Arterial Stiffness Is Associated with Clinical Outcome and Cardiorenal Injury in Lateralized Primary Aldosteronism

Abstract

Context

The association between arterial stiffness and clinical outcome in lateralized primary aldosteronism (PA) patients after adrenalectomy has not been clearly identified.

Objective

We hypothesized that arterial stiffness estimated by brachial-ankle pulse wave velocity (baPWV) before adrenalectomy was associated with the clinical outcomes and cardiorenal injury in lateralized PA patients after adrenalectomy.

Design and Patients

We designed a retrospective observational cohort study. We collected lateralized PA patients who had undergone adrenalectomy between 2013 and 2016 from the Taiwan Primary Aldosteronism Investigation database. The primary outcome was achieving complete clinical success at 1 year after adrenalectomy. The secondary outcome was estimated glomerular filtration rate declining over 20% and improved left ventricular mass index.

Results

We enrolled 221 patients with lateralized PA (50.7% men; mean age, 51.9 years), of whom 101 patients (45.7%) achieved complete clinical success at the 1-year follow-up assessment after adrenalectomy. Lower baPWV before adrenalectomy (odds ratio = 0.998; 95% confidence interval, 0.996-0.999; P = 0.003) correlated with higher likelihood of complete clinical success by multivariate logistic regression analysis. Multifactorial adjusted generalized additive model demonstrated that preoperative baPWV<1600 cm/sec was significantly associated with complete cure of hypertension. In addition, higher preoperative baPWV was associated with renal function decline and less left ventricular mass regression after adrenalectomy in lateralized PA patients during the follow-up period.

Conclusions

Our study demonstrated that the preoperative severe arterial stiffness was associated with absent complete clinical success in lateralized PA patients after adrenalectomy, and this effect may contribute to cardiorenal injury, which at least partially explains kidney function deterioration and lessened regression of heart mass.

primary aldosteronism, hypertension, arterial stiffness, adrenalectomy, clinical outcome, cardiorenal injury

Primary aldosteronism (PA), characterized by an autonomous aldosterone overproduction, is the most common form of secondary hypertension (1, 2). The prevalence of PA is reported to be 5% in the general hypertension population (3) and 15% to 20% among refractory hypertension patients (2). Beyond the effects of hypertension, patients with PA had higher risk of cardiac and renal dysfunction compared with essential hypertension patients (4-7). Targeted treatment with adrenalectomy or mineralocorticoid receptor antagonists can improve the outcomes of PA patients (8). Although adrenalectomy is currently the standard treatment in aldosterone-producing adenoma patients (9, 10), some postoperative patients maintain hypertension or need antihypertensive medications after adrenalectomy.

In addition to deteriorated cardiorenal syndrome (11), high levels of aldosterone can cause vessel endothelial dysfunction, collagen synthesis in the vascular wall, increased arterial wall stiffness, atherosclerosis, and heart failure (12, 13). Previous studies demonstrated that arterial stiffness is related to blood pressure (BP) (14), cardiovascular events (15), and decline in kidney function (16) in a non-PA cohort; however, the association between preoperative arterial stiffness and clinical outcomes/cardiorenal injury (ie, poorer recovery of the cardiac and renal function) after adrenalectomy in PA patients has not been investigated.

We conducted this study to investigate the association between preoperative arterial stiffness and clinical outcomes in lateralized PA patients after adrenalectomy with criteria set by the Primary Aldosteronism Surgery Outcome (PASO) consensus. We hypothesized that the severity of arterial stiffness was associated with clinical outcome and cardiorenal injury in lateralized PA patients after adrenalectomy.

Participants and Methods

Patients

This is an observational cohort study. From 2013 to 2016, 360 patients were diagnosed as unilateral PA in our cohort, and 245 of them (68%) had undergone adrenalectomy. We enrolled 221 of those 245 patients who had undergone adrenalectomy and were also followed-up with their full clinical outcomes up to 2017. All patients signed the informed consent and were registered in the Taiwan Primary Aldosteronism Investigation (TAIPAI) database (5, 10, 17-23). Consent had been obtained from each patient or subject after full explanation of the purpose and nature of all procedures used. The study was approved by the institutional review board of the National Taiwan University Hospital (200611031R).

