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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-1632
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 1 31-35
Copyright © 2006 by The Endocrine Society

Impaired Vascular Reactivity in African-American Patients with Type 2 Diabetes Mellitus and Microalbuminuria or Proteinuria Despite Angiotensin-Converting Enzyme Inhibitor Therapy

A. Jawa, S. Nachimuthu, M. Pendergrass, S. Asnani and V. Fonseca

Department of Medicine (A.J., S.A., V.F.), Section of Endocrinology, Tulane University Medical Center, New Orleans, Louisiana 70112-2699; Huey P. Long Medical Center (S.N.), Pineville, Louisiana 71361; and Brigham and Women’s Hospital (M.P.), Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Vivian A. Fonseca, M.D., Professor of Medicine and Pharmacology, Tullis Tulane Alumni Chair in Diabetes, Chief, Section of Endocrinology, Tulane University Medical Center, SL-53, 1430 Tulane Avenue, New Orleans, Louisiana 70112-2699. E-mail: vfonseca{at}tulane.edu.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Microalbuminuria, an early indicator of diabetic nephropathy that reflects other vascular abnormalities, usually improves or resolves with angiotensin-converting enzyme inhibitor (ACEI) therapy. Persistent microalbuminuria despite ACEI therapy may be associated with poor prognosis for cardiovascular disease and mortality. African-Americans are reported to respond less well to ACEI and are at increased risk of disease progression.

Methods and Results: We compared flow-mediated dilatation (FMD) and nitroglycerine-dependent dilatation (NDD) in African-American diabetic subjects with persistent microalbuminuria (n = 35) despite ACEI therapy and those in whom microalbuminuria had resolved (n = 15). The two groups were not statistically different in terms of blood pressure, age, sex, lipids, and hemoglobin A1c. FMD was reduced in the microalbuminuria group, compared with subjects without microalbuminuria (4.2 vs. 11.4%; P < 0.0001). Similarly, NDD was reduced in the microalbuminuria group, compared with subjects without microalbuminuria (10.8 vs.16.6%; P = 0.011). The FMD in African-American patients with persistent microalbuminuria was also significantly lower than in clinically similar Caucasian patients whose microalbuminuria had persisted despite ACEI therapy (4.2 vs. 7.5%; P = 0.03). On multiple regression analysis, persistent microalbuminuria is the only predictor of abnormal endothelial function in these patients.

Conclusions: Our study clearly demonstrates that African-American type 2 diabetic subjects with persistent microalbuminuria have severely impaired FMD and NDD, compared with matched patients who had microalbuminuria that was eliminated by ACEI. This may explain the poor prognosis for cardiovascular disease in patients who have persistent microalbuminuria. Alternative strategies for reducing microalbuminuria in high-risk patients who do not respond adequately to ACEI therapy such as African-Americans are needed.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
DIABETES MELLITUS IS associated with two to four times increased risk of coronary heart disease (1, 2). Type 2 diabetes mellitus is 1.4–2.2 times more prevalent in African-Americans than Caucasians (3). African-American adults with diabetes are three times more likely to have early decline in renal function than are whites (4). Microalbuminuria is an early indicator of diabetic nephropathy but also reflects other vascular abnormalities (5). Endothelial dysfunction, and in particular the loss of flow-mediated dilatation (FMD), is an early marker of atherosclerotic degeneration in medium-sized arteries (6, 7, 8) and has been shown to be associated with several risk factors for cardiovascular disease such as diabetes (9, 10) and hypertension (10). The prognosis of patients with microalbuminuria has improved considerably with the use of angiotensin-converting enzyme (ACE) inhibitors, which reduces proteinuria, slows the decline in glomerular filtration rate and reduces cardiovascular risk. Persistent or progressive microalbuminuria despite blockade of the renin-angiotensin system may be associated with poor prognosis for cardiovascular disease and mortality, even in the absence (11) of diabetes mellitus.

