(Hypertension. 1997;30:741.)
© 1997 American Heart Association, Inc.
Articles |
Plasma Adrenomedullin Concentrations and Cardiac and Arterial Hypertrophy in Hypertension
From the Hypertension Center (T.S., M.M., K.M., E.M.), Kinki Central Hospital, Itami, and the Research Institute (T.N, A.M., H.M., K.K.) and Department of Medicine (S.T.), National Cardiovascular Center, Osaka, Japan.
Correspondence to Toshio Nishikimi, MD, Division of Hypertension, National Cardiovascular Center, 5-7-1, Fujishirodai, Suita, Osaka 565, Japan. E-mail nishikim{at}jsc.ri.ncvc.go.jp
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Abstract |
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Abstract It has been reported that plasma concentrations of adrenomedullin (AM), a novel vasodilator peptide, are higher in patients with essential hypertension than those in normotensive subjects. To clarify the clinical significance of increased levels of AM in patients with essential hypertension, in this study we examined the relationship between plasma concentrations of AM and the structure of the left ventricle or carotid artery. Plasma AM concentrations; renin activity; and norepinephrine, epinephrine, and creatinine concentrations in 50 patients with untreated essential hypertension without renal dysfunction and heart failure were measured. We also measured the mean wall thickness of the left ventricle and left ventricular mass index by M-mode echocardiography and intimal-medial thickness and arterial distensibility of the carotid artery by ultrasonography. Hypertensive patients were divided into two groups: hypertensives with and those without left ventricular hypertrophy. Plasma AM concentrations in hypertensive patients with left ventricular hypertrophy were significantly higher than in hypertensive patients without left ventricular hypertrophy (7.87±2.70 vs 5.74±1.65 fmol/mL, P<.01). In all hypertensive patients, plasma AM concentrations were not correlated with blood pressure, plasma renin activity, plasma norepinephrine, plasma epinephrine, or plasma creatinine concentration. Plasma AM concentrations were positively correlated with left ventricular mass index or mean wall thickness (r=.37, P=.009; r=.40, P=.004, respectively) and inversely correlated with carotid artery distensibility (r=-.33, P=.02), whereas plasma AM concentrations were not correlated with intimal-medial thickness. These results suggest that the observed elevation of plasma AM in patients with essential hypertension with normal renal function may be partly related to cardiac hypertrophy and decreased carotid artery distensibility.
Key Words: left ventricular hypertrophy • carotid artery • hypertension • adrenomedullin
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Introduction |
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Adrenomedullin (AM), originally isolated from human pheochromocytoma, is a novel vasodilatory peptide with 52 amino acid residues.1 AM, which has a slight homology with calcitonin gene–related peptide, causes a potent and sustained hypotensive effect in rats.1 Recent studies demonstrated that vascular smooth muscle cells contain specific AM receptors that are functionally coupled to adenylate cyclase.2 3 Immunoreactive AM is present in human blood at a concentration of several femtomoles per milliliter, comparable to that of atrial natriuretic peptide.4 Plasma AM concentrations have been shown to be increased in heart failure or chronic renal failure.5 6 7 These results suggest that AM may play a role in the regulation of the cardiovascular system. Previous reports have shown that plasma AM concentrations are increased in patients with essential hypertension, especially those with organ damage, compared with healthy control subjects.7 8 9 However, which organ damage is associated with higher plasma AM concentrations in essential hypertension remains unknown. Earlier reports have shown that AM mRNA is not expressed solely in the adrenal gland but also in the heart, kidney, lungs, and aorta,1 10 suggesting the possibility that hypertensive lesions involving any of these organs may relate to increased AM concentrations in essential hypertension.
Hypertension results in left ventricular hypertrophy (LVH) and arterial hypertrophy. Several studies have demonstrated that LVH is an important and independent risk factor for cardiovascular complications in hypertension.11 12 13 Similarly, carotid wall changes by ultrasonography are associated with the extent of coronary atherosclerosis and coronary events.14 15 No study has been reported to demonstrate an association between organ damage by hypertension and plasma AM concentrations. In the present study, to clarify the clinical significance of increased plasma AM concentrations in patients with essential hypertension, we examined the relationship between plasma AM concentrations and the structure of the left ventricle or carotid artery in those without renal dysfunction.
