Primary aldosteronism (PA), also known as Conn’s syndrome, is a potentially curable form of secondary hypertension. PA is characterized by autonomous adrenal production of aldosterone, independent of renin production, resulting in a high aldosterone-to-renin ratio (ARR) (1). Studies in the general hypertensive population have found a PA prevalence of 5-15% (2–4). Hypertension due to PA results in a higher rate of cardiovascular events including stroke when compared with blood pressure (BP) matched essential hypertension. A meta-analysis of 31 studies, including 3838 patients with PA and 9284 patients with essential hypertension found that after a median of 8.8 years from hypertension diagnosis, compared to patients with essential hypertension, patients with PA had an increased risk of stroke with an odds ratio [OR] of 2.58 (95% CI 1.93-3.45) (5). Furthermore, we now know PA is more prevalent in patients with cardioembolic stroke and atrial fibrillation (AF) (6). PA is a treatable condition, either with curative surgery in the setting of a unilateral aldosterone producing adenoma or mineralocorticoid receptor antagonists (MRA) for bilateral adrenal disease. Targeted treatment leads to lower rates of cardiovascular events and stroke (7, 8). Despite the availability of targeted treatment, there is an absence of recommendations to screen for PA in stroke management guidelines (9–12). This systematic review and meta-analysis was performed to answer the clinical research question: what is the prevalence of PA in adults with acute stroke or transient ischaemic attack (TIA)? This evidence will inform future studies and may assist with guideline development.

For This systematic review adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (13). The review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (URL: https://www.crd.york.ac.uk/PROSPERO/; unique identifier: CRD42022328644).

Hypertension is a major modifiable risk factor for ischemic and hemorrhagic stroke (21). Despite PA being the most common endocrine cause of secondary hypertension with an increased risk of AF, stroke and TIA compared to patients with BP matched essential hypertension, there is a lack of research on its prevalence and management in acute stroke or TIA (5). Studies over the last decade have reported a PA prevalence of 5-15% in the general hypertensive population (2–4). Based on 738 patients from three studies, this meta-analysis found a PA pooled prevalence of 5.8% in patients with stroke or TIA.

The sex distribution of PA in this meta-analysis was consistent with that previously reported, where approximately half were men (2). Nguyen et al. and Tang et al. both reported a similar sex distribution of PA in stroke or TIA (66.7% in both studies) (6, 16). Miyaji et al. had fewer men in the cohort (56%) than Nguyen et al. and Tang et al, which may explain the lower proportion of men with PA (29.4%). There were no sub analyses of the sex distribution of PA in patients with TIA.

Difference in patients with PA compared to patients without PA are striking for the higher systolic BP (170-180mmHg vs 148-162mmHg), and lower serum potassium (3.1-3.7mmol/L vs 4.0-4.1mmol/L) in patients with PA. This is consistent with PA being more likely to cause resistant hypertension and hypokalaemia (1). Blood pressure was taken 3 months post stroke with a trend for a higher number of antihypertensive agents in patients with PA compared to without PA (1.7 vs 1.0 respectively) which may account for the lack of difference in SBP between groups in Nguyen et al. (6) The markedly higher DBP in patients with PA compared to without PA (125.9mmHg vs 94.1mmHg) in the younger cohort of Tang et al. has previously been seen in PA when stratified by age (16, 22). There was also a higher prevalence of PA in people with a history of hypertension. Only a small proportion of people were diagnosed with PA but without hypertension (0% - 17.6%). Clinical presentation of stroke or TIA with elevated blood pressure may be a useful trigger for PA testing.