This study enrolled patients who were referred to the TAIPAI study group and underwent aldosterone-to-renin ratio (ARR) measurement for case detection of possible PA. There were 2 medical centers, 3 affiliated hospitals, and 2 regional hospitals in different cities in Taiwan participated in this study (24). Patients with other secondary hypertension, including renovascular hypertension, “clinically obvious” Cushing syndrome, hyperthyroidism, and pheochromocytoma were excluded from this study (25). Patients were instructed to maintain their usual sodium intake during the study, and adherence was assessed by measuring urinary sodium excretion at each visit. All antihypertensive medications were discontinued for at least 21 days before screening tests. Doxazosin and/or diltiazem were administered to control markedly high BP when required (26).

Diagnosis and further lateralization of PA

The diagnosis of PA was established in hypertensive patients based on the following criteria (5, 21, 27).

Confirmation

Lateralized PA was identified on the basis of the following 4 criteria: (i) autonomous excess aldosterone production evidenced with an ARR >35, a TAIPAI score larger than 60%, and seated post-saline loading plasma aldosterone concentration >16 ng/dL or ARR >35 (ng/dL)/(ng/mL/h) shown in a post-captopril test; (ii) adenoma evidenced with a computed tomography (CT) scan (6); (iii) lateralization of aldosterone secretion at an adrenal vein sampling (AVS) without cosyntropin stimulation or during a dexamethasone suppression NP-59 single photon emission computed tomography/CT (SPECT/CT) (28); and (iv) pathologically proven CYP11B2 adenoma or aldosterone-producing cell clusters via immunohistochemistry after adrenalectomy (29), and subsequent emergence of biochemical correction (27, 30).

Selectivity and lateralization indices of AVS

The selectivity index is defined as the ratio of the sampled cortisol concentration of each adrenal vein to that of the peripheral vein. The lateralization index (LI) is defined as the ratio of the aldosterone/cortisol concentration on the dominant side to that of the contralateral side. Successful AVS is defined as a selectivity index value ≥2.0 bilaterally. After confirming successful bilateral AVS, lateralization of the PA was determined by an LI value ≥2.0 (31).

Clinical parameters

We recorded age, sex, body mass index (BMI), medical history of diabetes mellitus, BP, the categories and quantities of antihypertension medications, hypertension duration, serum creatinine, cystatin C, lowest serum potassium, ARR, urine albumin-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR; calculated using the Chronic Kidney Disease Epidemiology Collaboration cystatin C equation) (32), left ventricular mass index (LVMI), as well as brachial-ankle pulse wave velocity (baPWV) before adrenalectomy.

The data at 1 year after adrenalectomy, including BP, antihypertensive medications, lowest serum potassium, renin and aldosterone levels, baPWV, eGFR, and LVMI were examined to evaluate the outcomes after adrenalectomy. The delta LVMI (ΔLVMI) was defined as the postoperative LVMI minus preoperative LVMI. Moderate and severe left ventricular hypertrophy (LVH) was defined as LVMI ≥131 g/m² in men and ≥108 g/m² in women (33).

PWV measurements

PWV was measured using an automatic waveform analyzer (Colin VP-2000, Omron Inc., Japan) after the patient rested for 15 minutes in a supine position (34). This machine simultaneously recorded the waveforms of bilateral brachial and carotid arteries, phonocardiograms, and electrocardiogram. Occlusive cuffs connected to oscillatory and plethysmographic sensors were wrapped around the upper arms and ankles to measure and analyze BP and pulse waveforms. Differences in conduction times were estimated according to the wavefront theory. We measured the baPWV for both sides twice separately and calculated the mean baPWV for each side. The final baPWV was defined as the higher value of the right and left side baPWV.

LVMI measurements

All echocardiography was performed using a Hewlett-Packard 5500 ultrasound system with an S3 transducer (1.0-3.0 MHz). Transthoracic echocardiographic images were obtained in fundamental imaging modes. Two-dimensional, M-mode, Doppler, and tissue Doppler ultrasonography were performed in each patient, and the dimensions of the chamber, wall thickness, and left ventricular ejection fraction (M-mode) were measured according to the guidelines of the American Society of Echocardiography (33). LVMI was derived from echocardiography according to the formula reported by Devereux and Reichek: 0.8 × [1.04[([LV end-diastolic dimension + interventricular septal thickness at end-diastole + posterior wall thickness at end-diastole]³ − LV end-diastolic dimension³)]] + 0.6 (35) indexed to the body surface area.