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Methods |
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Study Population
Among hypertensive patients in the outpatient clinic of Kinki Central Hospital, 50 essential hypertensives (mean age, 59±9 years; 27 men and 23 women) in whom both echocardiography and carotid ultrasonography were carried out satisfactorily were included in the study. Patients with evidence of angina, previous myocardial infarction, cerebrovascular disease, diabetes mellitus, congestive heart failure, or renal impairment were excluded from the study. Patients either had never been treated or had been free from antihypertensive drugs for at least 1 year at the time of the study. Secondary hypertension was ruled out in all patients by clinical history, physical examination, and routine laboratory tests, including measurements of creatinine, electrolytes, plasma renin activity, aldosterone, and catecholamine. Blood pressure (BP) was measured after 10 minutes of rest in the sitting position by using a standard mercury sphygmomanometer (Korotkoff phase V as diastolic BP) on at least three separate visits to our outpatient clinic over 2 months. The mean of three recordings was used for analysis. Hypertension was defined as systolic BP
150 mm Hg, diastolic BP
90 mm Hg, or both. Informed consent was obtained from each
subject. The study protocol was approved by the institutional ethics
committee.
Echocardiography
All subjects underwent standard M-mode and two-dimensional
echocardiography performed by an experienced
investigator using an echocardiograph equipped with a 2.5-
or 3.5-MHz transducer. Left ventricular
end-diastolic dimension (LVDd), end-systolic
dimension (LVDs), interventricular septal thickness (IVST),
and left ventricular posterior wall thickness (LVPWT) were
measured according to the recommendations of the American Society of
Echocardiography16 by a single
investigator blinded to the patient’s identity. Left
ventricular mass was calculated from the Penn convention,
according to the equation of Devereux and Reichek17 : Left
ventricular mass
(g)=1.04x[(IVST+LVPWT+LVDd)3-LVDd3]-13.6.
Left ventricular mass index (LVMi) was calculated for each
patient by dividing left ventricular mass by body surface
area. Mean wall thickness was calculated using the following formula:
Mean wall thickness (mm)=(IVST+LVPWT)/2. All measurements were carried
out over at least three cardiac cycles and averaged. LVH was defined as
an LVMi >119 g/m2 in men and >110
g/m2 in women.18 In the present
study, all patients were allocated to one of two groups: hypertensives
with and those without LVH.
Carotid Ultrasonography
Carotid arteries were evaluated in all subjects using an
SSD-9000 echocardiograph (Aloka Co, Ltd) equipped with a
7.5-MHz transducer. The subject was examined in the supine position
with the neck in slight hyperextension to obtain optimal visualization
of the common carotid artery, carotid bifurcation, and carotid bulb. A
two-dimensionally guided M-mode tracing of the distal common carotid
artery, about 1 cm beneath the carotid bifurcation, was obtained and
recorded. All measurements were obtained for several cycles and
averaged. Intimal-medial thickness (IMT) as defined by Pignoli et
al19 was determined as the distance from the lumen-intima
interface to the collagen-containing upper layer of the tunica
adventitia (the distance between two echogenic lines separated by a
hypoechoic or an echoic space). IMT of the far wall at
end-diastole, internal end-diastolic dimension
(CADd), and end-systolic dimension (CADs) of the distal common
carotid artery were measured. IMT was never measured at the level of a
discrete plaque. Carotid artery distensibility was derived from
analysis of the pressure-volume relation. Carotid artery
distensibility was defined as (x10-3
mm Hg-1)=[(CADs/2)2-(CADd/2)2]/[(CADd/2)2xPP],
where PP is pulse pressure.
