 10 .014 81 ± 8 
Systolic BP % night fall 13.4 ± 7.3 NS 13.9 ± 8.5 
Diastolic BP % night fall 13.6 ± 8.2 NS 14.2 ± 7.9 
HR 24 h (beats/min) 72 ± 9 NS 71 ± 10 
HR day (beats/min) 78 ± 8 NS 80 ± 12 
HR night (beats/min) 64 ± 6 NS 62 ± 8 

NS = not significant.

With regard to the LV, end-diastolic diameter was normal (< 56 mm) in all patients and was similar between the two groups. Left ventricular hypertrophy (LV mass index > 130 g/m2 in men, > 110 g/m2 in women), based on increased (> 11 mm) septal and posterior wall thickness, was found in 11 hypertensive patients with normal UAE (18.6%) and in 16 hypertensive patients with microalbuminuria (57%) (χ2 test, P = .022). Mean LV mass index was significantly higher in hypertensive patients with microalbuminuria (Table 2). Peak shortening rate of LV diameter, index of LV systolic function, was normal (> 1.9 sec−1) in all patients, but was significantly lower in those with microalbuminuria (Table 2) . The LV diastolic dysfunction (peak lengthening rate of LV diameter < 3.6 sec−1 or peak wall thinning rate < 8.4 cm/sec) was found in 13 patients with normal UAE (22%) and in 19 patients with microalbuminuria (67.8%) (χ2 test, P = .013). Mean values of both indices of LV diastolic function were significantly lower in patients with microalbuminuria (Table 2). The difference remained significant also after the adjustment of diastolic parameters for age and 24-h heart rate (adjusted means: peak lengthening rate for MA+, 4.04 sec−1; for MA−, 5.08 sec−1, P = .001; peak thinning rate for MA+, 9.77 cm/sec; for MA−, 12.65 cm/sec, P = .001), for 24-h systolic BP (adjusted means: peak lengthening rate for MA+, 4.09 sec−1; for MA−, 4.97 sec−1, P = .002; peak thinning rate for MA+, 9.88 cm/sec; for MA−, 12.59 cm/sec, P = .001), for 24-h systolic and diastolic BP and LV mass index (adjusted means: peak lengthening rate for MA+, 4.23 sec−1; for MA−, 4.83 sec−1, P = .005; peak thinning rate for MA+, 10.23 cm/sec; for MA−, 12.14 cm/sec, P = .004), and for age, 24-h heart rate, 24-h BP, and LV mass index (adjusted means: peak lengthening rate for MA+, 4.18 sec−1; for MA−, 4.89 sec−1, P = .005; peak thinning rate for MA+, 10.13 cm/sec; for MA−, 12.21 cm/sec, P = .004).

Table 2

Mean values (± SD) of echocardiographic parameters in hypertensives with (MA+) and without microalbuminuria (MA−)

 MA+ P MA− 
DD (mm) 48 ± 5 NS 47 ± 6 
ST (mm) 10.9 ± 1.6 .002 9.8 ± 1.5 
WT (mm) 10.6 ± 1.4 .013 9.9 ± 1.1 
LVMi (g/m2139 ± 38 .009 113 ± 44 
−dD/dt (sec−13.2 ± 0.9 .004 3.9 ± 1.1 
+dD/dt (sec−14 ± 0.9 .001 5.1 ± 1.6 
dW/dt (cm/sec) 9.7 ± 3.5 .001 12.7 ± 4.1 
 MA+ P MA− 
DD (mm) 48 ± 5 NS 47 ± 6 
ST (mm) 10.9 ± 1.6 .002 9.8 ± 1.5 
WT (mm) 10.6 ± 1.4 .013 9.9 ± 1.1 
LVMi (g/m2139 ± 38 .009 113 ± 44 
−dD/dt (sec−13.2 ± 0.9 .004 3.9 ± 1.1 
+dD/dt (sec−14 ± 0.9 .001 5.1 ± 1.6 
dW/dt (cm/sec) 9.7 ± 3.5 .001 12.7 ± 4.1 

DD = LV end-diastolic diameter; ST = end-diastolic septal thickness; WT = end-diastolic posterior wall thickness; LVMi = LV mass index; −dD/dt = peak shortening rate of LV diameter; +dD/dt = peak lengthening rate of LV diameter; dW/dt = peak thinning rate of LV posterior wall.

