Download Relation Between Renal Function Within the Normal Range and

Relation Between Renal Function Within the Normal Range
and Central and Peripheral Arterial Stiffness
in Hypertension
Giuseppe Schillaci, Matteo Pirro, Massimo R. Mannarino, Giacomo Pucci, Gianluca Savarese,
Stanley S. Franklin, Elmo Mannarino
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Abstract—Chronic kidney disease is accompanied by increased large-artery stiffness, but the relation between glomerular
filtration rate within the reference range and central or peripheral arterial stiffness has been understudied. The link
between renal function and arterial stiffness was assessed in 305 patients with never-treated essential hypertension (men:
58%; age: 48⫾11 years, blood pressure: 151/95⫾20/11 mm Hg), free from overt cardiovascular disease and with serum
creatinine values ⬍1.4 mg/dL (men) and ⬍1.2 mg/dL (women), who underwent noninvasive aortic and upper-limb
pulse wave velocity (PWV) determination. Aortic PWV was strongly related to age (r⫽0.55; P⬍0.001), whereas
upper-limb PWV had a weaker nonlinear relation with age (␤⫽1.392; P⬍0.001 for age; ␤⫽⫺1.312; P⬍0.001 for age
squared) and a weak relation with aortic PWV (r⫽0.22; P⬍0.001). Glomerular filtration rate (GFR), estimated
according to the Mayo clinic equation for healthy subjects, was inversely correlated with large-artery stiffness, as
assessed by aortic PWV (r⫽⫺0.34; P⬍0.001), and with peripheral artery stiffness, as assessed by upper-limb PWV
(r⫽⫺0.25; P⬍0.001). In a multivariate linear regression, aortic PWV was independently predicted by age (␤⫽0.48;
P⬍0.001), mean arterial pressure (␤⫽0.14; P⫽0.013), and GFR (␤⫽⫺0.13, P⫽0.029). Upper-limb PWV was predicted
by GFR (␤⫽⫺0.24; P⬍0.001) and mean arterial pressure (␤⫽0.20; P⬍0.001). We conclude that, in hypertensive
patients with normal renal function, an inverse relationship exists between GFR and stiffness of both central elastic and
peripheral muscular arteries. These relations are in part independent from the effect of several confounders, including
age, sex, and blood pressure values. (Hypertension. 2006;48:616-621.)
Key Words: hypertension 䡲 glomerular filtration rate 䡲 pulse wave velocity 䡲 arterial stiffness 䡲 artery
C
transit time and, therefore, an estimate of arterial compliance,
and that study suggests a relation between arterial stiffness and
reduced GFR even in uncomplicated patients with essential
hypertension.
However, several questions remain unanswered in this regard.
First, it is unknown whether kidney function is related to arterial
stiffness within the reference range of estimated GFR. Second, it
is currently not clear whether a reduced GFR is not only a
correlate of arterial stiffness at the aortic level but also at the
level of the peripheral arteries. QKD interval is a combination of
transit time along the elastic ascending aorta and the predominantly muscular upper-limb arteries. Aorta and muscular upperlimb arteries are affected to a different extent by age and
cardiovascular risk factors; unlike aortic PWV, upper-limb PWV
is not affected by age significantly.13
The present investigation tested the hypothesis that in
subjects with uncomplicated essential hypertension, changes
ardiovascular disease is the leading cause of death in
chronic kidney disease,1 and the development of premature
and accelerated atherosclerosis in these patients is accounted for
only in part by traditional risk factors.2 One possible mechanism
for this association might be represented by increased arterial
stiffness, which is both a predictor of cardiovascular disease3–5
and a correlate of reduced glomerular filtration rate (GFR).6 – 8 In
patients with end-stage renal disease, a number of structural
alterations of the arterial system occur, including stiffening of
the aorta9 and of the radial artery, a muscular artery free of
atherosclerosis.10 Among people with mild renal failure, arterial
stiffness is directly related to GFR.11 In hypertensive patients,
Gosse and Safar12 have observed that the time interval between
the R wave on the ECG and the last Korotkoff sound heard
over the brachial artery when measuring blood pressure ([BP]
named the QKD interval) is directly related to estimated GFR.
