Aldosterone — A Key Driver of Hypertension^1,2

AstraZeneca Medical's ambition is to address unmet needs of people living with uncontrolled HTN despite being on multiple antihypertensives.

References 

1. Bioletto F, Bollati M, Lopez C, et al. Int J Mol Sci. 2022;23(9):4803. 

2. Brown JM, Siddiqui M, Calhoun DA, et al. Ann Intern Med. 2020;173(1):10-20.

Disease Burden of HTN
Aldosterone & HTN
Aldosterone & Outcomes
Scientific Resources
Connect with Us

Prevalence of HTN^1,a

∼120 Million

∼120 million adults aged ≥18 years in the US have HTN^b

∼93 Million

77.5% of adults with HTN are uncontrolled^b,c (BP ≥130/80 mm Hg)

∼33 Million

28% remain uncontrolled, despite antihypertensive treatment

Visualize the prevalence of uncontrolled HTN^1,a,b,c

Note: 1 shape represents ∼1 million people.

^aHTN prevalence and control estimates among US adults aged ≥18 years, applying criteria from the ACC/AHA 2017 HTN Clinical Practice Guideline utilizing data sourced by NHANES 2017-2020.¹ 

^bHTN is defined as a BP ≥130/80 mm Hg or currently using antihypertensive medication.¹ 

^cAll adults recommended lifestyle modifications only are considered uncontrolled as their BP is above the threshold.¹

HTN and Mortality

HTN was a primary or contributing cause of 685,875 US deaths in 2022²

Uncontrolled HTN is Associated with an Increased Risk of Mortality³

Treated but uncontrolled hypertensive patients are at an increased risk of mortality compared with normotensive adults^3,a:

~1.6 fold ↑

All-cause mortality

~3 fold ↑

Cerebrovascular-specific mortality

~2 fold ↑

Heart disease-specific mortality

~2 fold ↑

CVD-specific mortality

^aProspective cohort study of US adults aged ≥18 years (N=13,947) enrolled in the third National Health and Nutrition Examination Survey (NHANES III) (1988–1994; median follow-up of 19.1 years). HR (95% CI) for the outcomes of all-cause mortality=1.62 (1.35-1.95), cerebrovascular-specific mortality=3.01 (1.91-4.73), heart disease-specific mortality=2.19 (1.57-3.05), and CVD-specific mortality=2.23 (1.66-2.99).³

ACC	American College of Cardiology
AHA	American Heart Association
BP	blood pressure
CI	confidence interval
CVD	cardiovascular disease
HR	hazard ratio
HTN	hypertension
NHANES	National Health and Nutrition Examination Survey
US	United States

1. Million Hearts. Estimated hypertension prevalence, treatment, and control among U.S. adults. Million Hearts website. https://millionhearts.hhs.gov/data-reports/hypertension-prevalence.html

2. Centers for Disease Control and Prevention (CDC). High blood pressure facts. CDC website. https://www.cdc.gov/high-blood-pressure/data-research/facts-stats/index.html

3. Zhou D, Xi B, Zhao M, et al. Uncontrolled hypertension increases risk of all-cause and cardiovascular disease mortality in US adults: the NHANES III Linked Mortality Study. Sci Rep. 2018;8(1):9418. https://doi.org/10.1038/s41598-018-27377-2

Watch Aldosterone's Role in Hypertension

Looking beyond numbers, the role of aldosterone in hypertension.

Understanding Aldosterone

Aldosterone Regulation in Normal Physiology
Aldosterone Regulation in Abnormal Physiology

In normal physiology, aldosterone production is increased by low sodium concentrations, low BP, and low renal perfusion^1,2

Activation of RAAS in response to low BP^1,2

Increased aldosterone production causes water and sodium reabsorption leading to plasma volume expansion and increased BP^2-4

Feedback loop^2,3
Elevations in BP and sodium lead to:

Inhibition of renin release
Decreased RAAS activation
Reduced aldosterone production

Abnormal aldosterone production occurs when aldosterone levels remain elevated despite suppressed renin and high sodium balance^3,5,6,a,b

