Mineralcorticoid Antagonists in Heart F a i l u re Emilia D’Elia, MDa,b, Henry Krum, MBBS, PhD, FRACP, FCSANZ, FESCc,* KEYWORDS Mineralcorticoid receptor agonists Heart failure Aldosterone
KEY POINTS
INTRODUCTION Heart failure (HF) is a syndrome characterized by the activation of several neurohormonal mechanisms initially focused on maintaining an adequate peripheral perfusion, but potentially causing counterproductive physiopatological alterations such as hydrosaline retention, peripheral vasoconstriction, and myocyte degeneration/hypertrophy.1,2 The renin angiotensin aldosterone system (RAAS) and autonomic nervous system are important and interdependent mechanisms contributing to these pathophysiological responses. Both tissue and peripheral RAAS activation induce production of
angiotensin II, which is one of the more powerful vasoconstrictive peptide hormones in the body.3 RAAS activation takes place in vascular, renal, and cardiac structures, favoring the phenomenon of left ventricular remodeling: angiotensin II facilitates myocyte growth and represents a stimulus for norepinephrine release. The SOLVD (Studies of Left Ventricular Dysfunction) study demonstrated a significant reduction in left ventricular dimensions in HF patients treated with an angiotensinconverting enzyme (ACE) inhibitor (enalapril), likely due not only to a decrease in afterload, but also to blockade of local activation of myocardial RAAS.4 Many other clinical trials5–7 support the relevance
a Cardiovascular Department, Papa Giovanni XXIII Hospital, Piazza OMS 1, Bergamo 24127, Italy; b University of Pavia, Piazzale Golgi 1, Pavia 27100, Italy; c Department of Epidemiology & Preventive Medicine, Centre of Cardiovascular Research & Education (CCRE) in Therapeutics, Alfred Hospital, Monash University, Commercial Road, Melbourne, Victoria 3004, Australia * Corresponding author. E-mail address: [email protected]
Heart Failure Clin 10 (2014) 559–564 http://dx.doi.org/10.1016/j.hfc.2014.07.003 1551-7136/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
heartfailure.theclinics.com
Aldosterone is the most important corticosteroid hormone in the human body responsible for several critical pathophysiological contributions to the heart failure (HF) syndrome. Mineralcorticoid receptor agonists (MRAs) have been documented to be effective in opposing these adverse effects of aldosterone in HF, favoring reduction of congestion, hemodynamic improvement, decrease in vasoconstriction, and abrogation of pathologic cardiac fibrosis. With their antiremodeling effects, these drugs seems to be powerful in HF both early after myocardial infarction and in established disease. MRAs are recommended for all HF patients with persisting symptoms (New York Heart Association class II-IV) and a left ventricular ejection fraction no more than 35% despite treatment with an angiotensin-converting enzyme inhibitor and a beta-blocker, to reduce the risk of re-hospitalization and the risk of premature death (I-A recommendation). Further areas currently being explored for MRAs include their use in patients with heart failure with preserved ejection fraction (HFPEF) and early after MI. Renal function and serum potassium should be carefully monitored, particularly with the introduction of MRA.
560
D’Elia & Krum of these system interactions in HF patients, focusing on the role of ACE inhibitors in improving symptoms and reducing mortality.
ROLE OF ALDOSTERONE IN HF ACE inhibitors can cause an initial reduction of plasma angiotensin II and aldosterone levels, although over the long term, their efficacy is lowered, probably because of aldosterone escape, a phenomenon first observed in hypertensive patients when high-dose ACE inhibitors (captopril) were associated with an increase rather than decrease in aldosterone levels.8,9 With prolonged blockade of the ACE enzyme, it is reasonable to assume that other mechanisms (ie, increases in adrenocorticotrophin [ACTH], endothelin, or intracellular electrolytes) become more critical for aldosterone release. In the HF syndrome, plasma aldosterone levels are correlated with worsening
of HF and increased mortality, as has been demonstrated in the CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study) trial.10 Aldosterone is the most powerful corticosteroid hormone in the human body. It is responsible for salt and water balance, and its augmented production confers a critical negative role in the HF setting, where mineralcorticoid receptors (MR) are overexpressed.11 Aldosterone activation confers negative effects at several different levels (Figs. 1 and 2)12: At the renal distal tubule, it causes sodium retention and loss of potassium and magnesium. The consequent extravascular volume expansion determines volume overload and venous pressure increase, worsening edema and congestion, with further RAAS activation. At the myocardial level, it favors myocyte fibrosis, increased oxygen demand, and
Fig. 1. Negative effects of MR activation. ANGII, angiotensin II; MR, mineralcorticoids; NO, nitric oxide; RAAS, reninangiotensin-aldosterone system; SNS, sympathetic nervous system. (Adapted from Albaghdadi M, Gheorghiade M, Pitt B. Mineralocorticoid receptor antagonism: therapeutic potential in acute heart failure syndromes. Eur Heart J 2011;32:2627; with permission.)
