T h e Re n i n - A n g i o t e n s i n A l d o s t e ro n e S y s t e m an d H e a r t F a i l u re Gabriel Sayer, MDa,b, Geetha Bhat, PhD, MDa,b,* KEYWORDS Renin-angiotensin-aldosterone system Neurohormonal Heart failure Aldosterone Angiotensin II Angiotensin-converting enzyme inhibitors Angiotensin-receptor blockers
KEY POINTS The renin-angiotensin-aldosterone system plays a critical role in the pathogenesis of chronic heart failure with a reduced ejection fraction by promoting adverse left ventricular remodeling. Blockade of the renin-angiotensin-aldosterone system has been achieved at multiple points, and can significantly reduce morbidity and mortality from heart failure. Angiotensin-converting enzyme inhibitors are the primary therapeutic agents for heart failure with reduced ejection fraction, regardless of cause or degree of symptoms. Additional inhibition of the renin-angiotensin-aldosterone system can be achieved by addition of an angiotensin-receptor blocker or an aldosterone antagonist. Aldosterone antagonists have an additional mortality benefit when added to an angiotensinconverting enzyme inhibitor, whereas angiotensin-receptor blockers only have a morbidity benefit.
The development of the neurohormonal model of heart failure (HF) has underpinned a tremendous growth in basic and clinical investigations into HF physiology and clinical management. Through a strategy that has sequentially targeted individual neurohormonal systems, clinical trials have achieved incremental improvements in HF mortality during the past 25 years.1,2 The reninangiotensin-aldosterone system (RAAS) shown in Fig. 1 was the first neurohormonal system to be studied in HF, because of its role in systemic vasoconstriction. Attempts to alleviate the symptoms of HF through the reduction of systemic vascular resistance (SVR) led to the pivotal finding that blockade of the RAAS significantly improves survival.3 Further research has formed
the basis of current professional guidelines, which uniformly recommend inhibition of RAAS with an angiotensin-converting enzyme (ACE) inhibitor as first-line therapy for symptomatic and asymptomatic HF.4–6
RAAS PHYSIOLOGY Renin is an aspartyl protease produced in the juxtaglomerular cells of the renal afferent arteriole, where it is cleaved from its precursor, prorenin. Baroreceptors in the wall of the afferent arteriole respond to reduced perfusion pressure by stimulating the release of renin from secretory granules.7 A decrease in systemic volume may also be sensed by arterial baroreceptors and the macula densa of the distal tubule, which initiate signaling pathways to promote further renin
The authors received no funding support and have nothing to disclose. a Center for Heart Transplant and Assist Devices, Advocate Christ Medical Center, 4400 West 95th Street, Suite 407, Oak Lawn, IL 60453, USA; b University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA * Corresponding author. Center for Heart Transplant and Assist Devices, Advocate Christ Medical Center, 4400 West 95th Street, Suite 407, Oak Lawn, IL 60453. E-mail address: [email protected] Cardiol Clin 32 (2014) 21–32 http://dx.doi.org/10.1016/j.ccl.2013.09.002 0733-8651/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
cardiology.theclinics.com
INTRODUCTION
22
Sayer & Bhat
Renin-Angiotensin-Aldosterone System Angiotensinogen Renin inhibitor
Renin
Bradykinin
Angiotensin I Angiotensin converting enzyme inhibitor
Angiotensin converting enzyme, chymase and other non-ACE pathways (Cathepsin)
Inactive peptides Angiotensin II
AT1 Receptor Vasoconstriction Aldosterone secretion
Sodium retention
Cellular proliferation
Oxidative stress
Aldosterone antagonist Mineralocorticoid receptor Fig. 1. Schematic depiction of the RAAS. ACE, angiotensin-converting enzyme.
