Abstract
Context
Primary aldosteronism (PA) causes left ventricular hypertrophy (LVH) via hemodynamic factors and directly by aldosterone effects. Specific treatment by mineralocorticoid receptor antagonists (MRA) or adrenalectomy (ADX) has been reported to improve LVH. However, the cardiovascular benefit could depend on plasma renin concentration (PRC) in patients on MRA.
Patients and objective
We analyzed data from 184 patients from the Munich center of the German Conn’s Registry, who underwent echocardiography at the time of diagnosis and 1 year after treatment. To assess the effect of PRC on cardiac recovery, we stratified patients on MRA according to suppression (n = 46) or non-suppression of PRC (n = 59) at follow-up and compared them to PA patients after ADX (n = 79).
Results
At baseline, patients treated by ADX or MRA had comparable left ventricular mass index (LVMI, 61.7 vs 58.9 g/m2.7, P = 0.591). Likewise, patients on MRA had similar LVMI at baseline, when stratified into treatment groups with suppressed and unsuppressed PRC during follow-up (60.0 vs 58.1 g/m2.7, P = 0.576). In all three groups, we observed a significant reduction in LVMI following treatment (P < 0.001). However, patients with suppressed PRC had no decrease in pro-BNP levels, and the reduction of LVMI was less intense than in patients with unsuppressed PRC (4.1 vs 8.2 g/m2.7, P = 0.033) or after ADX (9.3 g/m2.7, P = 0.019). Similarly, in multivariate analysis, higher PRC was correlated with the regression of LVH.
Conclusion
PA patients with suppressed PRC on MRA show impaired regression of LVH. Therefore, dosing of MRA according to PRC could improve their cardiovascular benefit.
Introduction
Primary aldosteronism (PA) represents the most frequent cause of endocrine arterial hypertension and affects at least 5–10% of patients with elevated blood pressure (1). The deleterious combination of aldosterone excess and inadequate high oral sodium ingestion exerts its effects via the mineralocorticoid receptor (MR) resulting in hypertension and target organ damage far beyond blood pressure effects (2, 3). Thereby, the MR is not only expressed in epithelial (e.g. kidney, colon, sweat, and salivary gland) but also in other tissues, such as the heart, namely in cardiomyocytes (4). Cardiac damage including left ventricular dilatation, myocardial fibrosis, and left ventricular hypertrophy (LVH) has been frequently reported (5). Compared to patients with essential hypertension, LVH is more distinct in patients with PA, explained by direct aldosterone effects independent of blood pressure levels (4, 5, 6, 7, 8). Treatment strategies for PA are based on unilateral adrenalectomy in case of unilateral disease and on medical treatment with mineralocorticoid receptor antagonists (MRA) in case of bilateral disease. Both strategies are proven to decrease cardiovascular risk (9, 10). While the favorable effect of unilateral adrenalectomy, allowing biochemical cure, is beyond dispute, it is still under discussion if the effects of MRA treatment are comparable concerning cardiometabolic outcomes (11, 12, 13, 14). This is further underlined by previous echocardiographic studies reporting a superiority of adrenalectomy compared to MRA treatment on the regression of LVH (14, 15, 16, 17).
Hundemer and colleagues recently showed in a retrospective cohort study that patients with PA on MRA had elevated cardiovascular risk compared to patients with essential hypertension when plasma renin activity remained suppressed at follow-up (18). If confirmed in prospective trials, this could explain different findings in patients on MRA and would have a relevant effect on MRA dosing. However, uptitration of MR antagonists, to reach stimulated renin levels, could bear a risk for adverse effects such as hyperkalemia in this vulnerable population.
To provide further data on this issue, we postulated that suppression of plasma renin concentration (PRC) in patients with PA on MRA could have negative effects on the recovery of left ventricular remodeling and increases the risk for cardiovascular morbidity and mortality (19). Therefore, we investigated the impact of suppressed PRC on echocardiographic findings in PA patients treated with MRA.
Methods
Patients and methods
In total, we screened 212 prospective patients with PA from the Munich center of the German Conn’s Registry, who attended baseline and follow-up visits 1 year after initiation of treatment, including echocardiography examination, for study participation. Thereof 184 patients, who underwent unilateral adrenalectomy (n = 79) or MRA treatment (n = 105), had a technically accurate echocardiography examination and adequate data set, which represent the cohort included in this study. Patients were studied prospectively within the registry, whereas analysis of echocardiography data represented post-hoc analyses. All patients gave written informed consent, and the protocol of the German Conn’s Registry was approved by the Ethics Committee of the University of Munich.
