Background
Hypertension is the prime risk factor for stroke [
1], and treatment of hypertension is highly effective in the prevention of stroke [
2,
3]. Secondary hypertension is identified in a relatively small proportion of adult patients with hypertension. However, particular attention should be paid to this condition, because the hypertension can be cured by appropriate specific treatment. Primary aldosteronism (PA) is caused by the autonomous secretion of aldosterone from adrenocortical lesions and is associated with hypertension and hypokalemia. PA has attracted much attention in recent years because PA is more frequent than previously recognized, occurring in 3–10 % of hypertensive patients [
4‐
6]. PA patients have a higher rate of vascular complications [
7,
8] and a poorer long-term prognosis than patients with essential hypertension [
9]. Interestingly, the occurrence of cerebrovascular comorbidities in patients with PA is reported to be independent of hypertension and hypokalemia [
8,
10]. Therefore, aside from vascular injury due to hypertension, the direct action of aldosterone on the mineralocorticoid receptor may cause increased oxidative stress and collagen remodeling, which results in endothelial dysfunction and fibrosis in the blood vessels [
11].
Most PA patients are successfully treated by unilateral adrenalectomy or with mineralocorticoid receptor antagonists [
12,
13], and the blood pressure becomes normalized [
14,
15]. Furthermore, some reports have demonstrated improvement of left ventricular hypertrophy, renal function, and the cardiovascular prognosis with PA treatment [
16‐
18].
Although early diagnosis and treatment of PA are important for these reasons, stroke patients are not included among the subjects for aggressive PA screening in the guidelines [
12,
13,
19], and there have been no previous reports about the screening of PA in patients with acute stroke. The aim of this prospective study was to elucidate the prevalence and risk factors of PA in patients with acute stroke.
Methods
Study population
Consecutive patients with acute stroke including transient ischemic attack (TIA) who were admitted to Yokohama Sakae Kyosai Hospital between April 2013 and March 2014 were prospectively enrolled for this study. The definition for “acute stroke inpatient” in this study was “emergency admission” and “the requirement of acute management of stroke”. The time from the onset of stroke to admission was 0.6 ± 1.1 days (mean ± SD; range, 0–6; median, 0). In addition to clinical evaluation, including a history of vascular risk factors, all patients underwent brain computed tomography and/or magnetic resonance imaging, chest X-ray, electrocardiography, and standard blood tests. The vascular risk factors examined were hypertension, diabetes mellitus, dyslipidemia, history of smoking, and habitual drinking. The Trial of Org 10172 in Acute Stroke Treatment criteria were used for the classification of ischemic stroke [
20]. TIA was defined as a transient episode of neurological dysfunction without evidence of acute cerebral infarction on neuroimaging [
21].
The study was done in accordance with the principles of the Helsinki declaration and was approved by The Ethics Committee of Yokohama Sakae Kyosai Hospital (approval number: 2013041601). Written informed consent was obtained from all patients in compliance with the committee’s requirements. This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR, identifier: UMIN000011021).
Screening test
For the screening of PA, plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were measured simultaneously, and the PAC to PRA ratio (ARR) was calculated, as previously described [
22]. The criteria for a positive screening test for PA were ARR ≥200 and PAC ≥12 ng/dL [
13]. The screening tests were performed twice at the initial visit and about a week after the admission, and the confirmatory test was performed when both screening tests were positive. Although patients who were positive only on a single screening test were in principle excluded from the confirmatory test, exceptions were made for some patients because of the potential effect of prehospital use or new administration of antihypertensive drugs.
Confirmatory test
The rapid adrenocorticotropic hormone (ACTH) test was performed as the confirmatory test, and patients with a positive result were given the definitive diagnosis of PA. The mechanism of the rapid ACTH test is confirmation of the hyperactivation of aldosterone by ACTH stimulation in cases with aldosterone hypersecretion [
23]. The test was performed as follows. The patient was asked to lie on a bed in the supine position for 30 min in the morning fasting state, and blood samples were collected 30 and 60 min after the intravenous injection of 0.25 mg ACTH. If the ratio of the maximal PAC to the simultaneously-measured cortisol was ≥8.5, PA was diagnosed [
24]. The primary endpoint was a final diagnosis of PA.
Statistical analysis
Data were analyzed with the use of Excel (version 2010; Microsoft Corp, Redmond, WA) and Dr. SPSS II (SPSS Inc, Chicago, IL). Demographic characteristics were compared using Mann-Whitney’s U-test for continuous variables, and the Chi-square test or Fisher’s exact test for categorical variables. The differences were considered significant with a P value <0.05.
