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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-2199
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 5 1754-1760
Copyright © 2006 by The Endocrine Society

Carotid Vascular Remodeling in Patients with Pheochromocytoma

Giampaolo Bernini, Ferdinando Franzoni, Fabio Galetta, Angelica Moretti, Chiara Taurino, Michele Bardini, Gino Santoro, Lorenzo Ghiadoni, Matteo Bernini and Antonio Salvetti

Department of Internal Medicine, University of Pisa, 56100 Pisa, Italy

Address all correspondence and requests for reprints to: Giampaolo Bernini, M.D., Department of Internal Medicine, University of Pisa, Via Roma 67, 56100 Pisa, Italy. E-mail: g.bernini{at}med.unipi.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The influence of catecholamines on vascular remodeling in humans was investigated.

Objective: The objective was to study the carotid vascular wall in patients with pheochromocytoma (PHEO).

Design and Setting: An observational study was conducted in a university referral center for blood pressure diseases.

Patients: Fourteen patients with PHEO, 15 matched high-normal essential hypertensives, 15 mild essential hypertensives, and 15 controls underwent two-dimensional conventional ultrasonography and ultrasonic tissue characterization of the carotid wall.

Main Outcome Measures: Intimal media thickness (IMT), diameter, and corrected ultrasonic integrated backscatter signal (C-IBS) of carotid arteries were evaluated.

Results: IMT in PHEOs (0.844 ± 0.18 mm, mean ± SD) was greater than not only controls (0.596 ± 0.09 mm, P < 0.0002) but also high-normal (0.710 ± 0.17 mm, P < 0.03), and even mild (0.727 ± 0.20 mm, P = 0.06) hypertensives. IMT in the latter was higher than in controls (P < 0.03), without difference in comparison with high-normal hypertensives. C-IBS values in PHEOs (–21.71 ± 2.0 dB, mean ± SD) were greater than in controls (–26.20 ± 1.73 dB, P < 0.0001) but also than in high-normal (–23.84 ± 1.16 dB, P < 0.002) and mild (–23.37 ± 1.99 dB, P < 0.01) hypertensives. C-IBS values in controls were lower than in high-normal (P < 0.0005) and mild (P < 0.0001) hypertensives. Carotid diameter was not significantly different in the four groups. In PHEOs, C-IBS was associated with urinary noradrenaline (r = 0.640, P < 0.01) and normethanephrine (r = 0.737, P < 0.009).

Conclusions: Carotid IMT of PHEOs is higher than in controls and matched groups of hypertensives with comparable or even higher blood pressure. This vascular rearrangement is characterized by increased IBS values due to collagen deposition and vascular fibrosis. Therefore, our data show that abnormal catecholamine levels take part per se in carotid wall remodeling of patients with PHEO.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
RECENT IN VITRO (1, 2, 3, 4) and in vivo (5, 6, 7, 8, 9, 10) studies show that catecholamines influence vascular wall growth and remodeling, independently of the hemodynamic discharge. This direct action of catecholamines on the vascular bed (1, 2, 3, 4, 11, 12, 13), which is mediated by {alpha}1A (1, 12, 14) and {alpha}1B (15, 16) adrenoceptors, concerns extracellular matrix protein activity with protein synthesis and collagen deposition (3, 10, 17, 18, 19, 20) and consequent vascular eutrophic remodeling. However, in experimental vascular injury (1, 12, 15, 21), this action becomes exacerbated with proliferation, hypertrophy, and migration of smooth muscle cells and adventitial fibroblasts, leading to hypertrophic remodeling.

Few data are available in humans on the vascular effects of catecholamines. Age-related increases in arterial wall thickness can be observed even in the absence of atherosclerosis and hypertension (22, 23), and sympathetic nerve activity may be involved in this phenomenon. Muscle sympathetic nerve activity and femoral intimal media thickness (IMT), which increase with advancing age, are strongly and positively related to each other, suggesting that tonic elevations in sympathetic nerve activity may be an important mechanism in the arterial remodeling that occurs with human aging (24). This finding seems to be confirmed in pathological conditions of hypercatecholaminergic states, at least in the microcirculation. Thus, in patients with pheochromocytoma (PHEO), sc small resistance arteries are characterized by eutrophic remodeling, i.e. extracellular matrix protein hyperactivity without smooth muscle cell or adventitial fibroblast hypertrophy or hyperplasia (25, 26, 27), a finding also observed in essential hypertensives (25).

