Pharmacologic Blockade of the Renin-Angiotensin System
Pharmacologic Blockade of the Renin-Angiotensin System
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are recognized primarily for their use in hypertension, in heart failure, and after myocardial infarction. New evidence, particularly with ACE inhibitors, has shown their ability to reduce acute coronary events associated with atherosclerosis in patients without a history of the aforementioned cardiac conditions. This is likely due to inhibitory effects on the renin-angiotensin system -- a system that adversely influences fibrinolytic balance, vascular endothelial function, and vascular inflammation, all key components of atherosclerotic progression and adverse coronary outcomes. Results of various studies suggest favorable effects of ACE inhibitors and ARBs on markers of these components, including effects on plasminogen activator inhibitor-1, endothelin-1, and nitric oxide by ACE inhibitors, and effects on vascular cell adhesion molecule-1 and C-reactive protein by ARBs. Although early evidence suggests that ACE inhibitors may provide a greater beneficial effect on some of these markers compared with ARBs, and that certain ACE inhibitors may provide greater vascular benefits than others, further investigation is required to verify such findings. Overall, understanding the distinct coronary vascular benefits of these agents will emphasize the importance of using them, particularly ACE inhibitors, to improve outcomes in patients with coronary atherosclerotic disease.
For years, pharmacologic agents that blunt actions of the renin-angiotensin system (RAS), particularly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), have been used in the management of various cardiovascular conditions. The benefits of ACE inhibitors in attenuating the actions of the RAS for hypertension are through vasodilatory effects secondary to decreasing production of the vasoconstrictor angiotensin II and by increasing levels of the vasodilator bradykinin. The ARBs primarily block the ultimate action of angiotensin II at the angiotensin type 1 receptor. Clinical trials of ACE inhibitors have shown improved survival and preserved cardiac function in patients with systolic heart failure and in patients with left ventricular systolic dysfunction after myocardial infarction. The ARBs have shown benefit in patients with systolic heart failure, but little experience has been reported in patients with previous myocardial infarction. Most of the benefit observed in these trials has been attributed to the hemodynamic effects and attenuation of left ventricular remodeling seen with these pharmacologic agents.
A less emphasized, yet equally important, element to these agents -- currently particularly with ACE inhibitors -- is in the ability to reduce atherosclerotic progression and acute coronary events associated with atherosclerosis. Both the Survival and Ventricular Enlargement (SAVE) trial and the Studies of Left Ventricular Dysfunction (SOLVD) trial found an approximately 25% reduction in the frequency of recurrent myocardial infarction in high-risk cardiac patients receiving ACE inhibitor therapy. More recently, the Heart Outcomes Prevention Evaluation (HOPE) trial investigators found that patients with atherosclerotic disease (including coronary artery disease, cerebrovascular disease, and peripheral vascular disease), without heart failure or left ventricular systolic dysfunction, experienced improved vascular-related outcomes with the ACE inhibitor ramipril compared with placebo, independent of blood pressure reduction. Various models show that the vascular endothelium and smooth muscle tissue play key roles in the progression of atherosclerosis and occurrence of adverse outcomes related to this disease, with many factors being influenced by the RAS. Thus, the results of the HOPE trial indicate that the RAS indeed influences vascular homeostasis, and that blunting this system leads to beneficial alterations in the physiologic processes that contribute to worsening atherosclerotic disease and associated outcomes.
Several factors contribute to the development and progression of atherosclerotic cardiovascular disease and lead to acute coronary events; these factors are a prothrombotic state, impaired vascular endothelial function, vascular inflammation, and impaired plaque stabilization (Figure 1). Three of these factors are strongly associated with the RAS, which likely contributes to worsening outcomes. First, the RAS unfavorably alters the fibrinolytic balance by increasing plasminogen activator inhibitor-1 (PAI-1), the primary endogenous inhibitor of tissue plasminogen activator (t-PA). Also, an understanding of the relationship between RAS activation and vascular endothelial dysfunction is well established. Finally, the influence of the RAS on vascular inflammation is gaining much interest.