release. The synthesis of prorenin is inhibited by conditions of increased renal perfusion, including elevated systemic blood pressure and volume overload. Additionally, there is a negative feedback mechanism in response to increased levels of circulating angiotensin II. Renin cleaves 10 amino acids from angiotensinogen to form angiotensin I, which is subsequently cleaved by ACE to form angiotensin II. An alternative pathway for the conversion of angiotensin I to angiotensin II, involving the protease chymase, has also been identified.8 Circulating angiotensin II is the primary mediator of the acute systemic response to volume depletion and hypotension after RAAS stimulation. However, local production of angiotensin II has been identified in numerous body tissues, including the heart.9,10 Tissue-level production of angiotensin II may be responsible for the chronic maintenance of cardiovascular (CV) homeostasis, particularly in the setting of disease states, such as HF.11
Systemic Actions of Angiotensin II Angiotensin II primarily acts through the AT1 receptor, activating multiple CV and renal processes:
Systemic arterial vasoconstriction Renal arteriolar vasoconstriction Stimulation of renal tubular reabsorption of sodium and water Vascular smooth muscle contraction Aldosterone release from the adrenal glands The role of the AT2 receptor is less well defined. In HF, the immediate result of angiotensin II formation is the maintenance of systemic blood pressure. An increase in plasma volume follows, through a direct augmentation of renal tubular sodium collection and as a secondary consequence of an increase in circulating aldosterone. In the kidney, increased efferent arteriolar resistance preserves the glomerular filtration rate in the setting of decreased renal perfusion. Angiotensin II also stimulates the release of prostaglandins, which prevent excess vasoconstriction in the systemic and renal circulation.12
Cardiac Actions of Angiotensin II and Aldosterone In the myocyte, stimulation of the AT1 receptor by angiotensin II produces cellular hypertrophy that is independent of the secondary effects of systemic vasoconstriction.13,14 Angiotensin II
Renin-Angiotensin-Aldosterone System also stimulates fibroblast hypertrophy and collagen deposition, ultimately promoting myocardial fibrosis.15,16 Increased fibrosis and the expansion of the extracellular matrix are two of the hallmarks of the ventricular remodeling that is characteristic of chronic HF with a reduced ejection fraction (HFrEF). In a substudy of clinical trial patients, the role of RAAS activation in the development of HFrEF was confirmed by a strong correlation of renin levels with worsening degrees of ventricular function and more severe HF symptoms.17 In addition to adrenal production of aldosterone, angiotensin II may also stimulate myocardial generation of aldosterone. In the failing heart, aldosterone receptor density is upregulated, suggesting an increase in local production of aldosterone that is associated with activation of the RAAS.18 Studies of cultured fibroblasts have demonstrated that aldosterone can stimulate collagen synthesis, and aldosterone may also increase the level of ACE in the heart, leading to increased production of angiotensin II.19,20
RAAS BLOCKADE WITH ACE INHIBITORS In addition to blocking the generation of angiotensin II, ACE inhibitors also prevent bradykinin degradation, which increases the stimulation of nitric oxide and has positive effects on endothelial function.21 By decreasing SVR, ACE-inhibitors lead to improvements in cardiac hemodynamics and exercise capacity.22,23 However, their prominent role in the management of HFrEF stems from the finding of reduced mortality with ACE inhibitor treatment, a finding first noted in a rat model of myocardial infarction (MI) and subsequently confirmed in numerous human clinical studies.3
ACE Inhibitors and Cardiac Remodeling ACE inhibitor administration was initially shown to reduce left ventricular (LV) size and maintain LV function after MI in animal studies.24 These findings were translated to humans in a small randomized trial showing a reduction in indices of remodeling with captopril treatment after MI.25 Subsequently, two large, randomized clinical investigations confirmed that the reverse remodeling benefits of ACE inhibition extended out to 1 year.26,27 This effect was also demonstrated in patients with LV dysfunction but no symptoms of HF.28