Ultrasound imaging of the vascular wall not only identifies wall thickness, but it also contains information on texture that may be revealed by acoustic tissue characterization. The latter can be quantified through videodensitometric analysis of standard echographic images or through ultrasonic back-scatter signal analysis. Ultrasonic integrated backscatter signal (IBS) is composed of low-amplitude, phase-sensitive, omnidirectional echoes arising from tissue heterogeneity within the vascular wall. The extracellular matrix has been shown to represent an important source of myocardial IBS (28), and several experimental studies have demonstrated that IBS correlates with collagen content within the myocardium (29, 30, 31). The same seems to occur in vascular beds where IBS reflects the histological features of media and intima (32, 33). Therefore, this technique, which is noninvasive, can be expected to provide a relative estimate of myocardial or vascular fibrosis in humans.

The aim of our study was to use this procedure for evaluating the carotid artery wall in patients with chronic elevation in plasma catecholamines, as in patients with PHEO. The purpose was to establish, by this new technical approach, whether remodeling in PHEO is present, whether fibrosis contributes to vascular rearrangement in this pathological condition, and to compare the results with those obtained in essential hypertensives and normotensive controls.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Fourteen patients with PHEO (mean maximum mass diameter 4.0 ± 0.6 cm, ±SE) were studied. Diagnosis was made on the basis of appropriate clinical, hormonal, and morphological (magnetic resonance and 131I-metaiodobenzylguanidine-scintigraphy) investigations and confirmed by histological examination of resected tumors. Eight patients had sporadic PHEO, two had PHEO associated with von Hippel-Lindau disease, two associated with multiple endocrine neoplasia 2A, and two associated with neurofibromatosis type 1 (von Recklinghausen). These data were confirmed by genetic analysis. No patient showed paroxysmal hypertension and no patient was under antihypertensive treatment because hypertension had been only recently diagnosed and blood pressure values were, on average, only slightly abnormal (Table 1Go). No patient was under hypocholesterolemic drugs. Thus we had the opportunity to select a very "clean" group of patients unaffected by previous drugs that could have interfered with vascular remodeling. Thirty consecutive patients with a new diagnosis of essential hypertension were also enrolled. Diagnosis had been established after exclusion, by appropriate biochemical and morphological investigations, of all detectable causes of hypertension. The group, never treated, involved 15 high-normal and 15 mild (grade 1) essential hypertensives, as classified according to recent guidelines (34). A control group of 15 normotensive subjects (blood pressure < 129/84 mm Hg) was also investigated. PHEO and high-normal hypertensives were matched for blood pressure, duration of hypertension, and demographic characteristics (age, sex, and body mass index), whereas PHEO, mild hypertensives, and controls were matched only for demographic characteristics. The controls were defined as age- and body mass index-matched with the patients when the differences between the cases and controls were less than 3 yr and 1 kg/m2 for age and body mass index, respectively (Tables 1Go and 2Go).


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  		TABLE 1. Demographic, hemodynamic, and humoral characteristics of controls (C), mild essential hypertensives (MEH), high-normal essential hypertensives (HNEH), and PHEOs

 

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  		TABLE 2. Hormonal data of controls (C), mild essential hypertensives (MEH), high-normal essential hypertensives (HNEH), and PHEOs

 
Experimental design

Patients and controls, maintaining their usual diet, presented between 0800 and 0900 h in the morning, after overnight fasting. Twenty-four-hour urine was collected for noradrenaline, adrenaline, normethanephrine, and metanephrine determination. Blood samples for catecholamine measurement were taken in supine position 10 min after the insertion of a cannula into an antecubital vein. Clinic blood pressure was measured according to the recent guidelines (three different recordings spaced 1–2 min apart in patients seated for several minutes in a quiet room) (34). Ambulatory blood pressure monitoring was also recorded.

The study was approved by the Local Ethical Committee and the patients gave their informed consent.

Hormones

Plasma catecholamines were measured by HPLC (35). Intraassay and interassay coefficients of variation were 14 and 20% for noradrenaline and 17 and 22% for adrenaline, respectively. Intraassay and interassay coefficients of variation of urinary hormones were respectively: noradrenaline, 14 and 20%; adrenaline, 17 and 22%; normethanephrine, 7 and 12.7%; and metanephrine, 18.7 and 11.9% (Immuno Biological Laboratories, Hamburg, Germany).

