Author + information
- William C. Little, MD⁎ ( and )
- Paul M. Kirkman, MD
- ↵⁎Reprint requests and correspondence:
Dr. William C. Little, Cardiology Section, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1045
- chronic kidney disease
- arterial stiffness
- left ventricular mass
- renin-angiotensin-aldosterone system
The renin-angiotensin-aldosterone system plays an important role in the development and progression of cardiovascular disease. Initial therapeutic interventions focused on angiotensin II, whose production from angiotensin I can be reduced by angiotensin-converting enzyme (ACE) inhibitors or whose action can be inhibited through the use of angiotensin receptor blockers (ARBs) (1).
Angiotensin II is a vasoconstrictor and stimulates the production of aldosterone by the adrenals (2). Both angiotensin II and aldosterone stimulate volume retention, ventricular hypertrophy, and fibrosis (ventricular, vascular, and renal) as well as systemic inflammation and coagulation. Reducing the generation or action of angiotensin II with ACE inhibitors and ARBs is effective in treating arterial hypertension (3), improving outcome in patients with reduced left ventricular ejection fraction (4), decreasing the development of diabetes (5), slowing the progression of vascular disease (6), and protecting renal function (7). Thus, ACE inhibitors and ARBs play an important role in the treatment and prevention of cardiovascular disease by reducing the adverse consequences of angiotensin II and aldosterone. More recently, aliskiren has been used to block the action of renin, the most proximal step in the production of angiotensin II and subsequently aldosterone (8).
It is important to recognize that angiotensin II is not the only stimulus for the production of aldosterone. An increase in serum potassium is a strong stimulant of adrenal production of aldosterone. Other potential stimuli of aldosterone include catecholamines, endothelin, and arginine vasopressin (9). Substantial levels of aldosterone may be present even in the presence of an ACE inhibitor (10). These observations suggest that blocking the effects of aldosterone could provide benefit when added to an ACE inhibitor or ARB. There is already substantial support for this concept. For example, aldosterone blockers have additional benefits when added to ACE inhibitors in selected patients with heart failure (11) and in ventricular dysfunction after myocardial infarction (12).
The study of patients with mild chronic renal impairment from Birmingham University in the United Kingdom (13), published in this issue of the Journal, extends these observations. The authors of this study found that the addition of the aldosterone blocker spironolactone for 36 weeks produced a clear reduction in left ventricular mass and aortic stiffness. These benefits occurred in patients who were already being treated with an ACE inhibitor or an ARB and had well-controlled blood pressure (<130/85 mm Hg).
Patients with chronic kidney disease (CKD) have a markedly increased risk of cardiovascular disease, which increases as the glomerular filtration rate decreases (14). Even patients with mild renal dysfunction have an increased cardiovascular risk. Both left ventricular hypertrophy and increased arterial stiffness are powerful risk factors for cardiovascular disease in the general population and in patients with renal dysfunction. The present study shows that aldosterone has an important role in regressing left ventricular hypertrophy and reducing increased arterial stiffness in CKD. These findings suggest that aldosterone blockade with spironolactone may be effective in reducing the risk of cardiovascular disease in these patients. It is important to recognize that although left ventricular hypertrophy and arterial stiffness are strong markers of increased cardiovascular risk, they may not be the mechanism of all of the risk (15). Thus, the benefit of aldosterone on clinical end points needs to be directly investigated.
Aldosterone blockade may have a role in the treatment of heart failure associated with a preserved ejection fraction (>0.50). There is no specific therapy that has been shown to be of benefit beyond the control of hypertension (16,17). Because left ventricular hypertrophy, fibrosis, and increased arterial stiffness may play an important role in the pathogenesis of this disorder, aldosterone is a very attractive therapeutic target. For these reasons, spironolactone is being investigated as a therapy for these patients in an ongoing large multicenter trial sponsored by the National Institutes of Health (TOPCAT [Therapy in Adults With Preserved Ejection Fraction Congestive Heart Failure]).
Treatment with spironolactone produced a significant decrease in albuminuria in the Birmingham study, suggesting that it has a renal protective effect beyond the use of an ACE inhibitor or ARB. However, it should be noted that treatment with an ARB in addition to an ACE inhibitor may decrease albuminuria, but not result in renal protection (18).
Aldosterone stimulates renal excretion of potassium. Thus, blocking aldosterone's actions may result in hyperkalemia, especially in patients with renal dysfunction who are also receiving an ACE inhibitor or ARB. For example, after the publication of the RALES (Randomized Aldactone Evaluation Study) study, in which the authors demonstrated an improved survival in patients with heart failure and a reduced ejection fraction treated with spironolactone, there was an abrupt increase in the occurrence of serious hyperkalemia in such patients in Canada (19). It is important to recognize that the patients in the Birmingham study underwent a 4-week, open-label, run-in phase of 25 mg of spironolactone daily before they were randomized to continue with spironolactone or placebo for the following 36 weeks (13).
During this run-in period, 1 patient was withdrawn because of serious hyperkalemia (6.5 mmol/l). In addition, 6 patients (5%) had potassium levels between 5.5 and 5.9 mmol/l during the run-in phase and, thus, were switched to receive spironolactone on alternate days. During the blinded treatment phase of the study, 4 patients had potassium levels between 5.5 and 5.9 mmol/l and required a dose reduction. Furthermore, serum potassium was greater in the spironolactone group than the placebo group at the end of the study (4.6 mmol/l vs. 4.4 mmol/l). This study and the previous observations (11,12) demonstrate that patients with mild renal insufficiency can tolerate spironolactone in addition to an ACE inhibitor, but their serum potassium must be carefully monitored.
The renin-angiotensin-aldosterone system is an important therapeutic target for the treatment and prevention of cardiovascular disease. The use of ACE inhibitors and ARBs has been an important therapeutic advance. Increasing observations suggest that aldosterone blockers have the potential to provide additional benefit (9–13). This has been proven in selected patients with systolic heart failure and patients with substantial left ventricular dysfunction after myocardial infarction, is being investigated in patients with heart failure with preserved ejection fraction, and the Birmingham study indicates it should be studied in patients with CKD.
Dr. Little has served as a consultant for Bristol-Myers Squibb, CorAssist Cardiovascular, Ltd., Celladon Corporation, Boston Scientific, Medtronic, Bio-Control Medical, CVRx, and CV Therapeutics.
↵⁎ Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of the JACCor the American College of Cardiology.
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