• biomarkers
• heart failure
• neurohormones
• prognosis
• systolic function

Abstract

Background: Neurohormonal activation has a central role in the pathophysiology and in the clinical course of the heart failure (HF) syndrome. Despite recent advances in pharmacological and non-pharmacological therapy, a subset of patients with systolic HF still presents elevation of circulating markers of the sympathetic and of renin-angiotenin-aldosterone-system, both promoting the progression of the disease and end-organ damage. Further, whether neurohormonal activation is present also in HF phenotypes with preserved or mildly impaired systolic function is still unknown.

Aims: With the present study, we aimed to assess the extent of neurohormonal activation in chronic HF across the whole spectrum of left ventricular systolic function, and to identify its clinical correlates and prognostic value.

Methods: Data from 2791 patients with chronic HF on stable pharmacological therapy for at least one month were retrospectively analyzed. Three categories were identified, according to current Guidelines: HF with reduced (HFrEF, LVEF <40%), mid-range (HFmrEF, LVEF 40-50%), and preserved ejection fraction (HFpEF, LVEF ≥50%). All patients underwent a thorough clinical, biohumoral and echocardiographic examination, including plasma renin activity (PRA), aldosterone, norepinephrine (NE), epinephrine (E) and N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP). Patients were then followed-up for all-cause and cardiac mortality (median of evaluation 39 months, interquartile interval 17-79). Non-cardiac causes for death were further investigated.

Results: In our population, patients with HFpEF were older (HFrEF: 68±12 years; HFmrEF: 69±13 years; HFpEF: 71±16 years; p<0.001) and more frequently of female sex (females were HFrEF: 24%; HFmrEF: 29%; HFpEF: 48%; p<0.001). No difference in comorbidities was observed between groups, except for hypertension (HFrEF: 52%; HFmrEF: 63%; HFpEF: 72%; p<0.001). Circulating markers of neurohormonal activation were higher in HFrEF than in HFmrEF (p<0.001 NT-proBNP, PRA, aldosterone and NE; p=0.670 E), while they were similar between HFmrEF and HFpEF. Elevation of PRA was observed in 39, 24 and 19% of patients with HFrEF, HFmrEF and HFpEF; aldosterone was increased in 45, 32 and 43%, E in 13, 14 and 11%, NE in 52, 38 and 40%, and NT-proBNP in 96, 84 and 86% of cases, respectively. Patients with HFrEF showed the worst 10-year outcome, either for all-cause and cardiac mortality (log rank 49.96, p<0.001; log rank 80.26, p<0.001, respectively); non-cardiac death was more frequent in HFmrEF and in HFpEF, compared to HFrEF (54, 61 and 34%). Patients with elevation of 4 biomarkers (NT-proBNP, PRA, aldosterone, NE) showed the highest mortality in each category of LVEF at 1, 5 and 10-year follow-up. NT-proBNP was an independent predictor of all-cause and cardiac mortality, except for cardiac death in HFpEF patients.

Conclusion: SNS and RAAS activation is present throughout the whole spectrum of LV systolic function. The assessment of circulating values of neurohormones may be useful in selecting subgroups needing a tailored and enhanced therapeutic effort.