Primary aldosteronism in premature coronary artery disease: A cross-sectional study from a tertiary center in India

Abstract

Background

Primary aldosteronism (PA) is the most prevalent cause of secondary hypertension and is associated with adverse cardiovascular outcomes. While its prevalence is well established among patients with resistant hypertension and hypokalemia, evidence regarding its occurrence in premature coronary artery disease (CAD) remains limited, particularly in South Asian populations with a high burden of early cardiovascular disease.

Objective

To determine the prevalence of PA in patients with premature CAD (≤45 years) and to describe their clinical and biochemical characteristics.

Methods

In this prospective observational study, 64 patients with premature CAD and 60 age-matched controls with CAD onset after 45 years were evaluated. Patients with a positive screening result—defined as plasma direct renin concentration (DRC) < 12 μIU/mL together with plasma aldosterone concentration (PAC) > 10 ng/dL—underwent a recumbent saline infusion test (SIT). A post-infusion PAC >5 ng/dL was considered confirmatory for the diagnosis of primary aldosteronism. Clinical, biochemical and cardiovascular parameters were systematically assessed.

Results

Among 64 patients with premature CAD, 2 (3.1%) were diagnosed with PA, whereas no cases were identified in the control group. PA-positive patients exhibited significantly higher systolic (161 ± 15.6 mmHg) and diastolic (94.0 ± 5.7 mmHg) blood pressures, longer hypertension duration, and echocardiographic evidence of left ventricular hypertrophy compared with PA-negative patients.

Conclusion

PA may represent an underrecognized contributor to premature CAD in young adults. Larger multicenter studies are needed to validate these observations. Routine PA screening in young CAD patients could enable earlier diagnosis and targeted management, potentially reducing long-term cardiovascular morbidity.

Abbreviations

ARR

Aldosterone-to-renin ratio

CLIA

Chemiluminescence Immunoassay

CV

Coefficient of Variation

CAD

Coronary Artery disease

DBP

Diastolic Blood Pressure

DRC

Direct Renin Concentration

LOD

Limit of detection

LOQ

Limit of quantification

PAC

Plasma Aldosterone Concentration

PA

Primary Aldosteronism

PRA

Plasma Renin Activity

SBP

Systolic Blood Pressure

SIT

Saline Infusion Test

1. Introduction

Primary aldosteronism (PA) has emerged as the most common cause of secondary hypertension, with prevalence estimates of 5–15% in general hypertensive cohorts and up to 20-30% in resistant hypertension 1, 2, 3. Historically regarded as rare and predominantly hypokalemic, PA is now recognized as a spectrum disorder, often normokalemic and underdiagnosed without systematic screening.⁴

The significance of PA extends beyond hypertension. Aldosterone excess exerts direct cardiovascular toxicity through mechanisms including oxidative stress, endothelial dysfunction, vascular inflammation, and myocardial fibrosis 5, 6, 7. Consequently, patients with PA experience disproportionately higher rates of atrial fibrillation, stroke, and coronary artery disease (CAD), independent of blood pressure levels.

CAD remains the leading cause of premature mortality worldwide, with South Asia disproportionately affected at younger ages.⁸ Premature CAD (≤45 years) represents an especially severe phenotype in India, where clustering of metabolic risk factors and aggressive disease biology are common.^9,10 While traditional risk factors such as smoking, diabetes, and dyslipidemia are well described, the contribution of hormonal drivers such as PA is underexplored.

Studies have demonstrated that PA patients face excess coronary risk. In a landmark case–control study, Milliez et al reported a fourfold higher risk of myocardial infarction in PA compared with essential hypertension.¹¹ Monticone et al confirmed this association, showing increased rates of myocardial infarction (MI) and unstable angina in PA patients, even after blood pressure adjustment.¹² Japanese registry data involving over 2500 PA patients also reported ischemic heart disease prevalence of 2.1%.¹³ However, these studies have largely involved resistant hypertension or unselected PA cohorts, leaving the true prevalence of PA in young CAD patients unclear.

