(Hypertension. 2000;35:898.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Arterial Hypertension, Microalbuminuria, and Risk of Ischemic Heart Disease
From the Centre of Preventive Medicine, Glostrup County Hospital, The University of Copenhagen, Denmark.
Correspondence to Dr Jan Skov Jensen, MD, PhD, DMSc, Department of Cardiology 2141, The Heart Center, The State University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. E-mail jsje{at}dadlnet.dk
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Abstract |
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Abstract—Albumin excretion in urine is positively correlated with the presence of ischemic heart disease and atherosclerotic risk factors. We studied prospectively whether a slight increase of urinary albumin excretion, ie, microalbuminuria, adds to the increased risk of ischemic heart disease among hypertensive subjects. In 1983 and 1984, blood pressure, urinary albumin/creatinine concentration ratio, plasma total and HDL cholesterol levels, body mass index, and smoking status were obtained in a population-based sample of 2085 subjects, aged 30 to 60 years, who were free from ischemic heart disease, diabetes mellitus, and renal or urinary tract disease. Untreated arterial hypertension or borderline hypertension was present in 204 subjects, who were followed until 1993 by the National Hospital and Death Certificate Registers with respect to development of ischemic heart disease. During 1978 person-years, 18 (9%) of the hypertensive subjects developed ischemic heart disease. Microalbuminuria, defined as a urinary albumin/creatinine ratio above the upper decile (1.07 mg/mmol), was the strongest predictor of ischemic heart disease, with an unadjusted relative risk of 4.2 (95% CI 1.5 to 11.9, P=0.006) and a relative risk of 3.5 (95% CI 1.0 to 12.1, P=0.05) when adjusted for all other atherosclerotic risk factors, including age and gender. In conclusion, microalbuminuria confers a 4-fold increased risk of ischemic heart disease among hypertensive or borderline hypertensive subjects. Urinary albumin excretion should be measured regularly in a hypertension clinic, and a rigorous control of blood pressure and of other atherosclerotic risk factors is recommended in hypertensive patients with microalbuminuria.
Key Words: atherosclerosis • hypertension, arterial • ischemia • microalbuminuria • heart
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Introduction |
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Arterial hypertension is, in some patients, associated with a subclinical increase of the albumin excretion in the urine, ie, microalbuminuria, in spite of preserved renal function.1 2 In hypertensive subjects, microalbuminuria has often been related to an excess of atherosclerotic cardiovascular disease,2 3 which is more frequent in the hypertensive population,4 and to an increased level of atherosclerotic risk markers.5 6 7 In populations of diabetic patients as well as in the general population, microalbuminuria independently precedes atherosclerotic cardiovascular disease,8 9 10 11 12 but this has never been established among hypertensive subjects.
In the present study, we describe a 10-year follow-up analysis of all subjects with untreated arterial hypertension or borderline hypertension identified within the World Health Organization (WHO) Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study in Denmark, 1983 and 1984.13 14 Arterial hypertension was defined according to the WHO criteria. The definition of microalbuminuria has been used in previous studies by our group15 16 17 18 19 20 21 22 and follows a recommendation by Mogensen,23 ie, a urinary albumin excretion above the upper decile in the entire population under study. The aim of the analysis was to assess the predictive impact of microalbuminuria on the subsequent development of ischemic heart disease among young and middle-aged individuals with arterial hypertension or borderline hypertension.
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Methods |
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Subjects and Study Design
Between 1983 and 1984, blood pressure, urinary albumin excretion, and other atherosclerotic risk factors were measured in 2085 subjects born in 1922, 1932, 1942, or 1952. The ascertainment was 74%. Individuals were excluded from this analysis if they, at baseline, had ischemic heart disease (International Classification of Diseases, 8th revision [ICD-8] code No. 410-414),24 diabetes mellitus, renal or urinary tract disease, an abnormal ultrasonic examination of the kidneys or urinary tract, or dipstick-positive glucosuria or hematuria. The participants gave informed consent, and the study was in accordance with the Declaration of Helsinki.
With patients in the sitting position, systolic and diastolic blood pressures were measured 3 times within a 30-minute period with a London School of Hygiene sphygmomanometer and an appropriately sized cuff. Diastolic blood pressure was recorded at the disappearance of the Korotkoff sounds (phase V). Arterial hypertension or borderline hypertension, defined as systolic blood pressure >140 mm Hg and/or diastolic blood pressure >90 mm Hg, was observed in 204 participants not treated with antihypertensive medication.
