(Hypertension. 1997;30:654.)
© 1997 American Heart Association, Inc.
Articles |
Direct Magnetic Resonance Determination of Aortic Distensibility in Essential Hypertension
Relation to Age, Abdominal Visceral Fat, and In Situ Intracellular Free Magnesium
From the Division of Endocrinology/Hypertension, Department of Internal Medicine (L.M.R., D.M.), and the Magnetic Resonance Center, Department of Radiology (A.J.C., J.G.P., J.L.E., R.L.S.), Detroit Medical Center, Wayne State University Medical Center, Detroit, Mich.
Correspondence to Lawrence M. Resnick, MD, Division of Endocrinology/Hypertension, Wayne State University Medical Center, 4201 St Antoine, UHC-4H, Detroit, MI 48201.
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Abstract |
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Abstract To investigate the contribution of vascular compliance to essential hypertension (EH), we developed magnetic resonance imaging (MRI) techniques to directly measure aortic distensibility (AD) in the ascending and descending thoracic and abdominal aorta of fasting normal (n=10) and EH (n=20) subjects. These results were compared with concurrent MR-based measurements of left ventricular mass index (LVMI) and abdominal subcutaneous and visceral fat and with 31P-MR spectroscopic measurement of in situ intracellular free magnesium levels (Mgi) in brain and skeletal muscle. Aortic distensibility in EH was consistently and significantly reduced at all measured sites (2.5±0.4, 2.2±0.4, 2.3±0.4 versus 7.0±1.6, 5.1±0.3, 7.3±0.8 mm Hg-1x10-3, P<.05), as was Mgi in the brain (284±22 versus 383±34 µmol/L, P<.05) and skeletal muscle (397±10 versus 527±36 µmol/L, P<.05). For all subjects, systolic blood pressure (r=-.662, P<.0001) and LVMI (r=-.484, P<.01) were inversely related to AD. AD and brain Mgi were inversely related to age (AD, r=-.792, P<.0001; brain Mgi: r=-.673, P<.05). AD was inversely related to fasting blood glucose (r=-.413, P<.05) and to abdominal visceral fat (r=-.416, P<.05) but not to body mass index (BMI: r=-.328, P=NS) or subcutaneous fat (r=-.157, P=NS). AD was also significantly and positively related to in situ Mgi, both in the brain and skeletal muscle (brain: r=.712, P<.01; skeletal muscle: r=.632, P<.01). We conclude that (1) MR techniques can be used to coordinately and noninvasively assess cardiac, vascular, metabolic, and ionic aspects of hypertensive disease in humans; (2) increased systolic blood pressure and LVMI in EH may at least in part result from decreased AD; (3) decreased Mgi contributes to arterial stiffness in hypertension and may help to explain the characteristic age-related decreases in AD; and (4) decreased AD may be one mechanism by which abdominal visceral fat contributes to cardiovascular risk.
Key Words: magnetic resonance • vascular compliance • cardiac hypertrophy • obesity • aging
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Introduction |
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For over 100 years the measurement of blood pressure has been the most frequently utilized means available to assess the peripheral vasculature. However, other physical properties of the circulation, such as compliance, may be equally relevant to the onset and clinical course of vascular dysfunction associated with aging, as well as with specific disease states such as essential hypertension, coronary heart disease, and/or congestive heart failure.1 2 3 While the assessment of vascular compliance has until recently been an invasive or technically complicated procedure, limiting the availability of these measurements to specialized research facilities, MRI techniques have recently been developed that simplify the acquisition and analysis of data from which compliance and other indices of vascular function such as distensibility may be determined.4 5
Our approach to clinical hypertensive disease has utilized MR spectroscopic techniques to noninvasively measure various intracellular ionic species such as intracellular free magnesium levels, both in erythrocytes and more recently in situ in brain and skeletal muscle tissue.6 7 8 We found lower free magnesium concentrations in hypertension, which were closely linked not only to blood pressure but to other cardiac and metabolic aspects of hypertension such as left ventricular hypertrophy,9 peripheral insulin resistance,10 and the effects of dietary salt loading.11 On the basis of these observations, we formulated an "ionic hypothesis" in which each of these pathologic states represents different tissue manifestations of a common underlying cellular ionic lesion, characterized at least in part by suppressed intracellular free magnesium levels.12 If this hypothesis is correct, then alterations in vascular distensibility present in hypertension ought to be similarly predicted by and quantitatively proportional to concomitantly measured alterations of intracellular free magnesium content.
