Low-Grade Inflammation and Microalbuminuria in Hypertension
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《动脉硬化血栓血管生物学》
From the Dipartimento Cardio Toracico, Laboratorio Analisi Chimiche e Microbiologiche (R.P., G.D., V.D., G. Pellegrini), Azienda Ospedaliera Pisana (R.P., G.D., V.D., G. Pellegrini), Endocrinologia e Metabolismo (L.P., S.D., G. Penno), Università di Pisa, Italy.
Reprint requests to Roberto Pedrinelli MD, Università di Pisa, Dipartimento Cardio Toracico, Paradisa 2, Pisa, 56100 Italy. E-mail r.pedrinelli@int.med.unipi.it
ABSTRACT
Background— Albuminuria and C-reactive protein (CRP), a marker of systemic low-grade inflammation, are frequently elevated in essential hypertension and predict cardiovascular prognosis independent of conventional risk factors. However, in spite of their potentially important links, the interrelationships between the 2 parameters have not been explored in depth in hypertensive patients.
Methods and Results— Albuminuria (the mean of 3 overnight urine collections), high-sensitive CRP (hs-CRP), 24-hour blood pressure (BP), weight, lipids, poststimulative (75 g PO) plasma glucose, insulin, and insulin sensitivity by the homeostasis model assessment model were evaluated in 220 never treated, nondiabetic, uncomplicated essential hypertensive men. Albuminuria 15 μg/min was defined as microalbuminuria and hs-CRP values above and below median (2.3 mg/L) as high and low, respectively. Concentric left ventricular hypertrophy was diagnosed by echocardiography, and a full-blown metabolic syndrome was identified in presence of hypertension and at least 3 of following: obesity, subclinical hyperglycemia, low high-density lipoprotein (HDL) and high triglycerides. Microalbuminuria was present in 54 patients, 29 with high hs-CRP characterized by higher 24-hour systolic BP, postload glucose, body mass index, lower HDL cholesterol, more frequent metabolic syndrome, concentric LVH, and active smoking than those with either isolated microalbuminuria (n=27) or normoalbuminuria.
Conclusions— Microalbuminuria accompanied by evidence of subclinical inflammation is a strong correlate of metabolic abnormalities in essential hypertension and identifies a patient subset at very high cardiovascular risk. In contrast, isolated microalbuminuria may represent a distinct pathophysiological condition characterized by a more benign profile and possibly a better prognosis.
Microalbuminuria accompanied by high hs-CRP was characterized by higher 24-hour SBP, postload glucose, BMI, lower HDL cholesterol, more frequent metabolic syndrome, concentric LVH, and active smoking indicating that this phenotypic pattern is a strong correlate of metabolic abnormalities in essential hypertension and identifies a patient subset at very high cardiovascular risk.
Key Words: low-grade inflammation ? C-reactive protein ? microalbuminuria ? left ventricular hypertrophy ? essential hypertension
Introduction
C-Reactive protein (CRP), a marker of low-grade inflammation, predicts cardiovascular mortality and morbidity in patients with pre-existing cardiovascular disease and apparently healthy subjects,1 although perhaps less strongly than originally considered.2 CRP levels are frequently elevated in hypertension,3 and raised CRP precedes blood pressure (BP) elevation,4 implying an active involvement of inflammation in the development of the hypertensive syndrome. At similarity with CRP, microalbuminuria (MA), a slight elevation in urinary albumin excretion (UAE) above some preset threshold, characterizes a large proportion of nondiabetic essential hypertensive patients.5 At further similarity with CRP, MA is also an independent marker of cardiovascular risk, suggesting that its prognostic power is not mediated through the effect of conventional cardiovascular risk factors.5 Finally, MA and high CRP levels are more prevalent in metabolic syndrome (MS),6,7 a morbid constellation of metabolic abnormalities complicated by pervasive BP elevation.8 Thus, several factors link UAE with CRP, but scarce information is available about their interrelationships with hypertension-related cardiovascular and metabolic abnormalities. For this reason, we addressed that issue in a large and carefully screened sample of nondiabetic essential hypertensive men.
Materials and Methods
Subjects
The analysis was performed on 220 sedentary, white hypertensive men screened between the 2000 and 2003 calendar years in the context of a preventive program offered to never-treated subjects referred to our unit for hypertension screening. Main inclusion criteria were casual BP >140/90 mm Hg on at least 3 occasions as outpatients, fasting blood glucose levels 125 mg/dL, serum creatinine 1.4 mg/dL, serum triglycerides <500 mg/dL, no proteinuria at the dipstick test, negative urinoculture, normal sediment, and no evidence or history of congestive cardiac failure or left ventricular dysfunction (ejection fraction <50%), ischemic heart disease, or other vascular diseases.