This gap is clinically important. First, premature CAD patients often lack overt hypokalemia, a classical red flag for PA, leading to diagnostic under-recognition. Second, targeted therapy with surgical adrenalectomy or mineralocorticoid receptor antagonists significantly reduces cardiovascular morbidity compared with standard antihypertensive regimens. Despite this evidence, PA remains underdiagnosed worldwide, particularly in younger populations with premature CAD, where early identification could meaningfully alter prognosis.14, 15, 16.

Against this backdrop, we conducted a prospective cross-sectional study at a tertiary referral hospital in North India to estimate the prevalence of PA among patients with premature CAD, and to compare their clinical features with those without PA.

2. Methods

2.1. Study design and population

This prospective cross-sectional study was conducted at the All India Institute of Medical Sciences (AIIMS), New Delhi, from September 2020 to March 2022. Adults with age ≥18 years with documented premature CAD (MI, unstable angina, or angiographically proven CAD ≤45 years) were eligible.⁸ Exclusion criteria included renal parenchymal disease, renovascular hypertension, secondary endocrine causes of hypertension (pheochromocytoma, Cushing's syndrome, acromegaly, primary hyperparathyroidism), pregnancy, eGFR <60 mL/min/1.73 m², or refusal to consent. Age-matched patients with CAD onset >45 years, matched for sex and cardiovascular risk factors were recruited as control group in the study.

CAD event consisted of MI, history of prior MI and positive history of angina. MI definition included: detection of a rise of cardiac biomarker values (cardiac troponin), with at least one value above the 99th centile upper reference limit and with one of the following criteria - symptoms of ischemia, new significant ST segment–T wave changes or new left bundle branch block, development of pathological Q waves in the ECG or imaging evidence of regional wall motion abnormality. Any one of the following criteria met the diagnosis for prior MI: pathological Q waves with or without symptoms in the absence of non-ischemic causes, imaging evidence of loss of viable myocardium that fails to contract in the absence of non-ischemic entity and the positive history of angina with objectively recorded ischemia on exercise testing or significant stenosis on coronary angiography with or without prior treatment by percutaneous angioplasty or bypass surgery. Premature CAD is defined as coronary artery disease (CAD) in patients ≤45 years of age.¹⁷

Blood pressure was measured thrice in the right arm in a seated position after 5-min rest, with an appropriate size cuff using a digital sphygmomanometer (HEM-7203; OMRON Corp). The mean of the last two readings was recorded. Hypertension was defined as systolic blood pressure (SBP) ≥140 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg and/or use of antihypertensive medications.¹⁷ Hypertension was classified into three different grades: grade 1, SBP 140 to 159 mmHg and/or DBP 90 to 99 mmHg; grade 2, SBP 160 to 179 mmHg and/or DBP 100 to 109 mmHg; and grade 3, SBP ≥180 and/or DBP ≥110 mm Hg. Resistant Hypertension was defined as seated office blood pressure >140/90 mm Hg in a subject treated with three or more antihypertensive medications at optimal (or maximally tolerated) doses, including a diuretic and after excluding pseudoresistance (poor measurement technique, white coat effect, nonadherence and suboptimal choices in antihypertensive therapy) or controlled blood pressure (<140/90 mm Hg) on four or more antihypertensives.¹⁸ Age of hypertension onset was based on self-reported history and duration of hypertension was calculated accordingly.

Study patients were instructed for an overnight fast of 10 h and to remain in upright posture for at least 2 h and then seated for 15 min before sample collection. Blood samples were collected in early morning between 0800 and 1000 h. Medications which markedly affect aldosterone-to-renin ratio (ARR) such as mineralocorticoid receptor antagonists (MRA), amiloride, triamterene and direct renin inhibitors were withdrawn for at least 6 weeks before sample collection, while all other antihypertensive medications were continued. Hypokalemia was defined as serum potassium level <3.5 mmol/L. If hypokalemia was present, it was corrected by oral potassium chloride supplementation to achieve a minimum potassium level of 4.0 mmol/L before sampling and patients were instructed not to restrict sodium intake.¹⁹