Mineralcorticoid Antagonists in Heart Failure
Fig. 2. Resistance to diuretics and antialdosterone effects of MRAs. Sodium increase causes hyperplasia and hypertrophy at distal tubule level with activation of RAAS and SNS and consequently increase of aldosterone plasma levels. In HF patients, MRA favor natriuresis. * JGA, juxtaglomerular apparatus. (Adapted from Albaghdadi M, Gheorghiade M, Pitt B. Mineralocorticoid receptor antagonism: therapeutic potential in acute heart failure syndromes. Eur Heart J 2011;32:2632; with permission.)
pathologic myocardial collagen production; all of these effects contribute to ventricular stiffness and diastolic dysfunction. At the vascular level, it causes vasoconstriction, afterload increase, and endothelial dysfunction; spironolactone, an MR antagonist (MRA), improves endothelial function in HF patients already treated with ACE inhibitors.13 At the hemocoagulative level, it favors fibrinolysis, causing an increase in endothelial plasminogen activator inhibitor. At the neurohormonal level, it has an indirect sympathomimetic action, enhancing catecholamine effect and inhibiting norephinephrine reuptake.
MRAS IN HF CLINICAL TRIALS Spironolactone In the Randomized Aldactone Evaluation Study (RALES), a population of 1663 systolic HF patients with New York Heart Association (NHYA) class III to IV symptoms receiving standard medical therapy was randomized to receive spironolactone (25 mg daily) or placebo. Spironolactone was associated with a significant mortality (-30%, P
KEY POINTS
INTRODUCTION Heart failure (HF) is a syndrome characterized by the activation of several neurohormonal mechanisms initially focused on maintaining an adequate peripheral perfusion, but potentially causing counterproductive physiopatological alterations such as hydrosaline retention, peripheral vasoconstriction, and myocyte degeneration/hypertrophy.1,2 The renin angiotensin aldosterone system (RAAS) and autonomic nervous system are important and interdependent mechanisms contributing to these pathophysiological responses. Both tissue and peripheral RAAS activation induce production of
angiotensin II, which is one of the more powerful vasoconstrictive peptide hormones in the body.3 RAAS activation takes place in vascular, renal, and cardiac structures, favoring the phenomenon of left ventricular remodeling: angiotensin II facilitates myocyte growth and represents a stimulus for norepinephrine release. The SOLVD (Studies of Left Ventricular Dysfunction) study demonstrated a significant reduction in left ventricular dimensions in HF patients treated with an angiotensinconverting enzyme (ACE) inhibitor (enalapril), likely due not only to a decrease in afterload, but also to blockade of local activation of myocardial RAAS.4 Many other clinical trials5–7 support the relevance
a Cardiovascular Department, Papa Giovanni XXIII Hospital, Piazza OMS 1, Bergamo 24127, Italy; b University of Pavia, Piazzale Golgi 1, Pavia 27100, Italy; c Department of Epidemiology & Preventive Medicine, Centre of Cardiovascular Research & Education (CCRE) in Therapeutics, Alfred Hospital, Monash University, Commercial Road, Melbourne, Victoria 3004, Australia * Corresponding author. E-mail address: [email protected]
Heart Failure Clin 10 (2014) 559–564 http://dx.doi.org/10.1016/j.hfc.2014.07.003 1551-7136/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
heartfailure.theclinics.com
Aldosterone is the most important corticosteroid hormone in the human body responsible for several critical pathophysiological contributions to the heart failure (HF) syndrome. Mineralcorticoid receptor agonists (MRAs) have been documented to be effective in opposing these adverse effects of aldosterone in HF, favoring reduction of congestion, hemodynamic improvement, decrease in vasoconstriction, and abrogation of pathologic cardiac fibrosis. With their antiremodeling effects, these drugs seems to be powerful in HF both early after myocardial infarction and in established disease. MRAs are recommended for all HF patients with persisting symptoms (New York Heart Association class II-IV) and a left ventricular ejection fraction no more than 35% despite treatment with an angiotensin-converting enzyme inhibitor and a beta-blocker, to reduce the risk of re-hospitalization and the risk of premature death (I-A recommendation). Further areas currently being explored for MRAs include their use in patients with heart failure with preserved ejection fraction (HFPEF) and early after MI. Renal function and serum potassium should be carefully monitored, particularly with the introduction of MRA.
