Maintenance of long‐term blood pressure control and vascular health by low‐dose amiloride‐based therapy in hyperaldosteronism

Abstract

Whether aldosterone itself contributes directly to macro‐ or microcirculatory disease in man or to adverse cardiovascular outcomes is not fully known. We report our long‐term single‐practice experience in an unusual group of five patients with chronic hyperaldosteronism (HA, including three with glucocorticoid‐remediable aldosteronism, GRA) treated with low‐dose amiloride (a specific epithelial sodium channel [ENaC] blocker) 5‐10 (mean 7) mg daily for 14‐28 (mean 20) years. Except for one GRA diagnosed in infancy, all had severe resistant hypertension. In each case, BP was normalized within 1‐4 weeks after starting amiloride and office BP’s remained well controlled throughout the next two decades. 24‐hour ambulatory BP monitoring with pulse wave analysis (cardiac output, vascular resistance, augmentation index, reflection magnitude), regional pulse wave velocities, pulse stiffening ratio, ankle‐brachial index, serum creatinine, estimated glomerular filtration rate, and spot urinary albumin:creatinine ratio were measured after a mean of 18 years; all of these indicators were essentially normal. Over two additional years of observation (100 patient‐years total), no cardiovascular or renal event occurred. We conclude that long‐term ENaC blockade with amiloride can normalize BP and protect macro‐ and microvascular function in patients with HA. This suggests that either (a) putative vasculopathic effects of aldosterone are mediated via ENaC or (b) aldosterone may not play a direct role in age‐dependent vasculopathic changes in humans independent of blood pressure. These findings, coupled with our literature review in both animal and human results, underscore the need for additional studies.

1. INTRODUCTION

Primary hyperaldosteronism (HA) due to diverse causes, including genetic mutations (eg, glucocorticoid‐remediable aldosteronism, GRA), diffuse or nodular adrenal cortical hyperplasia, or adrenal adenoma often results in resistant or refractory hypertension.1 In animals and man, mineralocorticoid excess alone is not usually sufficient to elevate blood pressure; excess dietary salt intake is also required.2, 3 At a cellular level, the primary effect of aldosterone and other mineralocorticoids is stimulation of mineralocorticoid receptors (MR). A major function of the MR is to regulate the availability of ion channels, especially epithelial sodium channels (ENaC), in cell membranes.4, 5, 6 Recent studies suggest that ENaC originally found in renal tubular cells also exists in the brain and in other tissues and cell lines including mouse vascular endothelium and fibroblasts,4, 7, 8, 9, 10, 11, 12, 13, 14 so direct and indirect hemodynamic and volume regulatory effects of ENaC are plausible.

It is reported that the end‐organ damage profile in patients with HA is more severe than essential hypertension,15, 16, 17 including increased prevalence of cerebral hemorrhage,18 myocardial infarction,16 left ventricular hypertrophy,16 cardiac fibrosis,19 increased arterial stiffness,8, 9, 20, 21, 22, 23, 24 microalbuminuria,25, 26 and arterial wall‐to‐lumen ratio.27, 28 Attribution of HA‐associated target organ damage, however, is universally confounded by the effects of aging29 as well as the duration and degree of BP elevation (BP burden).29, 30 Furthermore, careful review of the literature suggests that the putative vasculopathic effects of aldosterone are far less clear than some investigators have suggested.

Nongenetic forms of HA are often treated surgically but chronic oral MR antagonism, generally with spironolactone, has also been used successfully to lower BP and maintain serum potassium.31, 32 A potentially useful but often forgotten drug is amiloride, a specific ENaC inhibitor.4, 5, 6 Persistent BP‐lowering effects of amiloride have been reported in short‐term studies in low‐renin hypertension5, 33 and HA,34 but there have been no long‐term or outcome trials with this agent. It is also not known if amiloride confers specific target organ benefits other than reducing microalbuminuria, which may simply reflect the degree of long‐term BP control.6

Because of the ongoing interest in aldosterone as a possible promoter of cardiovascular fibrosis and stiffness and the simultaneous possibility that ENaC may be involved in these processes, we report our experience with chronic amiloride therapy in a small group of patients with HA who were assessed clinically after 18 and 20 years of therapy for evidence of macrovascular disease (arterial stiffness) or microcirculatory disease (albuminuria and renal function). Because of the many conflicting reports in the literature, a review of related studies is also provided.

