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Aldosterone, Hypertension, and Antihypertensive Therapy: Insights From a General Population

      Abstract

      Objective

      To investigate the relationships among aldosterone level, use of antihypertensive (anti-HTN) medications, clinical profile, and atrial natriuretic peptide (ANP) level in individuals with HTN.

      Participants and Methods

      In a community-based cohort, we analyzed aldosterone plasma levels based on the presence (n=477) or absence (n=1073) of HTN. In individuals with HTN, we evaluated circulating aldosterone levels according to the number of anti-HTN drugs used, analyzed the associated clinical characteristics, and determined the relationship to the counterregulatory cardiac hormone ANP. Data were collected from August 25, 1997, through September 5, 2000.

      Results

      Participants with HTN had higher serum aldosterone levels than those without HTN (6.4 vs 4.1 ng/dL [to convert to pmol/L, multiply by 27.74]; P<.001). When individuals with HTN were stratified according to the number of anti-HTN medications used, the increase in number of medications (0, 1, 2, and ≥3) was associated with higher aldosterone levels (4.8, 6.4, 7.10, and 7.9 ng/dL, respectively; P=.002), worse metabolic profile, and higher prevalence of cardiovascular, renal, and metabolic disease. In participants with HTN, ANP plasma levels were inversely related to aldosterone levels when the latter was divided into tertiles.

      Conclusion

      In this randomly selected general population cohort, aldosterone levels were higher in individuals with HTN compared with normotensive participants. Aldosterone levels increased with anti-HTN medication use. These findings also suggest a relative ANP deficiency with increasing aldosterone levels and anti-HTN drug use. These studies have pathophysiologic and therapeutic implications for targeting aldosterone in the clinical treatment of HTN.

      Abbreviations and Acronyms:

      ACC/AHA (American College of Cardiology/American Heart Association), ACE (angiotensin-converting enzyme), ANP (atrial natriuretic peptide), ARB (angiotensin II receptor blocker), BB (β-blocker), BMI (body mass index), BP (blood pressure), CCB (calcium channel blockers), CKD (chronic kidney disease), CV (cardiovascular), DM (diabetes mellitus), GFR (glomerular filtration rate), HDL (high- density lipoprotein), HTN (hypertension), LDL (low- density lipoprotein), LVH (left ventricular hypertrophy), MDRD (Modification of Diet in Renal Disease), MI (myocardial infarction), MR (mineralocorticoid receptor), SBP (systolic blood pressure)
      Aldosterone is a hormone that plays a fundamental role in intravascular volume and blood pressure (BP) homeostasis. Beyond its physiologic role and through activation of the mineralocorticoid receptor (MR), aldosterone may also exert actions leading to organ damage in the heart, kidneys, and vasculature.
      • Brilla C.G.
      • Weber K.T.
      Mineralocorticoid excess, dietary sodium, and myocardial fibrosis.
      Seminal studies by the Calhoun Laboratory have importantly advanced aldosterone as a key factor in hypertension (HTN), most importantly in resistant HTN.
      • Calhoun D.A.
      Aldosterone and cardiovascular disease: smoke and fire.
      • Dudenbostel T.
      • Ghazi L.
      • Liu M.
      • et al.
      Body mass index predicts 24-hour urinary aldosterone levels in patients with resistant hypertension.
      • Gaddam K.
      • Corros C.
      • Pimenta E.
      • et al.
      Rapid reversal of left ventricular hypertrophy and intracardiac volume overload in patients with resistant hypertension and hyperaldosteronism: a prospective clinical study.
      Indeed, the successful use of the MR antagonist spironolactone in the PATHWAY-2 trial in individuals with resistant HTN led to the conclusion that aldosterone may be the predominant underlying pathophysiologic cause of resistant HTN through sodium retention.
      • Williams B.
      • MacDonald T.M.
      • Morant S.
      • et al.
      Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomized, double-blind, crossover trial.
      We recently reported in a general population study that plasma aldosterone levels, even within the reference range, are significantly associated with HTN as well as chronic kidney disease (CKD) and metabolic syndrome
      • Buglioni A.
      • Cannone V.
      • Cataliotti A.
      • et al.
      Circulating aldosterone and natriuretic peptides in the general community: relationship to cardiorenal and metabolic disease.
      and also predicted these diseases in the future.
      • Buglioni A.
      • Cannone V.
      • Sangaralingham S.J.
      • et al.
      Aldosterone predicts cardiovascular, renal, and metabolic disease in the general community: a 4-year follow-up.
      The influence of aldosterone in early-stage HTN is also supported by Vasan et al,
      • Vasan R.S.
      • Evans J.C.
      • Larson M.G.
      • et al.
      Serum aldosterone and the incidence of hypertension in nonhypertensive persons.
      who reported that increased aldosterone levels within the reference range are associated with new-onset HTN in participants without HTN.
      Most recently, the American College of Cardiology and the American Heart Association (ACC/AHA) released the 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults.
      • Whelton P.K.
      • Carey R.M.
      • Aronow W.S.
      • et al.
      2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      In part, the new landmark recommendations were a product of the Systolic Blood Pressure Intervention Trial (SPRINT).
      • Wright Jr., J.T.
      • Williamson J.D.
      • Whelton P.K.
      • et al.
      SPRINT Research Group
      A randomized trial of intensive versus standard blood-pressure control.
      This seminal study validated the importance of optimizing anti-HTN therapy to achieve BP control (systolic BP [SBP] <120 mm Hg), improve survival, and reduce the onset of adverse cardiovascular (CV) outcomes in patients with HTN at high CV risk. The relevance of SPRINT to the general US population was recently supported by Bress et al,
      • Bress A.P.
      • Tanner R.M.
      • Hess R.
      • Colantonio L.D.
      • Shimbo D.
      • Muntner P.
      Generalizability of SPRINT results to the US adult population.
      who reported that a substantial percentage of US adults meets the eligibility criteria for SPRINT, supporting its generalizability to the general US population. Because the 2017 ACC/AHA guidelines propose more aggressive goals for treatment, a high priority is to better characterize the clinical phenotype of adults treated with 1 or more anti-HTN agents. The in-depth characterization could provide pathophysiologic and therapeutic insights, which may help optimize anti-HTN strategies. Furthermore, with the growing role of aldosterone as a therapeutic target as well as a biomarker in HTN, there is also a strong rationale to investigate the relationship between aldosterone levels and anti-HTN therapy in patients with HTN.
      Hence, the present study used a well-characterized, randomly selected, adult, community-based cohort using the Rochester Epidemiology Project in Olmsted County, Minnesota.
      • Rocca W.A.
      • Yawn B.P.
      • St Sauver J.L.
      • Grossardt B.R.
      • Melton III, L.J.
      History of the Rochester Epidemiology Project: half a century of medical records linkage in a US population.
      We hypothesized that aldosterone levels would be increased in participants with HTN compared with those without a diagnosis of HTN. We also tested the hypothesis that aldosterone levels would be progressively higher with increasing number of anti-HTN drugs used. Last, based on previous studies, we hypothesized that in participants with HTN, plasma aldosterone levels would be characterized by an inverse relationship with the counterregulatory hormone atrial natriuretic peptide (ANP).
      • Buglioni A.
      • Cannone V.
      • Cataliotti A.
      • et al.
      Circulating aldosterone and natriuretic peptides in the general community: relationship to cardiorenal and metabolic disease.
      • Macheret F.
      • Heublein D.
      • Costello-Boerrigter L.C.
      • et al.
      Human hypertension is characterized by a lack of activation of the antihypertensive cardiac hormones ANP and BNP.
      • Wang T.J.
      • Larson M.G.
      • Levy D.
      • et al.
      Impact of obesity on plasma natriuretic peptide levels.
      • Bajaj N.S.
      • Gutiérrez O.M.
      • Arora G.
      • et al.
      Racial differences in plasma levels of N-terminal pro-B-type natriuretic peptide and outcomes: the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

