Tissue Sodium
23
Na Magnetic Resonance Imaging of Tissue Sodium
Christoph Kopp, Peter Linz, Lydia Wachsmuth, Anke Dahlmann, Thomas Horbach, Christof Schöfl,
Wolfgang Renz, Davide Santoro, Thoralf Niendorf, Dominik N. Müller, Myriam Neininger,
Alexander Cavallaro, Kai-Uwe Eckardt, Roland E. Schmieder, Friedrich C. Luft, Michael Uder, Jens Titze
Abstract—Hypertension is linked to disturbed total-body sodium (Na⫹) regulation; however, measuring Na⫹ disposition
in the body is difficult. We implemented 23Na magnetic resonance spectroscopy (23Na-MR) and imaging technique
(23Na-MRI) at 9.4T for animals and 3T for humans to quantify Na⫹ content in skeletal muscle and skin. We compared
23
Na-MRI data with actual tissue Na⫹ content measured by chemical analysis in animal and human tissue. We then
quantified tissue Na⫹ content in normal humans and in patients with primary aldosteronism. We found a 29% increase
in muscle Na⫹ content in patients with aldosteronism compared with normal women and men. This tissue Na⫹ was
mobilized after successful treatment without accompanying weight loss. We suggest that, after further refinements, this
tool could facilitate understanding the relationships between Na⫹ accumulation and hypertension. Furthermore, with
additional technical advances, a future clinical use may be possible. (Hypertension. 2012;59:167-172.)
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Key Words: aldosterone 䡲 MRI 䡲 sodium 䡲 hypertension
rinary sodium (Na⫹), and initially chloride (Cl⫺), was
used to estimate salt (NaCl) balance in the early 20th
century.1,2 Timed urinary Na⫹ excretion has commonly been
used to reflect dietary adherence in randomized, controlled
clinical trials of salt reduction in hypertension.3,4 These tools
have been helpful but are oftentimes unsatisfactory. Longterm balance studies, even in a clinical research center
environment, have given results that are difficult to interpret.5,6 Clinicians have generally equated exchangeable extracellular Na⫹ as residing within the extracellular fluid
volume, with perhaps some Na⫹ storage in bone. We have
raised the possibility that other sites, such as skin and muscle,
could serve to store Na⫹ nonosmotically by binding of the
Na⫹ ion to proteoglycans.7 Careful review of the literature
subsequently taught us that this idea is not new and was
shown to be the case by Russian physiologists ⬎30 years
ago.8 In any event, conducting such measurements requires
ashing of tissue and atomic absorption spectrometry, which
are not suitable in the clinical setting. Needed is a noninvasive method, suitable for repetitive use in probands and
patients, that could show Na⫹ storage and also the rate of
immobilization with changes in dietary intake or therapy. The
Na⫹ atom has an uneven atomic number and, therefore, is
U
suitable for detection with magnetic resonance spectrometry
and MRI. The sole stable isotope is 23Na. We present
preliminary results that this approach promises utility in
animals models, normal human subjects, and patients with
hypertension.
Methods
Study Design
Local government authorities approved the animal studies according
to American Physiological Society guidelines. The University of
Erlangen-Nürnberg committee on human subjects approved the
human studies (Re-No. 3948), and written informed consent was
obtained from all of the participants.
Na-MRI Quantification of Tissue Naⴙ Content
in Animals
23
Twenty Sprague-Dawley rats were randomly assigned to 4 different
groups (n⫽5 per group). Groups 1 and 2 were untreated control
groups, whereas groups 3 and 4 received deoxycorticosterone acetate
(DOCA) pellets implanted subcutaneously under methohexital anesthesia. DOCA pellets were replaced after 3 weeks. Groups 1 and 3
received tap water to drink (low salt), whereas groups 2 and 4
received 1% saline (high salt) for 5 consecutive weeks. All of the
animals were fed a chow containing ⬍0.1% NaCl by weight.
Directly after euthanizing, both quadriceps muscles from each
Received September 16, 2011; first decision October 16, 2011; revision accepted November 8, 2011.