2. METHODS

Four patients were referred originally for management of resistant hypertension (BP uncontrolled on appropriate doses of at least three drug classes, including a diuretic). The fifth was the daughter of GRA1, who was the kindred proband and who received dexamethasone as a child; all three GRAs were described in the original work of Lifton and coworkers.35 Two other patients had primary HA and resistant hypertension: one with a large aldosterone‐producing adenoma and the other with apparent nodular hyperplasia (biopsy was declined); both refused adrenal surgery. After presentation of therapeutic alternatives, all patients agreed to the administration of amiloride monotherapy for better BP control. Within a few weeks, when it was established that amiloride had achieved this goal without causing noticeable side effects, all patients elected to remain on amiloride indefinitely. Vascular studies represent a single point in time after many years of amiloride therapy; all patients signed informed consent for noninvasive investigation of vascular function.

2.1. Patient profiles

Our initial patient, GRA1 had resistant hypertension uncontrolled by lisinopril, atenolol,and furosemide. Her condition was diagnosed at age 40 by genotyping following that of GRA2, her daughter. Initial workup included an undetectable plasma renin activity (<0.01 ng/mL/min) and a markedly elevated 24‐hour urinary 18‐hydroxycorticosterone excretion rate (802 mcg/day)36; hypokalemia was never observed. Serum Cr values ranged from 0.7 to 1.0; mean 0.8 mg/dL during the first 2 years of follow‐up. She had received spironolactone 25 mg daily in combination with other agents for about 2 months prior to referral but had discontinued it because of abdominal discomfort and menstrual irregularities. She also had a history of estrogen receptor‐positive breast cancer, and despite no evidence that spironolactone increased her risk of recurrence, she feared the weak estrogenic effects of spironolactone and declined to continue its use. Amiloride monotherapy (10 mg daily) was immediately effective, reducing BP from 183/115 mm Hg on presentation to 120‐140/80‐90 mm Hg within 1 month. A lower dose (5 mg daily) was investigated after 3 months with no loss of BP control; on this therapy, office values ranged from about 120‐140/70‐85 mm Hg for the next 26 years, when the vascular studies were performed. She has had no adverse cardiovascular events for 28 years.

GRA 2 (daughter of GRA1) was treated with dexamethasone throughout early childhood; based on her mother's favorable response to amiloride and in consultation with the senior author (JLI), her physician switched to amiloride 5 mg daily at age 11. BP values prior to age 14 were not available but all subsequent BP values were <120/80 mm Hg. Vascular studies were performed after 14 years on amiloride monotherapy, and she has had no adverse cardiovascular events for 16 years.

GRA 3 (sister of GRA1) was also diagnosed by genotyping. She lived in a remote location and except for a plasma renin activity <0.01 ng/mL/min, initial biochemical testing for GRA was not performed. Initial serum K was 4.1, serum Cr was 0.9 mg/dL, and urinary albumin/Cr was 13 mg/g. After telephone consultation for severe hypertension at age 41, her primary care physician started amiloride 10 mg daily; on telephone follow‐up 2 months later, she was reported to be “controlled.” Five years later, her physician retired, she temporarily lost health insurance, and she discontinued amiloride for 1 year. At that time, her office BP was 180/120 mm Hg. Reinstitution of amiloride 10 mg daily resulted in normalization of her BP within 1 month and persistent BP control thereafter (<135/85 mm Hg on multiple readings). Vascular studies were performed after 22 years of amiloride, and she has had no adverse cardiovascular events during 24 years of follow‐up.