      Patients and Methods

      Study Population

      The Mayo Clinic Institutional Review Board approved this study, and the participants gave informed consent. Using the resources of the Rochester Epidemiology Project at Mayo Clinic, we analyzed a previously studied random sample of individuals from the general population of Olmsted County.
      • Rocca W.A.
      • Yawn B.P.
      • St Sauver J.L.
      • Grossardt B.R.
      • Melton III, L.J.
      History of the Rochester Epidemiology Project: half a century of medical records linkage in a US population.
      Specifically, 4203 residents were eligible for the study, and 2024 of these were enrolled. The design, selection criteria, and characteristics of this cohort have been previously described elsewhere.
      • Redfield M.M.
      • Jacobsen S.J.
      • Burnett Jr., J.C.
      • Mahoney D.W.
      • Bailey K.R.
      • Rodeheffer R.J.
      Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic.
      A trained nurse abstractor reviewed the medical record for each participant and documented the clinical diagnosis of HTN, myocardial infarction (MI), coronary artery disease, or diabetes mellitus (DM). Each participant underwent an in-depth physical examination including measurement of BP, height, and weight. For the present study, 1550 individuals who underwent a visit between August 25, 1997, and September 5, 2000, were analyzed. All the participants had plasma aldosterone and ANP levels measured, and their use and number of drugs or nonuse of anti-HTN medications were carefully documented, with 1550 of the 2024 participants having both aldosterone and ANP levels available. Of the 1550 participants, 1073 were without a diagnosis of HTN and 477 had a diagnosis of HTN.
      For anti-HTN therapy, we considered the following drugs: β-blockers (BBs), calcium channel blockers (including dihydropyridines and nondihydropyridines), vasodilators (including α1-blockers, reserpine, and central α2-agonists), angiotensin ll receptor blockers, angiotensin-converting enzyme inhibitors, and all classes of diuretics (thiazides, thiazides-like, loop diuretics, potassium-sparing, and MR antagonists). Lipid-lowering therapy was defined as the use of 1 or more of the following drugs: statins, fibrates, niacin, ezetimibe, and cholestyramine.
      To better define associated phenotypes to aldosterone and HTN, body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared) was defined using established criteria as previously described.
      • Buglioni A.
      • Cannone V.
      • Cataliotti A.
      • et al.
      Circulating aldosterone and natriuretic peptides in the general community: relationship to cardiorenal and metabolic disease.
      Obesity was defined as a BMI of 30 or greater. Waist circumference, measured at the top of the umbilicus, was expressed in centimeters, and central obesity was defined as waist circumference greater than 102 cm in men and greater than 88 cm in women. Hypertension was defined according to the use of Joint National Committee VII diagnosis criteria, and BP at the visit was measured 3 times at 5-minute intervals.
      • Buglioni A.
      • Cannone V.
      • Cataliotti A.
      • et al.
      Circulating aldosterone and natriuretic peptides in the general community: relationship to cardiorenal and metabolic disease.
      Smoking status was defined as never, former, or active. Chronic kidney disease was defined as a glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 based on the Modification of Diet in Renal Disease formula. Metabolic syndrome was defined in accordance with the National Cholesterol Education Program Adult Treatment Panel III, as previously described elsewhere.
      • Buglioni A.
      • Cannone V.
      • Cataliotti A.
      • et al.
      Circulating aldosterone and natriuretic peptides in the general community: relationship to cardiorenal and metabolic disease.

