Role of RAAS Inhibition in the Prevention of Cardiovascular Disease

The pathogenesis of cardiovascular disease is a complex and dynamic process. The renin-angiotensin-aldosterone system (RAAS) is a potent and powerful mediator in the homeostasis of the cardiovascular and renal systems. RAAS blockade via angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has been consistently proven to be an effective and safe strategy for the primary and secondary prevention of cardiovascular disease in patients across a wide spectrum of risk. Although the beneficial effects of RAAS blockade may be due to its effects on central and peripheral blood pressure, there are many additional mechanisms to consider that may contribute additional protection. While a combination of ACE inhibitors and ARBs has not yielded significantly positive results, the newer class of direct renin inhibitors (DRIs) may offer a novel and effective strategy for monotherapy as well as in combination.     

Reducing cardiorenal risk through combination therapy with a direct renin inhibitor

Interruption of the renin-angiotensin-aldosterone system (RAAS) cascade with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or more recently direct renin inhibitors (DRIs) is a safe and effective antihypertensive strategy that is in routine clinical use. The clinical utility of these agents in cardiorenal end-organ protection is increasingly being recognized. Although both ACE inhibitors and ARBs demonstrate substantial benefit in patients with cardiovascular and/or renal disease, considerable evidence indicates that they only partially suppress the RAAS pathway due to feedback upregulation of plasma renin activity. With the goal of providing more comprehensive RAAS blockade, combination ACE inhibitor/ARB therapy has been evaluated. However, this approach has not shown the anticipated improvements in composite cardiovascular and renal outcomes and appears to be associated with significant toxicity. Due to a unique mechanism of action, the combination of a DRI with an ACE inhibitor or ARB may represent an effective end-organ-protective therapeutic strategy.     

Renin-angiotensin-aldosterone blockade for cardiovascular disease prevention

The renin-angiotensin-aldosterone system (RAAS) plays a significant role in pathophysiology of multiple disease states. RAAS blockade is beneficial in patients with hypertension, acute myocardial infarction, chronic heart failure, stroke, and diabetic renal disease. RAAS blockade with the combination angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has demonstrated conflicting results in recent clinical trials. This article reviews the latest evidence of isolated ACEI or ARB use, their combination, and the role of aldosterone blockers and direct renin inhibitors in patients at risk, and makes recommendations for their use in the prevention of morbidity and mortality in cardiovascular disease.     

Clinical Impact of Renin-Angiotensin System Blockade: Angiotensin-Converting Enzyme Inhibitors vs. Angiotensin Receptor Antagonists

Clinical trials have proved that blockade of the renin-angiotensin-aldosterone system (RAAS) offers primary and secondary protection of the cardiovascular system, brain, and kidneys. Drugs that interrupt the RAAS do so by several diverse mechanisms but it remains to be fully proved whether these mechanistic differences are associated with meaningful differences in clinical outcomes. This review summarizes current information about the basic mechanisms of action of three classes of anti-RAAS drugs: angiotensin-converting enzyme (ACE) inhibitors, combined ACE-neutral endopeptidase inhibitors, and angiotensin receptor antagonists as well as results of major clinical outcome trials with these agents. Basic and clinical science information is then blended with insights from the clinical pharmacology of anti-RAAS drugs to address four current controversies in clinical medicine: whether ACE inhibitors and angiotensin receptor antagonists are interchangeable, optimal dosing of available agents, potential justification of ACE inhibitor/angiotensin receptor antagonist combinations, and first-line use of anti-RAAS drugs in antihypertensive therapy.     

Clinical Impact of Renin-Angiotensin System Blockade: Angiotensin-Converting Enzyme Inhibitors vs. Angiotensin Receptor Antagonists

Clinical trials have proved that blockade of the renin-angiotensin-aldosterone system (RAAS) offers primary and secondary protection of the cardiovascular system, brain, and kidneys. Drugs that interrupt the RAAS do so by several diverse mechanisms but it remains to be fully proved whether these mechanistic differences are associated with meaningful differences in clinical outcomes. This review summarizes current information about the basic mechanisms of action of three classes of anti-RAAS drugs: angiotensin-converting enzyme (ACE) inhibitors, combined ACE-neutral endopeptidase inhibitors, and angiotensin receptor antagonists as well as results of major clinical outcome trials with these agents. Basic and clinical science information is then blended with insights from the clinical pharmacology of anti-RAAS drugs to address four current controversies in clinical medicine: whether ACE inhibitors and angiotensin receptor antagonists are interchangeable, optimal dosing of available agents, potential justification of ACE inhibitor/angiotensin receptor antagonist combinations, and first-line use of anti-RAAS drugs in antihypertensive therapy.     