PA 1 had resistant hypertension for several years and was eventually referred for this problem. Diuretic had been avoided by the primary physician because of persistent hypokalemia (3.4 mg/dL on first visit with values as low as 2.3 mEq/L on chart review), and for several years, she received oral potassium supplementation (20‐40 mEq daily). When she changed primary care physicians, his workup revealed a 1.7 cm solitary adenoma of the right adrenal gland on CT scan and increased venous plasma aldosterone levels (32 and 49 ng/L) and a 24‐hour urinary aldosterone excretion of 62 mcg. Subsequent adrenal venous aldosterone sampling was uninterpretable (left adrenal = inferior vena cava; both > right adrenal). Serum Cr was 0.8 mg/dL but urinary microalbuminuria was not measured. Initial office was BP 215/105 on lisinopril, nifedipine, and metoprolol; amiloride 5 mg daily was substituted for metoprolol, and amlodipine 5 mg daily was substituted for nifedipine. Discontinuation of lisinopril was recommended, but the patient was adamant that it be continued because she believed that it was “protecting her kidneys.” Within 2 months, there was full BP control: home BP mean was about 130/70 mm Hg and office BP thereafter was <140/75 mm Hg. Lisinopril was subsequently discontinued but beta‐blocker therapy was started for symptomatic relief of episodic palpitations. Vascular studies were performed after 18 years of amiloride‐based therapy. She has remained in good general health for 20 years without adverse cardiovascular events.

PA2 had resistant hypertension for at least 2 years but no hypokalemia. At age 53, office BP was 172/98 mm Hg while taking hydrochlorothiazide 25 mg, amlodipine 10 mg, and valsartan 320 mg daily. Elevated 24‐hour urinary aldosterone was documented on two occasions (22.1 and 23.2 mcg/day, with corresponding urinary sodium values of 248 and 157 mg/day). Serum Cr was 0.9 mg/dL. Imaging studies did not reveal any adenoma or significant glandular enlargement. After discussion of potential side effects of spironolactone, the patient opted to have amiloride 5 mg daily added to his prior regimen. One month later, office BP was 142/98 mm Hg and amiloride was increased to 10 mg daily; 2 months later, the patient's BP was 132/92 mm Hg and valsartan was discontinued. For the next 5 years, office BP remained borderline controlled (mean office BP < 145/95 mm Hg). Combination HCTZ/spironolactone (25/25 mg daily) was substituted for HCTZ and office BP values over the next 6 years ranged from < 130/70 to about 145/90 mm Hg. Vascular studies were performed after 12 years of amiloride, and he has taken the drug for 14 years without adverse cardiovascular events.

2.2. BP monitoring, arterial function, and hormonal studies

Baseline values were not obtained. After a mean follow‐up of 18 years, standard seated clinic BP values (mean of 3) were determined by oscillometry (Omron905CP) along with 24‐hour ambulatory monitoring studies, plasma aldosterone, renal function, pulse wave velocity, and ankle‐brachial index.

Arterial stiffness and ankle‐brachial index were assessed on one occasion by measuring foot‐to‐foot (2‐point) pulse wave velocities (PWV, Colin VP1000) in three different arterial regions: the mixed carotid‐femoral region (cfPWV), the aorta (heart‐femoral [hf] PWV), and peripheral muscular arteries (femoral‐ankle [fa] PWV). We and others have noted a scalar problem with “raw” PWV values determined by Colin VP1000 created by the manufacturer's incorrect algorithms for arterial path length.37 Based on our data from direct measurements in a reference cohort of patients (n = 40), we developed simple correction factors (corr) that were applied to the uncorrected (uncorr) values: hfPWV_corr = 0.8 hfPWV_uncorr, cfPWV_corr = 0.7 cfPWV_uncorr, and faPWV_corr = 1.1 faPWV_uncorr. Because PWV values are also highly dependent on age and systolic BP, we created normative models for expected age‐ and SBP‐adjusted PWV values. These were derived from a reference population (n = 162, age 16‐91) constructed to mimic closely the strong age‐BP relationship found in the US NHANES III cohort.38, 39 The predictive model equations were:

$${\text{hfPWV}}_{\text{uncorr}}=-340+{11}^{\ast }\text{age}+6.4^{\ast }\text{systolic}\text{BP}(r^2=0.76)$$

$${\text{cfPWV}}_{\text{uncorr}}=-627+{16}^{\ast }\text{age}+9.0^{\ast }\text{systolic}\text{BP}(r^2=0.60)$$

$${\text{faPWV}}_{\text{uncorr}}=217+4.5^{\ast }\text{diastolic}\text{BP}+2.2^{\ast }\text{systolic}\text{BP}+1.9^{\ast }\text{age}(r^2=0.58)$$

All three models were independent of gender, heart rate, height, or weight (excluded variables). In each case, the age‐ and BP‐adjusted (predicted) data were compared with the corrected observed by paired t test.

Ambulatory 24‐hour BP and pulse wave analysis was performed using a Mobil‐O‐Graph (IEM, Stolberg, Germany), with BP determinations every 20 minutes. Mean ambulatory hemodynamic indicators (cardiac output, systemic resistance, augmentation index, reflected wave magnitude) were reported for 24‐hour, daytime, and nighttime values (based on sleep diaries). From the 24‐hour BP data, we calculated an additional arterial function indicator, the pulse stiffening ratio (PSR), which quantitatively describes the nonlinear responses of arteries to variations in pulse volume and the linear sensitivity of an artery to variation in distending pressure (Table 3).40 A stepwise multiple linear regression model for normative PSR values was derived from a separate ambulatory BP monitoring reference cohort (n = 76):

$$\text{PSR}=1.14+0.{01}^{\ast }\text{systolic}\text{BP}+0.{004}^{\ast }\text{age}-0.{017}^{\ast }\text{diastolic}\text{BP}(r^2=0.36)$$

As with PWV values, expected PSR values were compared with observed values by paired t test.

Statistical analyses were based on paired t tests, including the direct comparisons of mean model predicted and mean observed values for all vascular stiffness‐related variables as well as pre‐ and post‐therapy values as noted.

3. RESULTS

Table 1 summarizes basic demographic, laboratory, and pharmacological information for each case. Blood pressure values before amiloride treatment on standard triple therapy (four of five individuals) demonstrated hypertension refractory to three or more antihypertensive drugs. There was a response to amiloride monotherapy within 1 month in each case with stable office BP values thereafter.

Table 1.

Demographic, clinical, and laboratory values

Patient	GRA1	GRA2	GRA3	PA1	PA2	Mean (SD)
Gender	F	F	F	F	M	—
Age at onset of amiloride therapy (y)	43	11	41	64	53	42 (18)
Duration of amiloride therapy (y)
Until vascular study	26	14	22	18	12	18 (5.7)
Total CVD surveillance	28	16	24	20	14	20 (5.6)
Amiloride daily dose (mg)	5	5	5/10	5	10	7 (2)
Office BP (mm Hg)
Before amiloride	183/ 115	NA	180/ 120	215/ 105	172/ 98	188 (19)/ 110 (9.9)
At time of vascular study	120/ 74	114/ 71	107/ 66	145/ 62	124/ 83	122 (14)/ 71 (8.0)
Spot urinary aldosterone (mcg/g Cr) at time of vascular study	11	—	27	111	24	43 (46)
Most recent serum K (mEq/L)	4.1	4.0	4.2	3.8	4.3	4.1 (0.2)

Most recent office blood and urinary values occurred at the time of vascular studies or within a few months.

Abbreviations: GRA, glucocorticoid‐remediable hyperaldosteronism; NA, not available; PA, primary hyperaldosteronism.

Table 2 demonstrates 24‐hour ambulatory BP and hemodynamic monitoring variables after long‐term amiloride at the time the vascular studies were performed (mean follow‐up 18 years). Essentially, all indicators fell well within the normal range.

Table 2.