Two-dimensional conventional ultrasonography

The study was performed using an HP Sonos 5500 (Hewlett-Packard, Co., Andover, MA) phased-array echograph with M-mode, two-dimensional, and pulsed color-flow Doppler capabilities. The imaging protocol involved obtaining a single longitudinal lateral view of the distal segment of the right and left common carotid arteries. The high-resolution images were analyzed to calculate IMT at each arterial site (36). We obtained IMT in five consecutive regions of the far wall every 4–5 mm, beginning close to the bifurcation of the common carotid artery with use of the 7.5 MHz linear-array probe. The value attributed to each subject represents the average value among 10 IMT measures, five from the left and five from the right carotid artery (32, 37). Intraobserver and interobserver variabilities for IMT were 4.6 ± 0.4% and 5.2 ± 0.3%, respectively.

The mean common carotid diameter was defined as the line identifying the media-adventitia interface in the near to the far wall calculated automatically by averaging measurements at 0.1-mm intervals over 1 cm.

Ultrasonic tissue characterization

Ultrasonic characterization of the carotid wall was performed using a special software package available as an option on the HP Sonos 5500. This system is capable of providing IBS images in which the gray level is displayed proportional to the integrated backscattered power. The IBS values, expressed in decibels, were measured from an operator-defined region of interest (ROI). A maximum of 60 frames displayed at a real-time frame rate of 30 frames/sec are captured into cine-loop memory and stored on optical disk. IBS images were calibrated in decibels within a range of 0–64 dB. This system has the feature in which the transmit power, log compression, and time-gain compensation settings are displayed on a screen, allowing the operator to adjust the system to the same values at the examination of each subject. For further analysis of the image data, the IBS images were retrieved from disk into the system memory. Then IBS data were sampled using the posterior arterial wall in the same regions in which IMT was measured, by use of 11 x 11 or 21 x 21 pixel rectangular-shaped ROIs, placed in the intima-medial complex of the vessels. The system automatically calculated the average value of the IBS, which was also displayed in decibels. By adopting the adventitia as the reference object, we then corrected the IBS value (C-IBS) by subtracting the IBS value obtained from a reference ROI placed within the adventitia. The value of C-IBS attributed to each subject represents the average value among the 10 C-IBS measures (32) (Fig. 1Go).


Figure 1
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  		FIG. 1. Sample data acquisition for integrated backscatter of the carotid artery. IBS values, expressed in decibels, were measured from an operator-defined ROI placed within the intima-media complex (white arrow) of the posterior arterial wall for all 60 frames captured into cine-loop memory. The system automatically calculated the average value of the IBS, which was also displayed in decibels.

 
Intraobserver and interobserver variability for IBS were determined in 20 randomly selected recordings twice by the same observer and once each by two independent observers. Intraobserver and interobserver variabilities for IBS were 2.6 ± 0.8% and 2.8 ± 0.4%, respectively.

Statistical analysis

Data were expressed as mean ± SE and mean ± SD. One-way ANOVA was used to compare normal control subjects and subgroups of hypertensive patients. When appropriate, analysis of covariance was used to adjust for significant group difference. Linear correlation analysis was used to assess relationships between variables. Stepwise multiple regression analysis was carried out to test the joint effect of different variables on IMT parameters and on C-IBS values of carotid arteries. In the stepwise regression model, IMT and C-IBS values were the dependent variables, whereas hormones and major risk factors for cardiovascular disease [blood pressure, age, total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol] were the independent variables. Only clinic blood pressure, as mean values of three different recordings, was used for the analysis, because paroxysmal hypertension was not observed in our patients with PHEO, as confirmed by 24-h blood pressure measurement. Thus, the mean (±SE) of SD of the mean 24-h systolic (PHEOs, 13.17 ± 1.54 mm Hg; high-normal hypertensives, 14.27 ± 1.47 mm Hg; mild hypertensives, 15.47 ± 1.41 mm Hg; controls, 12.89 ± 0.76 mm Hg) and diastolic (PHEOs, 10.46 ± 0.77 mm Hg; high-normal hypertensives, 11.53 ± 1.05 mm Hg; mild hypertensives, 11.93 ± 0.79 mm Hg; controls, 10.8 ± 0.87 mm Hg) blood pressure was superimposable in the three groups of patients and in controls. Differences were considered significant when P < 0.05. All statistical procedures and curve fitting for linear regression analysis were performed by personal computer using the StatView program (Abacus Concepts, Inc., Berkeley, CA; version 4.57).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Sex, age, body mass index, duration of hypertension, heart rate, lipid profile, and plasma glucose were not significantly different in the four groups. Clinic systolic and diastolic blood pressure in PHEO and in both groups of hypertensives was significantly higher than in controls, whereas in PHEO and high-normal hypertensives, it was lower than in mild hypertensives (Table 1Go).

