ORIGINAL
PAPER
Ambulatory Blood Pressure Monitoring–Derived Short-Term Blood Pressure Variability in Primary Aldosteronism Andrea Grillo, MD;1 Stella Bernardi, MD;1 Andrea Rebellato, MD;2 Bruno Fabris, MD;1 Moreno Bardelli, MD;1 Jacopo Burrello, MD;3 Franco Rabbia, MD;3 Franco Veglio, MD;3 Francesco Fallo, MD;2 Renzo Carretta, MD1 From the Department of Medical, Surgical and Healthy Science, University of Trieste, Trieste, Italy;1 Department of Medicine-DIMED, University of Padova, Padova, Italy;2 and Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Torino, Torino, Italy3
The aim of this study was to investigate the short-term blood pressure (BP) variability (BPV) derived from ambulatory blood pressure monitoring (ABPM) in patients with primary aldosteronism (PA), either idiopathic hyperaldosteronism (IHA) or aldosterone-producing adenoma (APA), in comparison with patients with essential hypertension (EH) and normotensive (NT) controls. Thirty patients with PA (16 with IHA and 14 with APA), 30 patients with EH, and 30 NT controls, matched for sex, age, body mass index, and antihypertensive therapy, were studied. The standard deviation (SD) of 24-hour, daytime, and nighttime BP;
24-hour weighted SD of BP; and 24-hour BP average real variability were not different between patients with PA and those with EH (P=not significant). All BPV indices were higher in patients with PA, either IHA or APA subtypes, and patients with EH, compared with NT controls (P1.5 mg/dL in men and >0.135 mg/dL in women. Glomerular filtration rate was estimated by calculating creatinine clearance with the formula of Cockroft-Gault.13 Patients and NT controls with an
METHODS Study Population In this cross-sectional study, we examined 30 patients with PA (17 men and 13 women; mean age, 54.111.8 years; age range, 32–66 years) and 30 patients with EH
Address for correspondence: Francesco Fallo, MD, Department of Medicine-DIMED, University of Padova, Clinica Medica 3, Via Giustiniani 2, Padova 35128, Italy E-mail: [email protected] Manuscript received: December 24, 2014; revised: January 29, 2015; accepted: January 29, 2015 DOI: 10.1111/jch.12551
The Journal of Clinical Hypertension
Vol 17 | No 8 | August 2015
603
Pressure Variability in Primary Aldosteronism | Grillo et al.
alcohol intake >40 g/d for men or >20 g/d for women in the past year were considered current drinkers. Smoking habit was defined as at least one cigarette daily for 1 year in the past 5 years. After the first office visit at our clinics, all patients underwent diagnostic procedures as outpatients. During evaluation, they consumed a normal sodium and potassium diet (100–200 mEq/d sodium and 50–70 mEq/d potassium). All patients followed the diet under the control of the hospital staff. After at least a 7-day diet, the relationship between sodium and potassium intake with sodium and potassium urinary excretion was randomly checked in 24-hour urine specimens collected from the majority of patients. Each PA and EH patient group who underwent ABPM included the same number of newly diagnosed and never-treated patients (n=12). Among the remaining patients in either the PA or EH groups, only those receiving calcium channel blockers at the minimal doses required to achieve BP control (n=18) were selected. In these patients, any other antihypertensive medications were withdrawn for 3 weeks (up to 6 weeks for spironolactone) before diagnosis. This allowed to avoid the interference of diverse antihypertensive drugs on ABPM profile. Calcium channel blockers are known to have a neutral effect on renin and aldosterone levels and not to impair glucose and lipid parameters.14–16 These agents have been also found to slightly reduce BPV.17,18 All BP measurements were performed according to the European Society of Hypertension/European Society of Cardiology guidelines.12 Differential diagnosis criteria for the different forms of PA were in accordance with the Endocrine Society guidelines, as previously described.19,20 Briefly, for the diagnosis of PA, all patients with an upright plasma aldosterone to PRA ratio >40 (aldosterone in ng/dL and PRA in ng/mL/h), in the presence of aldosterone >15 ng/dL and suppressed PRA, underwent saline infusion (0.9% NaCl 500 mL/h for 4 hours) as a confirmatory test.21 Patients with plasma aldosterone levels that did not fall below 5 ng/dL after the saline infusion were diagnosed as having PA. In all of these patients, a computed tomography scan with fine cuts (2.5–3 mm) of the adrenal and/or an adrenal venous sampling were performed to differentiate between aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). Sampling was considered successful if the adrenal vein/inferior vena cava cortisol gradient was at least 3; lateralization was considered when the aldosterone to cortisol ratio from one adrenal was at least four times the ratio from the contralateral gland. The presence of the syndrome of glucocorticoidremediable aldosteronism was excluded by the long polymerase chain reaction test.22 Sixteen patients were classified as having IHA and 14 as having APA. AVS was performed in 18 of 30 patients. In all patients who underwent unilateral adrenalectomy, an adrenal adenoma was confirmed at surgery and histological examination. 604
The Journal of Clinical Hypertension
Vol 17 | No 8 | August 2015
Each patient provided informed consent for the study, which was approved by the local ethical committee. Within the assessed entire PA population from our three outpatient clinics, a total of 84 patients did not meet inclusion criteria for the study, mainly because of the presence of comorbidity and/or different antihypertensive treatment. There was no difference between included and excluded PA patients for sex, age, BMI, clinical BP values, and serum potassium and aldosterone/PRA levels. Among the assessed entire EH population, the majority of patients (more than 500) did not meet inclusion criteria for the same reasons reported above for PA patients; a random selection among the remaining patients, based on similar sex distribution, age, BMI, and antihypertensive therapy, was performed. Ambulatory BP Monitoring All patients underwent 24-hour ABPM (Takeda TM2430, Asahi, Japan), which was carried out as a part of the procedures before diagnosis, in a day separate from the first office visit. Recording started between 8:30 AM and 9 AM. Patients were instructed to closely report daily activities during the recordings. Recording was programmed for every 15 minutes during a 24-hour period. Measured values of systolic BP (SBP), diastolic BP (DBP), and heart rate were stored in a digital memory. The readings of the automatic recorder were checked against those obtained with a mercury sphygmomanometer at the beginning and at the end of each 24-hour monitoring session; a difference within 5 mm Hg was considered an adequate agreement between the two methods. Measured values of SBP, DBP, and heart rate were downloaded from the monitor to an IBM PC (IBM Co, New York, NY) using custom software. BP and heart rate measurements were excluded from the analysis when they were missing or labeled as technically erroneous by the monitor software. If a BP recording had less than 70% successful readings, it was rejected and repeated. During the monitoring period, a written diary of physical and mental activities as well as sleep duration was kept. BP readings of patients were discarded in case of a lack of sleep during the night (patients not included in the study). Daytime and nighttime periods used for ABPM were from 8 AM to 10 PM and from midnight to 6 AM, respectively. Short-Term BPV Measures Short-term BPV was derived from ABPM and calculated as the following: (1) standard deviation (SD) of 24hour, daytime, and nighttime BP;7 (2) the average of daytime and nighttime SD, each weighted for the duration of the day and night periods (24-hour “weighted” SD of BP), which allows to remove the mathematical interference from nighttime BP fall;7 and (3) average real variability (ARV), ie, the average of the absolute differences between consecutive BP measurements over 24 hours.6
Pressure Variability in Primary Aldosteronism | Grillo et al.