Renal ultrasound scans showed normal-sized kidneys and no evidence of cortical scarring or obstructive uropathy. Angiograms, when indicated, had excluded renal artery stenosis, whereas routine clinical and hematologic examinations excluded other secondary forms of hypertension.
Experimental evaluations were completed in a 2-week period. The study was performed in accordance with the Declaration of Helsinki and the protocol approved by the local ethics committee.
Experimental Procedures
UAE was measured by nephelometry (Behring; detection limit 0.1 mg/dL, interassay variation coefficient 3.5%). To minimize the confounding influence of daily physical activity and facilitate the collection procedure, urine was collected from 8:00 PM to 8:00 AM during 3 consecutive days.
CRP levels were measured with high-sensitivity latex-enhanced immunonephelometry on a Behring BN II Nephelometer (Dade Behring; lower sensitivity 0.1 mg/L, intra-assay and interassay coefficients of variation 3.3% and 3.2%, respectively) on blood samples obtained between 8:00 AM and 9:00 AM after overnight fasting and 15 minutes of supine rest. Serum fibrinogen concentrations were measured by the Clauss method (Dade Behring; 8% intra-assay variation coefficient).
Glucose tolerance test was performed in the morning with a 75-g glucose load. Individuals were asked to fast for 12 to 14 hours before the test, and specimens for plasma glucose and insulin were drawn basally and 0.5, 1, 1.5, and 2 hours after administration of the glucose load. Plasma glucose was measured by the glucooxidase method using a Beckman Glucose Analyzer II (Beckman Instruments), and plasma insulin by immunoradiometric assay (Biosource; no cross-reactivity with human proinsulin) with an interassay variation coefficient of 5%. Total high-density lipoprotein (HDL) cholesterol and triglycerides were assessed by enzymatic colorimetric techniques (Boehringer-Mannheim). Anthropometric measurements (height and weight) were made after each participant had removed his shoes and upper garments. Body weight was measured to the nearest 0.1 kg on a scale with attached height measure (SECA 207).
Systolic BP (SBP) and diastolic BP (DBP; Korotkoff phase V) were the mean of at least 3 sitting recordings taken by mercury sphygmomanometer in the morning before blood sampling using the appropriate size cuff. Twenty-four–hour BP was measured through an oscillometric monitor (Diasys Integra; Novacor) on a regular workday. Recording began between 8:30 AM and 9:00 AM, with readings every 15 minutes until midnight, and every 30 minutes from midnight to 8:00 AM, with at least 90% valid measurements.
Echocardiograms were obtained according to the recommendations of the American Society of Echocardiography using standard parasternal and apical views. No patients showed dyssynergic areas that would invalidate the theoretical assumptions behind the cardiac mass calculations. Wall thickness and chamber volumes were measured by monodimensional and bidimensional echocardiograms (Sonos 1000; Hewlett Packard) with 2.5- and 3.5-MHz transducers. The intraobserver coefficient of variation was 0.4%, 2.8%, and 3.2% for measurements of left ventricular end-diastolic diameter, septal, and posterior left ventricular wall thickness. The corresponding interobserver coefficients of variations were 1.6%, 3.8%, and 4.0%, respectively. Serum creatinine was measured by standard colorimetric methods.
Definitions and Data Processing
High-sensitive CRP (hs-CRP) distribution was split by the median (2.3 mg/L), and high and low values were defined accordingly. UAE was the mean of 3 consecutive overnight collections, and MA was a mean overnight UAE 15 and <200 μg/min.
Twenty-four-hour SBP and DBP values were the mean of the overall 24-hour recordings after artifact editing. Left ventricular mass (LVM) was derived according to the Penn Convention, and LVM index (LVMI) was obtained by correcting for height2.7 to provide a normalization criterion not related to body weight.9 Relative wall thickness (RWT) was measured at end-diastole as end-diastolic interventricular septum+posterior wall thickness/left ventricular internal end-diastolic diameter.10 Left ventricular hypertrophy (LVH) was defined as LVMI >51 g/m2.7,9 and a concentric pattern of LVH was diagnosed in presence of RWT >0.45.9
Body mass index (BMI) was calculated as weight/height2 (kg/m2), and BMI 30 kg/m2 was the cut-off for obesity.11 HDL cholesterol (HDL-C) <40 mg/dL and triglycerides 200 mg/dL were categorized as low and high, respectively.8 Low-density lipoprotein (LDL) cholesterol was calculated as .
Impaired fasting glucose (IFG) was defined as a fasting plasma glucose value between 100 and 125 mg/dL (5.6 and 6.9 mmol/L).12 Oral glucose tolerance data were summarized as the area under curve (AUC; trapezoidal rule) values.