Blood Sampling
Ten milliliters of blood was withdrawn from an antecubital vein
after 30 minutes of supine rest. Blood was immediately transferred into
two chilled glass tubes, one containing disodium EDTA (1 mg/mL)
and aprotinin (500 U/mL) for measurement of AM and the other containing
disodium EDTA (1 mg/mL) for measurement of plasma renin activity
and plasma catecholamine and plasma aldosterone
concentrations. Blood was centrifuged immediately at 4°C and
the plasma frozen and stored at -80°C until assayed. Age- and
sex-matched normotensive subjects (58±9 years old; 16 men, 11 women)
who had no history of hypertension and no evidence of cardiac disease
served as control subjects.
Assay for Plasma AM and Other Hormones
Stored plasma samples were extracted before
radioimmunoassay. Sep-Pak C18 cartridges (Millipore-Waters) were
sequentially prewashed with 5 mL each of chloroform, methanol, 50%
acetonitrile containing 0.1% trifluoroacetic acid (TFA), 0.1% TFA,
and saline. Plasma (2 mL) was acidified with 24 µL of 1 mol/L
HCl and diluted with 2 mL of saline and then loaded onto a Sep-Pak C18
cartridge. After being washed with 5 mL each of saline, 0.1% TFA, and
20% acetonitrile containing 0.1% TFA, the adsorbed materials were
eluted with 4 mL of 50% acetonitrile containing 0.1% TFA. The eluate
was then lyophilized. The lyophilized material was dissolved in
radioimmunoassay buffer and the clear solution radioimmunoassayed. The
radioimmunoassay for AM has been reported previously.8
Plasma catecholamine levels were measured by
high-performance liquid chromatography. Plasma
renin activity and plasma aldosterone levels were
determined by radioimmunoassay.
Statistical Analysis
All values in the text and tables are expressed as mean±SD. The
significance of differences between groups was determined by Student’s
unpaired t test. Pearson correlation coefficients were
calculated to evaluate the relation between variables. A value of
P<.05 was defined as significant.
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Results |
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The Table shows various parameters of hypertensive patients with and without LVH. There were no significant differences in sex distribution, age, body height, body weight, body surface area, BPs, serum creatinine, plasma renin activity, and plasma catecholamines between hypertensive patients with and those without LVH. As expected, mean wall thickness and the LVMi of hypertensive patients with LVH were significantly greater than those of hypertensive patients without LVH. IMT of hypertensive patients with LVH was greater than that in hypertensive patients without LVH, whereas carotid artery distensibility did not differ between the two groups.
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Plasma AM levels were significantly higher in all hypertensive patients than in age-matched healthy control subjects (6.51±2.31 versus 4.93±0.96 fmol/mL, P<.01). Fig 1 shows the comparison of plasma AM concentrations between hypertensive patients with and without LVH. Plasma AM concentrations in hypertensive patients with LVH were significantly higher than those of hypertensive patients without LVH (7.87±2.70 versus 5.74±1.65 fmol/mL).
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In all hypertensive patients, IMT was significantly correlated with LVMi or mean wall thickness (r=.417, P<.01 and r=.393, P<.05, respectively), although there was no significant correlation between carotid artery distensibility and LVMi or mean wall thickness. In addition, carotid artery distensibility was not correlated with IMT.
Plasma AM concentrations were not correlated with age, BPs, serum creatinine levels, plasma renin activity, plasma norepinephrine concentrations, or plasma epinephrine concentrations. Plasma AM concentrations were significantly correlated with LVMi and mean wall thickness and inversely correlated with carotid artery distensibility (Fig 2).