From the Department of Nephrology and Hypertension (C.K., P.L., A.D., M.N., K.-U.E., R.E.S., J.T.), Interdisciplinary Center for Clinical Research,
Nikolaus-Fiebiger-Center for Molecular Medicine (P.L., J.T.), Division of Endocrinology and Diabetes, Department of Medicine I (C.S.), Department of
Experimental Medicine I, Nikolaus-Fiebiger-Center for Molecular Medicine (D.N.M.), and Department of Radiology (A.C., M.U.), Friedrich-AlexanderUniversity Erlangen-Nürnberg, Erlangen, Germany; Research Group for Experimental Magnetic Resonance (L.W.), Westfälische-Wilhelms-University
Münster, Germany; Department of Surgery (T.H.), Hospital Schwabach, Schwabach, Germany; Siemens Healthcare (W.R.), Erlangen, Germany; Berlin
Ultrahigh-Field Facility and the Experimental and Clinical Research Center (W.R., D.S., T.N., D.N.M., F.C.L.), Charité Medical Faculty and
Max-Delbrück Center for Molecular Medicine, Berlin, Germany.
This paper was sent to John E. Hall, associate editor, for review by expert referees, editorial decision, and final disposition.
C.K. and P.L. contributed equally to this work.
Correspondence to Jens Titze, Nikolaus-Fiebiger-Center for Molecular Medicine, Glückstrasse 6, 91054 Erlangen, Germany. E-mail
[email protected]
© 2011 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.111.183517
167
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B
MR measurement
left quadriceps
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†
+
0
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†
tap water
1% saline water
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Ashing:
right quadriceps
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muscle Na / tissue water (mmol/L)
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January 2012
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control
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Figure 1. Muscle Na⫹ concentration in rats without (control) or with deoxycorticosterone acetate (DOCA) treatment receiving either a
low-salt (⬍0.1% NaCI chow with tap water) or a high-salt intake (⬍0.1% NaCI chow with 1% saline to drink). A, Magnetic resonance
(MR) spectrograms from 5 rat muscle samples are shown (right peak). Calibration signal derived from a 150-mmol/L Na⫹ standard with
shift reagent resulting in the shifted calibration signal (left peak) from which the Na⫹ muscle content was calculated. B, Na⫹ content
was measured by MR spectrometry or by chemical analysis (atomic absorption spectrometry) after ashing. DOCA ⫹ high salt increased
muscle Na⫹ content; MR spectrometry detected this increase in the same rats. C, Relationship between muscle Na⫹ content measured
noninvasively with MR spectrometry (abscissa) and chemical analysis (ordinate) in the same animal. †P⬍0.05 vs control; *P⬍0.05 vs
tap water.
animal were removed. Na⫹ concentration of the left quadriceps was
detected by chemical analysis, whereas Na⫹ content of the right
muscle was analyzed by 23Na-MR spectroscopy. Na⫹ content of the
right muscle was analyzed by 23Na-MR spectroscopy with a 9.4T
vertical bore magnet (Bruker, Karlsruhe, Germany) equipped with a
microimaging gradient system. Two grams of quadriceps tissue were
placed in test tubes. A 50-␮L glass capillary containing 150 mmol/L
of Na⫹ and 5 mmol/L of shift reagent (Na4HTmDOTP, M-155,
Macrocyclics, Dallas, TX), centered within the muscle samples, was
used as an external concentration standard. 23Na spectra were
obtained as 128 time-averaged, free-induction decay response signals using a repetition time of 1.5 seconds. Analysis of the 23Na
spectra was performed with the Bruker XWIN-NMR software
package. Total muscle Na⫹ content (in millimoles per liter) was
calculated by integrating the area under its signal, in relation to the
integrated area of the shifted Na⫹ signal of the reference solution.
Muscle water content was determined gravimetrically after desiccation of the tissue. Na⫹ concentration of muscle was obtained by
generating the ratio of total muscle Na⫹ content (MR spectroscopy)
and tissue water (desiccation).