The diagnostic procedures and subtype diagnosis were performed according to the Endocrine Society Practice Guidelines and are published elsewhere (9, 20, 21). At each visit, patients underwent standardized clinical phenotyping including the collection of anthropometric data and clinical characteristics such as duration of hypertension and current medication. Blood pressure measurement was performed in the sitting position with uncrossed legs, and the arm cuff was placed at the heart level. Blood pressure readings were obtained at the same site after not less than 10 min of rest using a validated automatic oscillometric device. The measurement was attended by a study nurse, and the first readings were analyzed.
In the case of unilateral disease of PA, all patients were offered unilateral adrenalectomy. Patients with unilateral disease, who had contraindications for adrenalectomy or refused surgery (n = 10), and all other patients were medically treated with MRA: treatment was started low-dose and was uptitrated according to blood pressure and serum potassium levels. All patients were re-evaluated about 1 year after treatment in a standardized fashion.
Laboratory analysis and derivation of cut-offs for PRC
Blood samples were drawn in a fasting state in a sitting position in the morning. Plasma aldosterone concentration was measured using the RIA 'Aldosterone Coat-a-Count' (Biermann DPC, Bad Nauheim, Germany) until 2014 and was replaced by the DiaSorin Liaison. PRC was measured with the DiaSorin Liaison in all patients, respectively.
The Endocrine Society Practice Guidelines report a plasma renin activity of 1 μg/L/ h being equivalent to a PRC of 12 mU/L, when measured by the DiaSorin CLIA (9, 22). As 1 μg/L/ h is generally regarded as a cut-off for suppression of plasma renin activity, a PRC < 12 mU/L was defined as suppressed in our cohort (18).
Cardiac ultrasound examination
Comprehensive transthoracic echocardiographic examination was performed by experienced examiners (Department of internal medicine I, cardiology, from the LMU Klinikum Munich), who were blinded with regard to diagnosis and clinical details. A transthoracic study included 2D and M-mode echocardiography, and the ultrasound machines used were of high quality (GE Healthcare Vivid 7, Philips iE 33). Echocardiographic parameters were measured according to the recommendation of the American Society of Echocardiography (23, 24). A detailed report of echocardiographic examinations with calculation of echocardiography-based left ventricular mass (LVM) and left ventricular mass index (LVMI) estimation in participants of German Conn’s Registry was published previously (16). LVH was defined as LVMI ≥ 50 g/m2.7 in males and ≥47 g/m2.7 in females (25). Depending on relative wall thickness (RWT), LVH was subdivided in concentric geometry with RWT ≥ 0.42 or eccentric with RWT < 0.42 (24). Concentric remodeling was defined as normal LVM and RWT ≥ 0.42.
Statistical analysis
All numerical values are expressed as median, 25th, and 75th percentile, if not mentioned otherwise. Data between groups were compared using Mann–Whitney U-test, Kruskal–Wallis test, or chi-square test for numerical or categorical variable, respectively. Within-group, changes from baseline to follow-up were calculated by Wilcoxon signed-rank test and McNemar’s test for numerical or categorical variable, respectively. Spearman’s rank correlation coefficient was used to perform bivariate correlation analysis. Stepwise multiple regression analysis was used for multivariate analysis.
Two-tailed probability values of <5% were considered to be statistically significant. Statistical analysis was performed using standard statistical software (IBM SPSS Statistics for Windows, Version 26, IBM Corp.).
Results
Patient characteristics
The clinical and biochemical features of the cohort are shown in Table 1. In total, 105 patients received MRA treatment (MRA group) and 79 patients underwent surgical treatment for PA (adrenalectomy group). As expected, at time of diagnosis, patients in adrenalectomy group had higher plasma aldosterone levels (234 vs 153 ng/L, P < 0.001), more intense antihypertensive treatment according to defined daily doses (DDD, 3.0 vs 2.0, P = 0.039), more pronounced proteinuria (160 vs 140 mmol/24 h, P = 0.017), and lower potassium levels (3.4 vs 3.7 mmol/L, P < 0.001) than patients in the MRA group. One year after initiation of treatment, systolic and diastolic blood pressure as well as serum potassium levels widely normalized after surgical or medical treatment (Table 1). DDDs of antihypertensive medication decreased significantly after adrenalectomy (3.0 vs 1.0, P < 0.001), whereas DDDs increased in the MRA group (2.0 vs 2.3, P = 0.021). Pro-BNP improved in both groups.