24‐hour ambulatory BP and hemodynamic variables after long‐term amiloride‐based therapy

Patient	GRA1	GRA2	GRA3	PA1	PA2	Mean (SD)
Systolic BP (mm Hg)
24‐h mean	111	111	103	118	124	113 (8.0)
Daytime mean	115	116	105	122	134	118 (11)
Nighttime mean	103	101	99	113	117	107 (7.9)
Nighttime decrease (“systolic dipping”)	−12	−15	−6	−9	−17	−12 (−4.7)
Diastolic BP (mm Hg)
24‐h mean	59	68	69	60	77	67 (7.4)
Daytime mean	62	74	70	64	91	72 (12)
Nighttime mean	55	57	64	54	68	60 (6.1)
Nighttime decrease (“diastolic dipping”)	−7	−17	−6	−10	−23	−13 (−7.2)
Other hemodynamic variables from 24‐hour monitoring (24‐h means)
Heart rate (b/min)	69	86	62	63	66	69 (9.8)
Cardiac output (L/min)	4.3	4.6	4.0	4.5	5.2	4.5 (0.4)
Total vascular resistance (mm Hg.sec/mL)	1.2	1.2	1.3	1.2	1.2	1.2 (0.04)
Augmentation index@75 (%)	35	20	33	24	16	26 (8.2)
Reflection magnitude (%)	69	57	70	69	68	67 (5.4)
Pulse pressure (mm Hg)	52	43	34	58	46	47 (9.1)

Values at the time of the vascular studies (see Table 1). Abbreviations as in Table 1.

Table 3 demonstrates that macro‐ and microvascular health indicators (central and peripheral pulse wave velocities, PSR, and ankle‐brachial index) as well as microcirculatory indicators (serum creatinine [Cr], estimated glomerular filtration rate, and urinary albumin:creatinine ratio) were within the normal or age‐expected range during long‐term amiloride therapy. Serum Cr values were emphasized over eGFR for two main reasons: (a) current eGFR calculation requires standardized Cr analysis, which was not universal at the beginning of observation; and (b) eGFR is not suitable for long‐term follow‐up because it assumes a uniform age‐related decline in renal function. In this cohort, mean serum Cr value (and thus actual GFR) did not change between age 42 and age 60 (0.87 to 0.88 mg/dL) but the corresponding mean eGFR decreased by 11% (81 to 72 mL/min).

Table 3.

Macro‐ and microvascular health indicators after long‐term amiloride‐based therapy

Patient	GRA1	GRA2	GRA3	PA1	PA2	Mean (SD)
Final macrovascular indicators (arterial stiffness and stiffening, ABI)a
hfPWVcorr (cm/s)
Observed	858	470	821	1141	869	832 (238)
Predicted	874	479	696	1156	877	817 (258)
P =						0.62
cfPWVcorr (cm/sec)
Observed	947	560	792	1239	698	847 (260)
Predicted	989	497	774	1354	1002	925 (317)
P =						0.29
faPWVcorr (cm/sec)
Observed	959	826	905	1113	985	958 (106)
Predicted	993	858	916	1049	1062	926 (87)
P =						0.47
Pulse stiffening ratio
Observed	1.5	0.99	1.1	1.3	0.94	1.16 (0.23)
Predicted	1.4	1.2	1.3	1.6	1.3	1.36 (0.15)
P =						0.07
Ankle‐Brachial Index (ABI)	1.2	0.93	1.0	1.2	1.2	1.1 (0.12)
Microvascular indicators
Serum Cr (mg/dL) Initialb	0.8	0.9	0.9	0.8	0.9	0.87 (0.05)
Final	1.0	0.79	0.90	0.86	0.95	0.88 (0.08)
P =						0.47
eGFR (mL/min)
Final	57	104	68	62	84	75 (17)
ACR (mg/g)
Final	3	5	13	28	27	15 (12)

See also Table 1 and Methods section. P‐value is observed vs predicted or final vs initial by paired t test.

Abbreviations: ACR, spot urinary albumin:creatinine ratio; cf, carotid‐femoral; corr, corrected; Cr, creatinine; fa, femoral‐ankle; hf, heart‐femoral; PWV, pulse wave velocity; SD, standard deviation.