Insulin sensitivity was estimated through the homeostasis model13 assessment (HOMA) of insulin resistance according to Matthews (fasting insulin (μU/mL)/)]). Increasing HOMA values denote progression from normal to impaired insulin sensitivity. As a categorical classification, patients with HOMA values above the 75th percentile (cut-off point 4.2 U) were defined as insulin resistant.14
According to National Cholesterol Education Program (NCEP)/Adult Treatment Panel III (ATP III) criteria,8 an MS was diagnosed when hypertension coexisted with at least 2 of the following 4 abnormalities: obesity, low HDL, IFG, triglycerides 150 mg/dL, and we defined a full-blown MS in presence of at least 3 of them. Because we did not measure abdominal obesity, data refer only to a measure of overall obesity (BMI 30 kg/m2). Smoking status was defined as active smoker versus nonsmoker, without distinction between former and never smoker. Creatinine clearance values were derived according to Cockcroft and Gault (/72xserum creatinine).15
Statistics
Differences among continuous (after log transformation for skewed data) variables were tested by ANOVA and between-group comparisons were performed by calculating the least significant difference. Means for the outcome measures were adjusted for confounders through analysis of covariance (ANCOVA). Statistical association was assessed by nonparametric Spearman’s correlation coefficients (5) for continuous variables and by logistic regression (maximum likelihood method) for a binary variable (coded as 0 and 1), with a backward stepwise procedure (p-to-remove <0.05) to identify independent regressors. Odds ratios (ORs) and 95% CIs were used to estimate relative risk. Descriptive statistics were arithmetic means±SD or medians (range) for skewed data. Statistical significance was set at P<0.05.
Results
Demographic, echocardiographic, and clinical characteristics of the overall sample are reported in Table 1.
TABLE 1. Demographic and Clinical Characteristics of the Sample (n=220)
hs-CRP values were dissociated from UAE (Figure 1, left) and associated positively with circulating fibrinogen, another inflammatory marker16 (Figure 1, right).
Figure 1. Scatterplot of hs-CRP vs UAE (left) and serum fibrinogen (right). n=220.
MA was found in 56 (25%) patients: 29 with high and 27 with low hs-CRP, respectively; normoalbuminuria was present in 164, 81 with high, and 83 with low hs-CRP, respectively. Microalbuminuric patients with high hs-CRP were somewhat older, with greater BMI, lower HDL-C, and higher postload plasma glucose, 24-hour SBP, and RWT (Table 2). Those variables did not differ in the 3 other subgroups, which also had lower odds for obesity, low HDL, full-blown MS, active smoking, and concentric LVH (Table 2; Figure 2). Prevalence of insulin resistance (IR) did not differ among subgroups.
TABLE 2. Demographic and Clinical Parameters by Combined hs-CRP and MA Stratification
Figure 2. Obesity (BMI 30 kg/m2), low HDL (<40 mg/dL), full-blown MS (at least 4 of the NCEP/ATP III component traits),12 active smoking, and concentric LVH (LVMI >51 g/m2.7 and RWT >0.45) by combined MA and hs-CRP stratification. ORs were calculated with MA and high hs-CRP as a reference. NA indicates normoalbuminuria. *P=0.01; &P=0.02.
Accounting for age by ANCOVA did not change that statistical trend. Adjustment for BMI abolished differences in postload plasma glucose and HDL but left unchanged those in 24-hour SBP and RWT (data not shown).
When the above parameters were entered in a multivariate logistic regression model, only BMI (OR/BMI unit rise, 1.6; 95% CI, 1.3 to 1.9; P<0.001), concentric LVH (OR/0.10 U rise, 1.14; 95% CI, 1.03 to 1.25; P=0.005), and active smoking (OR, 1.97; 95% CI, 1.001 to 3.98; P=0.016) were independent predictors of MA/high hs-CRP (Figure 3).
Figure 3. Increment in risk of MA and high hs-CRP by increasing BMI, concentric LVH (Conc LVH), and smoking status. ORs were calculated after a multivariate logistic model by making 1 the risk of a nonsmoking patient with BMI=20 kg/m2 and no concentric LVH. The multivariate analysis also accounted for age, 24-hour SBP, postload glucose (AUC 0 to 120 minutes), HDL-C, and full-blown MS (1=yes vs 0=no).
When substituting obesity for elevated hs-CRP as a stratification parameter, obese microalbuminuric subjects had higher 24-hour SBP and smoked more frequently than the normoalbuminuric counterparts, but dissonant with previous results, the difference in the rate of concentric LVH, full-blown MS, and low HDL-C did not achieve statistical significance. On the other hand, MA without concomitant obesity was accompanied by lower frequencies of IR, MS, IFG, and low HDL-C than the 2 obese subgroups (Table 3).