Baseline and 1-year follow-up characteristics of patients with primary aldosteronism according to treatment modality. Data are given as median (25th, 75th percentile).
| Patient characteristics | MRA group (n = 105) | Adrenalectomy group (n = 79) | ||||||
|---|---|---|---|---|---|---|---|---|
| Before treatment initiation | Follow-up after 1 year | Difference | P | Before treatment initiation | Follow-up after 1 year | Difference | P | |
| Age (years) | 49 (42; 58) | – | – | – | 50 (42; 58) | – | – | – |
| Sex (f/m) | 41/64 | – | – | – | 41/38 | – | – | – |
| Duration of hypertension (months) | 90 (24; 193) | – | – | – | 95 (46; 183) | – | – | – |
| BMI (kg/m2) | 26.9 (24.4; 30.5) | 26.8 (24.2; 30.1) | 0.0 (–0.5; 0.6) | 0.794 | 26.9 (23.8; 29.6) | 26.9 (23.8; 29.1) | 0.0 (–0.8; 0.6) | 0.403 |
| Plasma aldosterone (ng/L) | 153 (108; 223) | 218 (152; 367) | 68 (–18; 172) | <0.001 | 234 (146; 335)## | 70 (35; 115) | –155 (–249; –52) | <0.001 |
| Plasma renin concentration (mU/L) | 4.2 (2.1; 8.1) | 15.0 (5.4; 36.6) | 9.1 (1.5; 30.9) | <0.001 | 3.0 (2.0; 9.3) | 14.9 (7.4; 35.8) | 10.9 (1.9; 28.6) | <0.001 |
| SBP (mmHg) | 151 (139; 170) | 133 (124; 144) | –19 (–32; –6) | <0.001 | 152 (137; 170) | 133 (123; 141) | –22 (–37; –2) | <0.001 |
| DBP (mmHg) | 94 (87; 101) | 86 (81; 96) | –6 (–17; 3) | <0.001 | 91 (83; 102) | 87 (80; 96) | –4 (–13; 3) | 0.001 |
| Antihypertensive agents (DDD) | 2.0 (1.0; 3.5) | 2.3 (0.7; 4.4) | 0.3 (–0,7; 1.7) | 0.021 | 3.0 (1.5; 4.0)# | 1.0 (0.0; 3.5) | –1.2 (–2.8; 0.0) | <0.001 |
| Serum potassium (mmol/L) | 3.7 (3.4; 4.0) | 4.3 (4.0; 4.5) | 0.5 (0.2; 0.9) | <0.001 | 3.4 (3.0; 3.7)## | 4.3 (4.0; 4.6) | 0.9 (0.5; 1.4) | <0.001 |
| Serum creatinine (mg/dL) | 0.9 (0.7; 1.0) | 1.0 (0.8; 1.1) | 0.1 (0.0; 0.2) | <0.001 | 0.8 (0.7; 1.0) | 1.0 (0.8; 1.2) | 0.1 (0.0; 0.3) | <0.001 |
| Urinary sodium excretion (mmol/24 h)† | 177 (135; 237) | 190 (137; 243) | 11 (–41; 63) | 0.287 | 204 (162; 255) | 171 (129; 253) | –6 (–92; 36) | 0.043 |
| Proteinuria (mmol/24 h)† | 140 (112; 184) | 118 (95; 140) | –20 (–71; –1) | <0.001 | 160 (130; 252)# | 103 (88; 126) | –57 (–144; –32) | <0.001 |
| Pro-BNP (pg/mL)† | 80 (42; 139) | 62 (27; 113) | –12 (–50; 22) | 0.012 | 100 (55; 203) | 52 (25; 113) | –52 (–116; 1) | <0.001 |
| LVM (g) | 264 (219; 311) | 226 (186; 277) | –31 (–59; –8) | <0.001 | 274 (210; 337) | 234 (171; 280) | –37 (–76; –11) | <0.001 |
| LVMI (g/m2.7) | 58.9 (49.7; 71.3) | 50.9 (43.2; 60.9) | –6.2 (–13.4; –1.7) | <0.001 | 61.7 (49.4; 72.6) | 50.9 (41.2; 59.9) | –9.3 (–17.6; –3.0) | <0.001 |
| LVIDd (mm) | 50 (46; 52) | 47 (44; 51) | –2 (–4; 0) | <0.001 | 51 (47; 55) | 47 (45; 52) | –3 (–6; 0) | <0.001 |
| PWTd (mm) | 11 (10; 12) | 10 (9; 11) | 0 (–1; 0) | <0.001 | 10 (9; 12) | 10 (9; 11) | –1 (–2; 0) | 0.001 |
| IVSd (mm) | 12 (11; 13) | 11 (10; 13) | –1 (–1; 0) | <0.001 | 12 (10; 13) | 11 (10; 13) | –1 (–2; 0) | <0.001 |
| RWTd (cm) | 0.45 (0.41; 0.51) | 0.45 (0.40; 0.51) | 0.00 (–0.04; 0.02) | 0.325 | 0.43 (0.38; 0.48)# | 0.43 (0.38; 0.51) | 0.00 (–0.04; 0.04) | 0.739 |
Differences between baseline values of both groups were marked with # for P < 0.05 and ## for P < 0.001; †Due to incomplete data, the calculations for 24-h urinary sodium excretion and proteinuria (adrenalectomy: n = 68, MRA: n = 92) and for pro-BNP (adrenalectomy: n = 70, MRA: n = 100) were performed with a reduced number of patients as listed in brackets.