      Plasma Collection

      Blood samples were obtained from participants in the sitting position, and there was no discontinuation of any therapy or change in salt intake before the blood collection. Blood samples were collected in EDTA tubes and chilled until centrifugation at 4°C at 2500 g for 10 minutes; 0.5 mL of plasma was aliquoted into polystyrene tubes and stored at −80°C until assayed.

      Aldosterone and ANP Assays

      Plasma aldosterone level was measured using a competitive radioimmunoassay kit (Siemens) as previously defined elsewhere.
      • Buglioni A.
      • Cannone V.
      • Cataliotti A.
      • et al.
      Circulating aldosterone and natriuretic peptides in the general community: relationship to cardiorenal and metabolic disease.
      Samples were obtained in the morning at approximately 8:00 am. Plasma ANP level was measured as previously described elsewhere by a radioimmunoassay using antibody to human ANP (Phoenix Pharmaceutical).
      • Burnett Jr., J.C.
      • Kao P.C.
      • Hu D.C.
      • et al.
      Atrial natriuretic peptide elevation in congestive heart failure in the human.

      Echocardiography

      Echocardiography was performed as previously described.
      • Redfield M.M.
      • Jacobsen S.J.
      • Burnett Jr., J.C.
      • Mahoney D.W.
      • Bailey K.R.
      • Rodeheffer R.J.
      Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic.

      Statistical Analyses

      Characteristics of the patients were summarized after separation into various subgroups of interest. These characteristics are presented as number (percentage) for categorical variables or as mean ± SD for continuous variables that were approximately normally distributed. For continuous variables that were not normally distributed, medians (tertiles) were used to characterize the distribution. Group differences were tested using logistic regression for categorical variables or linear regression for continuous variables, after normalizing transformation. These models included sex as well as age and BMI as continuous covariates to test whether group differences were independent of these factors that were observed to be different between groups. When participants with HTN were stratified into groups based on number of anti-HTN drugs taken, these tests were performed using linear or logistic regression adjusted for age, sex, and BMI. Number of HTN drugs was used as an ordinal variable in these analyses, resulting in tests for trend across these groups. To investigate the association between aldosterone and ANP levels while controlling for potential confounders, a generalized linear regression model was used; ANP was log-transformed for this analysis. Age, sex, BMI, MI, heart failure, atrial fibrillation, and GFR were used as covariates, and adjusted means with corresponding 95% CIs for each tertile of aldosterone, considered as a nominal variable, were presented. To take advantage of the ordinal nature of the aldosterone tertiles and create a trend test, the P value is presented from a model where tertile (1-3) was considered as an ordinal variable. For all the analyses, 2-sided P<.05 were considered to be statistically significant. Analyses were performed using SAS software, version 9.4 (SAS Institute Inc).

      Results

      Characteristics of the Study Cohort According to the Diagnosis of HTN

      As shown in Table 1, compared with participants without HTN, those with HTN were older and had higher ANP and plasma aldosterone levels. Importantly, when we excluded individuals with aldosterone levels higher than the upper limit of the reference range of 16.2 ng/dL (to convert to pmol/L, multiply by 27.74),
      • Buglioni A.
      • Cannone V.
      • Cataliotti A.
      • et al.
      Circulating aldosterone and natriuretic peptides in the general community: relationship to cardiorenal and metabolic disease.
      participants with HTN still had significantly higher aldosterone levels than those without HTN (5.65 ng/dL [1.7, 16.2 ng/dL] vs 4.00 ng/dL [2.5, 16.2 ng/dL]; age-, sex-, and BMI-adjusted P<.001). As expected, the HTN group presented with higher SBP and diastolic BP values, lower GFR, higher circulating insulin and glucose levels, more prevalent use of antilipemic treatment, increased BMI, greater prevalence of obesity and abdominal obesity, CKD, metabolic syndrome, DM, coronary artery disease, MI, heart failure, and cerebrovascular accident. Echocardiography revealed a greater prevalence of reduced ejection fraction, left ventricular hypertrophy (LVH), concentric LVH, and mild to moderate/severe diastolic dysfunction. In the non-HTN group (n=1073), a subgroup of 174 individuals were taking medications classified as anti-HTN in this study.
      Table 1Clinical Characteristics of the 1550 Study Participants With and Without a Diagnosis of HTN
      ANP = atrial natriuretic peptide; BMI = body mass index; CKD = chronic kidney disease; GFR = glomerular filtration rate; HDL = high-density lipoprotein; HTN = hypertension; LDL = low-density lipoprotein; LVH = left ventricular hypertrophy; MDRD = Modification of Diet in Renal Disease.
      SI conversion factors: To convert aldosterone values to pmol/L, multiply by 27.74; to convert ANP values to pmol/L, multiply by 0.325; to convert cholesterol values to mmol/L, multiply by 0.0259; to convert triglyceride values to mmol/L, multiply by 0.0113; to convert creatinine values to μmol/L, multiply by 88.4; to convert insulin values to pmol/L, multiply by 6.945; to convert glucose values to mmol/L, multiply by 0.0555.
      CharacteristicNon-HTN group (n=1073)HTN group (n=477)P value
      Age-, sex-, and BMI-adjusted P values.
      Age (y), mean ± SD62±1067±10<.001
      Female sex (No. [%])615 (57)270 (57).92
      Aldosterone (ng/dL), median (range)4.10 (2.5-51.1)6.40 (1.7-91.0)<.001
      Aldosterone in tertiles (No. [%])<.001
       1400 (37)114 (24)
       2393 (37)128 (27)
       3280 (26)235 (49)
      ANP (pg/mL), median (Q1-Q3)11.10 (7.40-15.70)13.40 (8.60-19.40).01
      BMI, mean ± SD28±530±6<.001
      Obesity (No. [%])287 (27)213 (45)<.001
      Waist circumference >102 cm in men, >88 cm in women (No. [%])303 (28)213 (45)<.001
      Systolic blood pressure (mm Hg), mean ± SD129±20143±23<.001
      Diastolic blood pressure (mm Hg), mean ± SD72±1075±11<.001
      Total cholesterol (mg/dL), mean ± SD205±37200±35.03
      HDL cholesterol (mg/dL), mean ± SD47±1545±15.40
      LDL cholesterol (mg/dL), mean ± SD129±33123±31.007
      Triglycerides (mg/dL), mean ± SD143±83156±93.10
      Calculated GFR (mL/min/1.73 m2) (MDRD formula), mean ± SD82.32±16.9574.62±20.29<.001
      CKD (No. [%])117 (11)119 (25)<.001
      Creatinine (mg/dL), median (Q1-Q3)0.80 (0.70-0.90)0.90 (0.70-1.00)<.001
      Insulin (μIU/mL), median (Q1-Q3)4.70 (3.40-7.30)6.70 (4.40-10.00)<.001
      Serum glucose (mg/dL), median (Q1-Q3)92 (87-99)97 (90-105).001
      Diabetes (No. [%])58 (5)69 (14)<.001
      Metabolic syndrome (No. [%])179 (17)154 (32).001
      Current/former smoker (No. [%])538 (50)213 (45).20
      Atrial fibrillation/flutter (No. [%])47 (4)37 (8).40
      Coronary artery disease (No. [%])107 (10)98 (21).002
      Heart failure (No. [%])13 (1)28 (6)<.001
      Myocardial infarction (No. [%])34 (3)43 (9).003
      Cerebrovascular accident (No. [%])13 (1)18 (4).01
      Antilipemic therapy (No. [%])153 (14)128 (27)<.001
      Anti-HTN therapy (No. [%])174 (16)418 (88)<.001
      Ejection fraction <40% (No. [%])8 (1)16 (3).01
      LVH (No. [%])
      A number of subjects were missing LV mass, so numbers used for LVH overall are 1219.
      242/861 (28)177/358 (49)<.001
      Concentric LVH (No. [%])118 (14)120 (34)<.001
      Diastolic dysfunction (No. [%])(n=970)(n=417)<.001
       No747 (77)207 (50)
       Mild167 (17)148 (35)
       Moderate/severe56 (6)62 (15)
      a ANP = atrial natriuretic peptide; BMI = body mass index; CKD = chronic kidney disease; GFR = glomerular filtration rate; HDL = high-density lipoprotein; HTN = hypertension; LDL = low-density lipoprotein; LVH = left ventricular hypertrophy; MDRD = Modification of Diet in Renal Disease.
      b SI conversion factors: To convert aldosterone values to pmol/L, multiply by 27.74; to convert ANP values to pmol/L, multiply by 0.325; to convert cholesterol values to mmol/L, multiply by 0.0259; to convert triglyceride values to mmol/L, multiply by 0.0113; to convert creatinine values to μmol/L, multiply by 88.4; to convert insulin values to pmol/L, multiply by 6.945; to convert glucose values to mmol/L, multiply by 0.0555.
      c Age-, sex-, and BMI-adjusted P values.
      d A number of subjects were missing LV mass, so numbers used for LVH overall are 1219.

      Characteristics of Participants With HTN Stratified by Number of Anti-HTN Medications Taken

      As reported in Table 2, in the HTN group(n=477), 228 individuals were treated with 1 anti-HTN drug, 145 were taking 2 drugs, 45 were taking 3 or more anti-HTN drugs, and 59 were taking no drug. More specifically, in individuals with HTN treated with 1 drug, the most commonly prescribed anti-HTN treatment was a diuretic. When participants with HTN were taking 2 anti-HTN medications, the most common combination was a diuretic with a BB. In the group taking 3 or more drugs, the most common combination consisted of a diuretic (non–MR antagonist), a BB, and a calcium channel blocker. Overall, 50% of participants with HTN were taking a diuretic and 35% were taking a BB.
      Table 2Anti-HTN Drugs Prescribed in the 477 Study Participants With a Diagnosis of HTN
      ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; BB = β-blocker, CCB = calcium channel blocker; HTN = hypertension.
      DrugParticipants (No. [%])
      Percentages are calculated based on the total number of participants with a diagnosis of HTN (n=477).
      Taking 1 drug (n=228)
       Diuretic83 (17.4)
       BB72 (15.1)
       ACE inhibitor34 (7.1)
       CCB25 (5.2)
       Vasodilator9 (1.9)
       ARB5 (1.0)
      Taking 2 drugs (n=145)
       BB + diuretic51 (10.7)
       ACE inhibitor + diuretic32 (6.7)
       CCB + diuretic16 (3.4)
       BB + ACE inhibitor13 (2.7)
       ARB + diuretic8 (1.7)
       BB + CCB8 (1.7)
       CCB + ACE inhibitor7 (1.5)
       CCB + vasodilator4 (0.8)
       Diuretic + vasodilator2 (0.4)
       CCB + ARB2 (0.4)
       ACE inhibitor + vasodilator1 (0.2)
       BB + vasodilator1 (0.2)
      Taking ≥3 drugs (n=45)
       BB + CCB + diuretic8 (1.7)
       BB + ACE inhibitor + diuretic6 (1.3)
       Diuretic + vasodilator + ARB4 (0.8)
       ACE inhibitor + diuretic + vasodilator4 (0.8)
       CCB + diuretic + ARB4 (0.8)
       CCB + ACE inhibitor + diuretic4 (0.8)
       BB + diuretic + ARB4 (0.8)
       CCB + diuretic + vasodilator3 (0.6)
       CCB + ACE inhibitor + diuretic + vasodilator2 (0.4)
       BB + CCB + ACE inhibitor2 (0.4)
       BB + CCB + ACE inhibitor + diuretic2 (0.4)
       BB + ACE inhibitor + diuretic + vasodilator1 (0.2)
       BB + CCB + vasodilator1 (0.2)
      a ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; BB = β-blocker, CCB = calcium channel blocker; HTN = hypertension.
      b Percentages are calculated based on the total number of participants with a diagnosis of HTN (n=477).
      Aldosterone level progressively increased according to the number of anti-HTN medications (Figure 1). Table 3 reports the HTN group stratified by number of anti-HTN medications. In all the participants with HTN, mean SBP was above the SPRINT goal of 120 mm Hg. Importantly, increasing use of anti-HTN medications was associated with a modest increase in ANP level, higher BMI, lower high-density lipoprotein cholesterol level, higher triglyceride levels, lower GFR, and higher insulin and glucose levels. Furthermore, it was also associated with increased prevalence of clinical comorbidities such as obesity, CKD, DM, CV diseases, and use of lipid-lowering agents. In contrast to these comorbidities, increasing use of anti-HTN medications did not correlate with increasing cardiac structure and functional abnormalities that included ejection fraction, LVH, concentric LVH, and diastolic dysfunction.
      Figure thumbnail gr1
      Figure 1Plasma aldosterone levels in individuals with hypertension (HTN) stratified by number of anti-HTN drugs taken. The horizontal line in the middle of each box indicates the median; lower box, Q1; upper box, Q3; and diamond, mean. The whiskers extend to 1.5 × the interquartile range (IQR) above and below the box (or the maximum or minimum values if there are no points outside of 1.5 × IQR from the box). The circles are outliers. Unadjusted P< .001. To convert aldosterone values to pmol/L, multiply by 27.74.
      Table 3Participants With Hypertension Stratified by Number of Antihypertensive Drugs Used
      ANP = atrial natriuretic peptide; BMI = body mass index; CKD = chronic kidney disease; GFR = glomerular filtration rate; HDL = high-density lipoprotein, LDL= low-density lipoprotein; LVH = left ventricular hypertrophy; MDRD = Modification of Diet in Renal Disease.
      SI conversion factors: To convert aldosterone values to pmol/L, multiply by 27.74; to convert ANP values to pmol/L, multiply by 0.325; to convert cholesterol values to mmol/L, multiply by 0.0259; to convert triglyceride values to mmol/L, multiply by 0.0113; to convert creatinine values to μmol/L, multiply by 88.4; to convert insulin values to pmol/L; to convert glucose values to mmol/L, multiply by 0.0555, multiply by 6.945.
      VariableNo. of antihypertensive drugsP value
      Age-, sex-, and BMI-adjusted P values.
      0 (n=59)1 (n=228)2 (n=145)≥3 (n=45)
      Age (y), mean ± SD66±1165±970±1069±11<.001
      Female sex (No. [%])31 (53)144 (63)78 (54)17 (38).02
      Aldosterone (ng/dL), median (range)4.80 (2.5-21.1)6.40 (1.7-91.0)7.10 (2.5-67.5)7.90 (2.5-79.2).002
      Aldosterone in tertiles (No. [%]).004
       120 (34)59 (26)28 (19)7 (16)
       219 (32)59 (26)39 (27)11 (24)
       320 (34)110 (48)78 (54)27 (60)
      ANP (pg/mL), median (Q1-Q3)11.80 (7.30-15.60)12.75 (8.05-18.50)14.80 (10.60-21.10)15.60 (9.10-25.90).005
      BMI, mean ± SD29±629±630±632±6<.001
      Obesity (No. [%])20 (34)101 (44)65 (45)27 (60).002
      Waist circumference >102 cm in men, >88 cm in women (No. [%])21 (36)101 (44)67 (46)24 (53).02
      Systolic blood pressure (mm Hg), mean ± SD152±22141±22139±22152±22.05
      Diastolic blood pressure (mm Hg), mean ± SD81±975±1173±1177±11<.001
      Total cholesterol (mg/dL), mean ± SD213±34202±35191±33197±41.02
      HDL cholesterol (mg/dL), mean ± SD49±1946±1342±1542±16.05
      LDL cholesterol (mg/dL), mean ± SD136±32125±31116±28118±29<.001
      Triglycerides (mg/dL), mean ± SD137±64149±79166±80184±185.004
      Calculated GFR (mL/min/1.73 m2) (MDRD formula), mean ± SD78.74±19.7977.28±18.0570.76±23.2368.18±18.40.005
      CKD (No. [%])11 (19)37 (16)51 (35)20 (44).001
      Creatinine (mg/dL), median (Q1-Q3)0.80 (0.70-1.00)0.80 (0.70-1.00)0.90 (0.80-1.20)1.00 (0.80-1.30).02
      Insulin (μU/mL), median (Q1-Q3)5.60 (4.20-8.90)6.25 (4.00-10.00)7.20 (4.90-10.30)7.90 (5.50-12.00).06
      Serum glucose (mg/dL), median (Q1-Q3)95 (88-101)95 (89-104)101 (93-110)102 (94-119).005
      Diabetes (No. [%])5 (8)22 (10)29 (20)13 (29).002
      Metabolic syndrome (No. [%])14 (24)64 (28)61 (42)15 (33).26
      Current/former smoker (No. [%])27 (46)92 (40)69 (48)25 (56).22
      Atrial fibrillation/flutter (No. [%])3 (5)7 (3)16 (11)11 (24).002
      Coronary artery disease (No. [%])7 (12)32 (14)39 (27)20 (44)<.001
      Heart failure (No. [%])05 (2)13 (9)10 (22)<.001
      Myocardial infarction (No. [%])2 (3)17 (7)17 (12)7 (16).13
      Stroke (No. [%])1 (2)4 (2)10 (7)3 (7).06
      Antilipemic therapy (No. [%])11 (19)59 (26)39 (27)19 (42)0.05
      Echocardiographic parameters
       Ejection fraction <40% (No. [%])1 (2)5 (2)6 (4)4 (9).14
       LVH (No. [%])
      A number of subjects were missing LV mass, so numbers used for LVH overall are 1219.
      23/45 (51)78/177 (44)53/107 (50)23/29 (79).59
       Concentric LVH (No. [%])19 (42)49 (28)35 (33)17 (59).92
       Diastolic dysfunction (No. [%])(n=51)(n=210)(n=120)(n=36).60
      No21 (41)118 (56)53 (44)15 (42)
      Mild22 (43)73 (35)40 (33)13 (36)
      Moderate/severe8 (16)19 (9)27 (23)8 (22)
      a ANP = atrial natriuretic peptide; BMI = body mass index; CKD = chronic kidney disease; GFR = glomerular filtration rate; HDL = high-density lipoprotein, LDL= low-density lipoprotein; LVH = left ventricular hypertrophy; MDRD = Modification of Diet in Renal Disease.
      b SI conversion factors: To convert aldosterone values to pmol/L, multiply by 27.74; to convert ANP values to pmol/L, multiply by 0.325; to convert cholesterol values to mmol/L, multiply by 0.0259; to convert triglyceride values to mmol/L, multiply by 0.0113; to convert creatinine values to μmol/L, multiply by 88.4; to convert insulin values to pmol/L; to convert glucose values to mmol/L, multiply by 0.0555, multiply by 6.945.
      c Age-, sex-, and BMI-adjusted P values.
      d A number of subjects were missing LV mass, so numbers used for LVH overall are 1219.
      In consideration of the effect of diuretic therapy on intravascular volume and, consequently, the renin-angiotensin-aldosterone system, we compared aldosterone levels in individuals with HTN taking diuretics (n=234) vs those with HTN taking medications other than diuretics (n=184). The median (Q1-Q3) aldosterone levels were 9.3 ng/dL (8.5-10.2 ng/dL) and 5.0 ng/dL (4.5-5.6 ng/dL), respectively; age-, sex-, and BMI-adjusted P<.001.

      Relationship Between Aldosterone and ANP Plasma Levels

      Given the counterregulatory roles played by aldosterone and ANP, we sought to determine the relationship between these 2 hormones in the context of HTN. Aldosterone level was divided into tertiles: the first tertile ranged from 2.5 to 3.1 ng/dL, the second tertile ranged from 3.2 to 6.5 ng/dL, and the third tertile ranged from 6.6 to 79.2 ng/dL; ANP was analyzed as a continuous variable. As illustrated in Figure 2, in all participants with HTN, ANP levels decreased as aldosterone levels increased, and we found a strong inverse relationship between aldosterone and ANP levels that remained significant after adjustment for age, sex, BMI, MI, heart failure, atrial fibrillation, and GFR, all of which may affect ANP circulating levels (P=.007). In consideration of the potential confounding effect of diuretics on the production of aldosterone and ANP, we also analyzed the relationship between these 2 hormones in participants with HTN who were not taking diuretics and the inverse relationship remained similar (adjusted P=.04).
      Figure thumbnail gr2
      Figure 2Inverse relationship between plasma aldosterone and atrial natriuretic peptide (ANP) levels in participants with hypertension. Aldosterone is analyzed by tertiles and ANP as a continuous variable (mean [95% CI]). P = .007 adjusted for age, sex, body mass index, myocardial infarction, heart failure, atrial fibrillation, and glomerular filtration rate.

      Discussion

      The present study is the first to analyze circulating aldosterone and its relationship with HTN, the use of anti-HTN medications, and ANP in the general population. From this randomly selected population, we report that 31% of the general community had an established diagnosis of HTN and that plasma aldosterone levels were higher in these individuals compared with those without a diagnosis of HTN. Importantly, in the post-SPRINT era of intensifying HTN treatment to achieve optimal BP control and improve outcomes, we found that aldosterone levels were progressively higher with the increasing number of anti-HTN medications. Moreover, participants with HTN taking diuretics had significantly higher aldosterone levels than those taking other anti-HTN medications. This study also reports an inverse relationship between ANP and aldosterone levels. Indeed, in individuals taking anti-HTN medications, modest increases in plasma ANP levels correspond to higher increases in plasma aldosterone levels, underscoring an imbalance between these 2 counterregulatory BP-regulating hormones.
      Aldosterone, through the well-characterized MR present on the renal tubular epithelium, is a hormone that induces reabsorption of sodium, thus preserving intravascular volume and BP at times of sodium deficit. In modern society, with the presence of high-sodium diets and increasing longevity, a pathophysiologic role for aldosterone has emerged. Indeed, inappropriately increased levels of aldosterone, even within the reference range, are associated with HTN and renal and metabolic disease and also predicts future onset of these disease entities in the general population.
      • Buglioni A.
      • Cannone V.
      • Cataliotti A.
      • et al.
      Circulating aldosterone and natriuretic peptides in the general community: relationship to cardiorenal and metabolic disease.
      • Buglioni A.
      • Cannone V.
      • Sangaralingham S.J.
      • et al.
      Aldosterone predicts cardiovascular, renal, and metabolic disease in the general community: a 4-year follow-up.
      In the present investigation using a randomly selected and well-characterized general population cohort of adults, we observed that higher plasma aldosterone levels were present in the HTN group and that this increase remained significant even after adjusting for age, sex, and BMI.
      SPRINT represents a seminal large-scale clinical trial that defines the impact of intensive BP control to achieve SBP levels less than 120 mm Hg in more than 9000 patients with HTN.
      • Wright Jr., J.T.
      • Williamson J.D.
      • Whelton P.K.
      • et al.
      SPRINT Research Group
      A randomized trial of intensive versus standard blood-pressure control.
      The major finding was that intensive therapy to achieve BP goals improved survival and reduced adverse CV outcomes. One observation in SPRINT was that an average of 2.5 medications was required to achieve the BP goal of less than 120 mm Hg. We believe that the potential of more intensive use of anti-HTN medications to reduce BP in HTN markedly increases the priority of understanding unwanted consequences and associations of the use of such medications, such as neurohumoral responses to therapy.
      Herein, we analyzed aldosterone levels in individuals with HTN taking no, 1, 2, or 3 or more anti-HTN medications. A highly significant association between aldosterone level and the number of anti-HTN medications was observed, even after adjusting for age, sex, and BMI. In the HTN group, the most commonly used anti-HTN agents were diuretics. The most common combination was diuretics and a BB. Only 6 participants were taking MR antagonists. Participants taking diuretics had higher aldosterone levels compared with those taking medications other than diuretics. Importantly, with the increasing number of anti-HTN agents we observed an increase in aldosterone levels and a higher prevalence of CV, renal, and metabolic diseases. These findings were prominent in participants with HTN taking 3 or more anti-HTN medications. An important conclusion from this study is that aldosterone excess is clearly a feature of treated HTN that progressively increases with the use of more anti-HTN drugs. What remains to be investigated is whether the progressive increase in aldosterone levels is secondary to the use of BP-lowering medication or reflects hormonal activation secondary to the severity of HTN or dysmetabolic state. In addition, further studies are necessary to evaluate the potential activation of various neurohumoral pathways associated with different anti-HTN therapy.
      Aldosterone and ANP play a counterregulatory role in body fluid and BP homeostasis, with aldosterone being sodium retaining and BP increasing and ANP being natriuretic, BP lowering, aldosterone production suppressive, and possibly MR antagonistic.
      • Nakagawa H.
      • Oberwinkler H.
      • Nikolaev V.O.
      • et al.
      Atrial natriuretic peptide locally counteracts the deleterious effects of cardiomyocyte mineralocorticoid receptor activation.
      Indeed, carriers of the ANP genetic variant rs5068, which is associated with higher circulating levels of ANP, have lower BP values and risk of HTN.
      • Cannone V.
      • Boerrigter G.
      • Cataliotti A.
      • et al.
      A genetic variant of the atrial natriuretic peptide gene is associated with cardiometabolic protection in the general community.
      • Cannone V.
      • Cefalu' A.B.
      • Noto D.
      • et al.
      The atrial natriuretic peptide genetic variant rs5068 is associated with a favorable cardiometabolic phenotype in a Mediterranean population.
      We previously reported an inverse relationship between aldosterone and ANP levels in a general population cohort that included a mix of HTN and normotensive adults.
      • Buglioni A.
      • Cannone V.
      • Cataliotti A.
      • et al.
      Circulating aldosterone and natriuretic peptides in the general community: relationship to cardiorenal and metabolic disease.
      In the present study, participants with HTN have higher aldosterone and ANP levels compared with those without HTN. Although this analysis allows us to compare the clinical characteristics of the 2 groups, it does not provide information regarding the relationship between the 2 hormones. In participants with HTN, the magnitude of aldosterone increase is greater than the modest increase in ANP, resulting in a reduction of the ANP to aldosterone ratio. Importantly, herein we report for the first time that in individuals with HTN, an elevation in aldosterone levels analyzed according to tertiles corresponds to a decrease in ANP levels such that an inverse relationship between 2 hormones was found. These findings are supported by studies that reported a relative NP deficiency in individuals with HTN and metabolic disease.
      • Macheret F.
      • Heublein D.
      • Costello-Boerrigter L.C.
      • et al.
      Human hypertension is characterized by a lack of activation of the antihypertensive cardiac hormones ANP and BNP.
      • Wang T.J.
      • Larson M.G.
      • Levy D.
      • et al.
      Impact of obesity on plasma natriuretic peptide levels.
      It would be tempting to speculate that a reduction in ANP production may be secondary to lower intravascular volume due to diuretic use. Notably, when we analyzed individuals with HTN who were not taking diuretics, the inverse relationship between aldosterone and ANP levels was confirmed. Furthermore, more advanced stages of HTN, especially obesity-associated HTN, are characterized by intravascular volume expansion despite the use of diuretics, suggesting that these medications might not contribute to lower levels of ANP in HTN.
      • Hall J.E.
      • do Carmo J.M.
      • da Silva A.A.
      • et al.
      Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms.
      In addition, type 2 DM, which is commonly found in association with HTN, is characterized by elevated insulin levels that may upregulate the NP clearance receptor, thus diminishing circulating ANP levels.
      • Bordicchia M.
      • Ceresiani M.
      • Pavani M.
      • et al.
      Insulin/glucose induces natriuretic peptide clearance receptor in human adipocytes: a metabolic link with the cardiac natriuretic pathway.
      Obesity represents another metabolic disease often associated with HTN, and it is also characterized by lower levels of natriuretic peptides.
      • Wang T.J.
      • Larson M.G.
      • Levy D.
      • et al.
      Impact of obesity on plasma natriuretic peptide levels.
      Importantly, aldosterone production is complexly regulated by several factors (renin, serum potassium, and adrenocorticotropic hormone levels). The inverse relationship between aldosterone and ANP levels observed in the present analysis along with the relative ANP deficiency reported in previous studies might be one of the numerous elements playing a role in aldosterone regulation. Future in vitro and in vivo studies are needed to investigate more in-depth the interaction between these 2 hormones.
      The present study has several strengths. First, the cohort consisted of a large number (n=1550) of randomly selected adults in the general population and not volunteers. Second, the participants were well characterized with plasma aldosterone and ANP measurements, extensive phenotyping, and echocardiography. Third, the cohort consisted of individuals 45 years and older at high risk for CV, renal, and metabolic disease. Moreover, this cohort is similar to participants in SPRINT and is of high relevance to the 2017 ACC/AHA BP guidelines that focus on 10-year CV risk, which is largely driven by age.
      • Whelton P.K.
      • Carey R.M.
      • Aronow W.S.
      • et al.
      2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      • Greenland P.
      • Peterson E.
      The New 2017 ACC/AHA Guidelines “Up the pressure” on diagnosis and treatment of hypertension.
      This study also has limitations. Plasma renin activity and potassium and adrenocorticotropic hormone plasma levels were not available and participants were not assessed for primary and secondary aldosteronism. To exclude individuals with a potential diagnosis of primary or secondary aldosteronism we performed further analyses in those with aldosterone levels below the upper limit of the reference range of 16.2 ng/dL.
      • Buglioni A.
      • Cannone V.
      • Cataliotti A.
      • et al.
      Circulating aldosterone and natriuretic peptides in the general community: relationship to cardiorenal and metabolic disease.
      Importantly, in this subgroup, individuals with HTN had aldosterone levels significantly higher than those without HTN. The study by Buglioni et al
      • Buglioni A.
      • Cannone V.
      • Cataliotti A.
      • et al.
      Circulating aldosterone and natriuretic peptides in the general community: relationship to cardiorenal and metabolic disease.
      confirms the present findings as it found a positive association between aldosterone levels and HTN in a similar cohort excluding individuals with aldosterone levels greater than 16.2 ng/dL. Future studies in well-characterized cohorts of individuals with HTN are warranted to further investigate the complex relationships among aldosterone level, anti-HTN drugs, and ANP level. Because the Olmsted County population is mostly white race, we cannot extend the present conclusions to black or other ethnic populations. Further investigations in black individuals would be relevant as recent studies have established a relative ANP deficiency in this ethnic group and studies have also reported excessive aldosteronism in black individuals that may increase the risk for metabolic disease and HTN.
      • Gupta D.K.
      • de Lemos J.A.
      • Ayers C.R.
      • Berry J.D.
      • Wang T.J.
      Racial differences in natriuretic eptide levels: the Dallas Heart Study.
      • Musani S.K.
      • Vasan R.S.
      • Bidulescu A.
      • et al.
      Aldosterone, c-reactive protein, and plasma b-type natriuretic peptide are associated with the development of metabolic syndrome and longitudinal changes in metabolic syndrome components: findings from the Jackson Heart Study.
      • Wang T.J.
      Natriuretic peptide deficiency: when there is too little of a good thing.
      • Gupta D.K.
      • Daniels L.B.
      • Cheng S.
      • et al.
      Differences in natriuretic peptide levels by race/ethnicity (from the multi-ethnic study of atherosclerosis).
      In addition, we do not know the sodium intake of each participant. However, recent studies have reported that the average dietary sodium intake in Minnesota is unchanged over the past 2 decades and exceeds the recommended upper limit of 2300 mg/d.
      • Meyer K.A.
      • Harnack L.J.
      • Luepker R.V.
      • et al.
      Twenty-two-year population trends in sodium and potassium consumption: the Minnesota Heart Survey.
      Finally, the present study was cross sectional and analyzed the relationships among aldosterone level, HTN, anti-HTN medications, and ANP level. Further mechanistic studies are warranted to investigate the pathophysiologic process underlying the associations observed.

