524996 research-article2014
JRA0010.1177/1470320314524996Journal of the Renin-Angiotensin-Aldosterone System 0(0)Chang et al.
Original Article
Hypokalemia correlated with arterial stiffness but not microvascular endothelial function in patients with primary aldosteronism
Journal of the Renin-AngiotensinAldosterone System 1–7 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1470320314524996 jra.sagepub.com
Yi-Yao Chang1*, Aaron Chen2*, Ying-Hsien Chen3, Chi-Sheng Hung3, Vin-Cent Wu3, Xue-Ming Wu4, Yen-Hung Lin3, Yi-Lwun Ho3, Kwan-Dun Wu3 and the TAIPAI Study Group
Abstract Introduction: Hypokalemia in primary aldosteronism (PA) patients correlates with higher levels of cardiovascular events and altered left ventricular geometry. However, the influence of aldosterone on microvascular endothelial function and the effect of hypokalemia on the vascular structure still remain unclear. Objectives: We investigated the peripheral arterial functions, including the endothelial function of microvasculature and arterial stiffness in PA and essential hypertension (EH) patients, and the correlation between hypokalemia and peripheral arterial function among PA patients. Methods: Twenty patients diagnosed as EH and 37 patients with PA were enrolled in this study. Reactive hyperemia index (RHI) and the augmentation index (AI) were obtained by non-invasive peripheral arterial tonometry. Results: Twenty EH patients and a total of 37 PA patients, including 21 patients with normokalemia and 16 patients with hypokalemia, were enrolled and divided into groups 1, 2 and 3 respectively. PA patients had significantly higher AI (p=0.024) but not RHI than EH patients. RHI showed no difference between groups 1, 2 and 3. Group 3 had higher AI than either group 1 or group 2. In the whole study population, serum potassium level, after multivariate regression analysis testing, was the only factor associated with AI (ß= −0.102; p=0.002). In PA patients, serum potassium level was the only significant factor correlated with AI. (r= −0.458; p=0.004) Conclusions: PA patients had higher arterial stiffness but comparable microvascular endothelial function to EH patients. Hypokalemia correlated with arterial stiffness but not microvascular endothelial function in PA patients. Keywords Primary aldosteronism, hypokalemia, arterial stiffness, peripheral arterial tonometry, augmentation index
Introduction
1Cardiology
Primary aldosteronism (PA), one of the most frequent causes of secondary hypertension, is caused by oversecretion of aldosterone. It has attracted increased attention in recent studies because its prevalence among secondary hypertension subjects is greater than previous estimates, about 5–13% of hypertensive patients of any causes.1 It has been suggested by several clinical studies that aldosterone itself could cause cardiovascular injuries by mechanisms other than sodium-water retention or hypertensive effects.2–4 Some investigations suggest that aldosterone is associated with arterial stiffness and endothelial dysfunction, which may lead to atherosclerosis or other cardiovascular complications.5–8 In our previous study, we demonstrated that PA patients have a higher
Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan 2Woodhull Medical and Mental Hospital, Brooklyn, New York, USA 3Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 4Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan. *The first two authors contributed equally. Corresponding authors: Yen-Hung Lin, Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei, 100, Taiwan. Email: [email protected] Xue-Ming Wu, Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan, No 6, Sinfu 2nd Rd., Sinwu Township, Taoyuan County 327,Taiwan. E-mail: [email protected]
Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (http://www.uk.sagepub.com/aboutus/openaccess.htm). Downloaded from jra.sagepub.com at HOWARD UNIV UNDERGRAD LIBRARY on January 26, 2015
2
Journal of the Renin-Angiotensin-Aldosterone System
degree of early atherosclerosis and vascular stiffness, and adrenalectomy reverses adverse vascular changes in PA patients.8 Hypokalemia plays an important role in various cardiovascular diseases.9 In a recent study, PA patients with hypokalemia had a higher cardiovascular morbidity than PA patients with normokalemia.10 This implies that, in PA patients, hypokalemia plays a significant role in cardiovascular comorbidities. In our recent study, serum potassium level was significantly associated with left ventricular mass in PA patients.11 However, the influence of hypokalemia on vascular function and stiffness remains unclear. Flow-mediated dilation (FMD) is a common noninvasive method to measure endothelial function.12 However, FMD is limited by its high operator dependence and wide difference between operators.13 Pulse amplitude tonometry (PAT), a recent United States Food and Drug Administration (FDA)-approved technology, has become a good alternative choice to measure endothelial function without subjective measurements of FMD.12,14,15 PAT presents peripheral endothelial function as the reactive hyperemia index (RHI); furthermore, arterial stiffness can be also calculated from PAT waveform as the augmentation index (AI). PAT measures endothelial functions of microvasculature. In contrast, FMD measures the endothelial function of median size vessels. The associations between FMD and RHI are low, even displaying no association.16,17 Therefore, it is also of interest to study whether aldosterone influences the endothelial function of the microvasculature. In this study, we investigate the differences in microvascular endothelial function and arterial stiffness between PA and essential hypertension (EH) patients, and the correlation between serum potassium level and peripheral arterial function among PA patients.