Ashing Procedure and Chemical Analysis
Tissues were weighted (wet weight) and then desiccated at 80°C for
72 hours (dry weight). The difference between wet weight and dry
weight was considered as tissue water content. After desiccation, the
tissues were ashed at 200°C, 400°C, and 600°C for 24 hours at each
temperature level and then dissolved in 5% HNO3. Na⫹ and K⫹
concentrations were measured by atomic absorption spectrometry.7
Human amputated upper and lower legs were cut into slices with a
thickness of ⬎3 cm and were deep frozen. For ex vivo 23Na-MRI
measurements the slices were thawed and heated to ⬇20°C. Directly
after 23Na-MR measurement, regions of interest were dissected and
underwent an ashing procedure followed by chemical analysis.7
Human Studies
Patients requiring extremity amputation (malignancy and diabetic
complications) were asked preoperatively whether they would allow
their extremities to be analyzed by 23Na-MRI and ashing. For the
muscle measurements, the extremities were placed inside the scanner
along with standards (below). For the skin 23Na-MRI measurements,
technical difficulties were encountered with the amputation specimens that precluded reproducible determinations in this nonviable
tissue. Therefore, the skin was removed from the specimens, and
skin Na⫹ content was measured separately in test tubes.
Normotensive men and women were recruited for noninvasive
Na-MRI measurements, as were 5 patients with primary aldosteronism, 4 with adenomas, and 1 with bilateral hyperplasia. The
primary aldosteronism patients were diagnosed based on plasma
renin activity, aldosterone values, and imaging. Subjects of the
control groups took no antihypertensive medication. Before 23NaMRI measurements, blood and urine samples were obtained, and
blood pressure was measured in a seated position with the RivaRocci method after 5 to 10 minutes of rest. Average blood pressure
was calculated after 3 consecutive measurements. Tissue Na⫹
content in patients with aldosteronism was determined before and
⬇4 weeks after adrenal adenoma surgery or ⱖ2 weeks after initiation
of spironolactone treatment.
23
Na-MRI Quantification of Tissue Naⴙ Content
in Humans
23
Tissue Na⫹ content was assessed noninvasively with a 3.0T clinical
MR system (Magnetom Tim Trio, Siemens Healthcare, Erlangen,
Germany). 23Na-MRI was performed with a gradient echo sequence
(D-FLASH [Fast Low Angle SHot], total acquisition time: 13.7
minutes, echo time: 2.7 ms [amputated legs]/echo time: 2.07 ms [in
vivo lower legs], repetition time: 100 ms, flip angle: 90°, 128 averages,
resolution: 3⫻3⫻30 mm3) and a frequency-adapted monoresonant
transmit/receive birdcage knee coil (32.6 MHz, Stark-Contrast,
Erlangen, Germany). 1H imaging was performed with the body
coil of the scanner using the scout sequence of the system (123.2
MHz, 2D-FLASH, total acquisition time: 4 s, echo time: 4 ms,
repetition time: 8.6 ms, flip angle: 20°, 2 averages, resolution:
0.375⫻0.375⫻7 mm3). For ex vivo analysis, slices from amputated lower legs were fixed in a polystyrene holder including
50-mL test tubes (Falcon) with 10, 20, 30, 40, and 50 mmol/L of
Na⫹ (as NaCl) as calibration solution. For in vivo measurements,
subjects placed their lower legs in the center of the 23Na knee coil.
23
Na-MRI grayscale measurements of standard solutions with
increasing Na⫹ concentration (10, 20, 30, and 40 mmol/L) served
to calibrate relative tissue Na⫹.
Data Analysis
Data are expressed as average⫾SD. Data from chemical analysis,
Na⫹ spectroscopy, 23Na-MRI measurements, and characteristics of
the study population were analyzed by multivariate analysis (general
linear model) and paired t test. SPSS software was used for statistical
analysis (version 17.0).
Kopp et al
A
Na-MRI and Naⴙ
23
169
B
Cross section of
lower leg
NaCl calibration
tubes
C
D
Muscle
100
90
80
y = 1.5 x + 13
R 2 = 0.87
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AAS Na + (mmol/kg WW)
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Skin
120
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y = 1.3 x + 31
R2 = 0.82
70
60
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MRI (TE 2.7 ms) Na + (mmol/L)
Figure 2. 23Na-MRI of lower extremities. A, Representative ex vivo 23Na-magnetic resonance (MR) image from a human lower leg, used
for muscle measurements, with standards (10, 20, 30, 40, and 50 mmol/L) is shown. The white circle indicates the muscle tissue site
used for quantification by chemical analysis (ashing and AAS measurements). B, Representative image of human skin within a test tube
(white circle), which was dissected from an amputated specimen. The skin is surrounded by standards containing 10, 20, 30, and
40 mmol/L of Na⫹. The skin specimen has the highest Na⫹ content. C, Relationship between 23Na-MR estimates (abscissa; millimoles
per liter relative to standards) and Na⫹ content per wet weight of muscle tissue by chemical analysis (ordinate). D, Relationships
between 23Na-MR estimates (abscissa; millimoles per liter relative to standards) and Na⫹ content per wet weight of skin tissue by
chemical analysis (ordinate). TE is echo time in milliseconds.
