Brachial Artery Reactivity in Asymptomatic Patients With Type 2 Diabetes Mellitus and Microalbuminuria (from the Detection of Ischemia in Asymptomatic Diabetics–Brachial Artery Reactivity Study)
Georgios I. Papaioannou, MD, Richard L. Seip, PhD, Neil J. Grey, MD,
Deborah Katten, RN, MPH, Amy Taylor, MS, Silvio E. Inzucchi, MD,
Lawrence H. Young, MD, Deborah A. Chyun, PhD, Janice A. Davey, MSN,
Frans J.Th. Wackers, MD, Ami E. Iskandrian, MD, Robert E. Ratner, MD,
Evelyn C. Robinson, RN, Stella Carolan, RN, Samuel Engel, MD, and
Microalbuminuria is a novel atherosclerotic risk factor in DM (p ؍ 0.03). Endothelium-dependent vasodilation at 1 patients with type 2 diabetes mellitus (DM) and predicts minute (p ؍ 0.01) and endothelium-independent vasodi- future cardiovascular events. Endothelial dysfunction and lation at 3 minutes (p ؍ 0.007) were significantly less in systemic inflammation have been proposed as common patients with microalbuminuria. In addition, 96% of pa- links between microalbuminuria and cardiovascular dis- tients with microalbuminuria and 76% of those with nor- ease. However, no study has assessed the relation be- moalbuminuria had impaired endothelium-dependent va- tween microalbuminuria and vascular dysfunction as mea- sodilation (<8%, p ؍ 0.01). Microalbuminuria was an sured by brachial artery reactivity (BAR) in DM. We independent predictor of endothelium-dependent vasodi- evaluated 143 patients (85 men; mean age 60.0 ؎ 6.7 lation in the entire cohort (p ؍ 0.045) and after excluding years) with DM (mean duration 8.2 ؎ 7.4 years) enrolled patients on hormone replacement therapy (p ؍ 0.01). in the Detection of Ischemia in Asymptomatic Diabetics Levels of C-reactive protein were significantly higher in study. Subjects were categorized as those with microalbu- patients with microalbuminuria than in those with nor- minuria (ratio of urinary albumin to creatinine 30 to 299 moalbuminuria (p ؍ 0.02). We conclude that in DM the
g/mg creatinine, n ؍ 28) and those with normoalbumin- presence of microalbuminuria is associated with impaired uria (ratio of urinary albumin to creatinine 0 to 29.9 endothelium-dependent and endothelium-independent va-
g/mg creatinine, n ؍ 115). High-resolution ultrasound sodilations of the brachial artery and a higher degree of BAR testing was used to measure endothelium-dependent systemic inflammation. In addition, microalbuminuria is an and endothelium-independent vasodilations. C-reactive independent predictor of endothelial dysfunction in asymp- protein was measured as a marker of systemic inflamma- tomatic patients with DM, especially in the absence of tion. Patients with microalbuminuria and normoalbumin- hormone replacement therapy. ᮊ2004 by Excerpta uria had similar baseline characteristics, with the exception Medica, Inc. that those with microalbuminuria had a longer duration of (Am J Cardiol 2004;94:294–299) Endothelial dysfunction occurs early in the athero- endothelium-dependent vasodilation (EDV) and endo-
thelium-independent vasodilation (EIV) of the bra-
chial artery has been proposed as a method to nonin-vasively assess endothelial function and smoothmuscle function, Microalbuminuria has
From the Cardiology Division, Henry Low Heart Center, Hartford
been associated with increased cardiovascular events
Hospital, Hartford and the University of Connecticut School of Medi-
in the general population and in patients with type 2
cine, Farmington, Connecticut; the Sections of Endocrinology and
diabetes mellitus Within the framework of
Cardiovascular Medicine, Yale University School of Medicine, New
the Detection of Ischemia in Asymptomatic Diabetics
Haven, Connecticut; the Cardiovascular Division, University of Ala-bama at Birmingham School of Medicine, Birmingham, Alabama; the
(DIAD) we investigated the relation between
Medstar Clinical Research Institute, Washington, DC; and the Section
impaired vascular reactivity and microalbuminuria in
of Endocrinology, Norwalk Hospital, Norwalk, Connecticut. This
study was supported by grants from the Hartford Hospital ResearchAdministration, Hartford, Connecticut, and Bristol-Myers Squibb Med-ical Imaging, North Billerica, Massachusetts. Manuscript received
December 12, 2003; revised manuscript received and accepted April
Patient population: The patient cohort consisted of
subjects enrolled in the DIAD study who underwent
Address for reprints: Gary V. Heller, MD, PhD, Division of Cardi-
ology, Hartford Hospital, 80 Seymour Street, Hartford, Connecticut
assessment of BAR (DIAD-BAR substudy). The
06102. E-mail: gheller@harthosp.org.
DIAD study is a prospective, multicenter, randomized
2004 by Excerpta Medica, Inc. All rights reserved.