Urinary albumin excretion was expressed as the
albumin/creatinine concentration ratio in an early
morning spot urine sample.25 The albumin
concentration was measured by an ELISA (lower detection limit, 0.1
mg/L; intra-assay variation, 2.1%; and interassay variation,
8.3%),26 and the creatinine concentration was
measured by a colorimetric method (intra-assay
variation, 1.0%; interassay variation, 2.0%)27 after 12
to 13 years of frozen storage. Microalbuminuria was
defined as a urinary albumin/creatinine ratio
>1.07 mg/mmol (the upper decile in the entire study population of 204
hypertensives, 1.05 mg/mmol in men and 1.08 mg/mmol in women);
normoalbuminuria was defined as a urinary
albumin/creatinine ratio 
1.07 mg/mmol.
A fasting blood sample was drawn for the measurement of plasma total cholesterol and HDL cholesterol (enzymatic colorimetric methods [CHOL CHOD-PAP and HDL CHOLESTEROL PRECIPITANT], Peridochrom, Boehringer-Mannheim GmbH). Body mass index was calculated as weight/height2, and smoking status was recorded.
On the basis of the Danish personal identification code, the 204 hypertensive individuals were followed until death, emigration, or December 31, 1993. Information regarding vital status, cause of death, hospital admissions, and diagnosis were traced by use of the National Register on Vital Status, the National Death Certificate Register, and the National Hospital Discharge Register, respectively. We identified 18 cases with fatal or nonfatal myocardial infarction, angina pectoris, or ischemic heart disease (ICD-8 code No. 410-414).24
Statistical Analysis
Differences in baseline characteristics between hypertensives
developing ischemic heart disease and hypertensive controls
were compared by the Student unpaired t test for continuous
variables and by the 
2 test with the Yates
continuity correction for categorical variables. The effects of the
baseline variables on the risk of developing ischemic heart
disease were analyzed by Cox proportional hazards regression
analysis. The final model for the optimal prediction of
ischemic heart disease was fitted by backward elimination of
insignificant baseline variables (P
0.05). Survival
free from ischemic heart disease during the follow-up period
was compared between microalbuminuric and
normoalbuminuric hypertensives by a Kaplan-Meyer plot with use
of log-rank test statistics. A value of P<0.05 was
considered to be of statistical significance. The statistical
analyses were run on the software package SPSS for Windows.
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Results |
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During 1978 person-years of follow-up, 18 of the 204 hypertensive subjects (9%) developed ischemic heart disease. At baseline, microalbuminuria was present in 28% (95% CI 7 to 49) of those who subsequently developed ischemic heart disease compared with only 8% (95% CI 4 to 12) of the controls (P=0.02, Table 1). Four of the cases were women with urinary albumin/creatinine ratios of 8.36, 1.08, 1.06, and 0.89 mg/mmol. Hypertensives who developed ischemic heart disease were furthermore characterized by higher systolic blood pressure (153 [95% CI 148 to 158] mm Hg versus 148 [95% CI 147 to 149] mm Hg, P=0.05) and plasma total cholesterol concentration (7.2 [95% CI 6.6 to 7.8] mmol/L versus 6.5 [95% CI 6.3 to 6.7] mmol/L, P=0.03) than those who remained free from ischemic heart disease (Table 1).
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Table 2 shows the predictive impact of the baseline variables on the development of ischemic heart disease. Microalbuminuria, urinary albumin/creatinine ratio, plasma total cholesterol, and systolic blood pressure were all significantly and positively associated with the development of ischemic heart disease, whereas smoking failed, by a small margin, to obtain statistical significance. When adjusted for the effects of age, gender, total and HDL cholesterol, body mass index, and blood pressures, the relative risk of microalbuminuria for development of ischemic heart disease increased, whereas adjustment for the effect of smoking led to a slight decrease of the relative risk (Table 3). Survival free from ischemic heart disease in microalbuminuric and normoalbuminuric hypertensives is illustrated by a Kaplan-Meyer plot (Figure).