QKD interval is considered an approximate measure of arterial
Received May 31, 2006; first decision June 20, 2006; revision accepted August 2, 2006.
From the Unit of Internal Medicine (G. Schillaci, M.P., M.R.M., G.P., G. Savarese, E.M.), Angiology and Arteriosclerosis, University of Perugia,
Perugia, Italy; and the Heart Disease Prevention Program (S.S.F.), University of California, Irvine, Calif.
This paper was presented in part on November 14, 2005. at the American Heart Association Scientific Sessions, Dallas, TX. See Abstract: Schillaci
G, Pirro M, Mannarino MR, Savarese G, Pucci G, Gemelli F, Vaudo G, Mannarino E. Renal dysfunction as an independent predictor of arterial stiffness
in essential hypertension. Circulation. 2005;112:II-607.
Correspondence to Giuseppe Schillaci, Unit of Internal Medicine, Angiology and Arteriosclerosis, University of Perugia Medical School, Hospital “S.
Maria della Misericordia,” piazzale Menghini, 1, IT-06132 Perugia, Italy. E-mail [email protected]
© 2006 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000240346.42873.f6
616
Schillaci et al
in GFR may be related to changes in pulse wave velocity
(PWV) at the level of the aorta and/or peripheral arteries. To
investigate this hypothesis, we estimated GFR and determined aortic and upper-limb PWV in a consecutive series of
hypertensive patients. To exclude the confounding effects of
drug treatment, concomitant diseases, and overt chronic
kidney disease, we examined a group of untreated, nondiabetic patients with essential hypertension who had normal
serum creatinine levels.
Methods
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We examined 305 consecutive patients with essential hypertension
(men: 58%; age: 48⫾11 years; BP: 151/95⫾20/11 mm Hg) who had
been referred to our outpatient hypertension clinic between January
2003 and May 2005. Patients with uncomplicated essential hypertension were included in the study if they had been diagnosed with
hypertension within the previous 3 years and had never received
antihypertensive drug treatment. Exclusion criteria were clinical or
laboratory evidence of heart failure, coronary heart disease, cerebrovascular disease, valvular defects, secondary causes of hypertension,
serum creatinine ⱖ120 ␮mol/L (1.4 mg/dL) in men and ⱖ106 ␮mol/L
(1.2 mg/dL) in women, proteinuria on the standard dipstick test, major
noncardiovascular disease, dyslipidemia requiring pharmacological
treatment, known diabetes or fasting glycemia ⱖ126 mg/dL, and
treatment with any cardiovascular drug, including nitrates. Written
informed consent was obtained from each patient, and the study protocol
was reviewed and approved by the institutional ethics committee.
All of the subjects underwent a careful clinical examination.
Serum creatinine concentration was measured in an autoanalyzer
(Technicon) by means of an automated technique measuring dialyzable Jaffe chromogen. This assay was calibrated daily by using the
uncompensated method during the study period. Given that the abbreviated Modification of Diet in Renal Disease equation14 systematically
underestimates GFR in high-GFR populations, and also the Cockcroft–
Gault equation15 has insufficient precision in persons without chronic
kidney disease,16 GFR was calculated according to the following
formula, which has been developed and validated in a population of
predominantly white adult subjects with normal renal function17: GFR
(mL/min per 1.73 m2)⫽224⫻serum creatine⫺0.490⫻age⫺0.192⫻0.923 (if
female), where serum creatinine is in milligrams per deciliter, and age is
in years.
Fasting blood samples were taken to perform routine blood
chemistry. Waist circumference was measured with a soft tape on
standing subjects at the iliac crest at the end of a normal expiration.