In patients with PHEO, both plasma and urinary catecholamines and metanephrines were significantly higher than in the other groups, and the difference was more pronounced for adrenaline rather than noradrenaline (Table 2Go).

As indicated in Fig. 2Go, carotid artery data show that IMT in PHEO was not only greater than in normal subjects (P < 0.0002), but also greater than in high-normal hypertensives (P < 0.03), approaching statistical significance even in comparison to mild hypertensives (P = 0.06). IMT in patients with mild hypertension was significantly higher than in controls (P < 0.03), without difference in comparison to high-normal hypertensives. C-IBS values in PHEO were significantly greater than in controls (P < 0.0001) but also greater than in high-normal (P < 0.002) and mild (P < 0.01) hypertensives. C-IBS values in controls were lower than in high-normal (P < 0.0005) and mild (P < 0.0001) hypertensives. Carotid diameter was not significantly different in the four groups (controls, 5.98 ± 0.15 mm, mean ± SE; mild hypertensives, 6.07 ± 0.13 mm; high-normal hypertensives, 5.75 ± 0.15 mm; PHEO, 5.96 ± 0.12 mm).


Figure 2
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  		FIG. 2. Mean (±SD) values of IMT (above) and C-IBS (below) in controls (C) and in patients with moderate-severe essential hypertensives (MEH), high-normal essential hypertensives (HNEH), and PHEO.

 
In the whole group, a correlation between IMT and age (r = 0.569, P < 0.0001) (Fig. 3AGo) and C-IBS values (r = 0.518, P < 0.0001) (Fig. 3BGo) was found, and the age parameter was still independently associated with IMT in multivariate analysis. No correlation was observed between IMT and the other demographic, humoral, and hemodynamic parameters. C-IBS values were positively and significantly associated with systolic (r = 0.331, P < 0.01) (Fig. 3CGo) and diastolic (r = 0.422, P < 0.0009) (Fig. 3DGo) blood pressure, even after correction for age. No correlation between C-IBS values and the demographic and humoral variables examined was found. In the group of essential hypertensive patients (high-normal and mild hypertensives), both C-IBS and IMT were significantly correlated only with age (r = 0.389, P < 0.03 and r = 0.642, P < 0.0001, respectively), and this relation proved to be independent in multivariate analysis. Finally, in the PHEO subgroup, C-IBS values were significantly and positively associated with urinary noradrenaline (r = 0.640, P < 0.02) and normetanephrine (r = 0.737, P < 0.01) (Fig. 4Go), and revealed no association with the other humoral, demographic, and hemodynamic parameters. Stepwise multiple regression analysis showed that when blood pressure, age, and total LDL and HDL cholesterol were entered in the regression model, the relation between C-IBS values and urinary noradrenaline and normetanephrine was still maintained. No association was found between IMT and the parameters studied. By performing multiple regression analysis including IMT and C-IBS as dependent variables and age, blood pressure, and membership in the PHEO group compared with the hypertensive group as the independent variables, we demonstrated that membership in the PHEO group was the most predictive variable for higher C-IBS (r2 = 0.27, P = 0.03), whereas aging proved to be the most predictive variable for higher IMT (r2 = 0.78, P < 0.0001).


Figure 3
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  		FIG. 3. Linear correlations between IMT values and age (A) and C-IBS (B), and linear correlations between C-IBS and systolic blood pressure (SBP) (C) and diastolic blood pressure (DBP) (D) in the whole group.

 

Figure 4
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  		FIG. 4. Linear correlations between C-IBS and urinary noradrenaline and normetanephrine in patients with PHEO.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study, we confirm that patients with PHEO are characterized by increased carotid IMT, independently of blood pressure levels and the other cardiovascular risk factors. In addition, this vascular alteration was demonstrated for the first time to be associated with a rise in C-IBS values, suggesting that elevated catecholamine tone influences the vascular wall, favoring mainly extracellular matrix activation with collagen synthesis and deposition and consequent vascular fibrosis.

Several in vitro (1, 2, 3, 4) and in vivo (5, 6, 7, 8, 9, 10) studies have shown that catecholamines exert a direct effect on the vascular wall, independently of the involvement of other humoral factors or blood pressure. This action concerns both protein synthesis with collagen deposition and fibrosis (3, 10, 17, 18, 19, 20), and proliferation, hypertrophy, and migration of smooth muscle cells and adventitial fibroblasts (1, 12, 15, 21). Thus, the impact of catecholamines on the vascular wall may be characterized by eutrophic or hypertrophic remodeling.