TABLE 3. Demographic and Clinical Parameters by Combined BMI (Obese Versus Nonobese) and MA Stratification
Discussion
The new finding of this study is the strong effect modification conferred by high circulating hs-CRP, a marker of low-grade systemic inflammation, to microalbuminuric, nondiabetic, essential hypertensive patients without overt cardiovascular and renal disease. In fact, when combined with high hs-CRP, MA was characterized by lower HDL-C, higher postload plasma glucose, greater BMI, higher rates of fully expressed MS, and active smoking, the latter consistent with the knowledge of smoking as a proinflammatory and dysmetabolic factor.17 That pattern, heretofore defined as inflammatory MA, was by and large independent of age-related influences and characterized by higher 24-hour SBP and more frequent concentric LVH, an overall highly adverse risk profile because each of those individual metabolic, cardiovascular, and behavioral parameters contributes independently to morbidity and mortality.18 In addition, MS per se promotes additional cardiovascular events even in nondiabetic europid subjects as a function of the number of component abnormalities.19,20 Along the same line, the results of the multivariate logistic regression were also of interest in showing a >100-fold higher risk of inflammatory MA in an obese patient with concentric LVH compared with his lean counterpart without LVH (Figure 3). That statistic, although suggesting a direct role of adiposity in concurring to the combined rise in UAE and CRP,21 also shows additional links of those 2 parameters with hypertensive LVH22,23 although cause-effect mechanisms cannot be assessed through cross-sectional studies. On a theoretical basis, in fact, inflammatory MA may precede and perhaps predispose to the development of the observed metabolic and cardiovascular abnormalities or rather represent a consequence of the impact of those noxious factors, a possibility to be evaluated only in prospective terms. Because of the known relationships between adiposity and low-grade inflammation21 and of its potential clinical usefulness, we also analyzed the effect of costratification by obesity. However, in spite of a trend to comparable results with the 2 methods, overall obesity did not discriminate high-risk subjects as efficiently as an elevated hs-CRP. Thus, low-grade inflammation combined with MA might perhaps provide a better prognostic tool than body size as such, a tentative conclusion to be substantiated prospectively in larger samples.
An obvious question regards the pathophysiological meaning of inflammatory MA, a point to which our data can answer only in inferential terms. As a first possibility, one might think of low-grade inflammation as the cause of higher UAE, for example, because of glomeruli made more permeant by inflammatory cytokines as in acute clinical conditions in which urine albumin behaves as an acute phase reactant.24 That possibility is unlikely in our patients, however, in whom hs-CRP was only minimally correlated with UAE in spite of a highly significant association with serum fibrinogen, the former indicating that those markers were driven by independent stimuli and the latter confirming a common modulation of inflammation-sensitive proteins even in the healthy range. In that respect, our data in nondiabetic hypertensive males are consistent with those of Festa et al,25 who reported correlation coefficients between hs-CRP and UAE closely similar to ours (r=0.06) after accounting for gender, diabetes, and hypertension. As an opposite alternative, MA coexisting with high hs-CRP might be seen as a random overlap of 2 totally independent biological parameters. However, that reductive hypothesis does not explain why those patients differed so strikingly regarding the metabolic and cardiovascular phenotype from those with isolated elevations of either urine albumin or hs-CRP. As a third possibility, urine albumin and CRP might represent unrelated variables sensitive to different aspects of a common pathological stimulus such as subclinical vascular damage. Previous data have shown a preferential affinity of MA and CRP for various domains of vascular disease26 or different degrees of vascular dysfunction, low-grade inflammation being preferentially associated with abnormal endothelial-dependent27 and MA also to endothelial-independent28 vasomotor responses. That hypothesis is consistent with the higher rates of inflammatory MA reported in presence of disparate clinical conditions characterized by increased cardiovascular risk and widespread vascular dysfunction such as severe hypertension,29 obesity,30 and MS.31
Some short comment also deserves the presence of MA and low hs-CRP levels in patients characterized by leaner body size, lower BP, and a better metabolic and cardiovascular profile than those sharing elevated UAE but higher CRP levels, a contrast suggestive of different pathophysiological determinants to the genesis of hypertensive MA. Thus, MA without evidence of low-grade inflammation might result from isolated abnormalities of glomerular permeability,32 or perhaps genetic predisposition33 in absence of systemic vascular and metabolic abnormalities. The concept might explain discrepant reports28,34 about the association of MA with endothelial (dys)function when tested in lean, normolipidemic subjects.34 A similar explanation, supported by the lower hs-CRP levels and the preserved insulin sensitivity in our group of subjects with MA and a lean body size, might apply to insulin sensitivity.35,36 However, IR, at least as assessed through the HOMA model, did not clearly differ by CRP levels in our microalbuminuric subgroups. Therefore, the hypothesis is plausible, although to be verified in more numerous groups, including females rather than an all-male hypertensive cohort such as ours, and possibly through more precise methods for the evaluation of insulin sensitivity.
In conclusion, MA associated with evidence of subclinical inflammation is a strong correlate of metabolic abnormalities in essential hypertension and identifies a high-risk patient subset in need of more aggressive treatment for cardiovascular prevention. In contrast, isolated MA may represent a distinct pathophysiological condition characterized by a more benign profile and possibly a better prognosis, although this hypothesis needs verification in prospective studies.