Materials and methods Patients This prospective study enrolled 37 patients diagnosed with primary aldosteronism after an initial evaluation and who were recorded in the Taiwan Primary Aldosteronism Investigation (TAIPAI) database from October 2006–October 2011. The database was constructed for quality assurance at one medical center (National Taiwan University Hospital, Taipei, Taiwan) one branch hospital (National Taiwan University Hospital Yun-Lin branch, Yun-Lin, southern Taiwan), and two cooperative hospitals (Far-Eastern Memorial Hospital, Taipei; Tao-Yuan General Hospital, Tao-Yuan, central Taiwan).8,11,18–25 The serum biochemistry studies (including potassium levels) were measured at the first evaluation of these patients at the National Taiwan University Hospital. Medical histories, including demographics and medication were carefully recorded. Patients with a hypokalemia history were defined as those who had known hypokalemia (K10 ng/dl; (b) lateralization of aldosterone secretion at adrenal vein sampling (AVS) or during dexamethasone suppression NP-59 single-photon emission computed tomography (SPECT)/computed tomography (CT);30 (c) evidence of adenoma at CT scan; and (d) pathologically proven adenoma after an adrenalectomy if operated, and cure of hypertension without antihypertensive agents or improved hypertension, potassium, PAC, and plasma renin activity (PRA) as described. Idiopathic hyperaldosteronism (IHA) was classified by the following criteria: (a) evidence of autonomous excess aldosterone production based on ARR>35 and TAIPAI score more than 60%; or urine ≥12 μg/24 h and post-saline loading PAC >10 ng/dl (b) non-lateralization of aldosterone secretion at AVS or during dexamethasone suppression NP-59 SPECT/CT;30 (c) evidence of bilateral diffuse enlargement on CT scan; and/or (d) evidence of diffuse cell hyperplasia in the pathology studies.
Assessment of peripheral vascular function by PAT Digital pulse amplitude was measured with a non-invasive PAT placed on the tip of both index fingers (EndoPAT2000, Itamar Medical, Caesarea, Israel). The PAT generates a pneumatic plethysmo-graph that applies uniform pressure to the finger surface, which allows measurement of changes in pulse volume. The inflation pressure of PAT was set to either 10 mmHg below diastolic blood pressure (DBP) or 70 mmHg. The process initially took a twominute measurement of baseline pulse amplitude. And then, the arterial flow was occluded for 5 min by a cuff placed on a proximal forearm with occlusion pressure higher than systolic blood pressure (SBP). Data was collected from both index fingers and analyzed by a computerized automated algorithm (Itamar Medical) that provided the average pulse amplitude for each 30 s interval after forearm cuff deflation up to 4 min.
Downloaded from jra.sagepub.com at HOWARD UNIV UNDERGRAD LIBRARY on January 26, 2015
3
Chang et al. Table 1. Clinical data of the patients.
Age, years Sex, male Body weight, kg Body height, cm APA Serum creatinine level, mg/dl SBP, mmHg DBP, mmHg Hypokalemia history Hypertension history, years Number of anti-hypertensive medication type Serum potassium level, mmol PAC, ng/dl PRA, ng/ml/hr Log-transformed PAC Log-transformed PRA Hypertension medication Thiazide CCB ACEI/ARB A-blocker B-blocker Usage of spironolactone
Group 1 control n=20
Group 2 normokalemia n=21
Group 3 hypokalemia n=16
p value
45±13 8 (40) 63±11 164±8 – 1.0±0.2 144±19a 87±1a 0d 3.9±4.3a 1.5±0.9 4.2±0.3d 25±12d,f 8.0±7.8d,h 1.4±0.2d,i 0.6±0.5d,h
43±8 9 (43) 69±15 162±8 18 (76) 0.9±0.2 149±17b 86±14c 2 (10)e 3.5±3.6c 1.8±0.8 4.0±0.5e 45±29g 0.7±0.8 1.6±0.3g –0.6±0.7
44±7 8 (50) 68±14 161±8 16 (100) 1.0±0.3 168±31 101±15 11 (100) 8.0±4.8 1.9±1.1 2.7±0.4 66±45 0.6±0.9 1.7±0.3 –0.6±0.7
1 (5) 10 (50) 11 (55) 3 (15) 5 (25) 0a,h
3 (14) 11 (52) 5 (24) 9 (43)g 8 (28) 10 (48)
1 (6) 11 (69) 9 (56) 2 (13) 7 (44) 6 (38)
0.744 0.829 0.327 0.392 0.243 0.544 0.010 0.005
JRA0010.1177/1470320314524996Journal of the Renin-Angiotensin-Aldosterone System 0(0)Chang et al.