^a“Final” refers to the value at the time of last observation for each individual (mean for the group = 18 y).

^b“Initial” refers to the value at the time of original workup.

There was a 2‐year time lag between completion of the vascular studies and the preparation of this manuscript, another 2 years elapsed. This allowed us to report on an additional 10 patient‐years of follow‐up (from a mean of 18‐20 years). Thus, during 100 patient‐years of follow‐up (mean of 20 years in five patients), there were no cardiovascular, cerebrovascular, or renal events noted.

4. DISCUSSION

The rationale for chronic amiloride therapy in HA arose from our initial GRA patient, who could not tolerate spironolactone. The immediate and long‐term success she experienced with amiloride persuaded her daughter and sister to request the same treatment, which was then offered to two other patients with HA who did not wish to have surgery. Although our cohort is very small, it is a rare group that actually represents the heterogeneous nature of HA. Our results are also very consistent. Thus, at least in some patients with HA, ENaC blockade with low‐dose amiloride‐based therapy is highly effective in controlling BP control and in protecting against macro‐ and microvascular disease over 18 years (90 patient‐years) and adverse cardiovascular, cerebrovascular, and renal events over 20 years (100 patient‐years) of follow‐up. Given the typical admonition that patients with HA experience more end‐organ damage and adverse cardiovascular events, present results are noteworthy5, 6, 7 but how much of the observed benefits are attributable to excellent BP control and how much to other mechanisms cannot be determined. However, amiloride is highly specific for ENaC and does not appear to affect aldosterone secretion, which remained high throughout. From these observations, it can be deduced that either: (a) ENaC is the final common pathway for aldosterone‐dependent tissue damage in man or (b) the persistent burden of hypertension may be more important than the degree of chronic MR stimulation in causing end‐organ damage.

In reviewing in vitro, in vivo, and clinical investigations, and despite strong opinion to the contrary,41, 42, 43, 44 it is not at all clear that aldosterone itself or MR stimulation per se inevitably causes premature macro‐ or microcirculatory disease. On the pro‐side, aldosterone stimulates cardiac fibroblasts in vitro to increase collagen syntheses,43 an effect that can be at least partially ameliorated by MR blockade with spironolactone.20, 21, 43 Also in rats, MR antagonists (spironolactone and eplerenone) reduce cardiac procollagen markers.45 However, the effects of MR antagonism in vivo on BP, vascular collagen content, and arterial stiffness (PWV) are less consistent.20, 21 Humans with high plasma aldosterone or overt HA tend to have stiffer arteries (higher PWV values)46, 47 but these individuals also tend to have a higher lifetime BP burden, which itself may be the primary explanation for high arterial stiffness or microcirculatory disease. Other confounders of the aldosterone‐hypertension‐vascular disease relationship include aging itself and importantly, dietary salt intake.48, 49 Perhaps more challenging to the belief that aldosterone has a unique role in vasculopathy is the quick onset of reported vascular benefits of MR antagonism. For example, arterial stiffness in patients with HA has been reported to decrease within a few weeks after adrenalectomy roughly in parallel with the BP,41 yet true human aortic remodeling would be expected to take much longer (months to years) according to known fibroblast‐collagen kinetics.50 With respect to understanding the pathogenesis of microcirculatory damage, confounding attributable to arterial pressure is always present. For example, HA in humans is believed to promote glomerular capillary hypertension, hyperperfusion, and microalbuminuria,8, 9, 23, 24 and MR antagonism reduces albuminuria.20, 21, 41, 43, 44, 46, 47, 51, 52, 53 However, simply lowering blood pressure would be expected to cause similar benefits.54, 55, 56, 57, 58 Finally, it is possible that the role of aldosterone in the pathogenesis of macro‐ and microcirculatory disease may differ between animals and man.