Hypertension is also a major independent risk factor for the development of renal failure. Rostand et al. (12) followed up the course of 94 patients who had hypertension and normal serum creatinine concentrations at the outset of the study. They found that African-American patients had twice the risk (30 vs. 15%) of having a significant increase in serum creatinine concentration during the 5-yr study. When the data from the Multiple Risk Factor Intervention Trial (13) were reanalyzed, it was determined that the decline in renal function was greater for black men than white men, despite similar control of blood pressure. The change in the level of proteinuria is a predictor of subsequent progression of hypertensive kidney disease at a given glomerular filtration rate (GFR) in African-American subjects with nondiabetic renal disease (14). African-Americans have decreased FMD, increased risk of chronic kidney disease, and hypertension and are reported to respond less well to ACE inhibitors (15, 16, 17). In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, neither lisinopril nor amlodipine was superior to chlorthalidone in reducing the rate of development of end-stage renal disease or a 50% or greater decrement in GFR in hypertensive patients with reduced GFR (18). Our primary hypothesis was that patients with type 2 diabetes with persistent microalbuminuria despite maximally tolerated ACE inhibition have worse endothelial function, compared with patients without microalbuminuria, contributing to an increased risk of cardiovascular disease. We also compared the endothelial function in these patients with matched Caucasians.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
All patients with diabetes mellitus in our clinic are screened for microalbuminuria and treated with ACE inhibitors or angiotensin receptor II blockers with dose titrated to optimize blood pressure. Some had responded with abolition of microalbuminuria, whereas others had persistent microalbuminuria. Patients with persistent microalbuminuria despite ACE inhibitor treatment were studied. African-American patients with diabetes mellitus who responded to ACE inhibitor therapy by abolition of microalbuminuria served as controls. African-American men and women with type 2 diabetes mellitus and between the ages of 30 and 70 yr on maximally tolerated doses of ACE inhibitors for optimal blood pressure control were included. Patients with advanced renal disease (creatinine > 2.0 mg/dl), overt liver disease, congestive heart failure, pregnancy, or history of solid organ transplantation and those currently on immunosuppressive therapy or malignancy were excluded from study.

All patients were enrolled in Tulane University Institutional Review Board-approved studies after obtaining informed consent. Baseline laboratory tests including complete blood count, basic metabolic profile, liver function test, and complete lipid profile were performed to exclude any medical condition that may affect the endothelial function. Thirty-five subjects with persistent microalbuminuria despite ACE inhibitor therapy and 15 subjects whose microalbuminuria abolished with ACE inhibitor therapy met inclusion and exclusion criteria and were enrolled in the study. The clinical characteristics of these patients is summarized in Table 1Go. All study participants were on stable antihypertensive and diabetes medication regimens for at least 3 months. In keeping with the recommendations on the use of diuretics in such patients, 95% of with microalbuminuria group subjects and 88% of without microalbuminuria subjects were also on a thiazide diuretic. All subjects were on maximally tolerated doses of ACE inhibitors before enrollment in the study. None of the subjects had any clinical signs and symptoms of peripheral vascular disease and had all palpable distal pulses. Study findings of flow-mediated and nitroglycerine-dependent dilatation in African-American subjects were compared with Caucasian American diabetic subjects with (n = 8) and without (n = 8) microalbuminuria as a secondary end point analysis. These patients’ clinical characteristics were also not significantly different from the African-Americans (data not in table).


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  		TABLE 1. Baseline characteristics of subjects with and without microalbuminuria

 
FMD and nitroglycerine-dependent dilatation

We compared endothelial function as assessed by brachial artery diameter response to occlusion measured by ultrasound (FMD) and nonendothelial-dependent dilatation using sublingual nitroglycerine (nitroglycerine-dependent dilatation; NDD) between these two groups using well-established methods (19). All testing procedures were conducted early in the morning in the fasting state. Patients were required to abstain from caffeine, smoking, and strenuous physical activity for 24 h before testing. Studies were conducted in a temperature-controlled room with the subject in a supine position and the upper torso comfortably inclined. Standing and supine blood pressure and supine brachial artery diameter were measured before commencing the FMD procedure. Brachial artery diameter was measured using the high-resolution 7.5-MHz central frequency linear ultrasound probe (VIVID 7, GE, Waukesha, WI) with the FMD technique. The machine contained an internal electrocardiogram monitor and a high-frequency vascular transducer. Imaging was performed on all occasions by the same, highly experienced certified sonographer blinded to the medication assignment of the subjects.