Acknowledgments
This work was supported in part through funds from the University of Pisa (Cofinanziamento di Ateneo 2002).
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Reprint requests to Roberto Pedrinelli MD, Università di Pisa, Dipartimento Cardio Toracico, Paradisa 2, Pisa, 56100 Italy. E-mail r.pedrinelli@int.med.unipi.it
ABSTRACT
Background— Albuminuria and C-reactive protein (CRP), a marker of systemic low-grade inflammation, are frequently elevated in essential hypertension and predict cardiovascular prognosis independent of conventional risk factors. However, in spite of their potentially important links, the interrelationships between the 2 parameters have not been explored in depth in hypertensive patients.
Methods and Results— Albuminuria (the mean of 3 overnight urine collections), high-sensitive CRP (hs-CRP), 24-hour blood pressure (BP), weight, lipids, poststimulative (75 g PO) plasma glucose, insulin, and insulin sensitivity by the homeostasis model assessment model were evaluated in 220 never treated, nondiabetic, uncomplicated essential hypertensive men. Albuminuria 15 μg/min was defined as microalbuminuria and hs-CRP values above and below median (2.3 mg/L) as high and low, respectively. Concentric left ventricular hypertrophy was diagnosed by echocardiography, and a full-blown metabolic syndrome was identified in presence of hypertension and at least 3 of following: obesity, subclinical hyperglycemia, low high-density lipoprotein (HDL) and high triglycerides. Microalbuminuria was present in 54 patients, 29 with high hs-CRP characterized by higher 24-hour systolic BP, postload glucose, body mass index, lower HDL cholesterol, more frequent metabolic syndrome, concentric LVH, and active smoking than those with either isolated microalbuminuria (n=27) or normoalbuminuria.
Conclusions— Microalbuminuria accompanied by evidence of subclinical inflammation is a strong correlate of metabolic abnormalities in essential hypertension and identifies a patient subset at very high cardiovascular risk. In contrast, isolated microalbuminuria may represent a distinct pathophysiological condition characterized by a more benign profile and possibly a better prognosis.
Microalbuminuria accompanied by high hs-CRP was characterized by higher 24-hour SBP, postload glucose, BMI, lower HDL cholesterol, more frequent metabolic syndrome, concentric LVH, and active smoking indicating that this phenotypic pattern is a strong correlate of metabolic abnormalities in essential hypertension and identifies a patient subset at very high cardiovascular risk.
Key Words: low-grade inflammation ? C-reactive protein ? microalbuminuria ? left ventricular hypertrophy ? essential hypertension
Introduction
C-Reactive protein (CRP), a marker of low-grade inflammation, predicts cardiovascular mortality and morbidity in patients with pre-existing cardiovascular disease and apparently healthy subjects,1 although perhaps less strongly than originally considered.2 CRP levels are frequently elevated in hypertension,3 and raised CRP precedes blood pressure (BP) elevation,4 implying an active involvement of inflammation in the development of the hypertensive syndrome. At similarity with CRP, microalbuminuria (MA), a slight elevation in urinary albumin excretion (UAE) above some preset threshold, characterizes a large proportion of nondiabetic essential hypertensive patients.5 At further similarity with CRP, MA is also an independent marker of cardiovascular risk, suggesting that its prognostic power is not mediated through the effect of conventional cardiovascular risk factors.5 Finally, MA and high CRP levels are more prevalent in metabolic syndrome (MS),6,7 a morbid constellation of metabolic abnormalities complicated by pervasive BP elevation.8 Thus, several factors link UAE with CRP, but scarce information is available about their interrelationships with hypertension-related cardiovascular and metabolic abnormalities. For this reason, we addressed that issue in a large and carefully screened sample of nondiabetic essential hypertensive men.
Materials and Methods
Subjects
The analysis was performed on 220 sedentary, white hypertensive men screened between the 2000 and 2003 calendar years in the context of a preventive program offered to never-treated subjects referred to our unit for hypertension screening. Main inclusion criteria were casual BP >140/90 mm Hg on at least 3 occasions as outpatients, fasting blood glucose levels 125 mg/dL, serum creatinine 1.4 mg/dL, serum triglycerides <500 mg/dL, no proteinuria at the dipstick test, negative urinoculture, normal sediment, and no evidence or history of congestive cardiac failure or left ventricular dysfunction (ejection fraction <50%), ischemic heart disease, or other vascular diseases.
Renal ultrasound scans showed normal-sized kidneys and no evidence of cortical scarring or obstructive uropathy. Angiograms, when indicated, had excluded renal artery stenosis, whereas routine clinical and hematologic examinations excluded other secondary forms of hypertension.
Experimental evaluations were completed in a 2-week period. The study was performed in accordance with the Declaration of Helsinki and the protocol approved by the local ethics committee.
