Ambulatory Blood Pressure Monitoring in Secondary Arterial Hypertension Due to Adrenal Diseases

Abstract

The aim of this study was to evaluate ambulatory blood pressure monitoring in patients with essential hypertension and hypertension caused by adrenal pathology. Sixty‐six patients with primary aldosteronism, 37 with pheochromocytomas, and 45 with adrenal incidentalomas were included. These patients were compared with 152 essential hypertensive patients and 64 normotensive subjects. Ambulatory blood pressure monitoring evaluated daytime and nighttime systolic and diastolic blood pressure and heart rate. The authors found that the “nondipper” phenomenon was present in 51.5% of patients with primary aldosteronism, 43.2% with pheochromocytomas, 42.2% with incidentalomas, 34.2% with hypertension, and 15% of subjects who were normotensive. In 58% of primary aldosteronism patients with idiopathic adrenal hyperplasia, there was an absence of the physiologic blood pressure nocturnal fall (nondipper), which was statistically significant (P<.001) compared with nondipper primary aldosteronism patients with adrenocortical adenoma (38%). In conclusion, the prevalence of the nondipping pattern was higher in patients with adrenal hypertension compared with patients with essential hypertension, suggesting an independent cardiovascular risk factor.

Hypertension resulting from a variety of adrenal pathologies may actually be more easily treatable than essential hypertension (EH). ¹ Currently, the diagnosis of adrenal disorders is based on using a combination of precise analytic methods for the measurement of abnormal secretions of adrenal hormones and sophisticated radiologic techniques for the localization and characterization of specific adrenal lesions. ² In recent years, several groups have described a disturbed circadian rhythm in blood pressure (BP) in some forms of endocrine hypertension by using indirect ambulatory measurements of BP. ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹²

Ambulatory BP monitoring (ABPM) has shown that BP tends to be higher during the day and lower at night in normotensive subjects. ¹³ , ¹⁴ , ¹⁵ , ¹⁶ Some hypertensive subjects do not exhibit the normal nocturnal BP decrease (systolic BP [SBP] decrease of >10 mm Hg). These subjects are known as non‐dippers, whereas subjects with normal circadian rhythm are known as dippers. ¹⁷ , ¹⁸ , ¹⁹

Studies using ABPM have reported that the reduction in nighttime BP is less in some secondary forms of hypertension. ²⁰ , ²¹ The mechanisms of these findings are not fully understood.

The aim of our study was to assess the behavior of BP by ABPM in patients with adrenal hypertension. Patients with EH and healthy subjects were recruited as controls.

MATERIALS AND METHODS

Patients

A large series of patients with arterial hypertension due to adrenal diseases were consecutively enrolled in our Day Hospital of Internal Medicine and Hypertension at the University of Rome “La Sapienza,” Rome, Italy, from January 2000 to December 2005.

Patients were divided into the following groups: 66 patients with primary aldosteronism (PA) (33 men and 33 women; mean age, 48±13 years), 37 patients with adrenal pheochromocytoma (PHEO) (23 men and 14 women; mean age, 47±15 years), and (3) 45 patients with adrenal incidentaloma (INC) (21 men and 24 women, mean age, 50±13 years). The control groups consisted of 152 patients with EH (76 men and 76 women; mean age, 49±12 years) without any sign of target organ damage and 64 normotensive subjects (23 men and 41 women; mean age, 50±11 years). None of the patients with adrenal disease and EH at diagnosis were treated with antihypertensive drugs for at least 4 weeks before the ABPM studies.

Diagnosis of Adrenal Diseases

Primary Aldosteronism. After an overnight fast and 1 hour of resting in the sitting position, a captopril test was performed between 7 AM and 9 AM. Plasma renin activity (PRA), plasma aldosterone (PA), and plasma cortisol (PC) were measured at baseline and again at 60 minutes after captopril (50 mg PO) administration. BP values were measured at baseline and after captopril with a Riva‐Rocci sphygmomanometer using phase V for the diastolic reading.