The brachial artery was scanned to identify the segment with best ultrasonographic visualization and distance above the antecubital fossa in the longitudinal plane was recorded. All subsequent brachial artery diameter measurements were performed at a same fixed distance to ensure consistency. The center of the artery was identified when the clearest picture of the anterior, and posterior wall layers were obtained. Depth and gain settings were optimized to identify the lumen to vessel wall interface. When a satisfactory transducer position was located, the skin was marked and the arm remained in the same position throughout the study. Transducer operating variables were not changed throughout the study. Brachial artery diameter, taken as the distance between anterior and posterior media interfaces, was assessed after 10 min in the supine position. A blood pressure cuff was then placed around the upper arm, proximal to the imaging site, inflated to 50 mm Hg above the systolic blood pressure reading at baseline for 5 min, and then quickly released, inducing reactive hyperemia. The diameter of the brachial artery was measured at 60 sec during reactive hyperemia. All measures were taken at the peak of the R wave to minimize possible errors resulting from variable arterial compliance. The maximum percent increase in brachial artery diameter was considered as the FMD. After 15 min of recovery, nitroglycerine-dependent dilatation was assessed by measuring brachial artery diameter after 400 µg sublingual glyceryl trinitrate (19, 20). The first measurement was taken 3 min after administration of glyceryl trinitrate. The maximum percent increase in brachial artery diameter 3 min after sublingual nitroglycerine administration was considered as the NDD. In normal Caucasian subjects in our laboratory, the mean FMD is 15 ± 2%, whereas it is 12 ± 2% in diabetics without any complication. In contrast, the NDD is 18 ± 2% in both normal subjects and diabetics free of complications.

Statistical analysis

Descriptive statistics of the variables in subjects with and without microalbuminuria are presented in Table 1Go. SPSS (version 11.0; SPSS Inc., Chicago, IL) was used to conduct the multiple linear regression analysis. Statistical analysis of FMD and NDD between subjects with and without microalbuminuria groups was performed. To address the effects of predictor variables on both FMD and NDD, two separate models were created from the information collected during preliminary analysis. The models have the same predictors, with different response variables:

Model 1: % FMD = ßo + ß1age + ß2ma + ß3sex + ß4sbp + ß5A1c + ß6LDL + ß7triglycerides + ß8HDL.

Model 2: % NDD = ßo + ß1age + ß2ma + ß3sex + ß4sbp + ß5A1c + ß6LDL + ß7triglycerides + ß8HDL.

Where ß1sex = age of study subjects (years); ß2ma = presence or absence of microalbuminuria; ß3sex = sex of study subjects; ß4sbp = systolic blood pressure (mm Hg); ß5A1c = hemoglobin A1c; ß6LDL = low-density lipoprotein; ß7triglycerides = triglycerides; and ß8HDL = high-density lipoprotein.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The mean FMD in African-American diabetic subjects with and without microalbuminuria is 4.2 and 11.4%, respectively. Similarly, mean NDD in African-American subjects with and without microalbuminuria is 10.8 and 16.6%, respectively (Fig. 1Go). The mean duration of diabetes mellitus (6.6 vs. 6.1 yr) and ACE inhibitors therapy (3.6 vs. 3.8 yr) were not statistically significant between groups with and without microalbuminuria, respectively. The two groups, with and without microalbuminuria, had similar body mass indices (32.9 vs. 34.3), total cholesterol ± SEM (SI) [187 ± 8 (4.84 ± 0.2 mmol/liter) vs. 179 ± 11 mg/dl (4.6 ± 0.29 mmol/liter)], hemoglobin A1c (9.0 vs. 8.9%), mean fasting glucose ± SEM (SI) [186 ± 16 mg/dl (9.6 ± 0.88 mmol/liter) vs. 175 ± 24 mg/dl (9.7 ± 1.3 mmol/liter)], and baseline plasma creatinine levels [1.1 vs. 1.1 mg/dl (93.8 vs. 87 µmol/liter)]. None of these differences were statistically significant.



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  		FIG. 1. Comparison of FMD and NDD between groups with and without microalbuminuria (MA).