Pleiotropic Effects of Inhibitors of the RAAS in the Diabetic Population: Above and Beyond Blood Pressure Lowering

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are indispensable therapeutic agents for treating hypertension and proteinuria in patients with diabetes mellitus. Studies have shown that the renin-angiotensin-aldosterone system (RAAS) has effects on various organ systems, including the central nervous system, heart, and kidneys. Angiotensin II has major deleterious effects on vascular compliance, vascular relaxation, and plasma markers of inflammation, which are surrogate markers of cardiovascular disease. Evidence is established from major trials that ACE inhibitors and ARB therapy improve these surrogate markers and reduce cardiovascular disease, renal disease, and stroke. Accumulating evidence also supports the newer class of medication, the direct renin inhibitor aliskiren, as beneficial in hypertensive persons with diabetes mellitus. In this article, we review the mechanisms through which inhibitors of the RAAS benefit persons with hypertension and decrease the development of cardiovascular and renal disease above and beyond blood pressure lowering.     

The renin-angiotensin-aldosterone system as a target in coronary disease

The renin-angiotensin-aldosterone system (RAAS) plays a fundamental role in the development of atherosclerosis and adverse cardiovascular events. Traditionally, the pathologic effects of the RAAS were assumed to result from vasoconstriction induced by angiotensin II, and salt and water retention due to aldosterone. However, these hormones also have powerful trophic effects, stimulating increased mass in both the arterial wall and left ventricle. In addition, angiotensin II and aldosterone predispose to vascular inflammation, thrombosis, oxidative stress, and sudden cardiac death. Therapy directed at RAAS overactivity is essential for normalizing the prognosis of most patients with atherosclerosis. An angiotensin-converting enzyme (ACE) inhibitor improves the prognosis of patients with atherosclerosis and/or diabetes even in the setting of normal baseline blood pressure. Angiotensin receptor blocking agents also improve cardiovascular structure and prognosis. Although these agents are better tolerated than ACE inhibitors, they do not appear to be as effective in reducing event rates. Aldosterone receptor blocking agents also improve cardiovascular structure, function, and prognosis. Aldosterone receptor blockers appear to provide additive benefit when used in conjunction with either an ACE inhibitor or an angiotensin receptor blocker.     

Rationale and design of a study to evaluate management of proteinuria in patients at high risk for vascular events: the IMPROVE trial

Declining kidney function predicts increasing cardiovascular risk in people with hypertension. Microalbuminuria is a marker for cardiovascular risk and declining kidney function. Agents that block the renin-angiotensin-aldosterone system (RAAS), notably angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), reduce proteinuria and microalbuminuria, lower blood pressure and slow the progression of proteinuric kidney disease. Evidence is accumulating that the combination of an ACE inhibitor and an ARB is the optimal means of RAAS blockade in this setting, slowing the progression of nephropathy independently of blood pressure lowering to a greater degree than can be achieved using maximum approved doses of either agent alone. However, the emerging therapeutic potential of ACE inhibitor/ARB combination therapy in hypertensive kidney disease requires further characterization. The Irbesartan in the Management of PROteinuric patients at high risk for Vascular Events trial aims to determine definitively whether the combination therapy of an ARB, irbesartan and an ACE inhibitor, ramipril, is more effective than ramipril alone in reducing the urinary albumin excretion rate in patients at high cardiovascular risk with hypertension and proteinuria or microalbuminuria.     

Polymorphism of the renin-angiotensin system and renal failure

The renin-angiotenin-aldosterone system (RAAS) is not only involved in cardiovascular disease but also in renal pathophysiology and progression of renal disease. Several polymorphisms of genes coding for components of the RAAS have been identified. The I/D polymorphism of the ACE gene, a variant of the angiotensiogen gen, the M235T polymorphism, and the variant A1166 C polymorphism of the angiotensin II type 1 receptor gene are the most important. Several studies have suggested a potential role for I/D polymorphism of the ACE gen in the progression of renal diseases and in the cardiovascular death rate of patients with renal failure. Data on RAAS polymorphisms as determinants of the prevalence of renal diseases and the response to renoprotective therapies are conflicting. Given the polygenic nature of renal and cardiovascular disease and the growing number of candidate genes, large prospective and collaborative studies are required to assess the effect of RAAS polymorphisms on the progression of renal disease and on the response to renoprotective therapies.     

Vascular and cardiac benefits of angiotensin receptor blockers

Angiotensin II not only is a vasoconstrictor, but it also affects cell growth and apoptosis, inflammation, fibrosis, and coagulation. Blockade of the renin-angiotensin system, either with inhibitors of the generation of angiotensin (angiotensin-converting enzyme [ACE] inhibitors) or with blockers of angiotensin receptors, reduces blood pressure and inhibits other pathophysiological actions. These other effects provide benefits in coronary heart disease, heart failure, diabetic nephropathy, and stroke beyond blood pressure reduction. These benefits were first demonstrated with ACE inhibitors. However, the mechanism of action of angiotensin receptor blockers, which block angiotensin II stimulation at the angiotensin type 1 receptor but not at the type 2 receptor, may have advantages, particularly for endothelial dysfunction and vascular remodeling, as well as cardiac and renal protection. Recent multicenter trials suggest that ACE inhibitors and angiotensin receptor blockers may reduce morbidity and mortality associated with cardiovascular and renal disease beyond blood pressure reduction. Several studies with different angiotensin receptor blockers, including comparisons with ACE inhibitors, are under way, and should provide further guidance for their clinical use.     