Meta-analyses of prevalence often have high statistical heterogeneity. This meta-analysis displayed high heterogeneity with an I² statistic of 87.6%. A study of 134 meta-analyses of prevalence revealed the median I² was 96.9% (IQR 90.5–98.7) (23) with larger I² in meta-analysis with a higher number of studies or extreme pooled estimates (defined as <10% or >90%). The high I² observed in the present meta-analysis is consistent with other prevalence studies with an extreme pooled prevalence <10%, in this case 5.8%. There are several prevalence modifying factors which contribute to the statistical heterogeneity in this study including differences in age of the populations sampled, hypertension prevalence, ARR threshold, confirmatory tests used and time from stroke to testing. Tang et al. had a younger population and higher prevalence of hypertension. Monticone et al. demonstrated in a prospective cohort study that the prevalence of PA increases with an increase in the stage of hypertension of the cohort (24). Uniformity in population sampling and testing methods may reduce heterogeneity of future meta-analyses.

Time from acute cerebral event to testing for PA differed in the three studies and is likely to impact reported prevalence. Miyaji et al. tested in the first week of the acute cerebral event which may lead to a false negative ARR (25). Miyaji et al. found the acute phase ARR was less reliable at predicting PA than the post stroke ARR, however the evidence is limited by the lack of confirmatory testing in every patient with either one or two positive ARRs (15). Nguyen et al. and Tang et al. tested ARR several months after the acute cerebral event, this subacute time frame for testing may be less prone to false negative ARR. A prospective human study on RAAS during acute ischaemic stroke found that angiotensin I, renin and aldosterone were significantly lower, angiotensin II was unchanged, and angiotensin converting enzyme activity was higher in the acute phase (within 48 hours) compared to post-stroke (8 months) (25). Acute stroke can affect ARR by various mechanisms including, dehydration which increases renin and aldosterone, high BP during the acute stroke phase with higher adrenaline and cortisol levels which lowers aldosterone and renin and interfering antihypertensive medications (25). Further research is required to establish the optimal ARR threshold for PA testing in the context of the acute hormonal changes during acute stroke.

The main limitation for PA testing in someone with established hypertension is the confounding effect of antihypertensive drugs. The Endocrine Society recommends a washout of all interfering antihypertensive medications with the use of substitute medications that have minimal effect on ARR but acknowledges that the ARR can be interpreted accordingly if medication switching is not feasible (1). In this systematic review, only Tang et al. adjusted antihypertensive agents for testing. To maintain stringent BP control during and shortly after stroke or TIA, both Miyaji et al. and Nguyen et al. continued interfering medications through the testing period. The frequent use of antihypertensive agents which can cause false negative screening results may contribute to the lower prevalence of PA in these two cohorts (6, 15). Of note, Nguyen et al. adopted a lower ARR threshold of >277 pmol/l per ng/ml/h (33.7 pmol/L per mU/L) to reduce the number of false negative results caused by interfering medications, although the evidence base for the threshold was not stated. However, only in the absence of medication interference, an ARR cut-off of >70 pmol/mU has a sensitivity and specificity greater than 95% (26). There is a paucity of data to provide any robust recommendation on ARR thresholds whilst on interfering medications (27–29).

Changing antihypertensive medications to non-interfering agents for PA screening can be challenging in the acute stroke period. For patients on ACEI’s, the aldosterone to angiotensin II ratio may be a more reliable marker of aldosterone excess than ARR (30). However, the assay to measure angiotensin II is not widely available and angiotensin II concentration is not reported in any of the three articles. Further research is needed to understand the utility of angiotensin II for the diagnosis of PA in patients with stroke or TIA.

Although ARR was the screening test of choice for each of the three studies, the number of positive ARR required to proceed to confirmatory testing differed. The reported prevalence of PA in Miyaji et al. was 4.0% (17 of 427) however, 26 patients did not have initial blood sampling and 28 patients did not have follow up blood sampling leaving 373 patients with both screening tests. If only patients with both screening tests were considered, the prevalence becomes 4.6% overall and 5.5% in those with hypertension (15). Nguyen et al.’s prospective cohort study found a slightly lower prevalence of 3.1% amongst all patients despite a lower ARR cut-off than Miyaji’s study (6, 15). Of note, in Nguyen et al, more than 50% of the participants with an abnormal ARR had hypokalemia (15 of 26). Previous studies show approximately 30% of patients with PA have hypokalemia, therefore it may be possible that some patients with PA and normokalemia were missed, rendering the prevalence rate an underestimate (1).