 
We estimated glomerular filtration rate (eGFR) in all subjects using both the Modification of Diet in Renal Disease Study (MDRD) and Cockcroft-Gault equations, the former taking race and the latter taking weight into account. The mean eGFR ± SD in groups with and without microalbuminuria was 89 ml/min ± 32 SD (1.48 ml/sec ± 0.5 SD) vs. 98 ml/min ± 34 SD (1.6 ml/sec ± 0.56) by MDRD and 114 ml/min ± 67 SD (1.9 ml/sec ± 1.1 SD) vs. 115 ml/min ± 65 SD (1.92 ml/sec ± 1.08 SD) by Cockroft-Gault calculation, respectively. There was no statistically significant difference between the groups in eGFR. Results of multiple linear regression analysis variables affecting the FMD are described in Table 2Go. As predicted, microalbuminuria status is the only highly significant (P < 0.0001) variable among all predictor variables. Results of multiple linear regression analysis variables affecting the NDD are described in Table 3Go. Again, microalbuminuria status is the only significant (P = 0.011) variable among all predictor variables. This is contrary to what we had expected; we had hypothesized that the NDD would not be different between the two groups, just as in Caucasian-American subjects in previously published studies. The comparison of FMD and NDD between groups with and without microalbuminuria is illustrated in Fig. 1Go. Another interesting finding was that the FMD in African-American diabetic subjects with microalbuminuria was reduced in statistically significant manner, compared with age- and blood pressure-matched Caucasian diabetic controls with microalbuminuria at our center (4.2 vs. 7.5%; P = 0.03), whereas NDD was not different between groups (10.8 vs. 12.3%; P = 0.6). Importantly, the FMD and NDD in African-American patients who no longer had microalbuminuria was not significantly different from Caucasians who no longer had microalbuminuria.


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  		TABLE 2. Multiple linear regression analysis of increase in FMD

 

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  		TABLE 3. Multiple linear regression analysis of increase in NDD

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Our study clearly demonstrates that African-American diabetic subjects with persistent microalbuminuria despite therapy have severely impaired FMD and NDD, compared with patients matched for race and clinical characteristics, who had microalbuminuria that was eliminated by ACE inhibitors. Furthermore, in African-American patients with persistent microalbuminuria, FMD is significantly less than in Caucasians with persistent microalbuminuria, possibly indicating a poorer endothelial response to ACE inhibition that may be mediated by race.

Endothelial function in normal healthy adults is influenced by variables such as race (17, 21), age (22), and prandial state (23). Endothelial dysfunction has been associated with several disease states, including obesity (24), diabetes mellitus (25), and hypertension (26). Healthy African-Americans have lower baseline FMD, compared with Caucasian-Americans (15, 17). African-Americans with microalbuminuria have higher mean SBP (P < 0.001) and diastolic blood pressure (P < 0.05) and prevalence of hypertension (P < 0.05) than those without microalbuminuria (27). These differences in blood pressure levels persisted when hypertensive subjects were excluded. It is therefore noteworthy that our African-American patients who did not have microalbuminuria on ACE inhibitors had normal FMD. Whether this is due to successful ACE inhibitor therapy or due to genetically determined difference in endothelial function, compared with patients with microalbuminuria, is not known.

Our study showed that, in addition to FMD, NDD is also impaired in African-American subjects with type 2 diabetes mellitus and persistent microalbuminuria despite ACE inhibitor therapy. Based on results of similar studies done in Caucasian-Americans, it is generally assumed that the NDD, a marker of endothelial response to exogenous nitric oxide, is preserved during the early stages of diabetes mellitus. This finding suggests that African-American subjects incur impairment in response to exogenous nitric oxide earlier than thought. To our knowledge, this is the first study to demonstrate impairment of NDD in African-Americans early in the course of diabetes mellitus. This may explain the increased cardiovascular morbidity and mortality in African-American subjects, compared with Caucasian-Americans. Papaioannou et al. (28) demonstrated that diabetes mellitus in the presence of microalbuminuria is associated with impaired endothelium-dependent and endothelium-independent vasodilatations of the brachial artery, compared with patients with no microalbuminuria. Our data clearly demonstrate similar findings of impaired FMD in African-American type 2 diabetic subjects with persistent microalbuminuria despite ACE inhibitor therapy in addition to impairment of NDD as well.