Outcomes of interest

The primary outcome was defined as achieving complete clinical success after adrenalectomy according to the PASO consensus (Supplemental Table 1) (36), indicating normal BP without antihypertensive medication. The secondary outcome was eGFR decline over 20% at 1 year after adrenalectomy and ΔLVMI at 1 year after adrenalectomy.

Statistical analysis

For baseline characteristics, continuous variables were expressed as mean ± standard deviation and categorical variables were expressed as frequency and percentage. For continuous variables, the differences among groups were compared using the Mann-Whitney U test. For categorical variables, the chi-squared or Fisher exact test was used. Logistic regression analysis and linear regression were performed to identify determinants of clinical outcome. To determine the variables of significance, those variables identified as known predictors by previous studies, or those with P value < 0.05 according to univariate analysis were subjected to multivariate regression analysis.

A generalized additive model (GAM) was plotted and adjusted for sex and age in individual patients (17, 37). The model incorporates the subject-specific (longitudinal) random effects, expressed as the logarithm of the odds (logit), and the optimal cutoff value was defined as a log odds value of zero (38).

We used R software, version 3.4.4 (Free Software Foundation, Inc., Boston, MA)) and IBM SPSS statistics version 24 (Armonk, NY: IBM Corp) software. A two-sided P value < 0.05 was considered statistically significant.

Results

Baseline characteristics of the study population

Two hundred twenty-one lateralized PA patients who had undergone adrenalectomy were enrolled in this study. The mean age of all participants was 51.9 ± 10.7 years, and the proportion of men was 50.7%. The mean baPWV level was 1709 ± 327 cm/sec and 1627 ± 323 cm/sec at the confirmatory period and 1 year after adrenalectomy, respectively (Table 1).

Table 1.

Basic Characteristics of Lateralized PA Patients with Outcome of Complete Clinical Success and No Complete Clinical Success After Unilateral Adrenalectomy

	All patients	Complete clinical success	No complete clinical success	P valuea
Preoperation
Patient No.	221	101	120
Age (years)	51.9 ± 10.7	50.7 ± 9.8	52.8 ± 11.3	0.102
Male, n (%)	112 (50.7)	43 (42.6)	69 (57.5)	0.027
DM, n (%)	41 (18.6)	14 (13.9)	27 (22.5)	0.100
Hyperlipidemia, n (%)	49 (22.2)	19 (18.8)	30 (25)156	0.270
Family history of HTN, n (%)	156 (70.6)	64 (63.4)	92 (76.7)	0.031
Number of antihypertensive medications	2.21 ± 1.27	1.85 ± 1.12	2.52 ± 1.32	<0.001
BMI (kg/m2)	25.5 ± 3.9	24.3 ± 3.3	26.5 ± 4.1	<0.001
SBP (mmHg)	154 ± 22	147 ± 20	160 ± 21	<0.001
DBP (mmHg)	91 ± 14	89 ± 13	94 ± 14	0.010
MBP (mmHg)	112 ± 15	108 ± 15	116 ± 15	<0.001
HTN duration (years)	7.6 ± 7.1	6.2 ± 6.8	8.8 ± ± 7.2	0.002
ARR (ng/dL per ng/mL/h)	1158 ± 2605	1302 ± 2480	1038 ± 2709	0.070
UACR (mg/g)	64.5 ± 195.8	34.9 ± 76.6	88.7 ± 252.5	0.020
Pre-eGFR (cystatin C) (mL/min/1.73 m2)	94.6 ± 25.9	103.8 ± 22.2	86.9 ± 26.3	<0.001
Lowest serum K (mEq/L)	3.4 ± 0.7	3.2 ± 0.6	3.6 ± 0.7	0.001
Pre-baPWV (cm/sec)	1709 ± 327	1608 ± 253	1794 ± 358	<0.001
Pre-LVMI (g/m2) (N = 135)	117 ± 30	111 ± 29	122 ± 31	0.005
Male (g/m2)	128 ± 30	119 ± 29	133 ± 29	0.017
Female (g/m2)	106 ± 27	106 ± 29	107 ± 25	0.824
1 year postoperation
Post-eGFR (cystatin C) (mL/min/1.73 m2)	85.3 ± 25.7	92.3 ± 21.9	79.7 ± 27.1	0.001
Post baPWV (cm/sec)	1627 ± 323	1477 ± 212	1753 ± 346	<0.001
Post LVMI (g/m2) (N = 135)	106 ± 23	97 ± 22	114 ± 20	<0.001
Male (g/m2)	115 ± 21	103 ± 22	121 ± 18	0.001
Female (g/m2)	98 ± 22	92 ± 22	105 ± 19	0.011
Outcome of vascular and cardiorenal injury
baPWV improvementa, n (%)	136 (67.3)	72 (78.3)	64 (58.2)	0.002
Post- and pre-eGFR ratio	0.91 ± 0.24	0.89 ± 0.13	0.92 ± 0.29	0.384
eGFR decline over 20%, n (%)	56 (28.3)	21 (23.6)	35 (32.1)	0.186
LVMI improvementb, n (%) (N = 135)	90 (66.7)	44 (74.6)	46 (60.5)	0.086
ΔLVMI (g/m2)	−10.5 ± 21.6	−13.8 ± 22.3	−7.9 ± 20.9	0.055