After the subject had been resting in a supine position for 5 minutes,
3 consecutive measurements of BP and heart rate were obtained and
averaged. Ambulatory BP was recorded with a validated oscillometric device (model 90207; SpaceLabs).18
After measuring BP, aortic and upper-limb PWV and pulse wave
analysis were determined noninvasively with the commercially available SphygmoCor system (AtCor Medical), as described previously.19,20
Aortic (carotid-to-femoral) PWV was calculated from measurements of
common carotid and femoral artery waveforms, and upper-limb
(carotid-to-radial) PWV from common carotid and radial artery waveforms. Central artery waveforms were derived from the radial artery
waveform, calibrated to brachial BP, by using a transfer function
validated previously.21,22 Aortic augmentation was expressed either in
absolute term or as a percentage of aortic pulse pressure (aortic
augmentation index). Given the known dependence of aortic augmentation on heart rate (in the present population, ␤⫽⫺0.45 in women and
␤⫽⫺0.26 in men; both P⬍0.001), augmentation index was adjusted by
heart rate on the basis of sex-specific regression equations. The same
observer, unaware of the patient’s clinical and biochemical data, carried
out all of the measurements.
Statistical Analysis
Continuous variables were tested to detect substantial deviations from
normality by computing the Kolmogorov–Smirnov Z. The assumption
of satisfactory normal distribution was met for all of the examined
Glomerular Filtration Rate and Arterial Stiffness
617
variables, except for serum triglyceride concentration, which, because of
its skewed distribution, was log-transformed before statistical analysis.
Patients were grouped by tertile of estimated GFR. Differences among
groups were tested using ANOVA and ␹2 test where appropriate, with
post hoc Tukey’s honestly significant differences. Pearson’s correlation
coefficients examined the bivariate associations between examined
variables.
Stepwise multiple regression analyses were used to evaluate which
factors were independently associated with aortic and upper-limb
PWV in the whole population. We investigated potential nonlinearity
of relations of age and PWV by fitting multivariable models
incorporating age and a quadratic term of age. Age, age squared, sex,
smoking habits, body height, body mass index, physical activity,
brachial mean arterial pressure, heart rate, duration of hypertension,
and serum cholesterol concentration were included as independent
variables in the multivariate models together with estimated GFR.
The linear regression assumptions were confirmed by verifying
normality of the distribution of residuals. Graphical inspection of
scatter plots between predicted values of the dependent variable and
regression-standardized residuals excluded any heteroscedasticity of
distribution (data not shown). The final models were evaluated for
other linear relationships among variables in the model (collinearity),
which have the potential of rendering significance testing unreliable.
Using standard diagnostic techniques, all of the models presented
were found to be free from collinearity (tolerance: 0.76 to 0.97).
Results
Selected clinical and demographic characteristics of the 305
study patients are given in Table 1. Patients were grouped by
tertiles according to their estimated GFR; partition values
among tertiles were 106 and 117 mL/min per 1.73 m2.
Patients in the bottom GFR tertile were older and more
frequently men and had higher serum creatinine and cholesterol values. Moreover, brachial and synthesized aortic systolic and pulse pressures increased with decreasing GFR. In
contrast, diastolic and mean BP values were not significantly
different in the 3 groups. The groups did not differ by body
mass index, waist circumference, smoking habits, and hypertension duration.
As reported in Table 1, aortic PWV increased progressively with decreasing GFR. Also, upper-limb PWV increased ongoing from the top to the bottom GFR tertile. As
depicted in the Figure, estimated GFR had a significant
inverse relation with aortic PWV (r⫽⫺0.34; P⬍0.001), as
well as with upper-limb PWV (r⫽⫺0.25; P⬍0.001).
Aortic and upper-limb PWV correlated weakly each other
(r⫽0.22; P⬍0.001). Both showed a direct association with
brachial mean arterial pressure. As expected, aortic PWV increased steeply with age and had a significant relation with waist
circumference and low body height (Table 2). No significant
relationship was found between the square of age and aortic
PWV. Upper-limb PWV had a significant nonlinear relation
with age (␤⫽1.392, P⬍0.001 for age; ␤⫽⫺1.312, P⬍0.001 for
age squared) and no significant associations with either waist
circumference or body height.
In a stepwise multiple regression model in which GFR was
included as an explanatory variable together with age, age
squared, sex, smoking habits, body height, body mass index,
physical activity, brachial mean arterial pressure, heart rate,
duration of hypertension, and serum cholesterol concentration, GFR was independently associated with aortic PWV
along with age and office mean arterial pressure (Table 3).