Considering the 87 patients together, UAE was directly correlated with LV mass index, (r = 0.27, P = .012) and inversely correlated with both indices of LV diastolic function (peak lengthening rate of LV diameter, r = −0.42, P = .0008; peak wall thinning rate, r = −0.34, P = .006). Both diastolic parameters were directly correlated with peak shortening rate of LV diameter, index of systolic function (peak lengthening rate, r = 0.25, P = .016, peak thinning rate, r = 0.21, P = .019), but the relationship was significantly weaker than that between diastolic indices and UAE. The correlations between UAE and LV diastolic parameters remained significant also after the adjustment of diastolic indices for age, 24-h heart rate, 24-h BP values, and LV mass index.

Discussion

In designing this study, we focused on a selected group of subjects with sustained hypertension, evaluating BP not only by means of repeated clinic measurements, but also by means of 24-h ambulatory BP monitoring and using an high cutoff BP value for the enrollment (mean 24-h BP > 140 and/or 90 mm Hg). Moreover, we selected only those subjects who had never been treated with antihypertensive drugs, as treatment can induce changes in both microalbuminuria and LV morpho-functional characteristics.20,21,22,23

Microalbuminuria was found in 28 (32%) of the 87 hypertensive patients examined, a prevalence that is in keeping with published reports of microalbuminuria in 20% to 40% of sustained hypertensive patients.6,7,24,25,26 As previously found,6,7,27,28,29 microalbuminuric hypertensive patients had significantly higher systolic and diastolic BP throughout the 24-h period compared with normoalbuminuric patients, whereas the extent of nocturnal BP decrease and the prevalence of nondippers were not significantly different. These latter observations appear to be in contrast with some previous findings.27,30 However, it must be considered that, as recently demonstrated,31,32,33 the classification of patients into “dippers” and “nondippers” on the basis of one 24-h BP monitoring has a poor test/retest reliability and a low reproducibility over time, and is therefore of questionable clinical value.

With regard to LV, our study confirmed the association of microalbuminuria with myocardial hypertrophy.5,6,7,8,9,10 In fact, the prevalence of myocardial hypertrophy (due to increased septal and wall thickness) was greater, and the mean value of LV mass index was significanty higher, in microalbuminuric patients than in normoalbuminuric ones. Moreover UAE directly correlated with LV mass index. Peak shortening rate of LV diameter, an index of LV systolic function, was normal in all the patients but was significantly lower in subjects with microalbuminuria. This finding is in agreement with the results of Pontremoli et al,10 who found a depressed LV systolic performance, as indicated by a reduced midwall fractional shortening, in microalbuminuric hypertensive patients.

The main result of our study concerns the relationship between microalbuminuria and LV diastolic function. The latter was evaluated by means of peak lengthening rate and peak wall thinning rate, both derived from digitized M-mode echocardiograms. These indices, which are used less than are Doppler-derived parameters, have been demonstrated to be more sensitive in discriminating between normal and impaired diastolic function in the presence of myocardial hypertrophy; they are also less influenced by heart rate and events occurring during isovolumic relaxation.34 Left ventricular diastolic function was significantly more impaired in patients with microalbuminuria: the prevalence of diastolic dysfunction was higher in this group, mean values of both diastolic parameters were lower compared with those of hypertensive patients with normal UAE, and this latter was inversely related to both LV diastolic parameters.

As noted above,11,12,13,14,15,16,17 diastolic dysfunction is a key feature of hypertensive cardiopathy and is negatively influenced by many factors, such as higher BP values and greater LV mass. It is, however, known that myocardial hypertrophy and diastolic impairment are not always linked, diastolic dysfunction being found in hypertensive patients in either the presence or absence of LV hypertrophy.14,17 Also, in our study, diastolic dysfunction was more frequent than myocardial hypertrophy and was found in patients with normal LV mass index. Because 24-h BP and LV mass index were significantly higher in the microalbuminuric group, we took into account the possibility that the reduced diastolic function in this group was solely a consequence of higher BP and greater myocardial hypertrophy. To test this hypothesis we compared the two groups after correction of diastolic indices for 24-h BP values and LV mass index; moreover, as both age and heart rate are known to influence LV diastolic function, we introduced age and 24-h heart rate as covariates. Despite the adjustment, diastolic function remained significantly lower in microalbuminuric patients, and the inverse correlation between UAE and diastolic parameters remained significant.

In conclusion, besides confirming the association of increased UAE with higher BP values and greater myocardial mass, our study demonstrates that the presence of microalbuminuria correlates with preclinical LV diastolic impairment. This relationship, independent from the presence of increased LV mass, strengthens the role of microalbuminuria as a reliable and early marker of preclinical cardiac involvement in patients with essential hypertension.

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