All quantitative and normally distributed variables are reported as mean ± standard.

Abbreviations: ARR, aldosterone-to-renin ratio; baPWV, brachial-ankle pulse wave velocity; BMI, body mass index; DBP, diastolic blood pressure; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HTN, hypertension; K, potassium; LVMI, left ventricular mass index; MBP, mean blood pressure; SBP, systolic blood pressure; UACR, urine albumin-creatinine ratio.

^aComplete clinical success versus No complete clinical success

^bImprovement definition: Post-operation level of baPWV or LVMI is less than preoperation level of baPWV or LVMI

In this cohort, 45.7% patients achieved complete clinical success after adrenalectomy at the 1-year follow-up. There were no statistically significant differences in age, ARR, or history with diabetes mellitus and hyperlipidemia between the 2 groups. However, the complete clinical success group had a lower proportion of men (42.6% vs 57.5%, P = 0.027) and family history of hypertension (63.4% vs 76.7%, P = 0.031), fewer antihypertensive medications (1.85 ± 1.12 vs 2.52 ± 1.32, P < 0.001), lower BMI (24.3 ± 3.3 kg/m² vs 26.5 ± 4.1 kg/m², P < 0.001), lower systolic BP (147 ± 20 mmHg vs 160 ± 21 mmHg, P < 0.001), lower UACR (34.9 ± 76.6 mg/g vs 88.7 ± 252.5 mg/g, P = 0.02), lowest serum potassium level (3.2 ± 0.6 mEq/L vs 3.6 ± 0.7 mEq/L, P = 0.001), and shorter hypertension duration (6.2 ± 6.8 years vs 8.8 ± 7.2 years, P = 0.002). The complete clinical success group had lower preoperative baPWV (1608 ± 253 cm/s vs 1794 ± 358 cm/s, P < 0.001), LVMI (in men) (119 ± 29 g/m² vs 133 ± 29 g/m², P = 0.017), and higher eGFR estimated by cystatin C (103.8 ± 22.2 mL/min/1.73 m² vs 86.9 ± 26.3 mL/min/1.73 m², P < 0.001). However, LVMI before adrenalectomy showed no statistical significance for women between the 2 groups.

At 1 year after adrenalectomy, the complete clinical success group had higher eGFR (92.3 ± 21.9 mL/min/1.73 m² vs 79.7 ± 27.1 mL/min/1.73 m², P = 0.001), lower baPWV (1477 ± 212 cm/s vs 1753 ± 346 cm/s, P < 0.001) and LVMI (103 ± 22 g/m² vs 121 ± 18 g/m², P = 0.001 in men; 92 ± 22 g/m² vs 105 ± 19 g/m², P = 0.011 in women). In addition, the complete clinical success group had higher proportion of the improvement of baPWV (78.3% vs 58.2%, P = 0.002), but there was no statistically significant difference between the ratio of eGFR 1 year after to before adrenalectomy, and the proportion of LVMI improvement after adrenalectomy between the 2 groups (Table 1).

In the subgroup analysis by forest plot, preoperative baPWV could predict the complete clinical success after adrenalectomy in most subgroups (Fig. 1).

Figure 1.