We have therefore begun to combine these magnetic resonance (MR) imaging and spectroscopy techniques to directly assess aortic distensibility in normal and essential hypertensive subjects and to investigate clinical as well as cellular-ionic factors that may contribute to as well as result from altered distensibility in hypertension.
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Methods |
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Subjects were recruited from among patients followed by one of the investigators (L.M.R.), who were determined to have essential hypertension on the basis of repeated outpatient blood pressure readings >150/90 mm Hg at least 4 weeks without antihypertensive medications, and in the absence of clinical or laboratory features of secondary hypertension. None of the subjects investigated had been on diuretic therapy prior to study. Control subjects were recruited from among unmedicated patients of the same investigator who were determined to be consistently normotensive, and from among normal volunteers. The study was approved by our institutional review committee, and all subjects gave informed consent for the procedures described below. All subjects arrived in the fasting state at the Magnetic Resonance Center between 8 and 10 AM for cardiovascular and abdominal fat MR imaging studies, and some of these subjects also returned for 31P-MR spectroscopic studies (10 hypertensive, 5 normotensive) of in situ skeletal muscle and brain intracellular free magnesium content, and for fasting blood glucose measurements (13 hypertensive, 5 normotensive). Because of technical difficulties (n=1) and/or patient refusal (n=1), two of the subjects having 31P-MR spectroscopic studies had skeletal muscle, but not brain spectra analyzed.
MRI Analysis of Aortic Distensibility
Using a 1-T superconducting magnet (Siemens Expert), cine MR
images in the transverse plane of the ascending and descending aorta
were obtained at the level of the bifurcation of the main
pulmonary artery, and of the abdominal aorta at the level of
L3, utilizing electrocardiographic gated gradient echo techniques
(TR=50 ms, TE=12 ms, FA=60, slice thickness=10 mm, FOV=350,
matrix=128x256). Twelve images were obtained/cardiac cycle. The aortic
areas of all the images were measured by tracing and computerized edge
finding software on a Sun Sparc 20 workstation.
Aortic distensibility was calculated according to the following
formula13 :
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P is the pulse pressure.
Methods of Cardiac MRI
Using a 1.0-T superconducting magnet, left
ventricular images were acquired in the short axis plane
using ECG-gated gradient echo techniques (TR=80, TE=10, FA=30, number
of slices=4, slice thickness=10 mm, distance factor=1,
matrix=128x256, FOV=350, number of acquisitions=2, number of
images/cardiac cycle=10). Two series of interleaved slices were
performed, for a total of 8 slices with no gap. A third series of 4
slices was obtained if necessary to cover the left ventricle.
Left ventricular mass was calculated from tracings of the epicardial and endocardial walls, including the septum, for all slices in all phases, utilizing Siemens cardiac analysis software, with an estimated specific gravity of 1.06 g/cm3. LV mass index was calculated from LV mass values divided by body surface area for each subject.
MRI Assessment of Visceral and Subcutaneous Abdominal Fat
A single T1 weighted spin echo image of the abdomen
(TR=500, TE=15, FA=50, matrix=128x256, FOV=500) at the level of L4 was
obtained. Measurement of visceral and subcutaneous fat was obtained by
tracing and automatic edge detection software to determine the
respective fat areas.