Despite suppression of the RAS, aldosterone secretion continues³

Increased aldosterone production causes water and sodium reabsorption leading to plasma volume expansion and increased BP^2-4

^aBased on diagnosis of primary aldosteronism caused by renin-independent aldosterone production. Suppressed renin is defined as low levels
(seated:<1.0 mcg/L/hr, supine: <0.6 mcg/L/hr) in the setting of high sodium balance.⁵

^bHigh sodium balance is defined as 200 milliequivalents of sodium daily.⁶

Effects of Aldosterone

Aldosterone Exhibits Effects Through Multiple Pathways^1,7

^aOccurs within the distal tubules and collecting ducts of the kidney. MRs are expressed in epithelial cells (eg, kidneys, bowel, salivary glands) and non-epithelial tissues (eg, vascular and skeletal smooth muscle, immune system cells, vascular endothelium, cardiac myocytes, and adipocytes).¹  

^bNon-genomic effects can also regulate Na⁺/K⁺ channel activities.⁷

Aldosterone Can Induce Direct Toxic Effects on the Blood Vessels, Heart, and Kidneys, Which May Occur Independent of BP⁸

CV Disease Outcomes

Explore data on the adverse outcomes aldosterone can induce on the blood vessels and heart.

Learn More

Kidney Disease Outcomes

Explore data on the adverse outcomes aldosterone can induce on the kidneys.

Learn More

Association of Aldosterone with BP and HTN Severity

Higher Levels of Aldosterone are Positively Correlated with Increases in BP⁹

Association Between Serum Aldosterone Concentrations and BP at Baseline.^9,a,b

^aStudy included 948 US adults (46 to 88 years of age) from the multicenter longitudinal cohort Multi-Ethnic Study of Atherosclerosis (MESA), recruited between July 2000 and August 2002, with follow-up through July 2015. Participants had measurements of serum aldosterone collected and had not taken antihypertensive medications. Results displayed represent the cohort of 700 participants who had follow-up coronary computed tomography scans.⁹

^bAdjusted for age, sex, CAC at Exam 2 or 3, race, education, insurance status, income, smoking status, alcohol intake, physical activity, statin prescription, BMI, LDL, serum and urinary potassium, serum and urinary sodium, and plasma renin activity.⁹

Aldosterone may be an overlooked driver of elevated BP and related adverse outcomes^10-12

Could targeting aldosterone represent a paradigm shift in the treatment of HTN?

ACE	angiotensin-converting enzyme
ACTH	adrenocorticotropic hormone
BMI	body mass index
BP	blood pressure
CAC	coronary artery calcium
CV	cardiovascular
DBP	diastolic blood pressure
GPER	G protein-coupled estrogen receptor
HTN	hypertension
K⁺	potassium
LDL	low-density lipoprotein
MR	mineralocorticoid receptor
Na⁺	sodium
RAAS	renin-angiotensin-aldosterone system
RAS	renin-angiotensin system
SBP	systolic blood pressure
US	United States

1. Crompton M, Skinner LJ, Satchell SC, et al. Aldosterone: essential for life but damaging to the vascular endothelium. Biomolecules. 2023;13(6):1004. https://doi.org/10.3390/biom13061004

2. Scott JH, Menouar MA, Dunn RJ. Physiology, aldosterone. In: StatPearls [Internet]. StatPearls Publishing; May 1, 2023. https://www.ncbi.nlm.nih.gov/books/NBK470339/

3. Papadopoulou-Marketou N, Vaidya A, Dluhy R, et al. Hyperaldosteronism. In: Feingold KR, Anawalt B, Blackman MR, et al, eds. Endotext [Internet]. MDText.com, Inc.; Last update August 6, 2020. https://www.ncbi.nlm.nih.gov/books/NBK279065/

4. Triebel H, Castrop H. The renin angiotensin aldosterone system. Pflügers Arch - Eur J Physiol. 2024;476:705-713. https://doi.org/10.1007/s00424-024-02908-1

5. Brown JM, Siddiqui M, Calhoun DA, et al. The unrecognized prevalence of primary aldosteronism: a cross-sectional study. Ann Intern Med. 2020;173(1):10-20. https://doi.org/10.7326/M20-0065

6. Yuan YE, Haas AV, Rosner B, et al. Elevated blood pressure and aldosterone dysregulation in young black women versus white women on controlled sodium diets. J Clin Endocrinol Metab. 2024;109(2):e773-e779. https://doi.org/10.1210/clinem/dgad512

7. Kritis AA, Gouta CP, Liaretidou EI, et al. Latest aspects of aldosterone actions on the heart muscle. J Physiol Pharmacol. 2016;67(1):21-30.