The present results are consistent with the notion that ENaC is the final common pathway of MR activation.5, 10, 59 In addition to its well‐known renal tubular location, ENaC has been found in vascular endothelial cells,6 brain,31 and in skin fibroblasts, in which there appears to be a stimulatory effect on collagen synthesis and fibrosis.11, 12 It has also been suggested that ENaC modulates the activity of vasopressinergic neurons.7 Current investigation centers on cytoskeletal modulating effects of local ENaC, including regulation of endothelial cell stiffness in conjunction with sodium and aldosterone.4, 10 In a mouse endothelial MR knockout model, a “Western diet” promoted ENaC overexpression, endothelial dysfunction, and arterial fibrosis/stiffness.13 Finally, when sub‐depressor doses of amiloride are given chronically to young rats, there is an apparent enhancement of endothelial function and a reduction in the development of (premature) arterial stiffness13 but whether these apparent salutary effects on arterial stiffness are mediated via larger arterial diameter (vasodilation or “outward remodeling” of the arterial system) or via a lower arterial elastic modulus (true histopathological change) is not yet known. These and other ongoing works4, 5, 7, 14, 59 are important but it is still unknown whether the findings extend to man. In actuality, current animal models address the potential role of ENaC in the development of end‐organ damage rather than the reversal existing damage. Aging effects must also be considered. The present data could be interpreted to mean that ENaC inhibition can normalize the age‐dependent rate of development of organ damage (eg, vascular stiffness and microcirculatory disease) but it is not clear that preexisting damage can be reversed.

Amiloride, a largely forgotten but potent inhibitor of ENaC, may be grossly under‐appreciated. It remains highly specific for ENaC and is a potent blocker of sodium transport, amiloride can limit sodium‐hydrogen exchange and in high doses may have other subsequent effects,7, 8 including blunting of angiotensin II‐dependent aldosterone release from cultured human adrenal cells.60 In man, it appears that there is little long‐term effect of amiloride on aldosterone. An initial increase in plasma aldosterone has been reported, possibly secondary to reflex activation of the renin‐angiotensin system by acute BP‐lowering or volume contraction,33, 61 but this effect does not persist.34, 62 Amiloride may have a nonuniform effect on BP and may be more effective in individuals with lower degrees of activation of the renin‐angiotensin system, including African Americans5 and patients with HA but further studies are needed.

There are obvious limitations to the present study, which is purely observational in nature and as such is hypothesis‐generating rather than hypothesis‐testing. The most obvious issue is the small sample size, potentially introduces sampling bias, and limits statistical analysis. There is also incomplete or absent baseline information for several variables because this was a post hoc (but real‐world) experience, not a scientific protocol. Nevertheless, this is a rare clinical cohort that allows unique insight not available elsewhere. While there is no case‐matched control group studied for the same time period, the arterial stiffness variables could be reasonably well interpreted by comparing the observed values in each individual to the corresponding model predicted values generated from an algorithm developed for a reference cohort adjusted for age and BP. Thus, a typical case‐control group was not necessary. Perhaps most importantly, our results were highly consistent across three different forms of HA: GRA, adenoma, and nodular hyperplasia.

5. SUMMARY

Long‐term low‐dose amiloride‐based therapy in patients with HA was highly effective in controlling BP and maintaining normal macrocirculatory (arterial stiffness and stiffening, ankle‐brachial index) and microcirculatory (glomerular filtration and urinary albumin excretion) function. Whether these benefits are attributable to superior BP control, are specific to ENaC blockade, or involve both mechanisms remains to be determined. Overall, it is hoped that these observations will spur additional thought and investigation.

DISCLOSURE

The authors have nothing to disclose.

AUTHOR CONTRIBUTION

All three coauthors (Hong, Hussain, and Osmond) were involved in data acquisition/data analysis and manuscript preparation but not in the conceptualization or other aspects of the work.

Izzo JL Jr., Hong M, Hussain T, Osmond PJ. Maintenance of long‐term blood pressure control and vascular health by low‐dose amiloride‐based therapy in hyperaldosteronism. J Clin Hypertens. 2019;21:1183–1190. 10.1111/jch.13597