Clinical and Laboratory Methods In all individuals, clinical parameters and blood samples for biochemical parameters were obtained in the morning after overnight fasting at the time of ABPM study. PRA and aldosterone were determined by radioimmunoassay kits from Sorin Biomedical Diagnostics, Saluggia, Italy.21 The normal range for upright PRA is 1.5 ng/mL/h to 5.2 ng/mL/h and the normal range for upright plasma aldosterone is 5 ng/dL to 35 ng/dL. For hormone measurements, intra-assay and interassay coefficients of variation were
PAPER
Ambulatory Blood Pressure Monitoring–Derived Short-Term Blood Pressure Variability in Primary Aldosteronism Andrea Grillo, MD;1 Stella Bernardi, MD;1 Andrea Rebellato, MD;2 Bruno Fabris, MD;1 Moreno Bardelli, MD;1 Jacopo Burrello, MD;3 Franco Rabbia, MD;3 Franco Veglio, MD;3 Francesco Fallo, MD;2 Renzo Carretta, MD1 From the Department of Medical, Surgical and Healthy Science, University of Trieste, Trieste, Italy;1 Department of Medicine-DIMED, University of Padova, Padova, Italy;2 and Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Torino, Torino, Italy3
The aim of this study was to investigate the short-term blood pressure (BP) variability (BPV) derived from ambulatory blood pressure monitoring (ABPM) in patients with primary aldosteronism (PA), either idiopathic hyperaldosteronism (IHA) or aldosterone-producing adenoma (APA), in comparison with patients with essential hypertension (EH) and normotensive (NT) controls. Thirty patients with PA (16 with IHA and 14 with APA), 30 patients with EH, and 30 NT controls, matched for sex, age, body mass index, and antihypertensive therapy, were studied. The standard deviation (SD) of 24-hour, daytime, and nighttime BP;
24-hour weighted SD of BP; and 24-hour BP average real variability were not different between patients with PA and those with EH (P=not significant). All BPV indices were higher in patients with PA, either IHA or APA subtypes, and patients with EH, compared with NT controls (P1.5 mg/dL in men and >0.135 mg/dL in women. Glomerular filtration rate was estimated by calculating creatinine clearance with the formula of Cockroft-Gault.13 Patients and NT controls with an
METHODS Study Population In this cross-sectional study, we examined 30 patients with PA (17 men and 13 women; mean age, 54.111.8 years; age range, 32–66 years) and 30 patients with EH
Address for correspondence: Francesco Fallo, MD, Department of Medicine-DIMED, University of Padova, Clinica Medica 3, Via Giustiniani 2, Padova 35128, Italy E-mail: [email protected] Manuscript received: December 24, 2014; revised: January 29, 2015; accepted: January 29, 2015 DOI: 10.1111/jch.12551
The Journal of Clinical Hypertension
Vol 17 | No 8 | August 2015
603
Pressure Variability in Primary Aldosteronism | Grillo et al.
alcohol intake >40 g/d for men or >20 g/d for women in the past year were considered current drinkers. Smoking habit was defined as at least one cigarette daily for 1 year in the past 5 years. After the first office visit at our clinics, all patients underwent diagnostic procedures as outpatients. During evaluation, they consumed a normal sodium and potassium diet (100–200 mEq/d sodium and 50–70 mEq/d potassium). All patients followed the diet under the control of the hospital staff. After at least a 7-day diet, the relationship between sodium and potassium intake with sodium and potassium urinary excretion was randomly checked in 24-hour urine specimens collected from the majority of patients. Each PA and EH patient group who underwent ABPM included the same number of newly diagnosed and never-treated patients (n=12). Among the remaining patients in either the PA or EH groups, only those receiving calcium channel blockers at the minimal doses required to achieve BP control (n=18) were selected. In these patients, any other antihypertensive medications were withdrawn for 3 weeks (up to 6 weeks for spironolactone) before diagnosis. This allowed to avoid the interference of diverse antihypertensive drugs on ABPM profile. Calcium channel blockers are known to have a neutral effect on renin and aldosterone levels and not to impair glucose and lipid parameters.14–16 These agents have been also found to slightly reduce BPV.17,18 All BP measurements were performed according to the European Society of Hypertension/European Society of Cardiology guidelines.12 Differential diagnosis criteria for the different forms of PA were in accordance with the Endocrine Society guidelines, as previously described.19,20 Briefly, for the diagnosis of PA, all patients with an upright plasma aldosterone to PRA ratio >40 (aldosterone in ng/dL and PRA in ng/mL/h), in the presence of aldosterone >15 ng/dL and suppressed PRA, underwent saline infusion (0.9% NaCl 500 mL/h for 4 hours) as a confirmatory test.21 Patients with plasma aldosterone levels that did not fall below 5 ng/dL after the saline infusion were diagnosed as having PA. In all of these patients, a computed tomography scan with fine cuts (2.5–3 mm) of the adrenal and/or an adrenal venous sampling were performed to differentiate between aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). Sampling was considered successful if the adrenal vein/inferior vena cava cortisol gradient was at least 3; lateralization was considered when the aldosterone to cortisol ratio from one adrenal was at least four times the ratio from the contralateral gland. The presence of the syndrome of glucocorticoidremediable aldosteronism was excluded by the long polymerase chain reaction test.22 Sixteen patients were classified as having IHA and 14 as having APA. AVS was performed in 18 of 30 patients. In all patients who underwent unilateral adrenalectomy, an adrenal adenoma was confirmed at surgery and histological examination. 604
The Journal of Clinical Hypertension
Vol 17 | No 8 | August 2015
Each patient provided informed consent for the study, which was approved by the local ethical committee. Within the assessed entire PA population from our three outpatient clinics, a total of 84 patients did not meet inclusion criteria for the study, mainly because of the presence of comorbidity and/or different antihypertensive treatment. There was no difference between included and excluded PA patients for sex, age, BMI, clinical BP values, and serum potassium and aldosterone/PRA levels. Among the assessed entire EH population, the majority of patients (more than 500) did not meet inclusion criteria for the same reasons reported above for PA patients; a random selection among the remaining patients, based on similar sex distribution, age, BMI, and antihypertensive therapy, was performed. Ambulatory BP Monitoring All patients underwent 24-hour ABPM (Takeda TM2430, Asahi, Japan), which was carried out as a part of the procedures before diagnosis, in a day separate from the first office visit. Recording started between 8:30 AM and 9 AM. Patients were instructed to closely report daily activities during the recordings. Recording was programmed for every 15 minutes during a 24-hour period. Measured values of systolic BP (SBP), diastolic BP (DBP), and heart rate were stored in a digital memory. The readings of the automatic recorder were checked against those obtained with a mercury sphygmomanometer at the beginning and at the end of each 24-hour monitoring session; a difference within 5 mm Hg was considered an adequate agreement between the two methods. Measured values of SBP, DBP, and heart rate were downloaded from the monitor to an IBM PC (IBM Co, New York, NY) using custom software. BP and heart rate measurements were excluded from the analysis when they were missing or labeled as technically erroneous by the monitor software. If a BP recording had less than 70% successful readings, it was rejected and repeated. During the monitoring period, a written diary of physical and mental activities as well as sleep duration was kept. BP readings of patients were discarded in case of a lack of sleep during the night (patients not included in the study). Daytime and nighttime periods used for ABPM were from 8 AM to 10 PM and from midnight to 6 AM, respectively. Short-Term BPV Measures Short-term BPV was derived from ABPM and calculated as the following: (1) standard deviation (SD) of 24hour, daytime, and nighttime BP;7 (2) the average of daytime and nighttime SD, each weighted for the duration of the day and night periods (24-hour “weighted” SD of BP), which allows to remove the mathematical interference from nighttime BP fall;7 and (3) average real variability (ARV), ie, the average of the absolute differences between consecutive BP measurements over 24 hours.6
Pressure Variability in Primary Aldosteronism | Grillo et al.
Clinical and Laboratory Methods In all individuals, clinical parameters and blood samples for biochemical parameters were obtained in the morning after overnight fasting at the time of ABPM study. PRA and aldosterone were determined by radioimmunoassay kits from Sorin Biomedical Diagnostics, Saluggia, Italy.21 The normal range for upright PRA is 1.5 ng/mL/h to 5.2 ng/mL/h and the normal range for upright plasma aldosterone is 5 ng/dL to 35 ng/dL. For hormone measurements, intra-assay and interassay coefficients of variation were