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Hypertension
October 2006
TABLE 1. Selected Demographic and Clinical Characteristics of 305 Hypertensive Subjects by
Tertile of Estimated GFR
Estimated GFR, mL/min per 1.73 m2
Data
ⱖ117
(n⫽101)
Age, y
44 (10)
Men, %
72
27.1 (4)
27.8 (4)
Body mass index, kg⫻m⫺2
⬍106
(n⫽101)
P (F)
49 (9)*
54 (10)*†
⬍0.001
46*
48*
0.002
27.6 (4)
0.50
106 –117
(n⫽103)
Waist, cm
94 (10)
95 (11)
95 (13)
0.73
Hypertension duration, y
1.4 (2)
1.5 (2)
1.3 (2)
0.37
Current smokers, %
26%
29%
27%
0.78
Serum cholesterol, mg/dL
197 (33)
208 (36)
214 (36)*
Serum creatinine, mg/dL
0.87 (0.1)
0.91 (0.1)
1.03 (0.1)*†
Brachial systolic BP, mm Hg
147 (16)
152 (21)*
155 (22)*
0.008
Brachial diastolic BP, mm Hg
94 (9)
95 (11)
95 (13)
0.79
111 (10)
114 (13)
115 (14)
0.08
Brachial mean BP, mm Hg
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Brachial PP, mm Hg
0.002
⬍0.001
53 (13)
56 (16)*
60 (17)*
0.003
Aortic systolic BP, mm Hg
135 (15)
141 (20)*
145 (20)*
⬍0.001
Aortic diastolic BP, mm Hg
96 (9)
96 (11)
95 (13)
0.83
109 (10)
111 (13)
112 (14)
0.10
Aortic mean BP, mm Hg
Aortic PP, mm Hg
39 (12)
45 (14)*
50 (15)*
⬍0.001
24-h systolic BP, mm Hg
130 (10)
130 (11)
133 (14)
0.24
24-h diastolic BP, mm Hg
83 (10)
84 (8)
82 (10)
0.47
24-h mean BP, mm Hg
99 (9)
99 (9)
99 (10)
0.89
24-h PP, mm Hg
47 (7)
46 (7)
50 (11)*†
0.002
Aortic PWV, m/s
8.4 (1.8)
8.8 (1.8)
10.0 (2.7)*†
⬍0.001
Upper-limb PWV, m/s
8.7 (1.6)
9.4 (1.5)*
9.6 (1.6)*
⬍0.001
Aortic augmentation, mm Hg
10 (7)
14 (8)*
16 (9)*
⬍0.001
0.25 (0.12)
0.30 (0.13)*
0.31 (0.11)*
⬍0.001
Augmentation index
Data are given as mean (SD). Augmentation index values are adjusted for heart rate. PP indicates pulse pressure.
*P⬍0.05 vs I tertile; †P⬍0.05 vs II tertile.
Low GFR, mean arterial pressure, and low body mass index
were independent predictors of upper-limb PWV.
Discussion
This is the first study to demonstrate that GFR within the
reference rang in patients with uncomplicated, untreated
essential hypertension has a strong, independent inverse
association with both central and peripheral arterial stiffness,
as reflected by increased carotid-to-femoral and carotid-toradial PWV, respectively; in addition, the finding of an
inverse relation between GFR and aortic augmentation index
provided further support for increased central artery stiffness.
Furthermore, the association between GFR and arterial stiffness remained significant after adjusting for the potential
confounding influences of age, sex, distending pressure, and
other major cardiovascular risk factors. The relation was also
independent of average 24-hour ambulatory BP, which is a
stronger predictor of cardiovascular risk than office BP in
hypertension.23
Because aortic stiffness has been identified as an independent predictor of cardiovascular mortality in the specific
setting of essential hypertension,4,5 we hypothesize that
changes in arterial stiffness may, in part, mediate the well-
known association between even mild reductions in GFR and
cardiovascular risk in patients with hypertension.24,25
Kidney Disease and Peripheral Muscular
Artery Stiffness
Both central elastic and peripheral muscular arteries have been
shown to be stiffer in end-stage renal disease. These findings
were obtained measuring elastic modulus by the technique of
high-resolution echo tracking,9,26 as well as measuring stiffness
under isobaric conditions at the level of the radial artery.10
Among people with nondialysis-dependent renal insufficiency, a
significant inverse relationship was found between GFR and
aortic PWV.6 – 8 Previous studies on the relation between GFR
within the reference range and arterial stiffness have been
inconclusive. In 112 hypertensive subjects with normal or mildly
reduced GFR, Mourad et al11 showed that reduced creatinine
clearance was associated with increased stiffness of the musculoelastic carotid artery but not of the muscular radial artery.