ACE Inhibitors and CV Outcomes in Chronic HF Selected trials that have demonstrated benefit of ACE inhibitors in chronic HFrEF are shown in Table 1.29–35 The first trial to address outcomes was CONSENSUS, in which 253 patients with
New York Heart Association (NYHA) Class IV HF were randomized to enalapril or placebo.29 Most patients had an ischemic cardiomyopathy. Because of a dramatic 40% reduction in 6-month mortality (26% with enalapril vs 44% with placebo), CONSENSUS was halted before full enrollment. In addition to the 6-month results, mortality was decreased by 31% at 1 year and death caused by progressive HF was reduced by 50%. CONSENSUS was followed by the SOLVD trials, which evaluated the use of ACE inhibitors in mild to moderate HF (NYHA Class II–III) and asymptomatic LV dysfunction (NYHA Class I).30,31 In the symptomatic HF trial, 2569 patients with a mean LVEF of 25% were followed for an average of 41 months. Enalapril lowered mortality from 40% to 35% (16% risk reduction) and lowered a composite of death and HF hospitalization from 57% to 48% (26% risk reduction). In the asymptomatic trial, 4228 patients with an LVEF less than or equal to 35% were followed for 3 years. There was no difference in mortality between the two arms (P 5 .30), but enalapril reduced the development of symptomatic HF by 37% and the risk of HF hospitalization by 44%. ACE inhibition in the post-MI patient with low EF (Table 1) was studied in three large randomized trials.32–34 SAVE and TRACE investigated the impact of ACE inhibitors in patients with asymptomatic LV dysfunction, whereas AIRE studied patients with symptomatic HF between 2 and 9 days after MI. ACE inhibitors produced a 19% reduction in mortality (20% vs 25%) in SAVE, and a 22% reduction in mortality (35% vs 42%) in TRACE. Both trials demonstrated significant decreases in the development of HF with treatment. AIRE enrolled 2006 patients with NYHA Class II to IV HF after an acute MI. At 15 months, mortality was reduced from 23% to 17% (P 5 .002), and progressive HF was reduced from 18% to 14%. The only large trial to compare an ACE inhibitor with an active treatment was the VHeFT II, in which 806 men with symptomatic HF and an LVEF less than or equal to 45% were randomized to enalapril or the combination of hydralazine-isosorbide dinitrate.35 After 2 years of follow-up, enalapril reduced mortality by 28% (P 5 .016), firmly establishing ACE inhibitors as superior to other vasodilator therapy used in HF at that time. The question of whether ACE inhibitor dose is important was answered by the ATLAS trial.36 Lowdose lisinopril (2.5–5 mg) was compared with high-dose lisinopril (32.5–35 mg) in 3164 patients with symptomatic HF and LVEF less than or equal to 30%. Higher doses of lisinopril did not improve mortality, but did reduce a composite end point including mortality and HF hospitalization by
23
24
Sayer & Bhat
Table 1 Selected ACE inhibitor clinical trials
Trial Name Heart failure CONSENSUS I29
SOLVD (treatment)30
Study Details
Mean Duration of Follow-up Primary Conclusion
NYHA Class IV HF Enalapril (N 5 127) Placebo (N 5 126)
188 d
NYHA Class II–III HF Enalapril (N 5 1285) Placebo (N 5 1284)
3.5 y
SOLVD (prevention)31 Enalapril up to 10 mg twice 3.1 y daily (N 5 2111) vs placebo (N 5 2117) LVEF 35% No CHF treatment Chronic HF, CT ratio >0.55 V-HeFT II35 2.5 y LVEF
KEY POINTS The renin-angiotensin-aldosterone system plays a critical role in the pathogenesis of chronic heart failure with a reduced ejection fraction by promoting adverse left ventricular remodeling. Blockade of the renin-angiotensin-aldosterone system has been achieved at multiple points, and can significantly reduce morbidity and mortality from heart failure. Angiotensin-converting enzyme inhibitors are the primary therapeutic agents for heart failure with reduced ejection fraction, regardless of cause or degree of symptoms. Additional inhibition of the renin-angiotensin-aldosterone system can be achieved by addition of an angiotensin-receptor blocker or an aldosterone antagonist. Aldosterone antagonists have an additional mortality benefit when added to an angiotensinconverting enzyme inhibitor, whereas angiotensin-receptor blockers only have a morbidity benefit.