The American Journal of Cardiology Vol. 94 August 1, 2004
trial that evaluates the prevalence of adenosine tech-
C-reactive protein had repeated measurements and
netium-99m sestamibi myocardial perfusion imaging
were excluded if there was evidence of infection or
abnormalities in asymptomatic patients with type 2
systemic inflammation. Urinary albumin and creati-
DM and its association with adverse clinical out-
nine concentrations were determined by immunotur-
comes. Eligible patients had asymptomatic type 2
bidimetric and kinetic methods, respectively. With
DM, were 50 to 75 years old, and had no known
these methods, the coefficients of variation for albu-
coronary artery disease. Exclusion criteria were (1)
min and creatinine were 2.7% and 3.5%, respectively.
known coronary artery disease, as documented by a
Measurements of EDV and EIV: All measurements of
history of angina, myocardial infarction, percutaneous
BAR were obtained in the morning after an overnight
coronary intervention, or coronary artery bypass sur-
fast, with medications withheld the morning of the
gery; Q waves; new deep negative T waves or ST-
study. Patients were also instructed to avoid caffeine-
segment depression at rest on electrocardiogram; pos-
containing products, smoking, and exercise Ն12 hours
itive results on noninvasive stress test, or coronary
before the test. Images were obtained with an Acuson
angiography with documentation of coronary artery
10.0-MHz linear array transducer and an Aspen car-
disease before recruitment; (2) signs or symptoms that
diac ultrasound system (Acuson Corp, Elmwood Park,
normally require cardiac evaluation, such as presence
New Jersey) according to a standard technique for all
of left bundle branch block, congestive heart failure,
participating centers. After initial baseline measure-
chest pain, or ventricular tachycardia; (3) any stress
ments of brachial artery diameter, a blood pressure
test or cardiac catheterization performed within 3
cuff was placed around the forearm distal to the seg-
years before study enrollment; (4) significant nondia-
ment of the artery scanned and inflated 60 mm Hg
betic co-morbidity affecting life expectancy (e.g., ma-
above the patient’s systolic blood pressure for 5 min-
lignancy); (5) pregnancy; (6) known medical noncom-
utes. After deflation, the brachial artery diameter was
pliance with follow-up; and (7) history, clinical
recorded at 1 minute and 3 minutes after occlusion.
findings, or treatment for significant bronchospasm.
After a 15-minute break, a second baseline measure-
One hundred forty-nine patients from 5 participating
ment of brachial artery diameter was recorded, and 0.4
centers were enrolled in the DIAD-BAR substudy.
mg of sublingual nitroglycerin was administered. Re-
Institutional review committees from all centers ap-
sponse of brachial artery diameter was recorded at 3
proved the study, and all patients gave informed
and 5 minutes after administration of nitroglycerin.
Ten cardiac cycles were analyzed for each scan, and
Study design: Baseline history, physical examina-
measurements were averaged. Brachial artery diame-
tion, and laboratory tests were obtained at patient
ter was measured at a fixed distance from an anatomic
centers. Subsequently, the 149 patients who agreed to
marker as the distance between the near and far in-
participate underwent a baseline study of BAR. Sub-
tima. EDV and EIV were calculated as percent max-
jects were then categorized as those with microalbu-
imal increases in artery diameter 1 minute and 3
minuria (ratio of urinary albumin to creatinine 30 to
minutes after occlusion and 3 and 5 minutes after
299 g/mg creatinine, n ϭ 28) and those with nor-moalbuminuria (ratio of urinary albumin to creatinine
nitroglycerin administration, respectively. Examina-
0 to 29.9 g/mg creatinine, n ϭ 115). Six subjects
tion of BAR from Hartford Hospital and Yale Univer-
were excluded from the final analysis (4 with mi-
sity were recorded with CVI acquisition software
croalbuminuria and 2 with unacceptable images of
(version 2.1, Data Translation Inc., Marlboro, Massa-
chusetts). Images from the other 3 participating cen-
Clinical and laboratory measurements: The follow-
ters were recorded on tape. Two different interpreters
ing clinical characteristics were collected for each
at Hartford Hospital analyzed all scans independently
patient: age, gender, smoking history, duration of DM,
by using CVI Analysis software. The intra- and inter-
type of DM therapy, history of hypertension and ther-
observer variabilities in our laboratory were 1.1% and
apy, history of hyperlipidemia and treatment, and
body mass index. Systolic and diastolic blood pres-
Statistical analysis: Results are presented as means
sures were defined as the mean of 3 measurements in
Ϯ SD unless otherwise stated. Chi-square or Fisher’s
the supine position. Blood and urine samples were
exact test was used to compare categorical data. For
obtained during morning hours after an overnight fast.