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Table 4 shows the best model for prediction of ischemic heart disease among hypertensives. When microalbuminuria, male gender, and plasma total cholesterol were included in the model, none of the other baseline variables measured in the present study contributed to any significant further increase in the relative risk.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This population-based prospective study of 204 subjects with untreated arterial hypertension or borderline hypertension has shown that the occurrence of microalbuminuria confers an increased risk of subsequent ischemic heart disease in hypertensives that is >4 times that in hypertensives or borderline hypertensives with normoalbuminuria, irrespective of the later use of antihypertensive therapy. Furthermore, the predictive effect of microalbuminuria seems to be independent of and stronger than the effect of the conventional atherosclerotic risk factors, such as smoking, dyslipidemia, obesity, high blood pressure, male gender, and advanced age.
Microalbuminuria was initially introduced as a predictor of impaired renal function among diabetic patients28 29 and was defined as a urinary albumin excretion of 30 to 300 mg over a 24-hour period.30 A later follow-up study of diabetics from our group has, in addition, suggested an increased risk of cardiovascular disease at even lower levels of urinary albumin excretion.10 Among subjects without diabetes mellitus, the urinary albumin excretion rarely exceeds 30 mg over a 24-hour period irrespective of present arterial hypertension.15 31 Within the Danish MONICA study, we recently observed an increased risk of ischemic heart disease confined to the 10% of the general population having the highest urinary albumin excretion.12 In accordance with this and a recommendation by Mogensen,23 we decided to define microalbuminuria as a urinary albumin excretion above the upper decile in the hypertensive population under study. To increase the compliance, we collected spot urine specimens and measured the albumin/creatinine concentration ratio, which is a precise index of urinary albumin excretion.25
This is the first prospective population-based study of hypertensives that reports an independent predictive effect of microalbuminuria in the development of ischemic heart disease. Among hypertensive subjects screened within another Danish population study, the Copenhagen City Heart Study, we have described a cross-sectional relation between urinary albumin excretion and ischemic heart disease,3 thus confirming a previous report by Agrawal et al.2 Bigazzi et al32 analyzed data obtained from a retrospectively selected hospital population of 141 hypertensives. They observed an unadjusted relative risk of 2.4 for the development of ischemic heart disease during a 7-year follow-up if microalbuminuria, defined as a urinary albumin excretion of 30 to 300 mg over a 24-hour period, had been present at baseline. In contrast, Jager et al33 were unable to detect any statistically significant predictive impact of microalbuminuria, defined as a urinary albumin/creatinine ratio >2.0 mg/mmol, in their 5-year follow-up study of 150 hypertensives without diabetes mellitus.
The present and other studies8 9 10 11 12 strongly indicate that microalbuminuria is tightly correlated with the development of atherosclerosis. If the urinary albumin excretion begins to increase late in the atherosclerotic process, microalbuminuria may be a marker of prevalent subclinical atherosclerosis, as suggested from other cross-sectional studies,34 35 36 and hence may be a predictor of clinical cardiovascular symptoms. If the urinary albumin excretion is already increased early in atherogenesis, as suggested by Jager et al,33 microalbuminuria may reflect an endothelial dysfunction and perhaps an augmented atherogenic susceptibility to other risk factors, including arterial hypertension. Solving this problem would require a longitudinal cohort study with repeated measurements of urinary albumin excretion and severity of atherosclerosis, eg, ultrasonic assessments of the intima-media thickness and flow-mediated vasodilation of arteries.37 38
Previous studies have demonstrated that microalbuminuria reflects a renal and systemic transvascular albumin leakage39 40 41 42 that is perhaps due to the low vessel wall content of heparan sulfate.43 44 45 46 In animal models, it has been shown that the transvascular leakage of albumin and lipoproteins are tightly correlated47 48 and that both are elevated in atherosclerosis49 and in atherosclerosis-prone sites of arteries.50
Study Limitations
It is a drawback of the present study that the
hypertensive population followed was rather small in size. However, the
population-based design and the high relative risk associated with
microalbuminuria allow valid conclusions to be drawn.