(Enlarge Image)
Contributing factors that lead to acute coronary events.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are recognized primarily for their use in hypertension, in heart failure, and after myocardial infarction. New evidence, particularly with ACE inhibitors, has shown their ability to reduce acute coronary events associated with atherosclerosis in patients without a history of the aforementioned cardiac conditions. This is likely due to inhibitory effects on the renin-angiotensin system -- a system that adversely influences fibrinolytic balance, vascular endothelial function, and vascular inflammation, all key components of atherosclerotic progression and adverse coronary outcomes. Results of various studies suggest favorable effects of ACE inhibitors and ARBs on markers of these components, including effects on plasminogen activator inhibitor-1, endothelin-1, and nitric oxide by ACE inhibitors, and effects on vascular cell adhesion molecule-1 and C-reactive protein by ARBs. Although early evidence suggests that ACE inhibitors may provide a greater beneficial effect on some of these markers compared with ARBs, and that certain ACE inhibitors may provide greater vascular benefits than others, further investigation is required to verify such findings. Overall, understanding the distinct coronary vascular benefits of these agents will emphasize the importance of using them, particularly ACE inhibitors, to improve outcomes in patients with coronary atherosclerotic disease.
For years, pharmacologic agents that blunt actions of the renin-angiotensin system (RAS), particularly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), have been used in the management of various cardiovascular conditions. The benefits of ACE inhibitors in attenuating the actions of the RAS for hypertension are through vasodilatory effects secondary to decreasing production of the vasoconstrictor angiotensin II and by increasing levels of the vasodilator bradykinin. The ARBs primarily block the ultimate action of angiotensin II at the angiotensin type 1 receptor. Clinical trials of ACE inhibitors have shown improved survival and preserved cardiac function in patients with systolic heart failure and in patients with left ventricular systolic dysfunction after myocardial infarction. The ARBs have shown benefit in patients with systolic heart failure, but little experience has been reported in patients with previous myocardial infarction. Most of the benefit observed in these trials has been attributed to the hemodynamic effects and attenuation of left ventricular remodeling seen with these pharmacologic agents.
A less emphasized, yet equally important, element to these agents -- currently particularly with ACE inhibitors -- is in the ability to reduce atherosclerotic progression and acute coronary events associated with atherosclerosis. Both the Survival and Ventricular Enlargement (SAVE) trial and the Studies of Left Ventricular Dysfunction (SOLVD) trial found an approximately 25% reduction in the frequency of recurrent myocardial infarction in high-risk cardiac patients receiving ACE inhibitor therapy. More recently, the Heart Outcomes Prevention Evaluation (HOPE) trial investigators found that patients with atherosclerotic disease (including coronary artery disease, cerebrovascular disease, and peripheral vascular disease), without heart failure or left ventricular systolic dysfunction, experienced improved vascular-related outcomes with the ACE inhibitor ramipril compared with placebo, independent of blood pressure reduction. Various models show that the vascular endothelium and smooth muscle tissue play key roles in the progression of atherosclerosis and occurrence of adverse outcomes related to this disease, with many factors being influenced by the RAS. Thus, the results of the HOPE trial indicate that the RAS indeed influences vascular homeostasis, and that blunting this system leads to beneficial alterations in the physiologic processes that contribute to worsening atherosclerotic disease and associated outcomes.
Several factors contribute to the development and progression of atherosclerotic cardiovascular disease and lead to acute coronary events; these factors are a prothrombotic state, impaired vascular endothelial function, vascular inflammation, and impaired plaque stabilization (Figure 1). Three of these factors are strongly associated with the RAS, which likely contributes to worsening outcomes. First, the RAS unfavorably alters the fibrinolytic balance by increasing plasminogen activator inhibitor-1 (PAI-1), the primary endogenous inhibitor of tissue plasminogen activator (t-PA). Also, an understanding of the relationship between RAS activation and vascular endothelial dysfunction is well established. Finally, the influence of the RAS on vascular inflammation is gaining much interest.
(Enlarge Image)
Contributing factors that lead to acute coronary events.