31P-NMR Spectroscopic Measurement of In Situ
Intracellular Free Magnesium
31P-NMR spectra were obtained from the brain and
gastrocnemius muscle of subjects using one-dimensional chemical shift
imaging (CSI) as follows: For brain CSI, the subjects were placed in
the magnet on their side with a 9-cm surface coil placed over the
temporal parietal region. For muscle CSI, the subjects were placed in
the magnet prone with an 8-cm surface coil placed over the
gastrocnemius muscle. The water 1H signal was used to
optimize the magnetic field homogeneity (ie, shim so that the water
line width was 10 to 15 Hz). One-dimensional CSI data sets were
acquired with a repetition time of 3 seconds, 60° adiabatic pulse
(roughly the optimum flip angle for the ATP peaks), 0.5-ms triangular
phase encoding gradients, 0.5-ms acquisition delay, 1024 data points
with a 512-ms acquisition time (4000 Hz spectral width), and 12 (brain)
or 6 (muscle) acquisitions for each of 32 phase encoding steps (total
acquisition time was 19.6 minutes for brain and 10.0 minutes for
muscle). This provided 31P-NMR spectra from contiguous
1.25-cm-thick 8- or 9-cm-diameter slices within the sensitive volume of
the surface coil.
The 31P CSI data sets were processed on the Siemens VAX 4000. A 1- to 5-Hz lorentzian filter was applied and the CSI data were Fourier transformed in two dimensions (one spatial and one chemical shift). For further analysis, a single spectrum was selected from each CSI data set on the basis of resolution, sensitivity, and, in the case of brain, PCr and PME levels consistent with brain 31P spectra. The baseline roll caused by the acquisition delay was removed by fitting and subtracting a cubic spline function to each spectrum. Peak positions were estimated from the spectra of interest using Siemens software.
Calculation of Intracellular Free Magnesium
The chemical shift difference of the phosphoryl resonances of
ATP is influenced by the extent of magnesium binding to
ATP.14 Hence, for the selected brain and muscle spectra,
the observed difference between the chemical shifts of the 
- and
ß-phosphoryl resonances of ATP,
ß(obs), allows the free
Mg2+ concentration (Mgi) to be calculated using the
following equation6 :
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=[ß(obs)-ß(MgATP)]/[ß(ATP)-ß(MgATP)]=the
free fraction of ATP in the experimental sample,
KDMgATP is the dissociation constant
for MgATP=38x10-6 mol/L at 37°C, and
ß(MgATP),
ß(ATP), and
ß(obs) are the chemical shift
differences between the -ATP and ß-ATP phosphoryl resonances for
totally magnesium bound ATP, for free ATP, and for the experimentally
observed sample, respectively. At pH 7.0, in solutions containing
155 mmol/L KCl, 5.0 mmol/L
Na2H2ATP, and MgCl2 ranging in
concentration from 0 to 45 mmol/L,
ß(ATP)=10.832 ppm and
ß(MgATP)=8.255 ppm relative to
phosphocreatine (PCr).
Data Analysis
Data analysis was performed using Statmost for Windows,
version 3.0. Data from normotensive and hypertensive subjects were
compared utilizing unpaired Student’s t tests for
continuous data, and with 
2 analysis of
categorical data (such as sex and racial distribution). Continuous
relations between aortic distensibility measurements and other measured
variables were analyzed with linear regression
analysis using Pearson correlation coefficients. The individual
correlation values reported and depicted in the Figures were obtained
by averaging the three aortic distensibility measurements for each
patient, and were then compared to the other parameters of
interest. Multiple regression analysis was also performed to
test the statistical independence among variables significantly
related to aortic distensibility. All data are expressed as
mean±SEM
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Results |
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Clinical characteristics of the normotensive (n=10) and hypertensive (n=20) subjects are reported in the Table. No significant differences were noted with respect to age, race, or sex distribution among the diagnostic groups. Systolic (P<.001) and diastolic (P<.001) blood pressures, as well as left ventricular mass index (P<.005), were significantly increased in the hypertensive versus the normotensive subjects, while in situ intracellular free magnesium levels in both skeletal muscle (P<.05) and brain (P<.05) were reciprocally suppressed.