Discussion
In the present study, the prevalence rate of PA in patients with acute stroke was 4.0 % of all patients and 4.9 % of patients with hypertension, which is comparable to that in previous reports of 3–10 % in the general hypertensive population [
4‐
6]. This study clearly demonstrated for the first time that the rate of PA among stroke patients is considerable, which has not been described previously. However, this prevalence rate is likely to be an underestimate, because confirmatory tests necessary for the definite diagnosis of PA were not performed in all 82 patients who were positive on at least one screening test. Therefore, the real prevalence rate of PA in stroke patients might be higher than that reported in this study.
The ARR of the screening tests may be easily affected by various factors, especially in stroke patients. A false-positive ARR elevation at the initial blood sampling might be caused by the elevation of PRA and PAC due to dehydration and by the decrease of PRA due to high blood pressure in the acute stroke phase. Therefore, confirmatory tests were not done when initial positive and follow-up negative results were obtained on the screening tests. However, the confirmatory test was performed in 5 patients (Fig.
1) who were administered antihypertensive agents after the stroke because such treatment may decrease ARR and lead to a false-negative result on the follow-up test. However, none of these patients (0.0 %) were finally diagnosed with PA.
As for the interpretation of initial negative and follow-up positive results on the screening tests, a false-negative result might have been due to prehospital administration of antihypertensive agents, and a false-positive ARR elevation on the follow-up screening test might have been caused by the effect of stopping or switching antihypertensive drugs after the stroke. Therefore, 7 patients who fit the above situation were selected, and the confirmatory test was performed (Fig.
1); of these, 2 patients (28.6 %) were diagnosed with PA.
Of the 17 patients with positive results on the initial and follow-up screening tests, 15 (88.2 %) were diagnosed with PA (Fig.
1), suggesting that dual-positive results on two screening tests are highly reliable as compared to a single-positive result (0.0 % and 28.6 % on initial and follow-up tests, respectively), which is consistent with the recommendation of the dual screening system in the guidelines [
13,
19]. The initial screening test was less reliable than the follow-up test, thus the first test might be better to be performed later than at the first visit. However, we have no data to verify this speculation. Because the confirmatory test for the definitive diagnosis of PA needs the test drug (ACTH) and more sets of laboratory tests, we believe the dual screening system may be easy and cost-effective to perform in acute phase of stroke.
Screening tests for PA are recommended as much as possible for all patients with hypertension [
13]. Because patients presenting with PA are reported to have a higher frequency of cerebrovascular events than patients with essential hypertension [
8], it is important to not overlook treatable PA for the prevention of recurrence in stroke patients. However, several limitations should also be taken into account when screening for PA in stroke patients. First, the strict screening protocol, such as cessation of antihypertensive drugs [
13], cannot be applied to stroke patients because treatment for stroke in the acute phase has a higher priority than the diagnosis of PA. Second, the older age and the low level of activities of daily living in stroke patients generally make it difficult to perform adrenalectomy even if the diagnosis of PA were made. In fact, the 17 patients diagnosed with PA in the present study neither underwent invasive adrenal venous sampling for the subtype and localization diagnosis nor adrenalectomy due to the reasons described above or the patients’ refusal of further examination. Third, the cost-effectiveness of the screening for PA in all stroke patients should also be considered.
Considering these special circumstances in stroke patients, intensive screening would be realistic in younger patients at high risk for PA. The results of the present study demonstrated that female sex, absence of diabetes, high blood pressure at the initial visit (including poorly-controlled blood pressure), lower potassium level, and intracerebral hemorrhage were the risk factors for PA (Table
1). Although small vessel occlusion is most related to hypertension among ischemic strokes [
25], we found no PA patients with this subtype. This result either may be incidental, or may indicate that the effect of PA on the occurrence of ischemic stroke largely depends on the direct action of aldosterone on the mineralocorticoid receptor.
We emphasize that it is important to recognize the high prevalence of PA in stroke patients and that intensive and efficient screening should be performed in patients with several of the risk factors for PA identified in this study.
Conclusions
In acute stroke, PA was diagnosed in 4.0 % of total patients and in 4.9 % of patients with a history of hypertension. In screening for PA, a dual screening system including initial and follow-up tests seemed reliable compared to a single screening system, because 88.2 % of patients positive on both tests were confirmed to have PA. The rapid ACTH test for the confirmation of PA was performed safely. It is important to pay more attention to the possibility of the existence of PA in acute stroke patients, and efficient screening of PA should be performed particularly for young patients, considering the risk factors clarified in this study.
Acknowledgments
We thank all participating hospitals, colleagues, nurses, imaging and laboratory technicians.