Blood samples were collected in an EDTA vial via cubital fossa venipuncture, transported at normal temperature to the laboratory, centrifuged within 3 h of collection (at 5000 RPM for 5 min), and analyzed immediately or plasma stored at −20 °C. Aldosterone was measured with a competitive chemiluminescent immunoassay and renin with a sandwich chemiluminescent immunoassay on the DiaSorin Liaison XL autoanalyzer. Calibration was performed using calibrators provided by the manufacturer to adjust the assigned master curve. Quality control was performed daily by running the manufacturer-specific aldosterone and direct renin controls. The assay measurement ranges for PAC and DRC are 0.97 to 100 ng/dL, and 0.5 to 500 mIU/L, respectively. For PAC values above the measuring range (>100 ng/dL), the exact value was reported after performing 1:10 dilution with a diluent provided by the manufacturer. The limit of detection (LOD) and limit of quantitation (LOQ) for PAC was 1.45 ng/dL and 1.91 ng/dL, respectively, while LOD and LOQ for DRC were 0.52 to 0.97 mIU/L and 1.60 to 1.96 mIU/L, respectively. The intra-assay and inter-assay coefficient of variations (CVs) were 1.8 to 4.2%, and 5.6 to 10.5%, respectively, for aldosterone and 2.1 to 4.9%, and 6.8 to 13.0%, respectively for renin. A positive screening for primary aldosteronism (PA) was defined by a suppressed direct renin concentration (DRC <12 μIU/mL) in conjunction with a plasma aldosterone concentration (PAC) > 10 ng/dL (332 pmol/L). In contemporary DiaSorin assays, a DRC of 12 μIU/mL approximately corresponds to a plasma renin activity (PRA) of 1 ng/mL/h. Patients with a positive screening result subsequently underwent a confirmatory saline infusion test (SIT) on a separate day. The SIT was performed by administering 2 L of 0.9% saline intravenously over 4 h, with the patient remaining recumbent for at least 1 h prior to and throughout the infusion. A post-infusion PAC >5 ng/dL (139 pmol/L) was taken as confirmatory of PA.¹⁸

2.2. Statistical analysis

Data analysis was performed using STATA version 15.1 (Stata Corp.). As this was an exploratory cross-sectional study evaluating PA prevalence in a relatively underexplored phenotype (premature CAD), a formal sample size calculation was not performed due to lack of reliable prevalence estimates in this population.Qualitative variables were described as number (percentage), while quantitative variables were expressed as mean ± SD or median (interquartile range), where appropriate. The comparison between two groups was done using chi-square test or Fisher's exact test for qualitative variables, as appropriate and Student's t test and Mann–Whitney U test for normally and non-normally distributed quantitative variables, respectively. A p-value of 0.05 was considered for significance.

3. Results

3.1. Prevalence of primary aldosteronism in premature CAD

Among 64 patients with premature CAD, PA was diagnosed in 2 patients, yielding a prevalence of 3.1% (95% CI: 0.37–10.6%). On the other hand, no PA case was identified in the control group.

3.2. Baseline characteristics of patients with premature CAD

Mean age was comparable (40.0 vs 42.0 years), and male predominance was lower in PA-positive patients (50% vs 85.4%). Notably, serum potassium was lower in PA patients (4.0 vs 4.4 mmol/L, p < 0.001) despite potassium levels remaining within the normal range, consistent with the normokalemic presentations frequently reported in contemporary cohorts (Table 1).

Table 1.

Baseline characteristics of premature CAD patients with and without PA.

Variable	PA positive (n = 2)	PA negative (n = 62)	Total (n = 64)	∗p value
Age, years	40.0 ± 7.1	42.0 ± 5.1	41.9 ± 5.1	0.59
Male gender	1 (50.0)	53 (85.4)	54 (84.3)	0.29
Age at onset of HTN, years	32.5 ± 7.8	39.2 ± 5.0	38.9 ± 5.1	0.07
Duration of HTN, months	102 ± 25.5	42.9 ± 48.3	45.3 ± 48.8	0.09
SBP, mmHg	161 ± 15.6	132.6 ± 22.4	133.5 ± 22.7	0.08
DBP, mmHg	94.0 ± 5.7	82.1 ± 12.7	82.5 ± 12.7	0.19
Grade 1 HTN	1 (50.0)	53 (82.8)	54 (84.3)	0.07
Grade 2 HTN	1 (50.0)	7 (10.9)	8 (12.5)	—
Grade 3 HTN	0 (0.0)	2 (3.1)	2 (3.1)	—
Family history of HTN	1 (50.0)	14 (22.5)	15 (16.7)	0.41
Serum potassium, mmol/L	4.0 ± 0.0	4.41 ± 0.64	4.39 ± 0.63	<0.001
Serum creatinine, mg/dL	1.00	0.98 ± 0.22	0.98 ± 0.21	0.91
PAC, ng/dL	12.5 ± 0.4	9.2 ± 7.6	9.3 ± 7.5	0.55
DRC, mIU/L	6.9 ± 4.5	97.3 ± 114.2	94.0 ± 113.4	0.27
Total cholesterol, mg/dL	159 ± 41.0	148 ± 42.6	148 ± 42.3	0.72
HDL cholesterol, mg/dL	57.0 ± 38.2	37.2 ± 15.3	37.8 ± 16.2	0.09
Triglycerides, mg/dL	232.5 ± 32.5	165.8 ± 77.5	167.9 ± 82.1	0.26
LDL cholesterol, mg/dL	57.5 ± 31.8	76.3 ± 33.4	75.7 ± 33.3	0.43