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MR-determined aortic distensibility was significantly decreased in hypertensive compared with normotensive subjects at each of the three anatomic sites measured, the ascending and descending thoracic aorta, and the abdominal aorta (Fig 1). Aortic distensibility values were also significantly related to other measured cardiovascular, demographic, metabolic, and cellular ionic values.
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Consistent with the physiological relation of vascular compliance to blood pressure and cardiac systolic wall stress, both systolic blood pressure (r=-.662, P=.000007) and left ventricular mass index (r=-.484, P=.0067) were inversely related to aortic distensibility (Fig 2). Diastolic blood pressure was also significantly and inversely related to abdominal aortic distensibility (r=-.531, P=.005).
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While not related to BMI (r=-.328, P=.08) or subcutaneous abdominal fat (r=.157, P=NS), aortic distensibility at all sites was significantly and inversely related to abdominal visceral fat (r=-.416, P=.023) (Fig 3, top). In those fewer subjects in whom fasting blood glucose measurements were also performed (13 hypertensive, 5 normotensive), a similar inverse relationship was observed: the higher the blood glucose, the less the aortic distensibility (r=-.413, P=.039) (Fig 3, bottom)
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Since magnesium is a well-known determinant of vascular tone in many in vitro and experimental animal models, we also investigated its relation to aortic distensibility in this study in those subjects in whom both MR imaging and spectroscopy studies were performed. In these subjects, we found a significant positive correlation between aortic distensibility and in situ Mgi, both in brain (r=.712, P=.006, n=13) and skeletal muscle tissue (r=.632, P=.01, n=15) (Fig 4). Lastly, for all subjects, aortic distensibility was strongly and inversely related to age (r=-.792, P=.0000002) (Fig 5, top).
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Not all of the above relations remained statistically significant when hypertensives and normotensives were analyzed separately, although both age (NL, r=-.729, P=.04; HiBP, r=-.7426, P=.0003) and SBP (NL, r=-.808, P=.015; HiBP, r=-.45, P=.05) were still significant correlates of aortic distensibility, in each BP group. However, other correlations, such as between Mgi (brain) values and aortic distensibility, were no longer statistically significant in each group, despite correlation coefficients similar to those observed for the group as a whole, presumably due to the smaller number of subjects, and/or the narrower range of values in each BP group (NL, r=.6478, P=.237, n=5; HiBP, r=.6271, P=.071, n=8). Similarly, correlations between aortic distensibility and LVMI, visceral fat, and fasting blood glucose were statistically significant for the combined, but not for the individual BP subgroups.
Using multiple regression analysis for aortic distensibility, the explanatory power (R2) attributable to Mgi-B values alone was .5065 (P=.0062). Adding Mgi-M to Mgi-B in a two-variable model added to the explanatory power of the combined "Mgi" model and suggested an independent contribution of both to aortic distensibility (R2=.7061, P=.0262 and .0064, respectively). While the contribution of age and Mgi-B were also independent when entered in a 2-variable model (R2=.7034, P=.0276, P=.0365, respectively), the effect of age was no longer significant when added to both Mgi-B and Mgi-M values in a 3-variable model [R2=.7761, P(age)=.1277, P(Mgi-M)=.1214], implying an interaction between age and Mgi-M, while Mgi-B was still a significant independent factor (P=.0257). The addition of visceral fat or fasting blood glucose, or both, to any 2-, 3-, 4-, or 5-variable models of aortic distensibility including any of the above factors did not further increase the explanatory power of the model (R2=.7762, .7709 for 4 and 5 variables), nor did it demonstrate a significant independent contribution of these variables. This is consistent with the interaction of age, Mgi, visceral fat, and fasting blood glucose values, the subject of both previous,7 current (Fig 5, bottom), and ongoing work.