continuous variables, differences between patients
This method is preferred because of the known diurnal
with microalbuminuria and those with normal albu-
variation in albumin Blood and urine spec-
minuria were compared with a 2-sample independent
imens were analyzed by a central laboratory (Lab-
t test or Mann-Whitney U test. To study the correla-
Corp, Raritan, New Jersey), with the exception of
tion of urinary albumin:creatinine ratio with BAR,
homocysteine and high-sensitivity C-reactive protein
Spearman’s rank correlation test was used. Each vari-
measurements, which were analyzed elsewhere (Lipo-
able was evaluated for its association with EDV and
Science, Raleigh, North Carolina). The Immulite 2000
EIV using univariate analysis. Variables with a p
Homocysteine assay and high-sensitivity C-reactive
value Ͻ0.1 were entered into a stepwise multivariate
protein assay (Diagnostic Products Corporation, Hol-
regression model to identify independent predictors of
liston, Massachusetts) were used to determine total
EDV and EIV. Results were considered statistically
levels of plasma homocysteine and C-reactive protein,
significant when p Ͻ0.05. Analysis was performed
respectively. Patients with high levels (Ͼ10 mg/L) of
with SPSS 10.1 (SPSS Inc., Chicago, Illinois).
CORONARY ARTERY DISEASE/BAR AND MICROALBUMINURIA IN TYPE 2 DM
TABLE 1 Baseline Clinical and Biochemical Characteristics of Patients
Ϯ Values are means Ϯ SD. *Data for C-reactive protein (mean Ϯ SEM) and homocysteine were available for 74 patients (microlbuminuria, n ϭ 12; normoalbuminuria, n ϭ 62). TABLE 2 Baseline Medications of Patients
*Hormone replacement therapy data refer to the subpopulation of 53 postmenopausal women (microalbuminuria, n ϭ 11; normoalbuminuria, n ϭ 42).
minuria (p ϭ 0.06). The results of the BAR test are
Baseline characteristics: The baseline clinical and
presented in EDV response was significantly
biochemical characteristics of the entire study population
less in patients with microalbuminuria than in those
are listed in There were no significant differ-
with normoalbuminuria at 1 minute (1.9 Ϯ 4.1% vs
ences between groups regarding use of medications
4.9 Ϯ 5.7%, p ϭ 0.01) and 3 minutes (0.6 Ϯ 5.7% vs
with the exceptions of thiazolidinediones being
2.8 Ϯ 5.1%, p ϭ 0.04) after occlusion. A similar
used more frequently in patients with microalbuminuria
significantly attenuated response was recorded for
(p ϭ 0.05), and hormone replacement therapy was less
EIV in patients with microalbuminuria compared with
prevalent in patients with microalbuminuria than in those
those with normoalbuminuria at 3 minutes (9.5 Ϯ
5.2% vs 13.4 Ϯ 7.2%, p ϭ 0.007) and 5 minutes (12.7
Relation between microalbuminuria and brachial ar-
Ϯ 5.5% vs 17.2 Ϯ 7.8%, p ϭ 0.005) after nitroglyc-
tery reactivity: There was a trend for larger baseline
brachial artery diameter in patients with microalbu-
Increasing levels of microalbuminuria had a sig-
296 THE AMERICAN JOURNAL OF CARDIOLOGYா TABLE 3 Endothelium-dependent and Endothelium-independent Vasodilations of
the Brachial Artery in Patients With Microalbuminuria Versus Those With NormalAlbuminuria
value, 27 of 28 patients with mi-croalbuminuria (96%) and 87 of 115
(76%) had abnormal EDV at 1minute (p ϭ 0.01). Microalbuminuria and C-reactive protein: For the subgroup of patients
with microalbuminuria (6.3 Ϯ 1.4mg/L) compared with those withnormoalbuminuria (3.9 Ϯ 0.5 mg/L,
TABLE 4 Multivariate Linear Regression Model of Endothelium-dependent
Vasodilation as a Dependent Variable (n ϭ 143, R2 ϭ 0.258).
on hormone replacement therapy, be-cause hormone replacement therapy
has been shown to increase C-reac-tive protein patients with
†The standardized coefficient  describes the unit-independent contribution of the independent vari-
R2 ϭ square of the multivariate correlation coefficient.