8. Verhovez A, Williams TA, Monticone S, et al. Genomic and non-genomic effects of aldosterone. Curr Signal Transduct Ther. 2012;7(2):132-141. https://doi.org/10.2174/157436212800376708

9. Inoue K, Goldwater D, Allison M, et al. Serum aldosterone concentration, blood pressure, and coronary artery calcium: the Multi-Ethnic Study of Atherosclerosis [article and online supplement]. Hypertension. 2020;76(1):113-120. https://doi.org/10.1161/HYPERTENSIONAHA.120.15006

10. Bakris G, Chen C, Campbell AK, et al. Association of uncontrolled blood pressure in apparent treatment-resistant hypertension with increased risk of major adverse cardiovascular events plus. J Clin Hypertens (Greenwich). 2023;25(8):737-747. https://doi.org/10.1111/jch.14701

11. Azizi M. Decreasing the effects of aldosterone in resistant hypertension - a success story. N Engl J Med. 2023;388(5):461-463. https://doi.org/10.1056/NEJMe2216143

12. Blazek O, Bakris GL. Novel therapies on the horizon of hypertension management. Am J Hypertens. 2023;36(2):73-81. https://doi.org/10.1093/ajh/hpac111

How Does Aldosterone Affect the Blood Vessels, Heart, and Kidneys?

Abnormal aldosterone production is associated with an increased risk of HTN as well as adverse CV and kidney disease outcomes^1-4

Aldosterone and the CV System
Aldosterone and the Kidneys

Aldosterone and the CV System

Aldosterone can induce direct toxic effects on the blood vessels and heart, which may occur independent of BP⁵

Blood Vessel Effects
Heart Effects

Blood Vessel Effects

↑ Cell adhesion

↓ NO bioavailability 

↑ ROS production 

↑ VSMC migration 

↑ VSMC proliferation 

↑ VSMC senescence 

↑ VSMC calcification

Consequences

Perivascular inflammation
Vascular fibrosis
Hyalinization
Fibrinoid necrosis
Thickening of the tunica media
Endothelial dysfunction

Heart Effects

↑ Myocyte hypertrophy 

↑ Myocyte apoptosis 

↑ EC matrix production 

↑ ROS production 

↑ Myofibroblast proliferation 

↑ Afterload 

~ Altered ion fluxes

Consequences

Cardiac hypertrophy
Cardiac fibrosis
Arrhythmias
Cardiac ischemia
Heart failure

Abnormal Aldosterone Production is Associated With an Increased Risk of Adverse CV Disease Outcomes²

Patients with abnormal aldosterone production are at an increased risk of coronary artery disease, atrial fibrillation, heart failure, and stroke compared to patients with HTN^2,a,b

~2 fold ↑

Coronary Artery Disease

~3.5 fold ↑

Atrial Fibrillation

~2 fold ↑

Heart Failure

~2.6 fold ↑

Stroke

^aMeta-analysis of 31 studies that evaluated cardiovascular risk in patients with primary aldosteronism (n=3838) compared to patients with essential HTN (n=9284). Median duration of HTN was 8.8 years (IQR 6.2-10.7).²

^bOR (95% CI) for the outcomes of coronary artery disease=1.77 (1.10-2.83), atrial fibrillation=3.52 (2.06-5.99); heart failure=2.05 (1.11-3.78), and stroke=2.58 (1.93-3.45).²

Aldosterone and the Kidneys

Aldosterone can induce direct toxic effects on the kidneys, which may occur independent of BP⁵

Kidney Effects

Kidney Effects

↑ ROS production 

↑ Mesangial deformability 

↑ Mesangial proliferation

↑ Podocyte damage

Consequences

Glomerular ischemia
Glomerular sclerosis
Capsular fibrosis
Proteinuria
Chronic renal failure

Abnormal Aldosterone Production is Associated with an Increased Risk of Adverse Kidney Disease Outcomes^3,4

Patients with abnormal aldosterone production are at an increased risk of...