Results
23
Figure 1A shows results of Na-MR spectrometry in rats.
MR spectrograms from 5 rat muscle samples are shown (right
peak). Calibration signal derived from a 150-mmol/L Na⫹
standard with shift reagent resulted in the shifted calibration
signal (left peak) from which the Na⫹ muscle content was
calculated. Figure 1B shows the 23Na-MR spectrometric
results in control and DOCA rats given tap water or 1% saline
to drink. DOCA increased muscle Na⫹ content, and 1%
saline increased the concentration further (P⬍0.05). With
direct ashing, Na⫹ content in response to DOCA and 1%
saline showed the same increases (P⬍0.05), although the
absolute values were higher with ashing than with 23Na-MR
spectrometry. Figure 1C shows the robust direct relationship
between 23NaMR spectrometry results and ashing (R2⫽0.70).
23
Na-MRI methodology was used for noninvasive quantification. Na⫹ content by referencing signal intensities was
compared with standard test tubes with increasing Na⫹
concentrations in muscle and skin. Figure 2A shows the 5
standards containing 10, 20, 30, 40, and 50 mmol/L of Na⫹
grouped around the MR image of a cross-section from an
amputated lower leg. The image was used for the muscle
concentration estimates. Figure 2B shows the image used for
the skin Na⫹ content estimates. The 4 standards are grouped
around the skin specimen, which was placed within a test
tube. Figures 2C and 2D show the robust relationships
between MRI estimates of Na⫹ content and results obtained
by ashing in muscle (R2⫽0.87) and skin (R2⫽0.82). The Na⫹
content was quite variable, as shown by the chemical analysis
(skin Na⫹ content: 77⫾16 mmol/kg of wet weight; muscle
Na⫹ content: 57⫾15 mmol/kg of wet weight; n⫽21), and
exhibited a broad range. In contrast, plasma Na⫹ concentrations in the same patients were stable within a very narrow
range (138⫾4 mmol/L). Again, the 23Na-MRI measurements
of human tissue Na⫹ were lower than direct measurements;
however, there was a close correlation between both methods.
Furthermore, repetitive 23Na-MRI measurements of the same
cross-section showed a high intramethod precision with an
SD of 1.4% for both, muscle and skin tissue (n⫽5; data not
shown), respectively.
The Table shows demographic data from control normal
women and men and from the 5 patients with primary aldosteronism, before and after treatment. Figure 3A shows 23Na-MRI
estimates of Na⫹ content in muscle, whereas Figure 3B shows
the same estimates for skin. In muscle, women and men had
similar Na⫹ content. Patients with primary aldosteronism had
decidedly higher muscle values (19.6⫾2.7 mmol/L; n⫽17 [men
control] versus 18.9⫾1.9 mmol/L; n⫽13 [women control] versus
26.1⫾3.1 mmol/L; n⫽5 [aldosteronism]; Paldosterone⬍0.05).
In the skin, men had higher Na⫹ content values than women
(24.1⫾5.6 versus 17.5⫾2.6 mmol/L; Psex⬍0.05). The 5 aldosteronism patients had skin values that were numerically higher
than normal, albeit not statistically significant.
The patients with primary aldosteronism were studied a
second time after treatment. Figure 4A shows muscle Na⫹
170
Hypertension
January 2012
Table. Demographic and Laboratory Data on Normotensive Men and Women, as Well as
Patients With Primary Aldosteronism (MeanⴞSD)
Primary Aldosteronism
Parameters
No., n
Age, y
Men
Normotensive
Women
Normotensive
Before
After
17
13
5
5
62⫾7
60⫾7
Weight, kg
77.1⫾9.9
66.2⫾7.5
82.2⫾8.5
81.6⫾9.1
BMI, kg/m2
24.7⫾3.0
23.8⫾3.0
27.0⫾4.0
26.9⫾4.5
SBP, mm Hg
125.5⫾9.0
119.1⫾8.8
149⫾12
133⫾20
DBP, mm Hg
80.4⫾5.9
74.8⫾6.4*
MAP, mm Hg
95.8⫾5.9
90.3⫾4.1*
31⫾20
41⫾23
330⫾133
43⫾23†
...