Racial differences in vascular function may also have implications for treatment of cardiovascular disease risk factors. We compared FMD between African-American and Caucasian type 2 diabetic subjects who have persistent microalbuminuria. African-American diabetic subjects with microalbuminuria have worse FMD, compared with comparable subjects of Caucasian race, suggesting an increased risk of cardiovascular morbidity and mortality. Our findings may have important implications for African-American patients. Data on cardiovascular outcomes with ACE inhibitors in African-Americans subjects are limited and suggest a possible lesser effect than in Caucasians. A recent study demonstrated the value of vasodilator therapy in African-American patients in contrast to Caucasian-Americans (29) and has stimulated controversy and discussion about race-based therapeutics (30). The Third National Health and Nutrition Examination Survey showed higher cardiovascular disease risk factors among African-American women and children of both sexes than among white women and children of comparable socioeconomic status (31, 32). Young adult blacks demonstrate a linear upward trend in blood pressure with a shift from normal glucose metabolism to impaired glucose metabolism and diabetes mellitus, not completely explained by obesity (33). Several studies have shown that elderly African-American subjects have lower coronary calcium scores (34, 35) yet interestingly higher risk of clinical coronary events (34), raising the question of whether the relationship of calcium to subsequent events differs by race. It would be interesting to see what the endothelial function is in these African-American diabetic subjects with microalbuminuria while off ACE inhibitors.

We do not have the endothelial function data before being placed on ACE inhibitors. It would be unethical to withdraw ACE inhibitors to see the effects on endothelial function because its efficacy is proven and is currently standard of care for treatment of diabetic nephropathy (36, 37). The fact that impairment of vascular reactivity between subjects with and without microalbuminuria was independent of glycemic, blood pressure, and lipemic control as well as duration of diabetes and ACE inhibitor therapy was very significant. This may suggest that African-American subjects develop irreversible injury to the endothelium early in the course of diabetes, leading to impaired vascular reactivity sooner than Caucasian subjects.

Our study has a few limitations. First, it is cross-sectional in nature, and we do not have accurate information regarding the severity of microalbuminuria before starting ACE inhibitor therapy. Therapy was started in these subjects based on spot urine samples measured in different laboratories and is not based on 24-h urine protein, which is not routinely done in our diabetes clinics. It was felt that it was inappropriate and possibly unethical to withdraw ACE inhibitor therapy before study entry to estimate the baseline microalbuminuria. Second, we measured only one index of vascular function, i.e. FMD and NDD, in a patient population that is likely to have many other abnormalities of vascular function.

Further studies are required to determine which functions of the many functions of the endothelium and vessel wall are abnormal and which ones are intact in such a population. We conclude that FMD and NDD in African-American diabetic patients with microalbuminuria that is persistent despite ACE inhibitor therapy is impaired, compared with patients who no longer have microalbuminuria after treatment. This may explain the poor prognosis for cardiovascular disease in patients who have persistent microalbuminuria. Alternative strategies for reducing microalbuminuria in high-risk patients who do not respond adequately to ACE inhibitor therapy such as African-Americans are needed.


   Acknowledgments
 
We thank Bobbi Thompson, R.N., Terrilyn Lemoine, C.V.T., and Elizabeth Newton, C.V.T., for their help and assistance in conduct of this study. We are deeply indebted to Monica Carlson, Holly Ann Scheib, and James Colborn for their help in biostatistical analysis.


   Footnotes
 
This work was partly supported by an unrestricted grant from GlaxoSmithKline. This study is supported in part by National Institutes of Health Grant 5M01RR05096 from the Division of Research Resources.

First Published Online October 11, 2005

Abbreviations: ACE, Angiotensin-converting enzyme; eGFR, estimated GFR; FMD, flow-mediated dilatation; GFR, glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MDRD, Modification of Diet in Renal Disease Study; NDD, nitroglycerine-dependent dilatation; SBP, systolic blood pressure.

Received July 22, 2005.

Accepted October 3, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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Endothelial Nitric Oxide Synthase Deficiency Produces Accelerated Nephropathy in Diabetic Mice
J. Am. Soc. Nephrol., October 1, 2006; 17(10): 2664 - 2669.
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