The development of the neurohormonal model of heart failure (HF) has underpinned a tremendous growth in basic and clinical investigations into HF physiology and clinical management. Through a strategy that has sequentially targeted individual neurohormonal systems, clinical trials have achieved incremental improvements in HF mortality during the past 25 years.1,2 The reninangiotensin-aldosterone system (RAAS) shown in Fig. 1 was the first neurohormonal system to be studied in HF, because of its role in systemic vasoconstriction. Attempts to alleviate the symptoms of HF through the reduction of systemic vascular resistance (SVR) led to the pivotal finding that blockade of the RAAS significantly improves survival.3 Further research has formed
the basis of current professional guidelines, which uniformly recommend inhibition of RAAS with an angiotensin-converting enzyme (ACE) inhibitor as first-line therapy for symptomatic and asymptomatic HF.4–6
RAAS PHYSIOLOGY Renin is an aspartyl protease produced in the juxtaglomerular cells of the renal afferent arteriole, where it is cleaved from its precursor, prorenin. Baroreceptors in the wall of the afferent arteriole respond to reduced perfusion pressure by stimulating the release of renin from secretory granules.7 A decrease in systemic volume may also be sensed by arterial baroreceptors and the macula densa of the distal tubule, which initiate signaling pathways to promote further renin
The authors received no funding support and have nothing to disclose. a Center for Heart Transplant and Assist Devices, Advocate Christ Medical Center, 4400 West 95th Street, Suite 407, Oak Lawn, IL 60453, USA; b University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA * Corresponding author. Center for Heart Transplant and Assist Devices, Advocate Christ Medical Center, 4400 West 95th Street, Suite 407, Oak Lawn, IL 60453. E-mail address: [email protected] Cardiol Clin 32 (2014) 21–32 http://dx.doi.org/10.1016/j.ccl.2013.09.002 0733-8651/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
cardiology.theclinics.com
INTRODUCTION
22
Sayer & Bhat
Renin-Angiotensin-Aldosterone System Angiotensinogen Renin inhibitor
Renin
Bradykinin
Angiotensin I Angiotensin converting enzyme inhibitor
Angiotensin converting enzyme, chymase and other non-ACE pathways (Cathepsin)
Inactive peptides Angiotensin II
AT1 Receptor Vasoconstriction Aldosterone secretion
Sodium retention
Cellular proliferation
Oxidative stress
Aldosterone antagonist Mineralocorticoid receptor Fig. 1. Schematic depiction of the RAAS. ACE, angiotensin-converting enzyme.
release. The synthesis of prorenin is inhibited by conditions of increased renal perfusion, including elevated systemic blood pressure and volume overload. Additionally, there is a negative feedback mechanism in response to increased levels of circulating angiotensin II. Renin cleaves 10 amino acids from angiotensinogen to form angiotensin I, which is subsequently cleaved by ACE to form angiotensin II. An alternative pathway for the conversion of angiotensin I to angiotensin II, involving the protease chymase, has also been identified.8 Circulating angiotensin II is the primary mediator of the acute systemic response to volume depletion and hypotension after RAAS stimulation. However, local production of angiotensin II has been identified in numerous body tissues, including the heart.9,10 Tissue-level production of angiotensin II may be responsible for the chronic maintenance of cardiovascular (CV) homeostasis, particularly in the setting of disease states, such as HF.11
Systemic Actions of Angiotensin II Angiotensin II primarily acts through the AT1 receptor, activating multiple CV and renal processes:
Systemic arterial vasoconstriction Renal arteriolar vasoconstriction Stimulation of renal tubular reabsorption of sodium and water Vascular smooth muscle contraction Aldosterone release from the adrenal glands The role of the AT2 receptor is less well defined. In HF, the immediate result of angiotensin II formation is the maintenance of systemic blood pressure. An increase in plasma volume follows, through a direct augmentation of renal tubular sodium collection and as a secondary consequence of an increase in circulating aldosterone. In the kidney, increased efferent arteriolar resistance preserves the glomerular filtration rate in the setting of decreased renal perfusion. Angiotensin II also stimulates the release of prostaglandins, which prevent excess vasoconstriction in the systemic and renal circulation.12
Cardiac Actions of Angiotensin II and Aldosterone In the myocyte, stimulation of the AT1 receptor by angiotensin II produces cellular hypertrophy that is independent of the secondary effects of systemic vasoconstriction.13,14 Angiotensin II