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Discussion |
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This study utilizes MR imaging and spectroscopic techniques to coordinately and noninvasively assess structural, functional, metabolic, and cellular-ionic aspects of the cardiovascular system in essential hypertension. This approach may have certain advantages over other techniques. Specifically, compared with echocardiographic techniques, MRI not only accurately reflects autopsy-based measurements of LV mass15 but also does not require a priori geometric assumptions of LV shape. This added degree of precision may be clinically relevant in assessing the potential subtle contribution of factors other than blood pressure per se to LV mass.16 MRI of the aorta is also the first technique to directly and noninvasively measure vascular compliance, for which more indirect echo-Doppler, pulse wave velocity, pulse waveform analysis, or other techniques have previously been used.2 3 17 Similarly, a single MR scan ("slice") of the abdomen is sufficient, without the accompanying radiation of CT scanning, to distinguish and quantify visceral versus subcutaneous fat stores,18 the former better predicting the contribution of obesity to insulin resistance and coronary mortality than measurements of total weight, BMI, truncal obesity, or even waist:hip ratios.19 20 21 22 23 Furthermore, all of the above measurements can be made in a single MR examination.
Lastly, MR spectroscopy has also been used to directly evaluate intracellular free ion content24 without requiring the removal of cells from their physiological environment and without the invasive perturbations associated with other currently utilized techniques. Thus, these integrated MR-based measurements of LV mass, vascular compliance, visceral fat mass, and cellular ion content can assess alterations in body function in a less time-consuming and more subtle, noninvasive, and precise manner than has previously been available.
In the present study, one MRI examination and a second 31P-MR spectroscopic study have allowed us to evaluate aortic distensibility in normotensive and essential hypertensive subjects and to study its cardiovascular consequences as well as some of its underlying determinants. We observed (1) that in essential hypertensive compared with normotensive control subjects, aortic distensibility, both at thoracic and abdominal sites, is significantly reduced; (2) that left ventricular mass as well as systolic and diastolic blood pressures are inversely related to aortic distensibility; (3) that in situ brain and skeletal muscle Mgi levels are also significantly reduced in essential hypertensive compared to normotensive control subjects; and (4) that age, visceral fat mass, and intracellular free magnesium levels are closely related to and may help to determine aortic distensibility in humans. These results support the contribution of decreased intracellular free magnesium levels to arterial stiffness in hypertension, and suggest that the decrease in Mgi levels with age may at least in part help to explain the characteristic age-related decreases in vascular distensibility. They also suggest that altered vascular distensibility may be one mechanism by which abdominal visceral fat contributes to cardiovascular risk. Lastly, these data emphasize the simplicity and utility of an integrated MR-based assessment of cardiovascular function.
Our results support and extend many reports in the literature emphasizing the importance of physical characteristics of the vasculature in addition to blood pressure per se. Of the various other ways of assessing blood vessels, the functional compliance or distensibility of blood vessels has been the focus of recent interest, which may be a more sensitive and perhaps pathophysiologically a more important factor than blood pressure in the onset and course of hypertensive1 25 as well as coronary artery disease.3 4 5 26 27 Our results (Fig 1) confirm many earlier observations in hypertension of decreased vascular compliance, and the one previous report using similar MR techniques.13
To study the potential clinical significance of these results, we also investigated the relation of aortic distensibility to other factors as well. First, consistent with data from experimental models, a primary decrease in arterial distensibility should be experienced by the left ventricle as increased systolic wall stress, resulting in both higher systolic blood pressures and longer term, in a compensatory increase in cardiac mass. This seems to be the case clinically as well: the less the aortic distensibility, the greater the SBP and LV mass index (Fig 2).