However, it cannot be completely excluded that the results observed are
explained by selection bias, eg, bias due to low urinary
albumin/creatinine ratio in nonresponders (26%)
who may be physically inactive51 and thereby "at risk"
for future ischemic heart disease.52 Furthermore,
because a glucose tolerance test was not performed, a minor proportion
of the population could have undiagnosed diabetes mellitus, thereby
confounding the association between urinary albumin excretion
and ischemic heart disease. The lack of knowledge about
medication that was instituted during follow-up is also a limitation.
It is well known that there is a considerable intrapersonal variation
of urinary albumin excretion even in early morning spot urine
samples.53 Because of regression dilution, this may have
caused an underestimation of the existing positive association between
urinary albumin excretion and the development of
ischemic heart disease. Moreover, because albumin
concentration in urine slightly declines during protracted frozen
storage,54 the "at risk" level of urinary
albumin/creatinine ratio (>1.07 mg/mmol) may have
been underestimated, unless creatinine concentration
declines similarly.
Conclusions
We conclude that microalbuminuria, defined as a
urinary albumin excretion in the upper 10% range, is the
strongest independent determinant of ischemic heart disease
among subjects with arterial hypertension. On this basis,
urinary albumin excretion should be measured regularly in a
hypertension clinic. Although intervention studies of the effect of
lowering urinary albumin excretion on
cardiovascular morbidity are missing, we recommend a
rigorous control of blood pressure and other modifiable atherosclerotic
risk factors in microalbuminuric hypertensives.
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Acknowledgments |
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The study was supported by the Danish Medical Research Council (grant No. J12-2008-1), the Danish Heart Foundation, and the Danish Hypertension Society.
Received August 30, 1999; first decision October 4, 1999; accepted November 16, 1999.
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C. D.A. Stehouwer and Y. M. Smulders Microalbuminuria and Risk for Cardiovascular Disease: Analysis of Potential Mechanisms J. Am. Soc. Nephrol., August 1, 2006; 17(8): 2106 - 2111. [Abstract] [Full Text] [PDF]
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D. de Zeeuw, H.-H. Parving, and R. H. Henning Microalbuminuria as an Early Marker for Cardiovascular Disease J. Am. Soc. Nephrol., August 1, 2006; 17(8): 2100 - 2105. [Abstract] [Full Text] [PDF]
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J. Segura, J. A. Garcia-Donaire, M. Praga, and L. M. Ruilope Chronic Kidney Disease as a Situation of High Added Risk in Hypertensive Patients J. Am. Soc. Nephrol., April 1, 2006; 17(4_suppl_2): S136 - S140. [Abstract] [Full Text] [PDF]
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H. Ibsen, M. H. Olsen, K. Wachtell, K. Borch-Johnsen, L. H. Lindholm, C. E. Mogensen, B. Dahlof, S. M. Snapinn, Y. Wan, and P. A. Lyle Does Albuminuria Predict Cardiovascular Outcomes on Treatment With Losartan Versus Atenolol in Patients With Diabetes, Hypertension, and Left Ventricular Hypertrophy?: The LIFE study. Diabetes Care, March 1, 2006; 29(3): 595 - 600. [Abstract] [Full Text] [PDF]
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 J. Arnlov, J. C. Evans, J. B. Meigs, T. J. Wang, C. S. Fox, D. Levy, E. J. Benjamin, R. B. D'Agostino, and R. S. Vasan Low-Grade Albuminuria and Incidence of Cardiovascular Disease Events in Nonhypertensive and Nondiabetic Individuals: The Framingham Heart Study Circulation, August 16, 2005; 112(7): 969 - 975. [Abstract] [Full Text] [PDF]
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 P. A. Swift, N. D. Markandu, G. A. Sagnella, F. J. He, and G. A. MacGregor Modest Salt Reduction Reduces Blood Pressure and Urine Protein Excretion in Black Hypertensives: A Randomized Control Trial Hypertension, August 1, 2005; 46(2): 308 - 312. [Abstract] [Full Text] [PDF]