Forest plot depiction of benefit of complete clinical success between lateralized PA patients with baseline baPWV≧1600 cm/s and with baseline baPWV <1600 cm/s after adrenalectomy. Abbreviations: baPWV, brachial-ankle pulse wave velocity; BMI, body mass index; CKD, chronic kidney disease; DM, diabetes mellitus; HTN, hypertension; K, potassium; OR, odds ratio; PA, primary aldosteronism; SBP, systolic blood pressure.

Factors associated with complete clinical success after adrenalectomy in lateralized PA patients

We used the GAM plot to find appropriate cut-point values of the continuous parameter to predict complete remission (Fig. 2). In our cohort, we found that lower preoperative baPWV (cutoff point: 1600 cm/s)(Fig. 2A) and lower mean BP (cutoff point: 110 mmHg) (Fig. 2B) had higher complete clinical success rates.

Figure 2A.

GAM plot for the association between baseline baPWV and complete clinical success. Optimal baPWV cut-point value (1600 cm/s) suggested by GAM plot. The association is between baPWV and the odds ratio for complete clinical success and is adjusted simultaneously by age and gender. The dotted curves indicate 95% CIs for the smoothed hazard. Abbreviation: baPWV, brachial artery pulse wave velocity.

Figure 2B.

GAM plot for the association between mean BP and complete clinical success. Optimal mean BP cut-point value suggested by GAM plot. The association is between mean BP (110 mmHg) and the odds ratio for complete clinical success and is adjusted simultaneously by age and gender. The dotted curves indicate 95% CIs for the smoothed hazard. Abbreviation: BP, blood pressure.

In multivariate logistic regression analysis (Table 2), lower preoperative baPWV (odds ratio [OR] = 0.998; 95% CI, 0.996-0.999; P = 0.003), lower BMI (OR = 0.862; 95% CI, 0.776-0.958; P = 0.006), higher eGFR (estimated by cystatin C) (OR = 1.030; 95% CI, 1.013-1.047; P < 0.001), lowest serum potassium level (OR = 0.313; 95% CI, 0.176-0.557; P < 0.001), family history of hypertension (OR = 0.445; 95% CI, 0.202-0.980; P = 0.044), and ≦1 antihypertensive medication (OR = 2.320; 95% CI, 1.058-5.076 P = 0.036) were independently predictive of complete clinical success after adrenalectomy. In addition, we shifted the continuous variable preoperative baPWV to categorical variable preoperative baPWV ≧1600 cm/s and found that baPWV over 1600 cm/s (OR = 0.282; 95% CI, 0.127-0.624; P = 0.002) could also be associated with worse complete clinical success in multivariate logistic regression analysis.

Table 2.

Baseline Correlates of Complete Clinical Success After Unilateral Adrenalectomy in Lateralized PA Patients. Analysis by Multivariate Logistic Regression

Model 1	Odds ratioa (95% CI)	P value	Model 2	Odds ratiob (95% CI)	P value
baPWV (cm/sec)	0.998 (0.996–0.999)	0.003	baPWV≧1600 cm/s (cm/sec)	0.282 (0.127-0.624)	0.002
BMI (kg/m  2)	0.862 (0.776-0.958)	0.006	BMI (kg/m  2)	0.857 (0.771-0.952)	0.004
cystatin eGFR (mL/min/1.73 m  2)	1.030 (1.013-1.047)	<0.001	cystatin eGFR (mL/min/1.73 m  2)	1.032 (1.015-1.049)	<0.001
Lowest serum K (mEq/L)	0.313 (0.176-0.557)	<0.001	Lowest serum K (mEq/L)	0.300 (0.167-0.537)	<0.001
Family history of HTN	0.445 (0.202-0.980)	0.044	Family history of HTN	0.392 (0.178-0.862)	0.020
≦1 Antihypertensive medication	2.320 (1.058-5.076)	0.036	≦1 Antihypertensive medication	2.387 (1.080-5.263)	0.031

Abbreviations: ARR, aldosterone-to-renin ratio; baPWV, brachial-ankle pulse wave velocity; BMI, body mass index; CI, confidence interval; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HTN, hypertension; K, potassium; LVMI, left ventricular mass index; SBP, systolic blood pressure

^aVariables with P > 0.05 in the multivariable logistic analysis: Age, ARR, DM, family history of HTN, Gender, Hyperlipidemia, HTN duration, MBP > 110 mmHg

^bVariables with P > 0.05 in the multivariable logistic analysis: Age, ARR, DM, Gender, Hyperlipidemia, HTN duration, MBP > 110 mmHg.