The three included studies used different confirmatory tests. Tang et al. and Nguyen et al. used captopril challenge test and saline suppression test respectively, which are two of the four recommended confirmatory tests of the Endocrine Society (1, 6, 16). Miyaji et al. used the rapid adrenocorticotropic hormone (ACTH) test which is not one of the tests recommended by the Endocrine Society (1, 15). A recent systematic review and meta-analysis, limited to English, on the performance of PA confirmatory tests did not find any studies on the validity of the rapid ACTH test (31). Only one study, published in Japanese, has compared the validity of the rapid ACTH test against the captopril challenge test or furosemide plus upright test and found the rapid ACTH test had a sensitivity and specificity of >95% (32). Clinical practice differs internationally for the preferred confirmatory test; this will impact the reported prevalence in each study.

The link between mineralocorticoids and stroke has been established experimentally in rodents (33, 34). Rocha et al. studied Stroke Prone Spontaneously Hypertensive (SHRSP) rats treated with either placebo or the mineralocorticoid antagonist eplerenone for 19 weeks (33). Blood pressure was equally raised in both groups. Placebo treated rats showed clinical signs of stroke earlier and all died by 18 weeks. By comparison, only one eplerenone treated rat showed signs of stroke and died at 18 weeks. Histopathology revealed severe ischemic and hemorrhagic stroke lesions in the placebo treated rats compared with mild cerebral injury in the eplerenone treated rats. Dorrance et al. induced stroke experimentally (thread-occlusion technique) in SHRSP rats of which half were treated with spironolactone and Wistar-Kyoto (WKY) normotensive rats which were treated with placebo (34). Spironolactone reduced cerebral ischemic damage by 50% in SHRSP rats. Dorrance and Rocha both found that despite the reduction in cerebral ischemia following treatment with a mineralocorticoid antagonist, there was no effect on SBP. Limited human studies have established several mechanisms for aldosterone’s adverse vascular effects including endothelial dysfunction, increased arterial wall stiffness, structural cardiac remodeling through atrial dilatation and fibrosis, and electrical remodeling through arrhythmogenicity (35–38). Nguyen et al. found patients with PA had a larger left atrial volume index, which predisposes to AF. Nguyen et al. also found the prevalence of PA in patients with stroke, hypertension and AF was 30%, similar to that found by Seccia et al. in patients with hypertension and AF (42%) (39). Milliez et al. found a 12-fold higher risk of AF in patients with PA compared to patients with essential hypertension (40). The results of these rodent studies confirm aldosterone has harmful actions on cerebral vasculature independent of its ability to increase BP and that treatment with a mineralocorticoid receptor antagonist such as spironolactone or eplerenone can reduce the frequency and severity of stroke.

To summarize, the underlying pathophysiological mechanisms leading to an increased risk of stroke has been explored in rodent studies and limited human studies, it goes beyond that purely due to aldosterone-mediated hypertension. These studies provide compelling evidence that timely diagnosis and targeted treatment can significantly reduce the severity of cerebral injury and the occurrence of stroke.

This systematic review and meta-analysis revealed that 3.1-12.9% of patients with acute stroke or TIA have PA, with a higher prevalence of up to 22% if only hypertensive patients are considered. However, there was significant variability between studies including the timing of the test, nature of confirmatory testing and medication use. A larger prospective study where patients are screened both in the acute and outpatient settings would help to inform the optimal timing and conditions of PA testing in patients with stroke and TIA. Furthermore, all three studies were in East Asian and South East Asian populations; data from other populations are needed. Additional research will facilitate the development of evidence-based guidelines for PA testing in patients with stroke or TIA so that this highly modifiable cardiovascular risk factor can be efficiently ameliorated.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

JM: Conceptualization, Writing – original draft, Writing – review & editing. MM: Writing – review & editing. BC: Writing – review & editing. PF: Writing – review & editing. JY: Conceptualization, Writing – review & editing. TP: Conceptualization, Writing – review & editing.