Data are presented as n (%), mean (±SD) and median (IQR), as appropriate. p value for comparison between variables in columns 2 and 3.DBP: Diastolic blood pressure; DRC: Direct renin concentration; HDL: High density lipoprotein; HTN: Hypertension; LDL: Low density lipoprotein; PAC: Plasma aldosterone concentration; PA: Primary aldosteronism; SBP: Systolic blood pressure.

3.3. Hypertension profile of patients with premature CAD

PA-positive patients displayed earlier onset of hypertension (32.5 vs 39.2 years) and longer hypertension duration (102 vs 43 months). Systolic blood pressure was markedly higher (161 vs 133 mmHg), with both PA patients classified as grade 2 hypertension, whereas most (83.8%) PA-negative patients had grade 1 hypertension. Diastolic BP was also elevated to a greater extent in PA patients (94.0 vs. 82.1 mmHg)(Table 1),.

3.4. Target organ damage

PA-positive patients demonstrated echocardiographic left ventricular hypertrophy (LVH), compared with 80.6% of PA-negative patients (p = 0.04). ECG LVH was present in one of two PA-positive patients versus 14.5% of PA-negative patients (Table 2).

Table 2.

Target organ damage in premature CAD patients.

Variable	PA positive (n = 2)	PA negative (n = 62)	p value
ECG LVH	1 (50.0)	9 (14.5)	0.29
ECHO LVH	2 (100.0)	50 (80.6)	0.04

Data are presented as n (%)CAD: Coronary artery disease; ECHO: Echocardiograph; ECG: Electrocardiogram; LVH: left ventricular hypertrophy; PA: primary aldosteronism.

3.5. CAD subtypes

Among PA-positive patients, one presented with ST-elevation MI (STEMI) and the other with chronic angina. The distribution of CAD subtypes did not differ significantly between groups(Table 3).

Table 3.

Types of CAD in premature CAD patients.

CAD subtype	PA positive (n = 2)	PA negative (n = 62)	p value
STEMI	1 (50.0)	39 (62.9)	0.52
NSTEMI	0 (0.0)	11 (17.7)	—
Chronic angina	1 (50.0)	12 (19.3)	—

Data are presented as n (%).

CAD: Coronary artery disease; STEMI: ST elevation myocardial infarction; NSTEMI: non ST elevation myocardial infarction; PA: primary aldosteronism.

4. Discussion

PA has emerged as the most common cause of secondary hypertension. Aldosterone excess exerts profound cardiovascular and cerebrovascular effects, including left ventricular hypertrophy, CAD, heart failure, atrial fibrillation, and stroke, independently of blood pressure elevation. These complications highlight the critical need for early detection and management, as timely intervention can significantly reduce target organ damage and improve long-term outcomes.^1,2

In this study, we prospectively evaluated the prevalence of PA among patients with premature CAD, defined as CAD occurring at or before 45 years of age. Among 64 subjects in this high-risk group, two were diagnosed with PA, corresponding to a prevalence of 3.1% (0.37–10.6%). While this prevalence is lower than some prior reports in acute stroke and hypertensive cohorts, it likely reflects our strict inclusion criteria, prospective design, and the use of standardized screening. Importantly, both PA-positive patients exhibited marked hypertension, dyslipidemia, and left ventricular hypertrophy, consistent with the severe cardiovascular phenotype typically observed in PA. This underscores that even modest prevalence translates into clinically significant disease, emphasizing the importance of screening in high-risk populations.