However, given the relatively weak association between GFR
and upper-limb PWV, small sample size may have precluded the
demonstration of a significant association in that study. In 263
hypertensive subjects with normal or mildly reduced GFR,
Gosse and Safar12 found a positive relation between plasma
Schillaci et al
Glomerular Filtration Rate and Arterial Stiffness
619
TABLE 3. Independent Determinants of Aortic and Upper-Limb
PWV in a Stepwise Multiple Linear Regression Analysis
Variable
Standardized
Regression
Coefficient
Multiple R2
P
Aortic PWV
Age, y
0.48
0.30
⬍0.001
Brachial mean pressure, mm Hg
0.14
0.32
⬍0.001
⫺0.13
0.34
0.029
⫺0.24
0.07
⬍0.001
0.20
0.11
⬍0.001
⫺0.12
0.12
0.034
GFR, mL/min per 1.73 m2
Upper-limb PWV
GFR, mL/min per 1.73 m2
Brachial mean pressure, mm Hg
Body mass index, kg⫻m⫺2
Age squared, sex, smoking habits, body height, physical activity, heart rate,
duration of hypertension, and serum cholesterol concentration were included
as explanatory variables but failed to enter the final models. Constant was 3.52
in the aortic PWV model and 10.47 in the upper-limb PWV model.
Downloaded from http://hyper.ahajournals.org/ by guest on April 28, 2017
Scatterplots illustrating the relation of estimated GFR with aortic
(top) and upper-limb (bottom) PWV.
creatinine and QKD interval. Although correlated with more
direct measures of arterial stiffness,27 the QKD interval depends
on several other variables, including ventricular activation and
body height, and represents a cumulative measure of aortic and
upper-limb PWV velocity, so the effects of renal function on
central and peripheral stiffness could not be distinguished in that
article.
Our study identifies for the first time a strong inverse
association between GFR and arterial stiffness at both the
aortic and peripheral level in a group of newly diagnosed,
never-treated nondiabetic hypertensive subjects. These data
demonstrate that significant alterations of the elastic properties of both elastic and muscular arteries appear at a very early
stage of the disease, that is, in patients with normal estimated
GFR.
How Does Arterial Stiffness Affect
Renal Function?
Our cross-sectional study cannot establish causality relations,
and it should be remembered that several cardiovascular risk
factors, including aging, diabetes, and high BP, are known to
TABLE 2. Bivariate Correlates of Aortic and Upper-Limb PWVs
and of Estimated GFR
Variable
Upper-Limb PWV
GFR
Age
0.55*
0.09
⫺0.42*
Brachial mean pressure
0.23*
0.23*
⫺0.11
Body height
Aortic PWV
⫺0.20*
Body mass index
Waist circumference
GFR
0.03
0.11
0.02
⫺0.11
⫺0.05
0.19†
⫺0.05
⫺0.04
⫺0.34*
*P⬍0.001; †0.05⬍P⬍0.001.
⫺0.25*
increase, per se, the levels of arterial stiffness and plasma
creatinine.28 However, we show that the association between
GFR and arterial stiffness is independent of the confounding
effect of age and other major risk factors. The possibility
cannot be excluded that aortic stiffness might be responsible
for a reduced GFR through an increase in aortic pulse
pressure.29 Glomerular capillaries are exposed to relatively
high mean and pulse pressures, approximating 60% of the
arterial values. While ensuring a high filtration fraction, these
high levels of pressure expose glomerular capillaries to
potentially damaging pulse pressure. A hemodynamic effect
of pulse pressure on the myogenic tone of afferent arterioles
has been demonstrated in vitro in a perfused hydronephrotic
rat kidney model.30 The glomerulus is selectively exposed to
pulsatile forces affecting capillary pressure,31 and these
mechanisms may contribute to glomerulosclerosis. However,
our data show that GFR has an independent impact not only
on aortic PWV, but also on peripheral PWV. This might have
pathogenetic implications. In fact, different arterial segments
respond differently to aging. Aorta, an elastic artery, loses its
compliance with advancing age, whereas compliance in the
peripheral, predominantly muscular arteries seems less
closely related to age.13 The common link of 2 unrelated
measures of arterial stiffness with GFR might suggest a
direct, age-independent implication of kidney function in
arterial stiffness. Interestingly, Bahous et al32 demonstrated
recently that healthy kidney donors develop increased aortic
PWV. The possibility cannot be ruled out, however, that
increased peripheral muscular artery stiffness might increase
early wave reflection by shortening the sites of wave reflection, thus increasing arterial pulsatility and cardiac afterload,
as well indirectly affecting renal function.