      Conclusion

      Despite remarkable achievements in HTN research, Mensah and colleagues
      • Mensah G.A.
      • Galis Z.S.
      • Fine L.J.
      • et al.
      Building on a legacy of hypertension research: charting our future together.
      at the National Heart, Lung, and Blood Institute recently emphasized that “hypertension remains the leading cause of global death and disability from heart disease and stroke and a major contributor to all-cause mortality worldwide.” The growing health burden of HTN reinforces the need to understand mechanisms and diagnostic and therapeutic opportunities for prevention and treatment of HTN. From this perspective, these findings have important pathophysiologic and clinical implications in human HTN. We report the elevation of circulating aldosterone levels in individuals with HTN randomly selected from the general population, and, importantly, this elevation is progressively higher with the number of anti-HTN medications taken. The prevalence of CV, renal, and metabolic disease was highest in participants with HTN with the highest levels of aldosterone. Moreover, in the HTN group, greater aldosterone levels were associated with lower circulating ANP levels. Additional studies are warranted to validate the importance of measuring plasma aldosterone and ANP levels in the setting of treated HTN. Further investigations are also warranted to define whether antagonizing aldosterone
      • Flatt D.M.
      • Brown M.C.
      • Mizeracki A.M.
      • et al.
      Mineralocorticoid receptor antagonists in the management of heart failure and resistant hypertension.
      or compensating for the relative ANP deficit
      • Ruilope L.M.
      • Dukat A.
      • Bohm M.
      • Lacourcière Y.
      • Gong J.
      • Lefkowitz M.P.
      Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomized, double-blind, placebo-controlled, active comparator study.
      • Meems L.M.G.
      • Burnett Jr., J.C.
      Innovative therapeutics: designer natriuretic peptides.
      may be effective strategies for the prevention and treatment of HTN.

      Acknowledgments

      Drs Cannone and Buglioni contributed equally to this work.

      Supplemental Online Material

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