Experimental Procedures
UAE was measured by nephelometry (Behring; detection limit 0.1 mg/dL, interassay variation coefficient 3.5%). To minimize the confounding influence of daily physical activity and facilitate the collection procedure, urine was collected from 8:00 PM to 8:00 AM during 3 consecutive days.
CRP levels were measured with high-sensitivity latex-enhanced immunonephelometry on a Behring BN II Nephelometer (Dade Behring; lower sensitivity 0.1 mg/L, intra-assay and interassay coefficients of variation 3.3% and 3.2%, respectively) on blood samples obtained between 8:00 AM and 9:00 AM after overnight fasting and 15 minutes of supine rest. Serum fibrinogen concentrations were measured by the Clauss method (Dade Behring; 8% intra-assay variation coefficient).
Glucose tolerance test was performed in the morning with a 75-g glucose load. Individuals were asked to fast for 12 to 14 hours before the test, and specimens for plasma glucose and insulin were drawn basally and 0.5, 1, 1.5, and 2 hours after administration of the glucose load. Plasma glucose was measured by the glucooxidase method using a Beckman Glucose Analyzer II (Beckman Instruments), and plasma insulin by immunoradiometric assay (Biosource; no cross-reactivity with human proinsulin) with an interassay variation coefficient of 5%. Total high-density lipoprotein (HDL) cholesterol and triglycerides were assessed by enzymatic colorimetric techniques (Boehringer-Mannheim). Anthropometric measurements (height and weight) were made after each participant had removed his shoes and upper garments. Body weight was measured to the nearest 0.1 kg on a scale with attached height measure (SECA 207).
Systolic BP (SBP) and diastolic BP (DBP; Korotkoff phase V) were the mean of at least 3 sitting recordings taken by mercury sphygmomanometer in the morning before blood sampling using the appropriate size cuff. Twenty-four–hour BP was measured through an oscillometric monitor (Diasys Integra; Novacor) on a regular workday. Recording began between 8:30 AM and 9:00 AM, with readings every 15 minutes until midnight, and every 30 minutes from midnight to 8:00 AM, with at least 90% valid measurements.
Echocardiograms were obtained according to the recommendations of the American Society of Echocardiography using standard parasternal and apical views. No patients showed dyssynergic areas that would invalidate the theoretical assumptions behind the cardiac mass calculations. Wall thickness and chamber volumes were measured by monodimensional and bidimensional echocardiograms (Sonos 1000; Hewlett Packard) with 2.5- and 3.5-MHz transducers. The intraobserver coefficient of variation was 0.4%, 2.8%, and 3.2% for measurements of left ventricular end-diastolic diameter, septal, and posterior left ventricular wall thickness. The corresponding interobserver coefficients of variations were 1.6%, 3.8%, and 4.0%, respectively. Serum creatinine was measured by standard colorimetric methods.
Definitions and Data Processing
High-sensitive CRP (hs-CRP) distribution was split by the median (2.3 mg/L), and high and low values were defined accordingly. UAE was the mean of 3 consecutive overnight collections, and MA was a mean overnight UAE 15 and <200 μg/min.
Twenty-four-hour SBP and DBP values were the mean of the overall 24-hour recordings after artifact editing. Left ventricular mass (LVM) was derived according to the Penn Convention, and LVM index (LVMI) was obtained by correcting for height2.7 to provide a normalization criterion not related to body weight.9 Relative wall thickness (RWT) was measured at end-diastole as end-diastolic interventricular septum+posterior wall thickness/left ventricular internal end-diastolic diameter.10 Left ventricular hypertrophy (LVH) was defined as LVMI >51 g/m2.7,9 and a concentric pattern of LVH was diagnosed in presence of RWT >0.45.9
Body mass index (BMI) was calculated as weight/height2 (kg/m2), and BMI 30 kg/m2 was the cut-off for obesity.11 HDL cholesterol (HDL-C) <40 mg/dL and triglycerides 200 mg/dL were categorized as low and high, respectively.8 Low-density lipoprotein (LDL) cholesterol was calculated as .
Impaired fasting glucose (IFG) was defined as a fasting plasma glucose value between 100 and 125 mg/dL (5.6 and 6.9 mmol/L).12 Oral glucose tolerance data were summarized as the area under curve (AUC; trapezoidal rule) values.