All patients with a PA/PRA (ng/dL:ng/mL/h) ratio ≥40 at baseline or ≥30 after captopril underwent a confirmation test. Two liters of saline (NaCl, 0.9%) were infused over 4 hours while the patients were kept in the supine position. PRA, PA, and PC were measured at baseline and again at the end of the saline infusion. An imaging test comprising high‐resolution computed tomography (CT) with 3‐mm slices and systematic use of a contrast medium and/or magnetic resonance imaging (MRI) was mandatory in all patients with a positive screening test and PA values >7.5 ng/dL after saline infusion, regardless of PA/PRA ratio. All patients had to undergo adrenal vein sampling, even if there was no evidence of adrenal nodules. Drugs affecting the renin‐angiotensin‐aldosterone system were not given to any patients.

In all cases, the diagnosis of adrenal cortical adenoma (APA) was confirmed by histopathologic diagnosis, while idiopathic adrenal hyperplasia (IHA) diagnosis was performed by technical imaging (e.g., adrenal vein sampling)

Pheochromocytoma. The diagnosis of PHEO was established on the basis of: (1) clinical symptoms (such as headache, tachycardia, hyperidrosis, and paroxysmal hypertension), and (2) elevated levels of 24‐hour urinary metanephrines and/or elevated plasma metanephrine levels.

In all patients, tumors were radiologically evident on CT or MRI scans. Monoiodobenzylguanidine scintigraphy was performed in patients if the CT or MRI scans did not show an adrenal mass.

Adrenal INC. In accordance with the definition of INC (adrenal mass incidentally discovered during a radiologic procedure performed for symptoms not correlated to adrenal diseases), hormonal data were obtained in all patients to exclude a secretive function. Patients who presented with a history of neoplasia that frequently metastasize to the adrenal gland, such as lung, breast, kidney, and skin tumors, were excluded.

Baseline hormonal evaluations included diurnal rhythm of PC, urinary free cortisol, plasma adrenocorticotropic hormone, plasma D₄ androstenedione, plasma dehydroepiandrosterone sulphate, plasma 17α‐hydroxyprogesterone, plasma testosterone, supine and upright PRA and PA, urinary excretion of metanephrines, and aldosterone. Tests included an overnight 1‐mg dexamethasone suppression test.

The demonstration of autonomous PC secretion in patients with INC helped to identify the so‐called subclinical Cushing's syndrome (SCS). ²² In the present study, we adopted criteria of 2 or more abnormal results in tests of the hypothalamic‐pituitary‐adrenal axis (such as the association of lack of PC suppressibility after 1 mg dexamethasone with either low adrenocorticotropic hormone levels and/or abnormal urinary free cortisol excretion) for defining SCS. ²³ No patients with Cushing's syndrome were found. In patients with normal hormonal data, the diagnosis of nonfunctioning adrenal adenoma was made.

Essential Arterial Hypertension. The diagnosis of EH was established based on the absence of clinical history and laboratory data of secondary hypertension: principally normal values for plasma and urinary electrolytes, renal function, urinary metanephrine, the renin‐angiotensin‐aldosterone system, urinary free cortisol, and calcium‐phosphorus system. All patients with white coat hypertension were excluded from the study.

Ambulatory BP Monitoring

ABPM was performed using the oscillometric technique, which involves a portable lightweight, noninvasive monitor with a self‐insufflating cuff (Spacelabs Medical, 90207, Issaquah, WA). ²⁴ ABPM readings were obtained at 15‐minute intervals from 6 AM to midnight and at 30‐minute intervals from midnight to 6 AM. The following ABPM parameters were evaluated: average daytime SBP; average daytime diastolic BP (DBP) and daytime heart rate (when awake); average nighttime SBP; average nighttime DBP and nighttime heart rate (when asleep); and average 24‐hour SBP, average 24‐hour DBP, and average 24‐hour heart rate. Periods were determined by the subjects' diaries.

The definitions of dipper and nondipper were established where nighttime SBP and DBP decrease was >10% and <10%, respectively. ²⁵ Ambulatory hypertension was defined as 24‐hour BP >125/80 mm Hg. ²⁶ , ²⁷

Subjects without a complete 24‐hour BP measurement (14 diurnal and 7 nocturnal measurements) were excluded from the study.

STATISTICAL ANALYSES

All data are reported as mean ± SD. The statistical analyses were performed with SigmaStat software (Aspire Software, Leesburg, VA), and all values were analyzed using the analysis of variance test, followed by the Student t test, whenever appropriate. A P value of <.O5 was considered statistically significant.