Original Article
Hypokalemia correlated with arterial stiffness but not microvascular endothelial function in patients with primary aldosteronism
Journal of the Renin-AngiotensinAldosterone System 1–7 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1470320314524996 jra.sagepub.com
Yi-Yao Chang1*, Aaron Chen2*, Ying-Hsien Chen3, Chi-Sheng Hung3, Vin-Cent Wu3, Xue-Ming Wu4, Yen-Hung Lin3, Yi-Lwun Ho3, Kwan-Dun Wu3 and the TAIPAI Study Group
Abstract Introduction: Hypokalemia in primary aldosteronism (PA) patients correlates with higher levels of cardiovascular events and altered left ventricular geometry. However, the influence of aldosterone on microvascular endothelial function and the effect of hypokalemia on the vascular structure still remain unclear. Objectives: We investigated the peripheral arterial functions, including the endothelial function of microvasculature and arterial stiffness in PA and essential hypertension (EH) patients, and the correlation between hypokalemia and peripheral arterial function among PA patients. Methods: Twenty patients diagnosed as EH and 37 patients with PA were enrolled in this study. Reactive hyperemia index (RHI) and the augmentation index (AI) were obtained by non-invasive peripheral arterial tonometry. Results: Twenty EH patients and a total of 37 PA patients, including 21 patients with normokalemia and 16 patients with hypokalemia, were enrolled and divided into groups 1, 2 and 3 respectively. PA patients had significantly higher AI (p=0.024) but not RHI than EH patients. RHI showed no difference between groups 1, 2 and 3. Group 3 had higher AI than either group 1 or group 2. In the whole study population, serum potassium level, after multivariate regression analysis testing, was the only factor associated with AI (ß= −0.102; p=0.002). In PA patients, serum potassium level was the only significant factor correlated with AI. (r= −0.458; p=0.004) Conclusions: PA patients had higher arterial stiffness but comparable microvascular endothelial function to EH patients. Hypokalemia correlated with arterial stiffness but not microvascular endothelial function in PA patients. Keywords Primary aldosteronism, hypokalemia, arterial stiffness, peripheral arterial tonometry, augmentation index
Introduction
1Cardiology
Primary aldosteronism (PA), one of the most frequent causes of secondary hypertension, is caused by oversecretion of aldosterone. It has attracted increased attention in recent studies because its prevalence among secondary hypertension subjects is greater than previous estimates, about 5–13% of hypertensive patients of any causes.1 It has been suggested by several clinical studies that aldosterone itself could cause cardiovascular injuries by mechanisms other than sodium-water retention or hypertensive effects.2–4 Some investigations suggest that aldosterone is associated with arterial stiffness and endothelial dysfunction, which may lead to atherosclerosis or other cardiovascular complications.5–8 In our previous study, we demonstrated that PA patients have a higher
Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan 2Woodhull Medical and Mental Hospital, Brooklyn, New York, USA 3Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 4Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan. *The first two authors contributed equally. Corresponding authors: Yen-Hung Lin, Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei, 100, Taiwan. Email: [email protected] Xue-Ming Wu, Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan, No 6, Sinfu 2nd Rd., Sinwu Township, Taoyuan County 327,Taiwan. E-mail: [email protected]
Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (http://www.uk.sagepub.com/aboutus/openaccess.htm). Downloaded from jra.sagepub.com at HOWARD UNIV UNDERGRAD LIBRARY on January 26, 2015
2
Journal of the Renin-Angiotensin-Aldosterone System
degree of early atherosclerosis and vascular stiffness, and adrenalectomy reverses adverse vascular changes in PA patients.8 Hypokalemia plays an important role in various cardiovascular diseases.9 In a recent study, PA patients with hypokalemia had a higher cardiovascular morbidity than PA patients with normokalemia.10 This implies that, in PA patients, hypokalemia plays a significant role in cardiovascular comorbidities. In our recent study, serum potassium level was significantly associated with left ventricular mass in PA patients.11 However, the influence of hypokalemia on vascular function and stiffness remains unclear. Flow-mediated dilation (FMD) is a common noninvasive method to measure endothelial function.12 However, FMD is limited by its high operator dependence and wide difference between operators.13 Pulse amplitude tonometry (PAT), a recent United States Food and Drug Administration (FDA)-approved technology, has become a good alternative choice to measure endothelial function without subjective measurements of FMD.12,14,15 PAT presents peripheral endothelial function as the reactive hyperemia index (RHI); furthermore, arterial stiffness can be also calculated from PAT waveform as the augmentation index (AI). PAT measures endothelial functions of microvasculature. In contrast, FMD measures the endothelial function of median size vessels. The associations between FMD and RHI are low, even displaying no association.16,17 Therefore, it is also of interest to study whether aldosterone influences the endothelial function of the microvasculature. In this study, we investigate the differences in microvascular endothelial function and arterial stiffness between PA and essential hypertension (EH) patients, and the correlation between serum potassium level and peripheral arterial function among PA patients.