168% ↑

Proteinuria^a,b

45% ↑

CKD progression^c,d.e

46% ↑

Developing ESKD^c,f

^aMeta-analysis of 46 studies that evaluated risk in patients with primary aldosteronism (n=6056) compared to patients with essential HTN (n=9733).³

^bOR (95% CI) for the outcome of proteinuria=2.68 (1.89-3.79).³

^cResults depicted are from a multicenter, prospective, observational cohort study (CRIC) of 3680 patients with known CKD, defined as eGFR 20-70 mL/min/1.73 m², over a median follow-up of 9.6 years. Results were analyzed using a multivariable model adjusted for age, sex, race, clinical center, BMI, diabetes mellitus, SBP, history of CV disease, HbA1c, history of hypercholesterolemia, serum albumin, serum potassium, ACEi/ARB use, loop diuretic use, statin use, smoking, BNP, 24‑hour urine sodium, 24-hour urine potassium, 24-hour urine protein, and baseline eGFR.⁴

^dCKD progression was defined as the composite of 50% decline in eGFR or incident ESKD.⁴

^eRisk of CKD progression=HR, 1.45; 95% CI, 1.22-1.73 for those in the highest quartile of serum aldosterone relative to lowest quartile.⁴

^fRisk of developing ESKD=HR, 1.46; 95% CI, 1.19-1.78 for those in the highest quartile of serum aldosterone relative to lowest quartile.⁴

ACEi	angiotensin-converting enzyme inhibitor
ARB	angiotensin receptor blocker
BMI	body mass index
BNP	B-type (brain) natriuretic peptide
BP	blood pressure
CI	confidence interval
CKD	chronic kidney disease
CRIC	Chronic Renal Insufficiency Cohort
CV	cardiovascular
EC	extracellular
eGFR	estimated glomerular filtration rate
ESKD	end-stage kidney disease
HbA1c	glycated hemoglobin
HR	hazard ratio
HTN	hypertension
IQR	interquartile range
NO	nitric oxide
OR	odds ratio
ROS	reactive oxygen species
SBP	systolic blood pressure
VSMC	vascular smooth muscle cell(s)

1. Vasan RS, Evans JC, Larson MG, et al. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med. 2004;351(1):33-41. https://doi.org/10.1056/NEJMoa033263

2. Monticone S, D'Ascenzo F, Moretti C, et al. Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2018;6(1):41-50. https://doi.org/10.1016/S2213-8587(17)30319-4

3. Monticone S, Sconfienza E, D'Ascenzo F, et al. Renal damage in primary aldosteronism: a systematic review and meta-analysis. J Hypertens. 2020;38(1):3-12. https://doi.org/10.1097/HJH.0000000000002216

4. Verma A, Vaidya A, Subudhi S, et al. Aldosterone in chronic kidney disease and renal outcomes. Eur Heart J. 2022;43(38):3781-3791. https://doi.org/10.1093/eurheartj/ehac352

5. Verhovez A, Williams TA, Monticone S, et al. Genomic and non-genomic effects of aldosterone. Curr Signal Transduct Ther. 2012;7(2):132-141. https://doi.org/10.2174/157436212800376708

Scientific Resources

This section offers scientific resources related to aldosterone, an underlying key driver of uncontrolled hypertension, including videos and slide decks. Our AstraZeneca Medical team has created this content as an information service for healthcare professionals. Updates are made to the content as new data become available.

Video

Watch Aldosterone's Role in Hypertension

Slide Deck

Aldosterone as an Underlying Driver of Hypertension & Adverse Cardiovascular & Kidney Outcomes

This presentation describes aldosterone and its association with HTN, CV, and kidney disease outcomes.

View Slide Deck

CV	cardiovascular
HTN	hypertension

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