RESULTS

All patients included in the study had good technical quality ABPM recordings. Fourteen (37% with PHEO) patients presented with neoplasia of the right adrenal gland and 19 of the left adrenal gland. In these patients, the mean diameter of the tumor was 2.8±1.2 cm. Four patients (10.8%) presented with adrenal medullary hyperplasia. Twenty (61%) patients with PA presented with an APA, whereas 26 (39%) presented with IHA. Of the 40 patients with APA, the neoplasia was localized to the right adrenal gland in 47.6%; it was localized to the left adrenal gland in 52.4%. The mean diameter of the APA was 1.85 cm. No differences with respect to sex, age, or body mass index were found in APA and IHA groups. Of 45 patients with INC, 38 (84%) had arterial hypertension. In patients with INC, the mean size of the adrenal mass was 3.6±2.5 cm, with localization in 26 (58%) to the right adrenal gland. In 10 (22.2%) patients with INC, a hormonal picture of SCS was found.

Mean values for 24‐hour daytime and nighttime SBP, 24‐hour daytime and nighttime DBP, and 24‐hour daytime and nighttime heart rate for all patients with PHEO, PA, INC, and EH and healthy subjects are reported in Table I, Table II, and Table III. As expected, mean 24‐hour BP (24‐hour SBP and 24‐hour DBP) obtained by ABPM was higher in the PHEO, PA, INC, and EH groups (P<.001) than in the healthy subject group.

Table I.

Demographic and Hemodynamic Parameters in Study Groups

							Ambulatory BP Monitoring
Study Group	Sex, M/F	Age, y	BMI, kg/m 2	G‐SBP, mm Hg	G‐DBP, mm Hg	G‐HR, bpm	D‐SBP, mm Hg	D‐DBP, mm Hg	D‐HR, bpm	N‐SBP, mm Hg	N‐DBP, mm Hg	N‐HR, bpm
Pheochromocytoma (n=37)	23/14	47.4±15.6	27±4.1	131.8±18*	81.3±11.3*	73.5±7.9	136.6±18.2*	85.6±11.9*	77.2±8.4	122.5±18.3*	72.9±10.6*	69±9.2
Primary aldosteronism (n=66)	33/33	48±13	26.5±4.4	140.8±15.3*	88.3±11.6*	71.9±8.9	143.7±14.9*	90.5±11.3*	74.2±9.6	135.6±19.3*	83.5±13.9*	65.7±8.3
Adrenal incidentaloma (n=45)	21/24	58.7±12.1	29.1±6.3	131.6±17.2*	79.6±9.1*	72.3±8.8	135.5±16.9*	83±10*	75.5±10	120.9±17*	71.1 ± 10.2*	67±9.2
Essential hypertension (n=152)	76/76	48.7±12.5	26.6±4.2	130.1±13.9*	81.3±10.2*	75.9±9.1	133±14.2*	84.5±11.7*	78.7±10.5	119±15.2*	73±12*	69.4±9.8
Healthy subjects (n=64)	23/41	50±11.2	25.9±3.2	114±6.3	72.3±5.8	75.5±7.4	117.5±6.4	75.8±6	79±7.8	105.9±8.8	65.4±7.3	67.6±7.7
BP indicates blood pressure; M, male; F, female; BMI, body mass index; G, global; SBP, systolic BP; DBP, diastolic BP; HR, heart rate; D, diurnal; and N, nocturnal; *P<.01 vs healthy subjects.

Table II.