Materials and methods Patients This prospective study enrolled 37 patients diagnosed with primary aldosteronism after an initial evaluation and who were recorded in the Taiwan Primary Aldosteronism Investigation (TAIPAI) database from October 2006–October 2011. The database was constructed for quality assurance at one medical center (National Taiwan University Hospital, Taipei, Taiwan) one branch hospital (National Taiwan University Hospital Yun-Lin branch, Yun-Lin, southern Taiwan), and two cooperative hospitals (Far-Eastern Memorial Hospital, Taipei; Tao-Yuan General Hospital, Tao-Yuan, central Taiwan).8,11,18–25 The serum biochemistry studies (including potassium levels) were measured at the first evaluation of these patients at the National Taiwan University Hospital. Medical histories, including demographics and medication were carefully recorded. Patients with a hypokalemia history were defined as those who had known hypokalemia (K10 ng/dl; (b) lateralization of aldosterone secretion at adrenal vein sampling (AVS) or during dexamethasone suppression NP-59 single-photon emission computed tomography (SPECT)/computed tomography (CT);30 (c) evidence of adenoma at CT scan; and (d) pathologically proven adenoma after an adrenalectomy if operated, and cure of hypertension without antihypertensive agents or improved hypertension, potassium, PAC, and plasma renin activity (PRA) as described. Idiopathic hyperaldosteronism (IHA) was classified by the following criteria: (a) evidence of autonomous excess aldosterone production based on ARR>35 and TAIPAI score more than 60%; or urine ≥12 μg/24 h and post-saline loading PAC >10 ng/dl (b) non-lateralization of aldosterone secretion at AVS or during dexamethasone suppression NP-59 SPECT/CT;30 (c) evidence of bilateral diffuse enlargement on CT scan; and/or (d) evidence of diffuse cell hyperplasia in the pathology studies.
Assessment of peripheral vascular function by PAT Digital pulse amplitude was measured with a non-invasive PAT placed on the tip of both index fingers (EndoPAT2000, Itamar Medical, Caesarea, Israel). The PAT generates a pneumatic plethysmo-graph that applies uniform pressure to the finger surface, which allows measurement of changes in pulse volume. The inflation pressure of PAT was set to either 10 mmHg below diastolic blood pressure (DBP) or 70 mmHg. The process initially took a twominute measurement of baseline pulse amplitude. And then, the arterial flow was occluded for 5 min by a cuff placed on a proximal forearm with occlusion pressure higher than systolic blood pressure (SBP). Data was collected from both index fingers and analyzed by a computerized automated algorithm (Itamar Medical) that provided the average pulse amplitude for each 30 s interval after forearm cuff deflation up to 4 min.
Downloaded from jra.sagepub.com at HOWARD UNIV UNDERGRAD LIBRARY on January 26, 2015
3
Chang et al. Table 1. Clinical data of the patients.
Age, years Sex, male Body weight, kg Body height, cm APA Serum creatinine level, mg/dl SBP, mmHg DBP, mmHg Hypokalemia history Hypertension history, years Number of anti-hypertensive medication type Serum potassium level, mmol PAC, ng/dl PRA, ng/ml/hr Log-transformed PAC Log-transformed PRA Hypertension medication Thiazide CCB ACEI/ARB A-blocker B-blocker Usage of spironolactone
Group 1 control n=20
Group 2 normokalemia n=21
Group 3 hypokalemia n=16
p value
45±13 8 (40) 63±11 164±8 – 1.0±0.2 144±19a 87±1a 0d 3.9±4.3a 1.5±0.9 4.2±0.3d 25±12d,f 8.0±7.8d,h 1.4±0.2d,i 0.6±0.5d,h
43±8 9 (43) 69±15 162±8 18 (76) 0.9±0.2 149±17b 86±14c 2 (10)e 3.5±3.6c 1.8±0.8 4.0±0.5e 45±29g 0.7±0.8 1.6±0.3g –0.6±0.7
44±7 8 (50) 68±14 161±8 16 (100) 1.0±0.3 168±31 101±15 11 (100) 8.0±4.8 1.9±1.1 2.7±0.4 66±45 0.6±0.9 1.7±0.3 –0.6±0.7
1 (5) 10 (50) 11 (55) 3 (15) 5 (25) 0a,h
3 (14) 11 (52) 5 (24) 9 (43)g 8 (28) 10 (48)
1 (6) 11 (69) 9 (56) 2 (13) 7 (44) 6 (38)
0.744 0.829 0.327 0.392 0.243 0.544 0.010 0.005