...
171⫾50
5⫾4†
Cr, mg/dL
0.96⫾0.11
0.77⫾0.13*
1.17⫾0.67
1.39⫾0.87
Serum Na⫹, mmol/L
140⫾1.6
140⫾1.2
142⫾2.3
139⫾2.7
Serum K⫹, mmol/L
3.9⫾0.2
3.8⫾0.2
3.0⫾0.3
4.3⫾0.6†
Na⫹ spot urine, mmol/g of Cr
141⫾66
157⫾91
85⫾107
99⫾38
Aldosterone, pg/mL
Aldosterone-renin ratio
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⫹
K spot urine, mmol/g of Cr
Albumin spot urine, mg/g of Cr
52⫾13
84⫾10
108⫾9
83⫾8
101⫾11
62⫾22
95⫾29*
47⫾15
59⫾22
4⫾2
18⫾38
48⫾57
15⫾21
Cr indicates creatinine; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP,
mean arterial pressure.
*Psex⬍0.05.
†Ptreatment⬍0.05.
content determined by 23Na-MRI before and after treatment.
The values decreased in every patient by approximately one
third (P⬍0.05). Figure 4B shows little or no effect on body
weight by these interventions. The patients had not been
given any dietary instructions. Figure 4C shows a representative 23Na-MRI from a single patient. A dramatic effect is
evident in the tissue, although the 4 control tubes appear
similar in the 2 studies.
Discussion
Our important finding is that body Na⫹ stores can be
monitored noninvasively and longitudinally with 23Na-MRI.
Our 23Na-MRI measurements suggest that the tissue Na⫹
content in humans is much more variable than expected.
Considerable amounts of Na⫹ are stored in muscle, and
particularly in skin, without apparent accompanying fluid
retention or changes in serum Na⫹ concentration in patients
with primary aldosteronism. We are not the first to develop
23
Na-MRI technology. Others have used 23Na-MRI to assess
Na⫹ content in infarcted myocardium.9,10 The 23Na-MRI
technique has also been used to quantify total Na⫹ in normal
and diseased human skeletal muscle.11,12
The noninvasive quantitative diagnostic approach toward
detecting disturbances in Na⫹ disposition may provide a
valuable new tool for patient-oriented research and perhaps
patient care. First, measurements of tissue Na⫹ content could
facilitate assessment of the environmental factor, dietary
NaCl, on cardiovascular disease in humans. Compared with
24-hour urine collections, direct detection of tissue Na⫹ with
23
Na-MRI may provide a superior end point for human
studies examining potential benefits of diuretic drug treatment or dietary salt restriction. Second, changes in tissue Na⫹
content in response to dietary interventions could further
substantiate the clinical evidence and support populationwide salt reduction as a means to prevent cardiovascular
disease.13,14 Third, 23Na-MRI measurements of tissue Na⫹
content in patients with hypertension might assist in the
diagnosis of primary aldosteronism. 23Na-MRI quantification
could perhaps serve for follow-up of patients with treated
aldosteronism. However, we are aware that any implications
regarding aldosterone and specific Na⫹ storage in tissues are
premature. Finally, phenotyping Na⫹ metabolism with 23NaMRI quantification of tissue Na⫹ storage may help us to
better understand and monitor the treatment of Na⫹ and water
retention. The latter is particularly relevant for patients with
hepatic, cardiac, and renal edema, as well as for dialysis
patients.15
We and others7,8 have performed earlier studies involving
Na⫹ storage in proteoglycan-rich regions of the body and
have presented data on how this storage could contribute to
salt-sensitive hypertension. These notions involve local tissue
osmolar sensing, presumably through Na⫹ content, via macrophages and regulation of lymphatic Na⫹ storage capacities.16 We showed that interrupting osmosensing resulted in
faulty Na⫹ storage and salt-sensitive hypertension. We speculate that 23Na-MRI may permit studying these issues noninvasively in patients.
We suggest that our findings could have relevance to testing
the role of Na⫹ in hypertension and in assessing long-term
cardiovascular risk in populations. Current methods for doing so
rely on 24-hour urine estimates of Na⫹ intake or more commonly on questionnaires concerning dietary habits. Both of these
techniques are fraught with problems. Although virtually all
guideline committees strongly recommend a reduction in dietary
Kopp et al
A
30
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26
26
24
24
22
22
20
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18
16
16
14
14
men
women
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20
20
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90
body weight (kg)
†
35
post
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40
MRI (TE 2.07 ms)
Na+ (mmol/L)
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MRI (TE 2.07 ms)
Na+ (mmol/L)
pre
Skin
40
Surgery
male
female
control
B
171
Aldosteronism
+
*
MRI (TE 2.07 ms)
Na+ (mmol/L)
MRI (TE 2.07 ms)
Na+ (mmol/L)
30
MRI (TE 2.07 ms) Na (mmol/L)
Triceps surae
Triceps surae
A
Na-MRI and Naⴙ
23
85
80
Spironolactone
75
70
65
60
men
women
Hyperaldo
control
pre
pre
23
Figure 3. Na-MRI lower-extremity measurements in normal
women and men and in patients with primary aldosteronism. A,
Measurements in the Triceps surae are shown. Women and men
were not different. Patients with primary aldosteronism had distinctly higher values. B, The same measurements are shown for
skin. Men had higher Na⫹ content than women in skin. The
aldosteronism patients had numerically higher values, albeit not
significant. *Paldosterone⬍0.05; †Psex⬍0.05; TE is echo time in
milliseconds.
Na⫹ as a public health measure, a recent epidemiological
analysis suggested that a lower Na⫹ intake was associated with
a higher cardiovascular disease mortality.17 We suggest that
23
Na-MRI determinations could provide greater precision to test
such hypotheses.
There are numerous limitations that confront these studies.
First, construction of 23Na coils was not trivial. The development also required certification by regulatory agencies. We
had available a 9.4T ultrahigh field scanner for our animal
work. We performed our human measurements with 3.0T.
The resolution for muscle tissue appeared satisfactory; however, we are not yet satisfied with the skin estimates that are
important to our central hypothesis about Na⫹ storage. We
have preliminary data that a 7.0T scanner might help us in
that regard (in preparation). Second, although we have no
reason for any health-related concerns, regulatory agencies
must be convinced before these measurements could be
performed on a wide scale. The time required is ⬇30 minutes
per measurement, which is a hindrance for population studies.
Third, we are aware that, before making further conclusions
regarding total body Na⫹ regulation, incorporation of careful
balance studies in such investigations would be necessary.
We were encouraged to find that our aldosterone patients
apparently lost Na⫹ without losing weight. However, this
observation requires confirmation. Finally, in our patients, we
post
C
post
Figure 4. 23Na-MRI determinations before and after treatment
for primary aldosteronism. A, Treatment decreased muscle Na⫹
content by 30% (26.1⫾3.1 [n⫽5] vs 18.3⫾2.7 mmol/L [n⫽5]). B,
Despite tissue Na⫹ removal, treatment did not affect body
weight. C, 23Na-MRI from a representative patient before and
after adenoma removal. #Ptreatment⬍0.05; TE is echo time in
milliseconds.
measured Na⫹ in the lower extremity and not the entire body.
We have no reason to believe that Na⫹ storage would be
heterogeneous; however, we are not certain in that regard.
Perspectives
We showed that 23Na-MRI could, in principle, measure Na⫹
in muscle and skin noninvasively and repeatedly. With
additional technical improvements, this technique could permit novel studies into Na⫹ balance in animals and humans.
Acknowledgments
We thank the Imaging Science Institute (Erlangen, Germany) for
providing us with measurement time at the 3T MRI scanner and for
the technical support.
Sources of Funding
The Interdisciplinary Center for Clinical Research Erlangen, the
German Federal Ministry for Economics and Technology
(50WB0620), the German Research Foundation (Ti345/2), the Imaging Science Institure (ISI), and a cooperative grant from the
Max-Delbrück Center for Molecular Medicine supported the study.
172
Hypertension
January 2012
Disclosures
None.
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23Na Magnetic Resonance Imaging of Tissue Sodium
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Hypertension. 2012;59:167-172; originally published online December 5, 2011;
doi: 10.1161/HYPERTENSIONAHA.111.183517
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