Studies in humans agree with these findings. It has been found that physiological tonic elevation in sympathetic nerve activity during life is associated with increased femoral IMT, suggesting that catecholamines may take part in the arterial remodeling that occurs with human aging (24). Moreover, patients with PHEO showed eutrophic remodeling (increased media to lumen ratio without changes in cross-sectional area, suggesting no smooth muscle cell or adventitial fibroblast hypertrophy or hyperplasia) at least in sc small resistance arteries, using a micromyographic technique (25, 26, 27).

Our study, performed in another vascular district (carotid artery) of patients with PHEO using a noninvasive procedure (ultrasonic tissue characterization) confirms and extends previous results. In fact, IMT in patients with PHEO proved to be not only more elevated than in the blood-pressure-matched hypertensive group but also more elevated than in essential hypertensives with higher blood pressure values. In addition, we showed that, in both groups of essential hypertensives, carotid IMT was greater than in normotensive controls. Similarly, vascular fibrosis in patients with PHEO, as evaluated by C-IBS, appeared to be not only more elevated than in the hypertensive group with comparable blood pressure but also more elevated than in the group with higher blood pressure values. Furthermore, in both groups of essential hypertensives, vascular fibrosis was greater than in normal subjects.

Taken together, our data show that blood pressure and catecholamines per se induce wall thickening and vascular fibrosis and that catecholamines have a more pronounced effect that is independent of the hemodynamic discharge, thus exerting a direct role in this vascular remodeling. The results obtained by multiple regression analysis confirm this possibility. Thus, in our series, the PHEO was associated with increased fibrosis of the carotid artery wall, possibly mediated by catecholamines, independently of age and blood pressure.

The technical approach we used does not allow evaluation of exact vascular wall morphology, as does the micromyographic technique. Thus we cannot rule out that a component of our vascular remodeling may also be characterized by hypertrophy and migration of smooth muscle cells and adventitial fibroblasts. However, ultrasonic tissue characterization offers several advantages. It is a noninvasive procedure, and it seems to reflect the histological features of media and intima, showing collagen content within the vascular wall (33).

In the present study, age was strongly correlated with IMT values, confirming a primary effect of aging on arterial wall hypertrophy in humans (24, 38, 39). But because age distribution in the four groups was comparable, the vascular alterations in patients with PHEO were age-independent. Our patients with PHEO also showed some cardiovascular risk factors, including smoking, elevated body mass index, and high cholesterol levels, which are independently related to IMT in humans (40, 41, 42, 43, 44). However, the PHEO group was matched with the other hypertensive groups for these factors, but IMT and C-IBS values were higher in the former. In addition, the relation between C-IBS and catecholamines in patients with PHEO still remained even after the influence of these cardiovascular risk factors was removed. The lack of correlation between blood pressure and IMT, but not C-IBS, is not surprising. Our group of patients had high-normal and mild hypertension, and the onset of known hypertension was recent. This may justify early vascular wall derangement characterized by vascular fibrosis (detectable only by IBS) but not yet showing an increase in IMT, which might develop over time. The same finding may explain the correlation in the PHEO group between noradrenaline and C-IBS but not IMT.

In conclusion, in the present study, we show that carotid IMT of patients with PHEO is increased compared with essential hypertensives, independently of blood pressure values. Using ultrasonic IBS, we report for the first time that carotid wall thickness in patients with PHEO is possibly sustained by collagen deposition and vascular fibrosis to a greater extent than observed in essential hypertensives. Therefore, our data show that abnormal catecholamine levels take part per se in carotid wall remodeling of patients with PHEO, thus confirming an important role of the catecholaminergic system in the development of vascular alterations in humans.


   Footnotes
 
All authors (G.B., F.F., F.G., A.M., C.T., M.B., G.S., L.G., M.B., and A.S.) have nothing to declare.

First Published Online February 21, 2006

Abbreviations: C-IBS, Corrected IBS; HDL, high-density lipoprotein; IBS, integrated backscatter signal; IMT, intimal media thickness; LDL, low-density lipoprotein; PHEO, pheochromocytoma; ROI, region of interest.

Received October 6, 2005.

Accepted February 14, 2006.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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G. Bernini, F. Galetta, F. Franzoni, M. Bardini, C. Taurino, A. Moretti, M. Bernini, P. Berti, P. Miccoli, and A. Salvetti
Normalization of catecholamine production following resection of phaeochromocytoma positively influences carotid vascular remodelling
Eur. J. Endocrinol., August 1, 2008; 159(2): 137 - 143.
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