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Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis

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Summary

Background

There is conflicting evidence, relying on heterogeneous studies, as to whether aldosterone excess is responsible for an increased risk of cardiovascular and cerebrovascular complications in patients with primary aldosteronism. We aimed to assess the association between primary aldosteronism and adverse cardiac and cerebrovascular events, target organ damage, diabetes, and metabolic syndrome, compared with the association of essential hypertension and these cardiovascular and end organ events, by integrating results of previous studies.

Methods

We did a meta-analysis of prospective and retrospective observational studies that compared patients with primary aldosteronism and essential hypertension, to analyse the association between primary aldosteronism and stroke, coronary artery disease (as co-primary endpoints), atrial fibrillation and heart failure, target organ damage, metabolic syndrome, and diabetes (as secondary endpoints). We searched MEDLINE and Cochrane Library for articles published up to Feb 28, 2017, with no start date restriction. Eligible studies compared patients with primary aldosteronism with patients with essential hypertension (as a control group) and reported on the clinical events or endpoints of interest. We also compared primary aldosteronism subtypes, aldosterone-producing adenoma, and bilateral adrenal hyperplasia.

Findings

We identified 31 studies including 3838 patients with primary aldosteronism and 9284 patients with essential hypertension. After a median of 8·8 years (IQR 6·2–10·7) from the diagnosis of hypertension, compared with patients with essential hypertension, patients with primary aldosteronism had an increased risk of stroke (odds ratio [OR] 2·58, 95% CI 1·93–3·45), coronary artery disease (1·77, 1·10–2·83), atrial fibrillation (3·52, 2·06–5·99), and heart failure (2·05, 1·11–3·78). These results were consistent for patients with aldosterone-producing adenoma and bilateral adrenal hyperplasia, with no difference between these subgroups. Similarly, primary aldosteronism increased the risk of diabetes (OR 1·33, 95% CI 1·01–1·74), metabolic syndrome (1·53, 1·22–1·91), and left ventricular hypertrophy (2·29, 1·65–3·17).

Interpretation

Diagnosing primary aldosteronism in the early stages of disease, with early initiation of specific treatment, is important because affected patients display an increased cardiovascular risk compared with patients with essential hypertension.

Funding

None.

Introduction

Primary aldosteronism is a clinical syndrome characterised by hypertension, suppressed plasma renin, and autonomous aldosterone overproduction, which can be either unilateral (usually aldosterone-producing adenoma) or bilateral (bilateral adrenal hyperplasia).1 In different animal models, experimental evidence has linked aldosterone excess with vascular and perivascular inflammation,2 oxidative stress,3 and fibrosis.4 In addition, aldosterone excess promotes insulin resistance5 and aldosterone levels have been found to be inversely correlated with plasma HDL,6 C-peptide and β-cell mass,7 and directly associated with plasma triglycerides in human studies.8 Nonetheless, current evidence regarding a pathophysiological link between primary aldosteronism and metabolic syndrome is conflicting; some studies point towards an increased risk of metabolic syndrome9 and others reporting no difference in fasting plasma glucose levels or in the prevalence of diabetes and metabolic syndrome between primary aldosteronism and patients with essential hypertension.10, 11 The incidence of left ventricular hypertrophy and myocardial infarction was reported to be higher in patients with primary aldosteronism than in those with essential hypertension in some studies,12 but not in others.13, 14 These differences might be due in part to the small number of the patients included in the studies or to the different features of the cohorts investigated and to variations in the diagnostic protocols for primary aldosteronism, making single study comparisons difficult to interpret.

Therefore, we aimed to provide an updated and precise quantitative estimate of the relative risk of target organ damage, cardiovascular and cerebrovascular events, and metabolic syndrome in patients with primary aldosteronism compared with patients affected by essential hypertension. To this end, we did a systematic meta-analysis of observational epidemiological studies with a primary outcome of prevalence of stroke and coronary artery disease.

Research in context

Evidence before this study

Primary aldosteronism is the most frequent form of endocrine hypertension. Experimental studies in different animal models have linked aldosterone excess with vascular and perivascular inflammation, oxidative stress, and fibrosis. Aldosterone promotes insulin resistance and its levels have been found to be inversely correlated with C-peptide and β-cell mass. Existing reported studies have often, but not always, linked autonomous aldosterone overproduction with an increased risk of cardiovascular and cerebrovascular events and cardiac target organ damage in patients affected by primary aldosteronism. Relevant articles with full text in English were evaluated in MEDLINE, and Cochrane Library in keeping with established methods with terms associated with primary aldosteronism (eg, “primary aldosteronism”, “hyperaldosteronism”, and “primary aldosteronism/hyperaldosteronism”, and the following terms: “left ventricular hypertrophy”, “myocardial infarction”, “atrial fibrillation”, “heart failure”, “percutaneous transluminal coronary angioplasty”, “stroke”, “metabolic syndrome”, and “diabetes”) up to Feb 28, 2017, with no start date restriction.

Added value of this study

Results from this comprehensive meta-analysis including 31 studies for 3838 patients with primary aldosteronism and 9284 patients with essential hypertension indicate that primary aldosteronism is associated with an increased rate of cardiovascular and cerebrovascular morbidity, including stroke, coronary artery disease, heart failure, and atrial fibrillation relative to patients with essential hypertension. Patients with primary aldosteronism also display an increased prevalence of metabolic alterations such as metabolic syndrome and diabetes.

Implications of all the available evidence

Findings from our systematic review and meta-analysis further support the importance of the early and systematic screening for primary aldosteronism in most, if not all, hypertensive patients to allow the initiation of specific treatment for primary aldosteronism that might reverse the excess cardiovascular risk.

Section snippets

Search strategy and selection criteria

We searched MEDLINE and Cochrane Library for relevant articles in keeping with established methods using terms associated with primary aldosteronism (eg, “primary aldosteronism”, “hyperaldosteronism”, and “primary aldosteronism/hyperaldosteronism”, and the following terms: “left ventricular hypertrophy”, “myocardial infarction”, “atrial fibrillation”, “heart failure”, “percutaneous transluminal coronary angioplasty”, “stroke”, “metabolic syndrome”, and “diabetes”) up to Feb 28, 2017, with no

Results

We identified 2345 citations through our search and evaluated them for eligibility at title or abstract level (figure 1). Of the 51 full text reports assessed, nine were excluded because of duplicate reports, six for lack of appropriate control group and five because the primary aldosteronism diagnosis was not in agreement with the US Endocrine Society Guidelines1, 18 or Japan Endocrine Society guidelines19 (appendix p 5–6). 31 studies9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30

Discussion

In this meta-analysis of 31 studies that included 3838 patients with primary aldosteronism and 9284 patients with essential hypertension, we found robust evidence for a significant increase in cardiovascular and cerebrovascular events, target organ damage (left ventricular hypertrophy), metabolic syndrome, and diabetes, in patients with primary aldosteronism compared with patients with essential hypertension. In the exclusive analysis of matched studies, this association was independent from

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