Recent guidance, including the 2025 Endocrine Society Clinical Practice Guidelines, recommends broader screening for PA in all hypertensive individuals, rather than limiting testing to traditionally high-risk groups.²⁰ Our findings support the relevance of these recommendations, as clinically important cases of PA were identified in a population, patients with premature CAD not previously prioritized for routine screening. The detection of PA in this subgroup highlights the potential to prevent further cardiovascular complications through early diagnosis and targeted therapy. Previous studies have assessed the prevalence of CAD in patients with PA. Milliez et al¹¹ demonstrated that non-fatal MI was diagnosed among 4.0 % of 124 patients with PA and 0.60 % of 456 patients with Essential Hypertension. A multicenter study in Japan which involved 2582 patients with PA found that the prevalence of IHD was 2.1 %, which included MI (0.9%) and angina pectoris (1.3%).¹³ (Supplementary Table 2) Differences in reported prevalence likely stem from variations in study design, population characteristics, assay methodology, and screening thresholds. In contrast, we did a systematic screening for PA in patients with premature CAD, providing insight into an underrecognized contributor to early cardiovascular disease.

This study has several strengths. The prospective design, the use of standardized PA screening and confirmatory protocols, and the provision of the first data on PA prevalence in premature CAD from South Asia lend robustness and novelty to our findings. However, certain limitations should be acknowledged. The small number of PA-positive patients limits statistical power for subgroup analyses, and the single-center design may affect generalizability. We relied on a single PAC measurement to determine screen positivity. Significant intra-individual variability has been reported for PAC, with values as low as 5 ng/dL in patients with confirmed PA. It is possible that some of the milder PA cases with PAC levels 5-10 ng/dL were missed by our screening approach, underestimating the prevalence of PA in this cohort.^21,22 Another limitation of our study is the absence of a control group comprising young hypertensive patients without CAD. Such a comparator would have allowed clearer assessment of whether CAD independently increases the probability of detecting PA beyond that attributable to young-onset hypertension alone. Additionally, further subtyping through adrenal vein sampling and longitudinal follow-up for recurrent CAD events were not performed.

Despite these limitations, the clinical implications of our findings are significant. Even a relatively low prevalence of PA in patients with premature CAD represents a high-risk subgroup for whom targeted intervention could yield substantial benefit. Both surgical and pharmacologic treatments for PA have been shown to reduce cardiovascular risk, with recent data suggesting improved outcomes with early surgical intervention. Consistent with the 2025 Endocrine Society recommendations, our data advocate for routine PA screening in patients with premature CAD, particularly those with hypertension, hypokalemia, or early-onset cardiovascular events. Early identification and treatment of PA in this population may prevent progression of target organ damage, reduce the risk of subsequent cardiovascular events, and improve the likelihood of achieving normotension.

In conclusion, PA prevalence among patients with premature CAD in this South Asian cohort was modest but clinically meaningful. PA-positive patients exhibited a more severe hypertensive phenotype and higher burden of cardiac target organ damage. Our findings underscore the importance of case detection in younger CAD patients in high-burden regions, justifying incorporation of routine PA screening into CAD evaluation pathways. Although larger studies are required to precisely define the incremental yield beyond young-onset hypertension alone, our findings support consideration of selective screening in appropriately chosen premature CAD patients, particularly those with additional suggestive features.

5. What this study adds

This study provides the first evidence from South Asia on the prevalence and clinical phenotype of PA among patients with premature CAD. Although the observed prevalence of 3.1% appears modest, individuals with PA demonstrated a more severe cardiovascular profile, including earlier onset and more severe hypertension and a higher burden of left ventricular hypertrophy. These findings establish PA as a clinically relevant yet underrecognized contributor to premature CAD in young adults within a high-burden region. The results support the incorporation of routine PA screening into the diagnostic evaluation of premature CAD to facilitate early identification and targeted treatment, ultimately aiming to reduce cardiovascular morbidity and improve long-term outcomes.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon request.

Funding

No funding was received for this study.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

The following is the supplementary data to this article: