Renin-angiotensin-aldosterone system and corticosteroids in heart failure

Greater renin-angiotensin-aldosterone system (RAAS) activity, as reflected by higher levels of renin and aldosterone, has been associated with worse prognosis in patients with chronic heart failure (HF). These findings provided the basis for clinical trials with RAAS inhibitors in these patients. Similarly, higher levels of cortisol have been correlated with worse outcomes in chronic HF. However, there is lack of information with respect to the activity of RAAS and glucocorticoid secretion in patients with decompensated HF. Is RAAS universally activated in patients with worsening HF? Are cortisol levels elevated in these patients? Furthermore, the prognostic importance of RAAS mediators and plasma glucocorticoid levels in patients with decompensated HF remains unknown. Diuretic therapy is one of the initial therapeutic strategies in patients with decompensated HF and fluid congestion. Diuretics decrease the extracellular volume and suppress natriuretic peptide levels while they in parallel stimulate RAAS activity early after initiation of therapy. However, it is unknown if the dissociation between RAAS and natriuretic peptides after initiation of diuretic treatment persists over time. If that remains present in the long term, augmentation of the natriuretic peptide actions on top of RAAS inhibition might be of further benefit in patients with HF, given their suppressing effects on RAAS and sympathetic nervous system (SNS) and vasodilating and natriuretic properties. The late steps in corticosteroid synthesis are mediated by aldosterone synthase for aldosterone and 11beta-hydroxylase for cortisol respectively. These enzymes are highly homologous and are encoded by genes that lie in tandem in chromosome 8 in humans. A common single nucleotide polymorphism (-344T/C) in the promoter region of aldosterone synthase gene (CYP11B2) has been associated with aldosterone levels and the aldosterone to renin ratio in healthy subjects and patients with hypertension. Similar findings have been shown for another polymorphism in the same gene, the Intron 2 conversion (IC). Moreover, these polymorphisms have been correlated with the 11-deoxycortisol to cortisol ratio, which represents an index of 11beta-hydroxylase activity. In patients with severe HF of African-American origin -344T/C polymorphism has been associated with prognosis. However, the data with regards to the -344T/C polymorphism (and the IC) in relation to gluco- and mineralo-corticoid secretion and survival in patients with HF of Caucasian origin remains to be elucidated. The hypothesis of the current thesis was that plasma levels of RAAS mediators and glucocorticoids are associated with markers of HF severity in patients with decompensated HF and in patients with stable HF. Moreover, the dissociation between RAAS activity and natriuretic peptides seen early after initiation of diuretic treatment persists in the medium to the long term. In addition, that higher levels of plasma renin, mineralo- and gluco- corticoids are associated with worse prognosis in patients with decompensated HF. Lastly, that CYP11B2 polymorphisms -344T/C and IC are associated with mineralo- and gluco-corticoid secretion and survival in these patients. In order to test these hypotheses, 722 patients with decompensated HF were enrolled in the current studies. Of these, 453 surviving patients returned for the follow-up visit 4-6 weeks after discharge. All these patients had detailed clinical and biochemical phenotyping and additionally genotyping of the -344T/C and IC CYP11B2 polymorphisms. In this thesis, it was shown that levels of RAAS mediators, plasma renin concentration (PRC) and aldosterone, are not on average elevated during hospital admission in patients with decompensated HF. RAAS activity has been previously shown to be activated in patients with advanced congestive HF. However, high doses of diuretics were used and a significant proportion of patients were taking an aldosterone blocker in these studies. The results of the current study are in accordance with early studies with small numbers of untreated patients with congestive HF that reported normal or low levels of renin and aldosterone. PRC and aldosterone levels were higher at follow-up compared with hospital admission likely due to a decline in the intravascular volume. In contrast, natriuretic peptide levels were lower at the follow-up visit and that is likely to contribute to the higher levels of RAAS mediators after discharge as these peptides exert suppressing effects on the RAAS and SNS. Similarly to PRC and mineralocorticoid levels, glucocorticoid concentrations were within the normal range in patients with decompensated HF. Furthermore, it was shown for the first time that cortisol levels during admission are associated with clinical status and prognostic markers of HF, such as B-type natriuretic peptide (BNP) and troponin. That may represent an association reflecting the greater stress response due to HF severity. However, growing evidence supports that cortisol under conditions of altered intracellular redox state becomes a mineralocorticoid agonist and that might contribute to these associations. Overall, these findings call into question the “normal range” of cortisol levels in patients with HF. Moreover, 11-deoxycortisol to cortisol ratio was shown to be lower in patients with left ventricular (LV) remodeling, lower blood pressure and greater RAAS activity during hospital admission. 11-deoxycortisol to cortisol ratio represents an index of 11beta-hydroxylase, which is an enzyme regulated by adrenocorticotropic hormone (ACTH). Lower 11-deoxycortisol to cortisol ratio represents higher enzyme activity and reflects a state of chronic ACTH stimulation. These findings indicate that patients with features of worse HF are characterised by activation of the hypothalamus-pituitary-adrenal (HPA) axis. PRC but not aldosterone was associated with an increased risk of all-cause mortality in patients with decompensated HF, even after adjustment for a combination of other variables shown to exert an independent prognostic value in the overall HF population. In contrast, cortisol was not an independent prognostic factor in patients with decompensated HF. Lastly, no association was seen between aldosterone levels and -344T/C or IC polymorphism in the current study. CYP11B2 -344TT genotype was associated with relative impairment of 11beta-hydroxylase, as reflected by the higher 11-deoxycortisol to cortisol ratio, in keeping with previous studies in healthy subjects and patients with hypertension. However, no association was found between CYP11B2 polymorphisms and prognosis in the current studies.