DBP, diastolic blood pressure; DDD, defined daily doses; IVSd, interventricular septum thickness in diastole; LVIDd, left ventricular internal dimension in diastole; LVM, left ventricular mass; LVMI, left ventricular mass indexed for height to the 2.7 power; MRA, mineralocorticoid receptor antagonist; PWTd, posterior wall thickness in diastole; RWTd, relative wall thickness in diastole; SBP, systolic blood pressure.
Echocardiographic findings
Table 1 summarizes echocardiographic geometric characteristics in patients undergoing adrenalectomy or MRA treatment, respectively. LVMI was increased, and the interventricular septum in diastole (IVSd) was thickened in both groups at baseline. The overall prevalence of LVH was 76% before initiation of treatment (adrenalectomy 77%; MRA: 75%), compared to 55% at follow-up (adrenalectomy: 54%, P < 0.001; MRA: 55%, P < 0.001). There was a shift from eccentric and concentric hypertrophy toward normal left ventricular geometry. As expected, LVMI improved in both adrenalectomy and MRA group (both: P < 0.001). The reduction of LVMI in absolute numbers was higher after adrenalectomy (9.3 vs 6.2 g/m2.7, P = 0.108; Fig. 1), with a significant decrease of left ventricular internal dimension in diastole (LVIDd, both: P < 0.001), posterior wall thickness (PWTd, MRA group: P < 0.001; adrenalectomy group: P = 0.001), and IVSd (both: P < 0.001) in both cohorts.
Reduction of LVMI in patients with PA treated with either MRA or adrenalectomy. Median and 95% CI of the difference in LVMI between baseline and follow-up are shown. Patients treated with MRA are split up for suppression or non-suppression of plasma renin concentration at follow-up. LVMI, left ventricular mass indexed for height to the 2.7 power; MRA, mineralocorticoid receptor antagonist treatment; PRC, plasma renin concentration.
Citation: European Journal of Endocrinology 185, 5; 10.1530/EJE-21-0018
Reduction of LVMI in patients with PA treated with either MRA or adrenalectomy. Median and 95% CI of the difference in LVMI between baseline and follow-up are shown. Patients treated with MRA are split up for suppression or non-suppression of plasma renin concentration at follow-up. LVMI, left ventricular mass indexed for height to the 2.7 power; MRA, mineralocorticoid receptor antagonist treatment; PRC, plasma renin concentration.
Citation: European Journal of Endocrinology 185, 5; 10.1530/EJE-21-0018
Reduction of LVMI in patients with PA treated with either MRA or adrenalectomy. Median and 95% CI of the difference in LVMI between baseline and follow-up are shown. Patients treated with MRA are split up for suppression or non-suppression of plasma renin concentration at follow-up. LVMI, left ventricular mass indexed for height to the 2.7 power; MRA, mineralocorticoid receptor antagonist treatment; PRC, plasma renin concentration.
Citation: European Journal of Endocrinology 185, 5; 10.1530/EJE-21-0018
Findings in the subgroup of patients undergoing MRA treatment
When parsing patients on MRA corresponding to suppression (PRC <12 mU/) or non-suppression of PRC at follow-up, both subgroups did not differ significantly for most baseline parameters such as age, blood pressure, DDDs, and plasma aldosterone levels as well as 24-h urinary sodium excretion (Table 2). However, renin levels were significantly lower in patients with suppression of PRC at follow-up. Baseline parameters of the left ventricular structure were similar in both subgroups (Table 2).
Baseline and 1-year follow-up characteristics of patients with primary aldosteronism on MRA according to suppressed and unsuppressed PRC at follow-up. Data are given as median (25th, 75th percentile).