Furthermore, we found that patients with baPWV≧1600 cm/s were associated with older age, higher diabetes prevalence and positive family history of hypertension rate, higher baseline BP, and UACR, longer hypertension duration, and decreased renal function in our cohort (Supplemental Table 2) (36). In multivariate logistic regression analysis, higher preoperative baPWV was associated with older age, higher family history of hypertension rate, higher mean BP, and reduced kidney function (Supplemental Table 3) (36).

In addition, we compared outcomes between patients with different LI levels in our cohort (group 1: LI 2-4 and group 2: LI >4), and found that higher preoperative PWV was associated with lower complete clinical success rate in the subgroup with LI from 2 to 4 (OR = 0.997; 95% CI, 0.994-1.000; P = 0.038). Although preoperative PWV >1600 mm/sec was also associated with lower complete clinical success rate in the subgroup with LI higher than 4 in a univariate analysis (57% vs 70%), there was no more statistical significant difference in a multivariate logistic regression analysis because of limited number of patients.

Factors associated with renal function decline after adrenalectomy in lateralized PA patients

In multivariate logistic regression analysis (Table 3), higher preoperative baPWV (OR = 1.001; 95% CI, 1-1.002; P = 0.020), male gender (OR = 2.887; 95% CI, 1.413-5.896; P = 0.004) and higher log UACR (OR = 1.859; 95% CI, 1.058-3.268; P = 0.031) had higher risk of renal function decline over 20% after adrenalectomy during the 1-year follow-up period.

Table 3.

Baseline Correlates of (a) Renal Function Decline Over 20% Analysis by Multivariate Logistic Regression and (b)ΔLVMI Analysis by Multivariate Linear Regression at One-Year After Unilateral Adrenalectomy in Lateralized PA Patients

a: Renal function decline over 20%a			b: ΔLVMIb
	Odds ratio (95% C.I.)	P value		ß (95% C.I.)	P value
baPWV (cm/sec)	1.001 (1-1.002)	0.020	baPWV (cm/sec)	0.012 (0-0.023)	0.044
Male	2.887 (1.413-5.896)	0.004	Moderate and severe LVH	-20.934 (-28.38 to −13.487)	<0.001
Log UACR (mg/g)	1.859 (1.058-3.268)	0.031	-	-

Abbreviations: ARR, aldosterone-to-renin ratio; baPWV, brachial-ankle pulse wave velocity; BMI, body mass index; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HTN, hypertension; MBP, mean blood pressure; UACR, urine albumin-creatinine ratio.

^aVariables with P > 0.05 in the multivariable logistic analysis: Age, ARR, BMI, DM, eGFR, Hyperlipidemia, HTN duration, Lowest serum K, MBP > 110 mmHg, family history of HTN.

^bVariables with P > 0.05 in the multivariable logistic analysis: Age, ARR, BMI, DM,

Factors associated with ΔLVMI after adrenalectomy in lateralized PA patients

In this cohort, 135 patients had ΔLVMI data. In multivariate linear regression analysis (Table 3), higher preoperative baPWV (β = 0.012; 95% CI, 0-0.023; P = 0.044) was associated with decreased LV mass regression after adrenalectomy in PA patients. In addition, patients with baseline moderate/severe LVH (β = −20.934; 95% CI, −28.38 to −13.487; P < 0.001) were associated with LV mass regression in the multivariate analysis.

Discussion

Our study is the first large cohort study to show a strong negative association of preoperative baPWV association with complete clinical success, as defined by PASO consensus, in lateralized PA patients after adrenalectomy. Our study revealed that preoperative baPWV was also associated with cardiorenal injury in postoperative lateralized PA patients.

Factors relating to complete clinical success after adrenalectomy in lateralized PA patients

Previous studies have shown that adrenalectomy of lateralized PA patients as a whole led to a significant decrease in BP and arterial stiffness parameters (34, 39, 40); additionally, herein we found that lateralized PA patients with more severe preoperative arterial stiffness (as evidenced by higher baPWV) gained a lower percentage of BP control from adrenalectomy. Lateralized PA patients with severe arterial stiffness in our cohort were associated with older age, family history of hypertension, and reduced renal function (Supplemental Table 3) (36), which may contribute to relatively poor BP control after adrenalectomy. Although Bouhanick et al (41) had demonstrated that preoperative arterial stiffness does not predict a beneficial effect of adrenalectomy on BP values, there were some limitations in that study, including small sample size, shorter follow-up duration, and not considering the change of the amount of antihypertensive medications.