patients with microalbuminuria, per-centages of subjects with low- (Ͻ1mg/L), moderate- (1 to 3 mg/L), and
TABLE 5 Multivariate Linear Regression Model of Endothelium-independent
Vasodilation as a Dependent Variable (n ϭ 143, R2 ϭ 0.247)
minuria. The percentage of high-riskpatients was significantly higher inthe group with microalbuminuria
nificant inverse correlation with EDV at 1 minute (r ϭ
than in the group with normoalbuminuria (82% vs
Ϫ0.20, p ϭ 0.02) and EIV at 3 minutes (r ϭ Ϫ0.27, 40%, p ϭ 0.012), whereas the percentage of low-riskp ϭ 0.001). With stepwise multivariate regression
patients was significantly lower (0% vs 28%, p ϭ
analysis, significant independent predictors of EDV
were baseline diameter, gender, current estrogen re-placement therapy, age, hemoglobin A1 , and pres-
DISCUSSION
The aim of this study was to investigate the relation
uria (standardized  coefficient Ϫ0.22, p ϭ 0.01) and
between microalbuminuria and BAR in asymptomatic
age (standardized  coefficient Ϫ0.20, p ϭ 0.02) were
patients with DM. Our results demonstrated that pa-
the only independent predictors of EDV after exclud-
tients with microalbuminuria have significant impair-
ing patients on hormone replacement therapy (n ϭ
ment of EDV and EIV compared with those with
119). Data concerning independent predictors of EIV
normoalbuminuria and a higher degree of systemic
are presented in Baseline diameter (standard-
inflammation. These data associated the presence of
ized  coefficient Ϫ0.30, p ϭ 0.001) and microalbu-
microalbuminuria in patients with DM with impaired
minuria (standardized  coefficient Ϫ0.20, p ϭ 0.026)
vascular reactivity secondary to smooth muscle dys-
were independent predictors of EIV after excluding
function rather than to endothelial dysfunction alone.
patients on hormone replacement therapy. Microalbuminuria and brachial artery reactivity: In
The exact value of EDV that represents a normal
patients with type 2 DM, the presence of microalbu-
endothelium-dependent response has not been estab-
minuria may necessitate screening for vascular disease
and aggressive interventions to decrease cardiovascu-
CORONARY ARTERY DISEASE/BAR AND MICROALBUMINURIA IN TYPE 2 DM
lar In contrast, endothelial dysfunction, at
populations, including the Framingham Heart Study
least in the coronary circulation, predicts cardiovas-
and the Cardiovascular Health Study, may determine
whether testing of BAR identifies patients at risk for
for microalbuminuria and cardiovascular disease in
developing coronary artery disease and whether it is a
Several studies have suggested that endothelial
practical clinical tool. Despite a lack of large epide-
dysfunction precedes the onset of microalbuminuria
miologic studies, impaired endothelial function of bra-
in patients with type 1 DIn type 2 DM, in-
chial arteries is present in patients with coronary risk
flammatory markers of endothelial dysfunction, mi-
factors without evidence of coronary disease and im-
croalbuminuria, and risk of death are parallel and
progress with Consistent with these results, our
study suggests that impaired vascular reactivity may
study correlates endothelial dysfunction with increas-
identify subjects with normoalbuminuria earlier in the
ing levels of microalbuminuria. The attenuated EIV
atherosclerotic process as candidates for more aggres-
response in subjects with microalbuminuria also sug-
sive medical therapy. However, such a recommenda-
gests vascular smooth muscle dysfunction due to in-
tion cannot be made at the moment because testing of
creased inactivation of nitric oxide or decreased reac-
BAR is a research rather than a clinically available
tivity of the vascular smooth muscle to nitric
tool and requires the care and precision of a well-
The exact values of normal brachial EDV and EIV
have not been established mainly due to differences in
Study limitations: Our study is limited by its cross-
age, gender, and In patients with periph-
sectional design and the absence of a control group. In
eral vascular disease, an EDV Ͻ8.1% was associated
addition, the interpretation of the results of EDV
with ninefold increases in rates of morbidity and mor-
should be viewed with caution because EIV was also
tality compared with those with EDV of ՆIn
impaired in subjects with microalbuminuria compared
healthy nonsmokers, mean EDV at 1 minute has been
with those with normoalbuminuria. However, the im-
reported to be and in our laboratory, an EDV
paired EDV in 76% of patients with normal albumin-
8% at 1 minute after lower arm occlusion was
uria was associated with a “preserved” EIV response
considered a normal response in healthy subjects of
similar age and body size. With this cut-off point, 76%of patients with normal albuminuria had EDV of
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B E R S E N A S J A C O B S E N C H O U E S T T H O M S O N B L A C K B U R N L L P Volume 1, Issue 9 LITIGATION NOTES October 2006 Pushing the Limits of Punitive Damages I n s i d e t h i s i s s u e : that it was not made in good faith. While the finding of dismissed without cause, one in the wrong”. This is a Superior Court Considers Form “G” also had preliminary