560
D’Elia & Krum of these system interactions in HF patients, focusing on the role of ACE inhibitors in improving symptoms and reducing mortality.
ROLE OF ALDOSTERONE IN HF ACE inhibitors can cause an initial reduction of plasma angiotensin II and aldosterone levels, although over the long term, their efficacy is lowered, probably because of aldosterone escape, a phenomenon first observed in hypertensive patients when high-dose ACE inhibitors (captopril) were associated with an increase rather than decrease in aldosterone levels.8,9 With prolonged blockade of the ACE enzyme, it is reasonable to assume that other mechanisms (ie, increases in adrenocorticotrophin [ACTH], endothelin, or intracellular electrolytes) become more critical for aldosterone release. In the HF syndrome, plasma aldosterone levels are correlated with worsening
of HF and increased mortality, as has been demonstrated in the CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study) trial.10 Aldosterone is the most powerful corticosteroid hormone in the human body. It is responsible for salt and water balance, and its augmented production confers a critical negative role in the HF setting, where mineralcorticoid receptors (MR) are overexpressed.11 Aldosterone activation confers negative effects at several different levels (Figs. 1 and 2)12: At the renal distal tubule, it causes sodium retention and loss of potassium and magnesium. The consequent extravascular volume expansion determines volume overload and venous pressure increase, worsening edema and congestion, with further RAAS activation. At the myocardial level, it favors myocyte fibrosis, increased oxygen demand, and
Fig. 1. Negative effects of MR activation. ANGII, angiotensin II; MR, mineralcorticoids; NO, nitric oxide; RAAS, reninangiotensin-aldosterone system; SNS, sympathetic nervous system. (Adapted from Albaghdadi M, Gheorghiade M, Pitt B. Mineralocorticoid receptor antagonism: therapeutic potential in acute heart failure syndromes. Eur Heart J 2011;32:2627; with permission.)
Mineralcorticoid Antagonists in Heart Failure
Fig. 2. Resistance to diuretics and antialdosterone effects of MRAs. Sodium increase causes hyperplasia and hypertrophy at distal tubule level with activation of RAAS and SNS and consequently increase of aldosterone plasma levels. In HF patients, MRA favor natriuresis. * JGA, juxtaglomerular apparatus. (Adapted from Albaghdadi M, Gheorghiade M, Pitt B. Mineralocorticoid receptor antagonism: therapeutic potential in acute heart failure syndromes. Eur Heart J 2011;32:2632; with permission.)
pathologic myocardial collagen production; all of these effects contribute to ventricular stiffness and diastolic dysfunction. At the vascular level, it causes vasoconstriction, afterload increase, and endothelial dysfunction; spironolactone, an MR antagonist (MRA), improves endothelial function in HF patients already treated with ACE inhibitors.13 At the hemocoagulative level, it favors fibrinolysis, causing an increase in endothelial plasminogen activator inhibitor. At the neurohormonal level, it has an indirect sympathomimetic action, enhancing catecholamine effect and inhibiting norephinephrine reuptake.
MRAS IN HF CLINICAL TRIALS Spironolactone In the Randomized Aldactone Evaluation Study (RALES), a population of 1663 systolic HF patients with New York Heart Association (NHYA) class III to IV symptoms receiving standard medical therapy was randomized to receive spironolactone (25 mg daily) or placebo. Spironolactone was associated with a significant mortality (-30%, P