PA patients have a thicker carotid intima-media layer (42), which could be reversed after adrenalectomy (34) and they also have more pronounced fibrosis in small resistance arteries than BP-matched essential hypertension patients (43). Additionally, aldosterone oversecretion is known to increase vascular oxidative stress and impairs vascular smooth muscle cell function (44), which thereby induces perivascular inflammatory cell infiltration and increases inflammation (45). The aforementioned factors may contribute to aldosterone-induced vascular fibrosis and stiffness in PA patients.

The relationship between arterial stiffness and hypertension is a classic chicken-and-egg conundrum. A common interpretation of known relationships between arterial stiffness and hypertension is that elevated BP increases pulsatile aortic wall stress, which accelerates elastin degradation (46-50). Thus, hypertension is viewed as an accelerated form of vascular aging that leads to aortic stiffening. On the other hand, several studies have shown that higher levels of carotid or aortic stiffness in normotensive individuals are associated with accelerated BP progression and increased risk for incident hypertension during follow-up (51-53).

In our cohort, we also found that patients with lower baPWV, lower BMI, lower lowest serum potassium level, better renal function (as evidenced by higher cystatin C-based eGFR before adrenalectomy), without family history of hypertension, and ≦1 antihypertensive medication before adrenalectomy had higher complete clinical success rate after adrenalectomy. There are wide variations in previously reported clinical remission rates (16%-72%) and different predictors in lateralized PA patients after adrenalectomy. Outcome results vary widely across studies and may under- or overestimate the outcome effects defined by PASO criteria (19) because of different and ill-defined criteria and varying follow-up intervals in assessing outcomes (54-58). The other predictors of complete clinical success in our study had been mentioned in the previous studies (59-61), and we firstly demonstrated that the baPWV and eGFR estimated by cystatin C before adrenalectomy were associated with complete clinical success. Morisaki et al (62) had demonstrated the additional independent predictors for BP normalization, including duration of hypertension, history of diabetes, and female sex. The differences between the 2 cohorts were follow-up duration and the disease severity. PA patients in our cohort had longer follow-up duration (1 year versus 6 months) and higher baseline BP. In addition, patients with higher baPWV had higher prevalence of diabetes and longer hypertension duration in our cohort (Supplemental Table 2) (36).

Factors associates renal function decline after adrenalectomy in lateralized PA patients

Excessive aldosterone exposure is known to result in progressive renal injury by inducing renal fibrosis, vascular disease, and podocyte injury (63). Long-standing PA may cause kidney structural damage, leading to a significant decline in renal function as well as albuminuria (5). However, it is difficult to accurately evaluate renal function in patients with PA due to glomerular hyperfiltration commonly found in PA patients. Most importantly, we used cystatin C to estimate GFR, which was reported to be more accurate in patients with glomerular hyperfiltration, for example, in diabetes (64) and PA (5) patients.

We are the first to show that preoperative higher baPWV and albuminuria were associated with renal function decline even after adrenalectomy in lateralized PA patients. Previous cohort studies have demonstrated that higher indices of arterial stiffness are associated with steeper decline in kidney function and higher risk of incident CKD in the general population (16). A possible hypothesis is that arterial stiffness increases circumferential and shear stress in the arterial lumen. This hemodynamic stress on the kidney vasculature may result in endothelial dysfunction and microvascular ischemia, leading to kidney injury (65).

In addition, the kidney could regulate arterial BP by maintaining sodium homeostasis and contributing to the development of hypertension through afferent sympathetic signals to the central nervous system and reduced nephron number (66). One of the possible reasons for poor resolution of BP control after adrenalectomy in lateralized PA patients with high baPWV may be relatively poor preservation of renal function. This finding may indirectly implicate the importance of identifying PA, especially lateralized PA, patients from the hypertensive population. An earlier confirmation of the lateralized PA diagnosis could offer these patients an earlier chance to have the target treatment of lateralized adrenalectomy, and the severity of the renal dysfunction and arterial stiffness at that time could be reversed. Thus, with supplemental validation of our results, this speculation may provide the best opportunity for these lateralized PA patients to be cured.

Factors associated with LV mass remodeling after adrenalectomy in PA patients

Our study indicated that preoperative baPWV is not only associated with LV mass but also associated with LV mass remodeling ability in lateralized PA patients after adrenalectomy. Because aldosterone stimulates myocardial hypertrophy through activating protein kinase C, extracellular signal-regulated kinase 1/2, and c-JUN N-terminal kinase (67, 68). PA patients have higher LVMI than essential hypertension or other types of secondary hypertension patients (69). Although previous studies demonstrated that the target treatments of PA could result in regression of LVH and improvement of myocardial fibrosis, PA patients with higher preoperative baPWV gained less benefit of LVH regression from adrenalectomy in our study.

Reduction in BP is an important predictor of LV mass reduction (70); however, lateralized PA patients with severe arterial stiffness were associated with a lower complete clinical success rate after adrenalectomy which may limit LV remodeling.

Limitations

There were still several limitations to our study. First, we did not evaluate the tumor size and the existence of subclinical Cushing syndrome as variables in our cohort. Second, our study only enrolled patients lateralized PA undergoing surgical treatment, which was thought to be the preferred treatment in patients with lateralized PA (71). Whether the association could be repeated in bilateral adrenal hyperplasia patients treated by aldosterone antagonists is uncertain and further investigations are necessary. Third, we lack ambulatory BP records at baseline and postsurgery to provide a continuous assessment of BP response to adrenalectomy. However, official BP is used for real-world practice and can be a proxy for hypertensive status according to the PASO definition. Fourth, the association between arterial stiffness and clinical outcome in lateralized PA patients whose LI >4 is uncertain, which may be related to the small sample size of our study or indicate that PWV are more relevant to the outcomes when the PA is less florid. To evaluate the effect of arterial stiffness on the clinical outcome in lateralized PA patients with different disease severity, further investigations are necessary.

Conclusions

The interactions between aldosterone-related arterial stiffness, BP, renal function decline, and LV remodeling are complicated among patients with lateralized PA. We demonstrated that preoperative higher baPWV was associated with less complete clinical success in lateralized PA patients after adrenalectomy. In addition, we also found that higher baPWV was associated with cardiorenal injury, including kidney function deterioration and less LV mass regression, in lateralized PA patients even after adrenalectomy. We further suggested that PA patients with higher baPWV (eg, >1600 cm/s) will need more frequent follow-up for cardiorenal function after adrenalectomy.

Abbreviations

Abbreviations
 
• ARR

  aldosterone-to-renin ratio

 
• AVS

  adrenal vein sampling

 
• baPWV

  brachial-ankle pulse wave velocity

 
• BMI

  body mass index

 
• BP

  blood pressure

 
• CI

  confidence interval

 
• CT

  computed tomography

 
• eGFR

  estimated glomerular filtration rate

 
• GAM

  generalized additive model

 
• LI

  lateralization index

 
• LVH

  left ventricular hypertrophy

 
• LVMI

  left ventricular mass index

 
• OR

  odds ratio

 
• PA

  primary aldosteronism

 
• PASO

  Primary Aldosteronism Surgery Outcome

 
• TAIPAI

  Taiwan Primary Aldosteronism Investigation

 
• UACR

  urine albumin-creatinine ratio

Acknowledgments

The authors would like to thank the staff of the Second Core Lab in the Department of Medical Research in National Taiwan University Hospital for technical assistance. The authors thank Mr. Eric B. Chueh, BA, MBA, of Case Western Reserve University, Cleveland, Ohio for English editing. We also express our sincere gratitude to all staff of the Taiwan Clinical Trial Consortium, TCTC, and Taiwan Primary Aldosteronism Investigation (TAIPAI) Study Group, Taiwan.

Financial Support: This study was supported by Ministry of Science and Technology (MOST) of the Republic of China (Taiwan) [grant number, MOST 106-2321-B-182-002, MOST 108-2314-B-002-058, 109-2314-B-002-174-MY3]. This study was partially supported by grants from National Taiwan University Hospital (NTUH 107-A141).

Additional Information

Disclosure Summary: All authors declare that there is no conflict of interest regarding the publication of this article.

Data Availability

All data generated or analyzed during this study are included in this published article or in the data repositories listed in References.

Author notes

TAIPAI, Taiwan Primary Aldosteronism Investigation Study Group, Taiwan