Insulin sensitivity was estimated through the homeostasis model13 assessment (HOMA) of insulin resistance according to Matthews (fasting insulin (μU/mL)/)]). Increasing HOMA values denote progression from normal to impaired insulin sensitivity. As a categorical classification, patients with HOMA values above the 75th percentile (cut-off point 4.2 U) were defined as insulin resistant.14
According to National Cholesterol Education Program (NCEP)/Adult Treatment Panel III (ATP III) criteria,8 an MS was diagnosed when hypertension coexisted with at least 2 of the following 4 abnormalities: obesity, low HDL, IFG, triglycerides 150 mg/dL, and we defined a full-blown MS in presence of at least 3 of them. Because we did not measure abdominal obesity, data refer only to a measure of overall obesity (BMI 30 kg/m2). Smoking status was defined as active smoker versus nonsmoker, without distinction between former and never smoker. Creatinine clearance values were derived according to Cockcroft and Gault (/72xserum creatinine).15
Statistics
Differences among continuous (after log transformation for skewed data) variables were tested by ANOVA and between-group comparisons were performed by calculating the least significant difference. Means for the outcome measures were adjusted for confounders through analysis of covariance (ANCOVA). Statistical association was assessed by nonparametric Spearman’s correlation coefficients (5) for continuous variables and by logistic regression (maximum likelihood method) for a binary variable (coded as 0 and 1), with a backward stepwise procedure (p-to-remove <0.05) to identify independent regressors. Odds ratios (ORs) and 95% CIs were used to estimate relative risk. Descriptive statistics were arithmetic means±SD or medians (range) for skewed data. Statistical significance was set at P<0.05.
Results
Demographic, echocardiographic, and clinical characteristics of the overall sample are reported in Table 1.
TABLE 1. Demographic and Clinical Characteristics of the Sample (n=220)
hs-CRP values were dissociated from UAE (Figure 1, left) and associated positively with circulating fibrinogen, another inflammatory marker16 (Figure 1, right).
Figure 1. Scatterplot of hs-CRP vs UAE (left) and serum fibrinogen (right). n=220.
MA was found in 56 (25%) patients: 29 with high and 27 with low hs-CRP, respectively; normoalbuminuria was present in 164, 81 with high, and 83 with low hs-CRP, respectively. Microalbuminuric patients with high hs-CRP were somewhat older, with greater BMI, lower HDL-C, and higher postload plasma glucose, 24-hour SBP, and RWT (Table 2). Those variables did not differ in the 3 other subgroups, which also had lower odds for obesity, low HDL, full-blown MS, active smoking, and concentric LVH (Table 2; Figure 2). Prevalence of insulin resistance (IR) did not differ among subgroups.
TABLE 2. Demographic and Clinical Parameters by Combined hs-CRP and MA Stratification
Figure 2. Obesity (BMI 30 kg/m2), low HDL (<40 mg/dL), full-blown MS (at least 4 of the NCEP/ATP III component traits),12 active smoking, and concentric LVH (LVMI >51 g/m2.7 and RWT >0.45) by combined MA and hs-CRP stratification. ORs were calculated with MA and high hs-CRP as a reference. NA indicates normoalbuminuria. *P=0.01; &P=0.02.
Accounting for age by ANCOVA did not change that statistical trend. Adjustment for BMI abolished differences in postload plasma glucose and HDL but left unchanged those in 24-hour SBP and RWT (data not shown).
When the above parameters were entered in a multivariate logistic regression model, only BMI (OR/BMI unit rise, 1.6; 95% CI, 1.3 to 1.9; P<0.001), concentric LVH (OR/0.10 U rise, 1.14; 95% CI, 1.03 to 1.25; P=0.005), and active smoking (OR, 1.97; 95% CI, 1.001 to 3.98; P=0.016) were independent predictors of MA/high hs-CRP (Figure 3).
Figure 3. Increment in risk of MA and high hs-CRP by increasing BMI, concentric LVH (Conc LVH), and smoking status. ORs were calculated after a multivariate logistic model by making 1 the risk of a nonsmoking patient with BMI=20 kg/m2 and no concentric LVH. The multivariate analysis also accounted for age, 24-hour SBP, postload glucose (AUC 0 to 120 minutes), HDL-C, and full-blown MS (1=yes vs 0=no).
When substituting obesity for elevated hs-CRP as a stratification parameter, obese microalbuminuric subjects had higher 24-hour SBP and smoked more frequently than the normoalbuminuric counterparts, but dissonant with previous results, the difference in the rate of concentric LVH, full-blown MS, and low HDL-C did not achieve statistical significance. On the other hand, MA without concomitant obesity was accompanied by lower frequencies of IR, MS, IFG, and low HDL-C than the 2 obese subgroups (Table 3).
