There have been several clinical studies examining the factors associated with cardiovascular disease (CVD) in patients with primary aldosteronism (PA); however, their results have left it unclear whether CVD is affected by the plasma aldosterone concentration or hypokalemia. We assessed the PA database established by the multicenter JPAS (Japan Primary Aldosteronism Study) and compared the prevalence of CVD among patients with PA with that among age-, sex-, and blood pressure-matched essential hypertension patients and participants with hypertension in a general population cohort. We also performed binary logistic regression analysis to determine which parameters significantly increased the odds ratio for CVD. Of the 2582 patients with PA studied, the prevalence of CVD, including stroke (cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage), ischemic heart disease (myocardial infarction or angina pectoris), and heart failure, was 9.4% (stroke, 7.4%; ischemic heart disease, 2.1%; and heart failure, 0.6%). The prevalence of CVD, especially stroke, was higher among the patients with PA than those with essential hypertension/hypertension. Hypokalemia (K ≤3.5 mEq/L) and the unilateral subtype significantly increased adjusted odds ratios for CVD. Although aldosterone levels were not linearly related to the adjusted odds ratio for CVD, patients with plasma aldosterone concentrations ≥125 pg/mL had significantly higher adjusted odds ratios for CVD than those with plasma aldosterone concentrations <125 pg/mL. Thus, patients with PA seem to be at a higher risk of developing CVD than patients with essential hypertension. Moreover, patients with PA presenting with hypokalemia, the unilateral subtype, or plasma aldosterone concentration ≥125 pg/mL are at a greater risk of CVD and have a greater need for PA-specific treatments than others.

The present study clearly demonstrates that CYP11B2 immunostaining is a powerful tool for histopathological diagnosis of aldosterone overproduction in PA and for subtype classification of APA, multiple APCCs, unilateral multiple adrenocortical micronodules, and diffuse hyperplasia.

Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and mortality rates than essential hypertension. The Japan Endocrine Society (JES) has developed an updated guideline for PA, based on the evidence, especially from Japan. We should preferentially screen hypertensive patients with a high prevalence of PA with aldosterone to renin ratio ≥200 and plasma aldosterone concentrations (PAC) ≥60 pg/mL as a cut-off of positive results. While we should confirm excess aldosterone secretion by one positive confirmatory test, we could bypass patients with typical PA findings. Since PAC became lower due to a change in assay methods from radioimmunoassay to chemiluminescent enzyme immunoassay, borderline ranges were set for screening and confirmatory tests and provisionally designated as positive. We recommend individualized medicine for those in the borderline range for the next step. We recommend evaluating cortisol cosecretion in patients with adrenal macroadenomas. Although we recommend adrenal venous sampling for lateralization before adrenalectomy, we should carefully select patients rather than all patients, and we suggest bypassing in young patients with typical PA findings. A selectivity index ≥5 and a lateralization index >4 after adrenocorticotropic hormone stimulation defines successful catheterization and unilateral subtype diagnosis. We recommend adrenalectomy for unilateral PA and mineralocorticoid receptor antagonists for bilateral PA. Systematic as well as individualized clinical practice is always warranted. This JES guideline 2021 provides updated rational evidence and recommendations for the clinical practice of PA, leading to improved quality of the clinical practice of hypertension.

Abstract. Although subclinical Cushing's syndrome has been commonly experienced, details of the clinical outcome and its indication for adrenalectomy have yet to be established. In the present study, we investigated the prevalence of cardiovascular risks, their clinical outcome during long-term follow up before and after adrenalectomy in 20 patients with subclinical Cushing's syndrome. We also correlated the hypercortisolism and age with the cardiovascular risks and the clinical outcome. The prevalence of hypertension, impaired glucose metabolism, dyslipidemia, and obesity was 45%, 65%, 65%, and 25%, respectively. In the non-operated group (n = 12), six patients (50%) showed deterioration of at least one of the cardiovascular risks. Four patients showed an increase of at least one risk, while none of the patients showed a decrease in the number of risks. One patient developed overt Cushing's syndrome. In the operated group (n = 10) including two operated patients of the non-operated group, eight patients (80%) showed an improvement of at least one of the cardiovascular risks after surgery and five patients (50%) showed a decrease of at least one risk. The prognosis in terms of the changes of the cardiovascular risks was significantly better in the operated group than in the non-operated group (p<0.001). Neither the hypercortisolism nor age correlated to the presence and the clinical outcome of the cardiovascular risks. The present study clearly demonstrated probability of deterioration during the clinical course and improvement after adrenal surgery in patients with subclinical Cushing's syndrome. Careful follow-up of the cardiovascular risks is therefore warranted. Adrenalectomy could be a treatment of choice despite the hypercortisolism and age of the patients, especially when the cardiovascular risks show signs of deterioration.