| Patient characteristics | MRA group with PRC <12 mU/L (n = 46) | MRA group with PRC ≥ 12mU/L (n = 59) | ||||||
|---|---|---|---|---|---|---|---|---|
| Before treatment initiation | Follow-up after 1 year | Difference | P | Before treatment initiation | Follow-up after 1 year | Difference | P | |
| Age (years) | 48 (40; 60) | – | – | – | 49 (43; 56) | – | – | – |
| Sex (f/m) | 19/27 | – | – | – | 22/37 | – | – | – |
| Duration of hypertension (months) | 100 (26; 220) | – | – | – | 87 (21; 178) | – | – | – |
| BMI (kg/m2) | 26.3 (24.1; 29.0) | 26.6 (23.8; 29.4) | 0.0 (–0.1; 0.6) | 0.228 | 27.8 (24.7; 30.8) | 27.2 (24.4; 30.5) | 0.0 (–0.6; 0.6) | 0.629 |
| Plasma aldosterone (ng/L) | 163 (110; 239) | 175 (127; 280) | 12 (–62; 75) | 0.702 | 146 (103; 188) | 276 (174; 391) | 117 (28; 226) | <0.001 |
| Plasma renin concentration (mU/L) | 3.1 (2.0; 6.4) | 5.0 (3.0; 8.9) | 1.4 (–0.2; 4.9) | 0.014 | 6.7 (3.1; 9.1)# | 32.5 (18.4; 64.5) | 28.6 (13.0; 62.5) | <0.001 |
| SBP (mmHg) | 150 (132; 173) | 136 (127; 150) | –14 (–33; 1) | <0.001 | 151 (143; 164) | 132 (123; 141) | –21 (–30; –8) | <0.001 |
| DBP (mmHg) | 95 (86; 105) | 89 (82; 99) | –4 (–15; 7) | 0.044 | 92 (89; 99) | 84 (79; 93) | –9 (–17; 0) | <0.001 |
| Antihypertensive agents (DDD) | 1.8 (0.5; 3.0) | 2.6 (0.7; 5.0) | 0.6 (–0.4; 2.3) | 0.012 | 2.0 (1.0; 4.0) | 2.3 (0.9; 3.8) | 0.2 (–1.1; 1.7) | 0.399 |
| MRA (DDD) | 0.0 (0.0; 0.0) | 0.7 (0.3; 0.7) | 0.7 (0.3; 0.7) | <0.001 | 0.0 (0.0; 0.0) | 0.7 (0.7; 0.7) | 0.7 (0.7; 0.7) | <0.001 |
| Serum potassium (mmol/L) | 3.7 (3.3; 3.9) | 4.2 (4.0; 4.4) | 0.5 (0.3; 0.8) | <0.001 | 3.8 (3.6; 4.0) | 4.3 (4.1; 4.6) | 0.5 (0.2; 0.9) | <0.001 |
| Serum creatinine (mg/dL) | 0.9 (0.8; 1.0) | 0.9 (0.8; 1.1) | 0.1 (0.0; 0.1) | <0.001 | 0.9 (0.7; 1.1) | 1.0 (0.8; 1.1) | 0.1 (0.0; 0.2) | <0.001 |
| Urinary sodium excretion (mmol/24 h)† | 174 (138; 274) | 195 (136; 242) | 11 (–65; 65) | 0.657 | 178 (134; 224) | 187 (137; 244) | 11 (–30; 63) | 0.320 |
| Proteinuria (mmol/24 h)† | 144 (118; 192) | 123 (99; 143) | –24 (–79; –2) | 0.001 | 135 (109; 178) | 118 (91; 138) | –17 (–65; –1) | <0.001 |
| Pro-BNP (pg/mL)† | 70 (43; 163) | 76 (45; 178) | 4 (–39; 30) | 0.800 | 81 (41; 139) | 48 (24; 87) | –29 (–58; 5) | <0.001 |
| LVM (g) | 254 (210; 303) | 226 (182; 272) | –20 (–51; –7) | <0.001 | 266 (226; 326) | 224 (196; 282) | –40 (–68; –16) | <0.001 |
| LVMI (g/m2.7) | 60.0 (46.1; 69.2) | 51.5 (43.2; 62.6) | –4.1 (–11.2; –1.0) | <0.001 | 58.1 (50.8; 73.3) | 49.9 (43.1; 60.4) | –8.2 (–15.0; –3.6) | <0.001 |
| LVIDd (mm) | 49 (46; 52) | 47 (44; 49) | –2 (–4; 1) | 0.003 | 51 (46; 53) | 48 (44; 51) | –3 (–4; 0) | <0.001 |
| PWTd (mm) | 10 (9; 12) | 10 (9; 11) | 0 (–1; 0) | 0.043 | 11 (10; 12) | 10 (9; 11) | –1 (–2; 0) | 0.002 |
| IVSd (mm) | 12 (11; 12) | 11 (10; 13) | 0 (–1; 0) | 0.133 | 12 (11; 13) | 11 (10; 13) | –1 (–2; 0) | <0.001 |
| RWTd (cm) | 0.44 (0.40; 0.51) | 0.46 (0.40; 0.49) | 0.00 (–0.03; 0.03) | 0.843 | 0.46 (0.43; 0.51) | 0.45 (0.40; 0.53) | 0.00 (–0.04; 0.03) | 0.227 |
Differences between baseline values of both groups were marked with # for P < 0.05 and ## for P < 0.001; †Due to incomplete data, the calculations for 24-h urinary sodium excretion and proteinuria (suppressed PRC n = 41, unsuppressed PRC n = 51) and for pro-BNP (suppressed PRC n = 46, unsuppressed PRC n = 54) were performed with a reduced number of patients as listed in brackets.
DBP, diastolic blood pressure; DDD, defined daily doses; IVSd: interventricular septum thickness in diastole; LVIDd, left ventricular internal dimension in diastole; LVM, left ventricular mass; LVMI, left ventricular mass indexed for height to the 2.7 power; MRA, mineralocorticoid receptor antagonist; PRC, plasma renin concentration; PWTd, posterior wall thickness in diastole; RWTd, relative wall thickness in diastole; SBP, systolic blood pressure.
Specific medical treatment for PA was initiated in 96 patients with spironolactone and in 9 patients, with eplerenone using a median dose of 50 mg per day at follow-up. Systolic as well as diastolic blood pressure levels significantly decreased at follow-up and were comparable between both subgroups (SBP 136 vs 132 mmHg, P = 0.131; DBP 89 vs 84 mmHg, P = 0.122). DDDs of antihypertensive agents significantly increased in the suppressed PRC group (P = 0.012), whereas in patients with unsuppressed PRC, there was only a trend toward higher DDDs (P = 0.399). The use of subclasses of other antihypertensive medication was comparable between the subgroups and is shown in Table 3. Potassium levels normalized, and 24-h urinary sodium excretion was unaltered and comparable in both subgroups (P = 0.962). Whereas PRC increased in both subgroups, aldosterone levels increased only in the subgroup with unsuppressed PRC (146 vs 276 ng/L, P < 0.001) and remained almost unchanged in the subgroup with suppressed PRC (163 vs 175 ng/L, P = 0.702).
Use of subclasses of antihypertensive medication at 1-year follow up in patients with PA treated with MRA. Data are given as the sum of defined daily doses and the percentage of treated patients. Data between groups were compared using Mann–Whitney U-test.
| MRA group with PRC <12 mU/L (n = 46) | MRA group ≥with PRC 12 mU/L(n = 59) | P | |
|---|---|---|---|
| Antihypertensive agents | 146 (100%) | 172 (100%) | 0.570 |
| MRA | 29 (100%) | 42 (100%) | 0.201 |
| Other diuretics | 4 (13%) | 8 (17%) | 0.504 |
| ACE inhibitors/AT1-receptor blockers | 47 (41%) | 52 (39%) | 0.611 |
| Beta blockers | 21 (41%) | 12 (29%) | 0.149 |
| Others | 45 (46%) | 58 (54%) | 0.662 |
ACE, angiotensin converting enzyme; AT1, angiotensin II type 1; DDD, defined daily doses of antihypertensives; MRA, mineralocorticoid receptor antagonist.
The extent of the regression of LVH was significantly higher in patients with unsuppressed than in patients with suppressed PRC (8.2 vs 4.1 g/m2.7, P = 0.033), with a significant decrease of LVIDd (P < 0.001), PWTd (P = 0.002), and IVSd (P < 0.001). In patients with suppressed PRC, only LVIDd (P = 0.003) and PWTd (P = 0.043) improved significantly. The reduction of LVMI at follow-up was not distinguishable between patients with unsuppressed PRC and patients with adrenalectomy (8.2 vs 9.3 g/m2.7, P = 0.610). In line with these findings, pro-BNP levels significantly improved in patients after adrenalectomy and in patients with unsuppressed PRC but not with suppressed PRC at follow-up.
Correlations of factors with impact on left ventricular structure and remodeling
In univariate analysis of all 184 patients with PA age (r = 0.187, P = 0.011), duration of hypertension (r = 0.215, P = 0.003), male sex (r =0.239, P = 0.001), systolic blood pressure and DDD (r = 0.241, P = 0.001; r = 0.302, P < 0.001), pro-BNP (r = 0.176, P = 0.022), and 24-h urinary sodium excretion (r = 0.219, P = 0.005) but not plasma aldosterone concentration (r = 0.129, P = 0.080) correlated with LVMI at time of diagnosis. At follow-up, findings were comparable except for 24-h urinary sodium excretion, which no longer correlated with LVMI.
Changes in LVMI in patients on MRA correlated in univariate analysis with renin and potassium levels at follow-up (r = –0.256, P = 0.006; r = –0.281, P = 0.003), but not with urinary sodium excretion (r = –0.165, P = 0.118) or plasma aldosterone concentration (r = –0.039, P = 0.694). Similarly, in multivariate analysis, renin levels and serum potassium at follow-up were correlated with the reduction in LVMI (P = 0.006, P < 0.001; Table 4). Neither baseline nor follow-up 24-h urinary sodium excretion nor plasma aldosterone levels did have a significant effect in this model.
Multivariate regression analysis for the reduction of left ventricular mass in patients with PA treated by MRA. Data are given as P-values for multivariable analysis.
| Regression coefficient | 95% CI | P | |
|---|---|---|---|
| Age | 0.071 | –0.115, 0.257 | 0.448 |
| Duration of hypertension | 0.000 | –0.015, 0.015 | 0.994 |
| Sex | 0.227 | –4.030, 4.485 | 0.916 |
| DDD | –0.002 | –0.920, 0.917 | 0.997 |
| 24-h urinary sodium excretion | –0.004 | –0.029, 0.021 | 0.739 |
| Pro-BNP | –0.004 | –0.011, 0.003 | 0.221 |
| SBP | –0.063 | –0.152, 0.026 | 0.162 |
| Follow-up | |||
| Serum potassium | –8.391 | –12.946, –3.836 | <0.001 |
| PRC | –0.044 | –0.075, –0.013 | 0.006 |
| Plasma aldosterone | 0.009 | –0.002, 0.020 | 0.115 |
DDD, defined daily doses of antihypertensives; PRC, plasma renin concentration; SBP, systolic blood pressure.
Discussion
Patients with PA are at greater risk for cardiovascular events, compared to patients with essential hypertension (2). Only a small subset of patients with unilateral PA can be cured by adrenalectomy, while the others are treated medically using MRA. There is an ongoing debate on the effectiveness of MRA treatment compared to adrenalectomy regarding cardiovascular, metabolic, and psychopathological outcomes. Moreover, it is unclear whether MRA treatment should not only be titrated to control blood pressure but also to achieve specific renin cut-offs (18, 26, 27, 28). In this regard, the latest Endocrine Society Guidelines still recommend low-dose treatment to avoid side-effects (9). This issue further gained attention after Hundemer and colleagues reported a higher risk for incident cardiometabolic events, atrial fibrillation, and death in PA patients on MRA, whose plasma renin activity remained suppressed, compared to patients with unsuppressed renin activity and patients with essential hypertension, suggesting an insufficient inhibition of the MR (18, 29, 30, 31).
Although MRA treatment is known to improve left ventricular geometry in patients with heart failure, echocardiographic studies comparing the effects of adrenalectomy or MRA treatment on left ventricular remodeling in patients with PA reported conflicting results with either an equality of both treatment strategies or a superiority of adrenalectomy (7, 13, 15, 32). However, plasma renin activity or PRC, a marker for the blockade of the MR, was not considered. Therefore, we focused on the question whether suppression of PRC in PA patients on MRA has negative effects on LV structure and geometry, compared to patients with unsuppressed PRC or after adrenalectomy.
In this cohort of patients with PA, we could show that the improvement of LVMI was associated with the rise in PRC at follow-up. In accordance with previous findings, MRA treatment resulted in a reduction of LVMI in our cohort, but the regression of LVH was more pronounced in patients with unsuppressed PRC than in patients with suppressed PRC at follow-up (8.2 vs 4.1 g/m2.7, P = 0.033). Interestingly, the impact of MRA treatment on regression of LVMI in patients with unsuppressed PRC was comparable with adrenalectomy (9.3 vs 8.2 g/m2.7, P = 0.610). In accordance with these findings, 70% (n = 32) of patients with suppressed PRC and 80% (n = 47) of patient with unsuppressed PRC fulfilled the criteria of LVH at baseline. At follow-up, the percentage of LVH was reduced in patients with unsuppressed PRC (80% vs 53%, P < 0.001), whereas in patients with suppressed PRC, there was only a trend toward lower levels (70% vs 59%, P = 0.063). This is also illustrated by the fact that we detected a decrease in pro-BNP levels at follow-up only in patients after adrenalectomy and in patients with unsuppressed PRC on MRA (both: P < 0.001). In the subcohort with suppressed PRC, pro-BNP was unaltered at follow-up (P = 0.800).