Renin-Angiotensin-Aldosterone System also stimulates fibroblast hypertrophy and collagen deposition, ultimately promoting myocardial fibrosis.15,16 Increased fibrosis and the expansion of the extracellular matrix are two of the hallmarks of the ventricular remodeling that is characteristic of chronic HF with a reduced ejection fraction (HFrEF). In a substudy of clinical trial patients, the role of RAAS activation in the development of HFrEF was confirmed by a strong correlation of renin levels with worsening degrees of ventricular function and more severe HF symptoms.17 In addition to adrenal production of aldosterone, angiotensin II may also stimulate myocardial generation of aldosterone. In the failing heart, aldosterone receptor density is upregulated, suggesting an increase in local production of aldosterone that is associated with activation of the RAAS.18 Studies of cultured fibroblasts have demonstrated that aldosterone can stimulate collagen synthesis, and aldosterone may also increase the level of ACE in the heart, leading to increased production of angiotensin II.19,20
RAAS BLOCKADE WITH ACE INHIBITORS In addition to blocking the generation of angiotensin II, ACE inhibitors also prevent bradykinin degradation, which increases the stimulation of nitric oxide and has positive effects on endothelial function.21 By decreasing SVR, ACE-inhibitors lead to improvements in cardiac hemodynamics and exercise capacity.22,23 However, their prominent role in the management of HFrEF stems from the finding of reduced mortality with ACE inhibitor treatment, a finding first noted in a rat model of myocardial infarction (MI) and subsequently confirmed in numerous human clinical studies.3
ACE Inhibitors and Cardiac Remodeling ACE inhibitor administration was initially shown to reduce left ventricular (LV) size and maintain LV function after MI in animal studies.24 These findings were translated to humans in a small randomized trial showing a reduction in indices of remodeling with captopril treatment after MI.25 Subsequently, two large, randomized clinical investigations confirmed that the reverse remodeling benefits of ACE inhibition extended out to 1 year.26,27 This effect was also demonstrated in patients with LV dysfunction but no symptoms of HF.28
ACE Inhibitors and CV Outcomes in Chronic HF Selected trials that have demonstrated benefit of ACE inhibitors in chronic HFrEF are shown in Table 1.29–35 The first trial to address outcomes was CONSENSUS, in which 253 patients with
New York Heart Association (NYHA) Class IV HF were randomized to enalapril or placebo.29 Most patients had an ischemic cardiomyopathy. Because of a dramatic 40% reduction in 6-month mortality (26% with enalapril vs 44% with placebo), CONSENSUS was halted before full enrollment. In addition to the 6-month results, mortality was decreased by 31% at 1 year and death caused by progressive HF was reduced by 50%. CONSENSUS was followed by the SOLVD trials, which evaluated the use of ACE inhibitors in mild to moderate HF (NYHA Class II–III) and asymptomatic LV dysfunction (NYHA Class I).30,31 In the symptomatic HF trial, 2569 patients with a mean LVEF of 25% were followed for an average of 41 months. Enalapril lowered mortality from 40% to 35% (16% risk reduction) and lowered a composite of death and HF hospitalization from 57% to 48% (26% risk reduction). In the asymptomatic trial, 4228 patients with an LVEF less than or equal to 35% were followed for 3 years. There was no difference in mortality between the two arms (P 5 .30), but enalapril reduced the development of symptomatic HF by 37% and the risk of HF hospitalization by 44%. ACE inhibition in the post-MI patient with low EF (Table 1) was studied in three large randomized trials.32–34 SAVE and TRACE investigated the impact of ACE inhibitors in patients with asymptomatic LV dysfunction, whereas AIRE studied patients with symptomatic HF between 2 and 9 days after MI. ACE inhibitors produced a 19% reduction in mortality (20% vs 25%) in SAVE, and a 22% reduction in mortality (35% vs 42%) in TRACE. Both trials demonstrated significant decreases in the development of HF with treatment. AIRE enrolled 2006 patients with NYHA Class II to IV HF after an acute MI. At 15 months, mortality was reduced from 23% to 17% (P 5 .002), and progressive HF was reduced from 18% to 14%. The only large trial to compare an ACE inhibitor with an active treatment was the VHeFT II, in which 806 men with symptomatic HF and an LVEF less than or equal to 45% were randomized to enalapril or the combination of hydralazine-isosorbide dinitrate.35 After 2 years of follow-up, enalapril reduced mortality by 28% (P 5 .016), firmly establishing ACE inhibitors as superior to other vasodilator therapy used in HF at that time. The question of whether ACE inhibitor dose is important was answered by the ATLAS trial.36 Lowdose lisinopril (2.5–5 mg) was compared with high-dose lisinopril (32.5–35 mg) in 3164 patients with symptomatic HF and LVEF less than or equal to 30%. Higher doses of lisinopril did not improve mortality, but did reduce a composite end point including mortality and HF hospitalization by
23
24
Sayer & Bhat
Table 1 Selected ACE inhibitor clinical trials
Trial Name Heart failure CONSENSUS I29
SOLVD (treatment)30
Study Details
Mean Duration of Follow-up Primary Conclusion
NYHA Class IV HF Enalapril (N 5 127) Placebo (N 5 126)
188 d
NYHA Class II–III HF Enalapril (N 5 1285) Placebo (N 5 1284)
3.5 y
SOLVD (prevention)31 Enalapril up to 10 mg twice 3.1 y daily (N 5 2111) vs placebo (N 5 2117) LVEF 35% No CHF treatment Chronic HF, CT ratio >0.55 V-HeFT II35 2.5 y LVEF