In the present study, an inverse relationship was also found
between GFR and aortic augmentation index. Augmentation
index, a composite parameter that depends on the reflective
properties of the distal arterial bed, as well as on elastic
properties of the large arteries, is a measure of the extra
hemodynamic burden imposed on the heart and a predictor of
cardiovascular events in patients with ischemic heart disease.33 This finding highlights the adverse potential cardiac
620
Hypertension
October 2006
consequences of even minor changes in renal function in
hypertension.
Can Chronic Kidney Disease Cause
Arterial Stiffness?
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Our results are in agreement with the hypothesis that a mildly
reduced kidney function might be responsible for increased
arterial stiffness. Interestingly, in a large longitudinal study of
patients with essential hypertension, Benetos et al34 found
that serum creatinine level was a major determinant of
accelerated progression of arterial stiffness.
Mechanisms causing increased arterial stiffness in renal
patients are not fully understood: over and above the effects
of age and standard cardiovascular risk factors, an increase in
the calcium content of the arterial wall has been demonstrated
in hemodialysis patients35,36 and also in patients with moderate chronic renal failure.37 Several other mechanisms could be
involved, including endothelial dysfunction,38 activation of
the renin–angiotensin–aldosterone system,39 and qualitative
and quantitative changes in the arterial wall, such as advanced
glycation end products, lipid peroxidation, elastin fragmentation, vascular smooth muscle cell hyperplasia, increased
collagen content, and reduced amount of elastic fibers.40,41
Limitations
Some limitations of this study should be acknowledged. Our
results were obtained in a middle-aged, white, uncomplicated,
untreated hypertensive population, and inferences with regard
to other ethnicities, older individuals, treated subjects, and
high-risk populations should be made with caution. The
Mayo clinic formula represents only an approximation of true
creatinine clearance, and it is well known that any formula for
estimating GFR tends to be less accurate in subjects with
normal renal function than in patients with chronic kidney
disease.17 However, in comparison with other widely used
formulas for the estimation of GFR, it has been shown to be
more accurate and less subject to systematic bias, at least in
populations with normal GFR.17 This being a cross-sectional
study, causations discussed above should be considered as
hypothetical.
Perspectives
By showing that GFR influences arterial functional properties
that are related to cardiovascular risk, our findings provide a
pathophysiological background for understanding the associations between renal function and arterial stiffness–related
cardiovascular morbidity and mortality. The fact that a
relation between GFR and significant changes in the elastic
properties of central and peripheral arteries is present in
hypertensive subjects with fully normal renal function suggests a role of even minimally impaired renal function in
affecting arterial stiffness and may give an explanation for the
strong link between creatinine values within the reference
range and cardiovascular complications in hypertensive subjects.24,25 Clearly, further studies are needed to elucidate the
pathophysiological implications of these findings.
Source of Funding
This work was supported in part by the grant 2004060902 from the
Italian Ministry for University and Scientific Research.
Disclosures
None.
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Relation Between Renal Function Within the Normal Range and Central and Peripheral
Arterial Stiffness in Hypertension
Giuseppe Schillaci, Matteo Pirro, Massimo R. Mannarino, Giacomo Pucci, Gianluca Savarese,
Stanley S. Franklin and Elmo Mannarino
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Hypertension. 2006;48:616-621; originally published online September 4, 2006;
doi: 10.1161/01.HYP.0000240346.42873.f6
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