TABLE 3. Demographic and Clinical Parameters by Combined BMI (Obese Versus Nonobese) and MA Stratification
Discussion
The new finding of this study is the strong effect modification conferred by high circulating hs-CRP, a marker of low-grade systemic inflammation, to microalbuminuric, nondiabetic, essential hypertensive patients without overt cardiovascular and renal disease. In fact, when combined with high hs-CRP, MA was characterized by lower HDL-C, higher postload plasma glucose, greater BMI, higher rates of fully expressed MS, and active smoking, the latter consistent with the knowledge of smoking as a proinflammatory and dysmetabolic factor.17 That pattern, heretofore defined as inflammatory MA, was by and large independent of age-related influences and characterized by higher 24-hour SBP and more frequent concentric LVH, an overall highly adverse risk profile because each of those individual metabolic, cardiovascular, and behavioral parameters contributes independently to morbidity and mortality.18 In addition, MS per se promotes additional cardiovascular events even in nondiabetic europid subjects as a function of the number of component abnormalities.19,20 Along the same line, the results of the multivariate logistic regression were also of interest in showing a >100-fold higher risk of inflammatory MA in an obese patient with concentric LVH compared with his lean counterpart without LVH (Figure 3). That statistic, although suggesting a direct role of adiposity in concurring to the combined rise in UAE and CRP,21 also shows additional links of those 2 parameters with hypertensive LVH22,23 although cause-effect mechanisms cannot be assessed through cross-sectional studies. On a theoretical basis, in fact, inflammatory MA may precede and perhaps predispose to the development of the observed metabolic and cardiovascular abnormalities or rather represent a consequence of the impact of those noxious factors, a possibility to be evaluated only in prospective terms. Because of the known relationships between adiposity and low-grade inflammation21 and of its potential clinical usefulness, we also analyzed the effect of costratification by obesity. However, in spite of a trend to comparable results with the 2 methods, overall obesity did not discriminate high-risk subjects as efficiently as an elevated hs-CRP. Thus, low-grade inflammation combined with MA might perhaps provide a better prognostic tool than body size as such, a tentative conclusion to be substantiated prospectively in larger samples.
An obvious question regards the pathophysiological meaning of inflammatory MA, a point to which our data can answer only in inferential terms. As a first possibility, one might think of low-grade inflammation as the cause of higher UAE, for example, because of glomeruli made more permeant by inflammatory cytokines as in acute clinical conditions in which urine albumin behaves as an acute phase reactant.24 That possibility is unlikely in our patients, however, in whom hs-CRP was only minimally correlated with UAE in spite of a highly significant association with serum fibrinogen, the former indicating that those markers were driven by independent stimuli and the latter confirming a common modulation of inflammation-sensitive proteins even in the healthy range. In that respect, our data in nondiabetic hypertensive males are consistent with those of Festa et al,25 who reported correlation coefficients between hs-CRP and UAE closely similar to ours (r=0.06) after accounting for gender, diabetes, and hypertension. As an opposite alternative, MA coexisting with high hs-CRP might be seen as a random overlap of 2 totally independent biological parameters. However, that reductive hypothesis does not explain why those patients differed so strikingly regarding the metabolic and cardiovascular phenotype from those with isolated elevations of either urine albumin or hs-CRP. As a third possibility, urine albumin and CRP might represent unrelated variables sensitive to different aspects of a common pathological stimulus such as subclinical vascular damage. Previous data have shown a preferential affinity of MA and CRP for various domains of vascular disease26 or different degrees of vascular dysfunction, low-grade inflammation being preferentially associated with abnormal endothelial-dependent27 and MA also to endothelial-independent28 vasomotor responses. That hypothesis is consistent with the higher rates of inflammatory MA reported in presence of disparate clinical conditions characterized by increased cardiovascular risk and widespread vascular dysfunction such as severe hypertension,29 obesity,30 and MS.31
Some short comment also deserves the presence of MA and low hs-CRP levels in patients characterized by leaner body size, lower BP, and a better metabolic and cardiovascular profile than those sharing elevated UAE but higher CRP levels, a contrast suggestive of different pathophysiological determinants to the genesis of hypertensive MA. Thus, MA without evidence of low-grade inflammation might result from isolated abnormalities of glomerular permeability,32 or perhaps genetic predisposition33 in absence of systemic vascular and metabolic abnormalities. The concept might explain discrepant reports28,34 about the association of MA with endothelial (dys)function when tested in lean, normolipidemic subjects.34 A similar explanation, supported by the lower hs-CRP levels and the preserved insulin sensitivity in our group of subjects with MA and a lean body size, might apply to insulin sensitivity.35,36 However, IR, at least as assessed through the HOMA model, did not clearly differ by CRP levels in our microalbuminuric subgroups. Therefore, the hypothesis is plausible, although to be verified in more numerous groups, including females rather than an all-male hypertensive cohort such as ours, and possibly through more precise methods for the evaluation of insulin sensitivity.
In conclusion, MA associated with evidence of subclinical inflammation is a strong correlate of metabolic abnormalities in essential hypertension and identifies a high-risk patient subset in need of more aggressive treatment for cardiovascular prevention. In contrast, isolated MA may represent a distinct pathophysiological condition characterized by a more benign profile and possibly a better prognosis, although this hypothesis needs verification in prospective studies.
Acknowledgments
This work was supported in part through funds from the University of Pisa (Cofinanziamento di Ateneo 2002).
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