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K. P. Klausen, H. Scharling, G. Jensen, and J. S. Jensen New Definition of Microalbuminuria in Hypertensive Subjects: Association With Incident Coronary Heart Disease and Death Hypertension, July 1, 2005; 46(1): 33 - 37. [Abstract] [Full Text] [PDF]
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K. R. Tuttle Renal manifestations of the metabolic syndrome Nephrol. Dial. Transplant., May 1, 2005; 20(5): 861 - 864. [Full Text] [PDF]
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R. Pontremoli, G. Leoncini, F. Viazzi, D. Parodi, V. Vaccaro, V. Falqui, A. Parodi, S. Vettoretti, E. Ratto, and G. Deferrari Role of Microalbuminuria in the Assessment of Cardiovascular Risk in Essential Hypertension J. Am. Soc. Nephrol., March 1, 2005; 16(3_suppl_1): S39 - S41. [Abstract] [Full Text] [PDF]
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F. Viazzi, G. Leoncini, D. Parodi, E. Ratto, S. Vettoretti, V. Vaccaro, A. Parodi, V. Falqui, C. Tomolillo, G. Deferrari, et al. Impact of Target Organ Damage Assessment in the Evaluation of Global Risk in Patients with Essential Hypertension J. Am. Soc. Nephrol., March 1, 2005; 16(3_suppl_1): S89 - S91. [Abstract] [Full Text] [PDF]
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H. Ibsen, M. H. Olsen, K. Wachtell, K. Borch-Johnsen, L. H. Lindholm, C. E. Mogensen, B. Dahlof, R. B. Devereux, U. de Faire, F. Fyhrquist, et al. Reduction in Albuminuria Translates to Reduction in Cardiovascular Events in Hypertensive Patients: Losartan Intervention for Endpoint Reduction in Hypertension Study Hypertension, February 1, 2005; 45(2): 198 - 202. [Abstract] [Full Text] [PDF]
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 A. R. Dyer, P. Greenland, P. Elliott, M. L. Daviglus, G. Claeys, H. Kesteloot, H. Ueshima, J. Stamler, and for the INTERMAP Research Group Evaluation of Measures of Urinary Albumin Excretion in Epidemiologic Studies Am. J. Epidemiol., December 1, 2004; 160(11): 1122 - 1131. [Abstract] [Full Text] [PDF]
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 J. R. Sowers Treatment of Hypertension in Patients With Diabetes Arch Intern Med, September 27, 2004; 164(17): 1850 - 1857. [Abstract] [Full Text] [PDF]
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A. R. Dyer, P. Greenland, P. Elliott, M. L. Daviglus, G. Claeys, H. Kesteloot, Q. Chan, H. Ueshima, and J. Stamler Estimating Laboratory Precision of Urinary Albumin Excretion and Other Urinary Measures in the International Study on Macronutrients and Blood Pressure Am. J. Epidemiol., August 1, 2004; 160(3): 287 - 294. [Abstract] [Full Text] [PDF]
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K. Klausen, K. Borch-Johnsen, B. Feldt-Rasmussen, G. Jensen, P. Clausen, H. Scharling, M. Appleyard, and J. S. Jensen Very Low Levels of Microalbuminuria Are Associated With Increased Risk of Coronary Heart Disease and Death Independently of Renal Function, Hypertension, and Diabetes Circulation, July 6, 2004; 110(1): 32 - 35. [Abstract] [Full Text] [PDF]
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L. M. Ruilope New European guidelines for management of hypertension: what is relevant for the nephrologist Nephrol. Dial. Transplant., March 1, 2004; 19(3): 524 - 528. [Full Text] [PDF]
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G. A. Kaysen and J. P. Eiserich The Role of Oxidative Stress-Altered Lipoprotein Structure and Function and Microinflammation on Cardiovascular Risk in Patients with Minor Renal Dysfunction J. Am. Soc. Nephrol., March 1, 2004; 15(3): 538 - 548. [Abstract] [Full Text] [PDF]
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J. K. Olijhoek, Y. van der Graaf, J.-D. Banga, A. Algra, T. J. Rabelink, F. L. J. Visseren, and for the SMART Study Group The Metabolic Syndrome is associated with advanced vascular damage in patients with coronary heart disease, stroke, peripheral arterial disease or abdominal aortic aneurysm Eur. Heart J., February 2, 2004; 25(4): 342 - 348. [Abstract] [Full Text] [PDF]