Demographic and Hemodynamic Parameters in Dipper Study Groups

							Ambulatory BP Monitoring
Study Group	Sex, M/F	Age, y	BMI, kg/m 2	G‐SBP, mm Hg	G‐DBP, mm Hg	G‐HR, bpm	D‐SBP, mm Hg	D‐DBP, mm Hg	D‐HR, bpm	N‐SBP, mm Hg	N‐DBP, mm Hg	N‐HR, bpm
Pheochromocytoma <(n=21)	14/7	45.1±12.9	26±4	127.3±13	80.7±8	73.8±6.2	133±14.6	85.5±9.4	77.7±7.4	114.1 ± 11.2	69.5±6.1	67.8±8.4
Primary aldosteronism (n=32)	12/20	48.8±9.9	25.9±4.4	139.5±14.6	86.7±12	71.2±9.3	144±13.5	89.9±11.2	74.2±9.9	130.9±20	80±14.8	66±8.7
Adrenal incidentaloma (n=26)	14/12	56.3±11.9	28.8±6	133.6±17.4	80.8±7.9	73.6±7.8	139.9±16.6	86.2±9.6	77.4±9	115.4±13	67.6±6.6	67±8
Essential hypertension (n=100)	51/49	48.2±12.8	27.2±4.2	129.1 ± 13.2	81.2±9.8	76.1±9	133.6±13	84.9±9.5	78.8±10.5	114.8±13	70.2±9.6	68.6±9.6
Healthy subjects (n=56)	26/30	48.5±11.9	26.3±3.6	113±6.4	71.4±5.5	75.7±8.2	117.4±6.8	75.4±5.9	79.4±8.5	102.7±8	63.1±6.7	67±8.7
BP indicates blood pressure; M, male; F, female; BMI, body mass index; G, global; SBP, systolic BP; DBP, diastolic BP; HR, heart rate; D, diurnal; and N, nocturnal.

Table III.

Demographic and Hemodynamic Parameters in Nondipper Study Groups

							Ambulatory BP Monitoring
Subjects	Sex, M/F	Age, y	BMI, kg/m 2	G‐SBP, mm Hg	G‐DBP, mm Hg	G‐HR, bpm	D‐SBP, mm Hg	D‐DBP, mm Hg	D‐HR, bpm	N‐SBP, mm Hg	N‐DBP, mm Hg	N‐HR, bpm
Pheochromocytoma (n=16)	9/7	51.2±14.3	29±4	136.8±22.3	82.4±14.9	73±9.9	141±22.6	85.8±15.5	76±9.9	134.3±20.9	77.9±13.9	70.5±10.7
Primary aldosteronism (n=34)	21/13	47±15.5	27.2±4.4	142.1±16	89.7±11.2	72.5±8.5	143.4±16.4	91.2±11.6	74.2±9.5	140.2±17.8	86.9±12.3	65.3±7.6
Adrenal incidentaloma (n=19)	7/12	62±12	29.7±6.9	128.7±17	77.9±10.7	70.5±9.8	130.3±16	79.3±9.4	73.3±10.8	127.3±19.1	75.2±12	67±10.7
Essential hypertension (n=52)	25/27	49.7±12	28.5±4.1	132±15	81.3±11	75.6±9.6	132±16.4	83.8±15	78.7±10.6	127.2±15.8	78.5±14.4	70.9±10.2
Healthy subjects (n=8)	3/5	53.9±8.3	25.3±2.5	116.7±5	74.6±6	74.9±5	118.6±5.4	76.8±6.4	78.3±5.8	113.9±4.4	71.3±5.1	68.9±4.2
BP indicates blood pressure; M, male; F, female; BMI, body mass index; G, global; SBP, systolic BP; DBP, diastolic BP; HR, heart rate; D, diurnal; and N, nocturnal.

In particular, we found that 21 (56.8%) patients with PHEO (14 men and 7 women) displayed a dipper pattern, while 16 (43.2%) (9 men and 7 women) were nondippers. Thirty‐four (54%) patients (21 men and 13 women) were dippers, 19 (47%) patients with INC had a nondipper pattern, and one third (52 of 152 patients) of the EH patients were considered nondippers. The nondipping phenomenon was present in only 8 of 56 (15%) healthy subjects (Figure 1). Seven (70%) of the 10 SCS patients exhibited the nondipper pattern (data not shown). Patients with IHA showed a nondipper phenomenon in 58% of cases compared with 38% of patients with APA; this was statistically significant, with a P value <.001 (Figure 2). Finally, in patients with PA, PHEO, and INC, there were no differences between dippers and nondippers with respect to the size of the adrenal tumors (diameter estimated by CT or MRI scans).

Figure 1.

Prevalence of dipping in patients with secondary arterial hypertension due to adrenal diseases during ambulatory blood pressure monitoring. PA indicates primary aldosteronism; PHEO, pheochromocytoma; INC, adrenal incidentaloma; EH, essential hypertension; and HS, healthy subjects.

Figure 2.

Prevalence of dipping during ambulatory blood pressure monitoring in patients with primary aldosteronism.