It is well known that the decrease of blood pressure levels, as well as the intensity of antihypertensive treatment, reduces the left ventricular mass in patients with essential hypertension (33). Anyhow, a major bias through blood pressure changes or antihypertensive treatment in our cohort is rather unlikely. First, systolic and diastolic blood pressure levels were comparable in patients on MRA with suppressed and unsuppressed renin levels at baseline (Table 2). Initiation of MRA treatment resulted in a decrease of blood pressure levels, which tended to be more pronounced in the unsuppressed PRC group (n.s.) and ended up with comparable blood pressure levels in both subgroups (SBP: P = 0.131; DBP: P = 0.122; Table 2). Secondly, defined daily doses of MRA (0.7 vs 0.7, P = 0.201; Table 2) and other subclasses of antihypertensive medication at follow-up were comparable between patients on MRA with unsuppressed and suppressed PRC (Table 3). Thirdly, in multivariate analysis to adjust for confounders (including blood pressure), renin levels and serum potassium at follow-up were correlated with the reduction in LVMI (P = 0.006, P < 0.001; Table 4). Finally, we showed evidence for a blood pressure-independent effect of insufficient MR blockade on the regression of LVH in PA patients, estimated by plasma renin concentration. Hereby we confirm and extend findings from Hundemer and colleagues by demonstrating specific effects of ongoing suppression of PRC on cardiac remodeling despite MRA treatment (18). In context with an association of PRC at follow-up with the decrease in LVMI in our study, it can be speculated that higher PRC levels than 12 mU/L could be even more beneficial concerning individual cardiovascular risk (Table 4). In line with these considerations, when using the 50th percentile of PRC values at follow-up as cut-off, we even could detect a more pronounced decrease in left ventricular mass (15.0 mU/L: 4.0 vs 9.6 g/m2.7; P = 0.003). If a cut-off for PRC of 12 mU/L, therefore, already reflects an adequate blockade of the MR needs to be addressed in further studies.
When applying our findings to previous echocardiographic studies, this could reconcile conflicting results by the fact that the improvement of left ventricular parameters in patients on MRA could rather result from insufficient inhibition of MR-mediated aldosterone effects, than only by persistence of nongenomic effects of aldosterone, an effect which to date has not been taken into account (7, 11, 12, 13, 14).
Funder already speculated in his editorial that suppressed PRC, besides an insufficient blockade of the MR, could also be a consequence of high dietary sodium intake (18, 31, 34, 35). In our study, dietary sodium intake, estimated by 24-h urinary sodium excretion, was much higher than recommended by the WHO but comparable between patients with unsuppressed and suppressed PRC at baseline and at follow-up (195 mmol/day vs 187 mmol/day, P = 0.962; Table 2) (36). A major bias by dietary salt intake seems, therefore, unlikely. Nevertheless, physicians should further encourage patients to reduce their dietary salt intake in order to ameliorate individual cardiovascular risk (2, 37).
Taking into account findings from Hundemer and ours, we think using plasma renin activity or PRC to monitor sufficient inhibition of the MR could be a helpful tool to further reduce cardiovascular mortality and morbidity in this vulnerable cohort of patients. In the case of well-controlled blood pressure levels, this could also necessitate a reduction of other antihypertensives to allow an increase of MRA dosage until stimulated renin levels are reached, as reported by Lechner et al. (28). Measurement of canrenone levels, which allows to consider differences in individual metabolism of the prodrug spironolactone, could be a promising future perspective (38, 39). Anyhow, prospective studies have to focus on this topic to prove potential benefits and risks for patients with increased MRA doses.
Our study has several limitations. The echocardiographic examinations in this study were performed by different experienced investigators and, therefore, individual measurement variance could influence wall thicknesses estimation. Furthermore, using M-mode measurement for the estimation of LVM is known to be less accurate compared to real-time three-dimensional echocardiography or three-dimensional imaging by MRI (40). However, the investigators were blinded with regard to the underlying cause of disease, which we consider strength of the study approach. Blood pressure measurement was performed in a standardized fashion; however, only the first readings at each visit could be analyzed in this study, which could have led to an overestimation of blood pressure levels (41).
In our study, we used PRC to estimate suppression of renin instead of plasma renin activity, using the specific conversion factor published in The Endocrine Society Guidelines (9, 22). Although plasma renin activity is supposed to be more sensitive in patients with low renin levels, the complexity of the laboratory procedure and different laboratory protocols limit the reproducibility of plasma renin activity, which prevented its wider use, and assays measuring PRC were invented (42, 43). As strengths of our study, we consider the prospective standardized collection of all data and biomaterial within the context of the German Conn’s Registry as well as the well-characterized study population, which included diagnosis and subtyping of PA according to The Endocrine Society Guidelines. The high level of data quality and integrity allowed us a sufficient follow-up investigation including standardized measurement of PRC in all patients as well as to adjust for confounding facts such as duration of hypertension.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.
Funding
This work was supported by the Else Kröner-Fresenius Stiftung in support of the German Conn’s Registry-Else-Kröner Hyperaldosteronism Registry (2013_A182, 2015_A171 and 2019_A104 to M R), the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 694913 to M R), by the Deutsche Forschungsgemeinschaft (DFG) (within the CRC/Transregio 205/1 ‘The Adrenal: Central Relay in Health and Disease’ to C A, D A H, H S, and M R) and within the Clinician Scientist PRogram In Vascular MEdicine (PRIME) MA 2186/14-1 to H S).
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