Second, although it has long been known that body weight is an important risk factor for atherosclerotic and hypertensive disease,28 29 30 only within the last decade has the use of CT and MR techniques to quantitatively assess intra-abdominal fat stores demonstrated that elevated blood pressure, cardiac hypertrophy, insulin resistance, and other components of "Syndrome X" best reflect increases in abdominal visceral, rather than subcutaneous fat accumulation.19 20 21 22 Our present results extend this concept by demonstrating a significant inverse linkage between visceral fat (but not subcutaneous fat or BMI) and aortic distensibility (Fig 3): the more visceral fat, the lower the aortic distensibility. The similar inverse relation between fasting blood glucose and aortic distensibility is also consistent with these data and with recent in vitro and clinical findings that increasing glucose concentrations may themselves, in an insulin-independent manner, contribute to vascular disease by elevating cytosolic free calcium and suppressing intracellular free magnesium levels.31 32 33 In diabetic subjects, both blood pressure and cardiac mass correlated better with fasting glucose, rather than insulin levels.9 Since insulin levels were not measured in this study, its contribution to the glucose-aortic distensibility relation cannot be ascertained. Nevertheless, we believe it is reasonable to suggest that decreased vascular distensibility mediates the contribution of obesity and/or of glucose to hypertension and cardiac hypertrophy.
Third, the clinical significance of magnesium in vascular disease has been suggested by observations that (1) decreased intracellular free magnesium levels are present in hypertension,6 insulin resistance,10 and frank diabetes mellitus7 34 ; (2) induction of experimental magnesium deficiency can also directly produce vasoconstriction, elevated blood pressure, and insulin resistance35 36 37 ; (3) epidemiologically, cardiovascular risk factors, including carotid artery thickness, are prospectively predicted by circulating magnesium levels38 ; and (4) long-term magnesium supplementation may improve vascular compliance even in the absence of a change in blood pressure.39 Our data, confirming lower basal Mgi levels in both skeletal muscle and brain of hypertensive subjects (Table) complements our earlier data in peripheral red cells, not implying, however, a dietary-nutritional origin for this cellular magnesium "deficiency." Additionally, the positive linear relations observed between Mgi and aortic distensibility for all subjects (Fig 4) extend these previous studies and strongly support the hypothesis that deficient Mgi levels contribute to vascular stiffness in clinical hypertensive disease. Last, consistent with previous reports,3 while age was the strongest single correlate of aortic distensibility measured in this study (Fig 5), it was no longer a significant predictor of aortic distensibility when both Mgi measurements were included in the multivariate model. This, the inverse relation of brain Mgi levels with age, and the direct relation of Mgi to aortic distensibility suggest age-dependent depletion of Mgi levels as one possible cellular mechanism mediating the effect of age on aortic distensibility.
An alternate interpretation of our data would be to consider many or all of the measured correlates of aortic distensibility reported here as merely independent consequences of aging per se, rather than being causally or physiologically mechanistically related to vascular distensibility. However, since factors such as age, visceral fat, and Mgi represent different levels of observation, at the whole organism, tissue, and cellular levels, respectively, the correlations reported here may rather represent the same phenomenon, aortic distensibility, viewed at each different level. For instance, at the cellular level, while altered Mgi levels may help to explain vascular stiffness independently of age and visceral fat, decreased Mgi may also be one "mechanism" linking age and visceral fat mass to vascular distensibility. This is so since both age per se40 and the increased free fatty acids and insulin resistance associated with visceral fat accumulation40 41 42 are also characterized by increased cytosolic free calcium and/or decreased free magnesium levels. This altered cellular ionic "profile" may thus help to translate, perhaps as a final common factor, the effects of aging and visceral fat on blood vessel cells.
Altogether, we suggest that this integrated, MR-based approach will be useful, not only in patients with established cardiovascular disease, to assess and monitor its clinical course, but in screening subjects without overt disease, to identify those in whom early intervention may prevent the onset of more advanced tissue damage.
Received March 18, 1997; first decision April 17, 1997; accepted June 2, 1997.
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