DISCUSSION

Nighttime sleep is associated with a BP decline not only in normotensives but also in many hypertensives. ¹⁹ , ²⁵ , ²⁶ Subjects whose BPs decrease during the night are called dippers, whereas those with attenuated BP decreases are referred to as nondippers ¹⁷ , ¹⁸ , ²⁸ , ²⁹

Some data indicate that the circadian BP variability is altered in patients with secondary arterial hypertension due to adrenal diseases. In particular, we have demonstrated an attenuation in circadian BP variations in patients with adrenal hypertension when compared with EH patients and normotensive subjects. The prevalence of nondippers was greater in patients with PA (51.5%) than in patients with PHEO (43.2%), INC (42.2%), or EH (34.2%).

Our data regarding the lack of reduction of the nighttime BP in adrenal hypertension are similar to results reported in the literature in several pathophysiologic conditions, eg, autonomic failure, ³⁰ severe renal failure, ³¹ PHEO, ⁵ , ⁶ , ³² hyperthyroidism, ³² , ³³ hyperparathyroidism, ¹² , ³⁴ diabetes mellitus, ³⁵ and Cushing's syndrome. ⁶ , ⁷ , ⁹ , ³² In particular, the nocturnal BP decrease was absent in a majority of patients with adrenal hypertension; these data are in accordance, in part, with results of other studies. ⁵ , ⁶ , ⁹ , ³² Middeke and Schrader ⁶ have shown that in 43 patients with endocrine hypertension (PHEO, PA, and Cushing's syndrome), the nocturnal decrease of BP was only one third of that found in healthy subjects. Spieker et al ⁸ reported in a small study that the circadian BP variability was altered in 8 patients with PHEO, but this did not appear in patients with PA due to APA. Zelinka et al ⁵ demonstrated in a large number of patients with adrenal hypertension that the nocturnal BP decrease was significantly lower than in patients with EH.

Two studies have previously been published with controversial results concerning diurnal BP variations in different forms of PA (APA and IHA). Rabbia et al ¹¹ found a significant attenuated nighttime BP decline in patients with PA in the APA group, whereas in the IHA group the diurnal BP variability was similar to that in EH patients. Zelinka et al ⁵ reported that the nighttime BP decline in the IHA group was slightly less and the 24‐hour BP values were higher than in the APA group. These authors suggested that the similarity of the night BP variability (dipping status) in both groups of patients with PA implied that only aldosterone was responsible for the diminished BP decline regardless of the mechanism of aldosterone secretion.

Results of our study in a larger number of patients with PA reveal that the IHA group showed a greater and significant prevalence of nondippers (58%) with respect to the APA group (38%). These data seem to indicate that the determination of nocturnal BPs may play an additional role in the distinction between the two major subtypes of PA, although this distinction may not be definitive.

Another finding was that nondipper hypertension in patients with INC was greater in comparison with EH subjects (42.2% and 34.2%, respectively). Moreover, 10 (22.2%) patients with SCS showed a significant (P<.01) prevalence of nondippers than dippers (data not shown).

These data seem to indicate that the borderline cortisol secretion in patients with SCS may modify the circadian BP profile. It has been reported that excessive production of glucocorticoids (classical Cushing's syndrome) ¹⁹ and exogenous glucocorticoid administration lead to an alteration of the circadian rhythm of BP.

The characteristics of diurnal BP variation in patients with INC, and in SCS patients in particular, were similar to those with PA and PHEO. We hypothesize that the disturbance in the hypothalamus‐pituitary‐adrenal axis may affect sympathetic nerve function ⁷ and also that the Na⁺‐retaining action of cortisol may contribute to the alteration of the circadian BP rhythm in these subjects. These results need confirmation. Nondipper status could be an independent cardiovascular risk factor in patients with adrenal disorders. Regarding this, it was reported in the literature that the lack of a resting time BP decrease of ≥10% was associated with increased cardiovascular risks; this is an important predictive risk factor for cardiovascular morbidity. ²⁵ , ²⁶

CONCLUSIONS

The present study demonstrates that endocrine disorders affecting sympathetic activity, such as PHEO, and affecting mineralcorticoids and/or glucocorticoids, such as PA and SCS, disturb the circadian BP variation; in particular, the lack of a nocturnal BP decrease might be considered an independent cardiovascular risk factors.