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M. F. Yuyun, K.-T. Khaw, R. Luben, A. Welch, S. Bingham, N. E. Day, and N. J. Wareham A Prospective Study of Microalbuminuria and Incident Coronary Heart Disease and Its Prognostic Significance in a British Population: The EPIC-Norfolk Study Am. J. Epidemiol., February 1, 2004; 159(3): 284 - 293. [Abstract] [Full Text] [PDF]
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 M. F Yuyun, K.-T. Khaw, R. Luben, A. Welch, S. Bingham, N. E Day, and N. J Wareham Microalbuminuria independently predicts all-cause and cardiovascular mortality in a British population: The European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population study Int. J. Epidemiol., February 1, 2004; 33(1): 189 - 198. [Abstract] [Full Text] [PDF]
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R. Pontremoli, G. Leoncini, F. Viazzi, D. Parodi, E. Ratto, S. Vettoretti, M. Ravera, C. Tomolillo, and G. Deferrari Cardiovascular and Renal Risk Assessment as a Guide for Treatment in Primary Hypertension J. Am. Soc. Nephrol., January 1, 2004; 15(90010): S34 - 36. [Abstract] [Full Text]
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 K. Wachtell, H. Ibsen, M. H. Olsen, K. Borch-Johnsen, L. H. Lindholm, C. E. Mogensen, B. Dahlof, R. B. Devereux, G. Beevers, U. de Faire, et al. Albuminuria and Cardiovascular Risk in Hypertensive Patients with Left Ventricular Hypertrophy: The LIFE Study Ann Intern Med, December 2, 2003; 139(11): 901 - 906. [Abstract] [Full Text] [PDF]
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S. Romundstad, J. Holmen, H. Hallan, K. Kvenild, and H. Ellekjaer Microalbuminuria and All-Cause Mortality in Treated Hypertensive Individuals: Does Sex Matter?: The Nord-Trondelag Health Study (HUNT), Norway Circulation, December 2, 2003; 108(22): 2783 - 2789. [Abstract] [Full Text] [PDF]
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A. V. Chobanian, G. L. Bakris, H. R. Black, W. C. Cushman, L. A. Green, J. L. Izzo Jr, D. W. Jones, B. J. Materson, S. Oparil, J. T. Wright Jr, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Hypertension, December 1, 2003; 42(6): 1206 - 1252. [Abstract] [Full Text] [PDF]
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G. Leoncini, F. Viazzi, D. Parodi, S. Vettoretti, E. Ratto, M. Ravera, C. Tomolillo, M. Del Sette, G. P. Bezante, G. Deferrari, et al. Mild Renal Dysfunction and Subclinical Cardiovascular Damage in Primary Hypertension Hypertension, July 1, 2003; 42(1): 14 - 18. [Abstract] [Full Text] [PDF]
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 L. Poulsen Review: Early renal involvement in Type 1 diabetes mellitus -- Part 2: ACE inhibitor intervention in Type 1 diabetes with low grade microalbuminuria Journal of Renin-Angiotensin-Aldosterone System, March 1, 2003; 4(1): 17 - 26. [Abstract] [PDF]
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L. Poulsen Blood pressure and cardiac autonomic function in relation to risk factors and treatment perspectives in Type 1 diabetes Journal of Renin-Angiotensin-Aldosterone System, December 1, 2002; 3(4): 222 - 242. [Abstract] [PDF]
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R. Pontremoli, G. Leoncini, M. Ravera, F. Viazzi, S. Vettoretti, E. Ratto, D. Parodi, C. Tomolillo, and G. Deferrari Microalbuminuria, Cardiovascular, and Renal Risk in Primary Hypertension J. Am. Soc. Nephrol., November 1, 2002; 13(90003): S169 - 172. [Abstract] [Full Text]
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J. Redon, E. Rovira, A. Miralles, R. Julve, and J. M. Pascual Factors Related to the Occurrence of Microalbuminuria During Antihypertensive Treatment in Essential Hypertension Hypertension, March 1, 2002; 39(3): 794 - 798. [Abstract] [Full Text] [PDF]
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 R. Pedrinelli, G. Dell'Omo, G. Penno, and M. Mariani Non-diabetic microalbuminuria, endothelial dysfunction and cardiovascular disease Vascular Medicine, November 1, 2001; 6(4): 257 - 264. [Abstract] [PDF]
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B. L. Kasiske The Kidney in Cardiovascular Disease Ann Intern Med, April 17, 2001; 134(8): 707 - 709. [Full Text] [PDF]
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