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Discussion |
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In the present study we have shown that plasma AM concentrations are increased in patients with hypertension. This finding is consistent with previous reports.7 8 9 Furthermore, we have demonstrated that plasma AM concentrations are increased in hypertensive patients with LVH than in those without LVH and that plasma AM concentrations are weakly but significantly correlated with LVMi and left ventricular mean wall thickness. Earlier reports showed that AM mRNA was highly expressed not only in the adrenal gland but also in the heart, lung, kidney, and aorta, suggesting that the heart is one of the organs contributing to plasma AM concentrations.1 10 Jougasaki et al5 previously reported that AM immunoreactivity was more intense in human failing hearts than in normal hearts. Very recently, they demonstrated that the heart actually secretes AM into the circulation by providing evidence for higher plasma AM concentrations in the coronary sinus than in the aorta of patients with severe heart failure.20 These results raise the possibility that the failing heart produces more AM and secretes AM into the circulation. Moreover, Shimokubo et al21 very recently reported that plasma AM concentrations were increased in Dahl salt-sensitive hypertensive rats than in Dahl salt-resistant normotensive rats and that plasma AM concentrations were significantly correlated with left ventricular weight and left ventricular AM concentrations. The result may support the idea that the hypertrophied heart produces more AM than the normal heart and that the AM produced in the hypertrophied ventricle may contribute to the increased plasma AM concentrations in hypertension. Our current results are very compatible with these reports. However, Kohno et al9 reported that plasma AM concentrations were very closely correlated with serum creatinine levels (a correlation coefficient of .91) but not with LVMi in essential hypertensive patients, suggesting that renal function is a determinant factor for increased plasma AM concentrations in essential hypertension. Their study included many patients with mild to moderate renal impairment. Therefore, the relation between plasma AM levels and LVMi might be obscured by a stronger relationship with renal dysfunction. On the contrary, the current study, in which patients with renal dysfunction were excluded, revealed a weak but significant correlation between plasma AM levels and LVMi, whereas no correlation was found between peptide levels and serum creatinine concentrations in the normal range. Thus, increased plasma AM concentrations in essential hypertensive patients without renal impairment may partly reflect LVH.
In the present study a significant correlation between IMT and LVMi or mean wall thickness was found. This result is in accord with previous studies showing that a significant increase in IMT parallels cardiac hypertrophic changes in patients with hypertension.22 23 However, there was no significant correlation between carotid artery distensibility and LVMi or mean wall thickness. Moreover, no significant correlation between carotid artery distensibility and IMT was observed in the present study. This indicates that IMT is not associated with parallel functional changes in the carotid artery. We observed that plasma AM concentrations were significantly correlated with carotid artery distensibility but not with IMT. Sugo et al24 25 reported that cultured vascular smooth muscle cells and endothelial cells actively synthesize and secrete AM into the media, suggesting that the systemic vascular wall is a potential site for AM production. In fact, AM mRNA expression has been observed in the aorta of rats.10 In addition, vascular smooth muscle cells possess specific receptors that are functionally coupled to adenylate cyclase.2 3 These results suggest that AM may play a role in the regulation of vascular tone as a paracrine and/or autocrine factor. It is considered that IMT thickening indicates both an intimal atherosclerotic process and medial hypertrophy due to the influence of hypertension. Recent reports have shown that AM is an antimigrating and antigrowth factor of vascular smooth muscle cells. These results suggest that AM may play an role in atherogenesis as a antiatherogenic factor.26 27
In the present study, although elevated plasma AM levels in essential hypertensive subjects were significantly correlated with LVMi or carotid artery distensibility, wide variations in plasma AM levels for any given level of LVMi or carotid artery distensibility were observed. Because peptide and mRNA levels of AM are widely distributed in various tissues,1 10 cardiac and arterial lesions may be only one of the many important organs. Thus, many tissues, including cardiac and arterial lesions, may contribute to increased plasma AM levels in hypertension.
In conclusion, we have shown that plasma AM concentrations are increased in patients with essential hypertension with normal renal function and that plasma AM concentrations are weakly but significantly correlated with LVMi and carotid artery distensibility. These results suggest that increased plasma AM concentrations in essential hypertension without renal impairment might reflect, in part, LVH or decreased distensibility of large arteries.
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Acknowledgments |
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This work was supported in part by Special Coordination Funds for Promoting Science and Technology (Encouragement System of COE) from the Science and Technology Agency of Japan, the Ministry of Health and Welfare, and the Human Science Foundation of Japan. We thank Yoko Saito for her technical assistance.
Received March 18, 1997; first decision April 17, 1997; accepted May 7, 1997.
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References |
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