Efficacy of Angiotensin Receptor Blockers in Cardiovascular Disease

The cardiovascular continuum describes the progression of pathophysiologic events from cardiovascular risk factors to symptomatic cardiovascular disease (CVD) and life-threatening events. Pharmacologic intervention early in the continuum may prevent or slow CVD development and improve quality of life. The renin–angiotensin–aldosterone system (RAAS) is central to the pathophysiology of CVD at many stages of the continuum. Numerous clinical trials of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have shown that RAAS blockade provides benefits to patients across the continuum. ARBs are as effective as ACE inhibitors in the treatment of hypertension; however tolerability and adherence to therapy appear to be improved with ARBs. Large clinical trials have shown that ARBs may provide therapeutic benefits beyond blood pressure control in patients with diabetes, heart failure or at risk of heart failure following a myocardial infarction. In addition, ARBs have been shown to provide protective effects in patients with impaired renal function or left ventricular hypertrophy. Additional clinical trials are ongoing to further characterize the role of ARBs in CVD management.     

The clinical use of angiotensin-converting enzyme inhibitors

Through an integrative understanding of cardiovascular pathophysiologic characteristics at the multiorgan level, significant achievements in cardiovascular therapeutics have been achieved and enabled the rationale design and development of drugs such as the angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). In this article, we present a detailed review of the physiologic features of the renin-angiotensin-aldosterone system (RAAS), ACE inhibitors and ARB clinical pharmacologic characteristics, and specific diseases in which they are considered to be the standard of the care as supported by important clinical trial data. It is envisioned that an updated and detailed understanding of ACE inhibitors and ARBs will facilitate their successful use in the treatment of heart failure, myocardial infarction, hypertension, renal failure, and diabetic nephropathy.     

Application of Direct Renin Inhibition to Chronic Kidney Disease

Purpose  

Chronic kidney disease has serious implications with a high risk for progressive loss of renal function, increased cardiovascular events as well as a substantial financial burden. The renin-angiotensin-aldosterone system (RAAS) is activated in chronic kidney disease, especially in diabetes and hypertension, which are the leading causes of chronic kidney disease. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) decrease the rate of progression of diabetic and non-diabetic nephropathy and are recommended therapy for chronic kidney disease.     

Current treatment options for CHF management: Focus on the renin-angiotensin-aldosterone system

Optional statement Heart failure (HF) is highly prevalent in our society and its incidence is increasing in concert with the growing aged population. Experimental and clinical studies have consistently shown that HF is ameliorated by inhibition of the reninangiotensin-aldosterone system (RAAS). Acknowledging that heightened activation of the RAAS contributes significantly to HF progression has led to the development of pharmacologic antagonists of RAAS components that have greatly improved both symptoms and prognosis of patients suffering from this syndrome. Angiotensinconverting enzyme (ACE) inhibitors represent the first developed agents that block the production of angiotensin II, and have been shown to be effective across a broad spectrum of patients with HF, including those with asymptomatic left ventricular dysfunction to overt HF. Initiation of ACE inhibitors prior to the onset of symptoms in those with left ventricular systolic dysfunction, and as early as feasible following a myocardial infarction, has been shown to reduce mortality and the development of overt HF in several clinical trials. Clinical data also support the use of angiotensin II receptor antagonists as an alternative to ACE inhibitors in patients who are allergic to, or intolerant of, ACE inhibitors. Agents that antagonize aldosterone via blockade of mineralocorticoid receptors improve clinical outcomes in patients with advanced HF or those with reduced ejection fraction and HF following an acute myocardial infarction. Maximally inhibiting the RAAS, in conjunction with other neurohormonal systems (eg, the sympathetic nervous system by β-adrenergic blockade), leads to improved clinical outcomes in HF, a highly prevalent and costly disease in our society.     

为什么血管紧张素转化酶抑制剂能降低高血压患者死亡率?

最新荟萃分析发现,肾素-血管紧张素(Ang)-醛固酮系统(RAAS)抑制剂能降低高血压患者死亡率,其治疗获益全部源于血管紧张素转化酶(ACE)抑制剂(ACEIs),而非血管紧张素受体拮抗剂(ARBs)。RAAS可以归纳为2条轴:ACE-AngⅡ(1-8)-AT1受体轴和ACE2-Ang(1-7)-Mas受体轴,ACEIs对RAAS的2条轴均发挥良好作用,而ARBs主要作用于前者。各个指南推荐高血压相关心血管疾病治疗优先选择ACEIs,对不能够耐受者选择ARBs。我们应当重视ACEIs在高血压、冠心病、心肌梗死和心力衰竭防治中的应用,目的是降低心血管疾病患病率和死亡率的风险。     

Angiotensin receptor blockers: evidence for preserving target organs

Hypertension is a major problem throughout the developed world. Although current antihypertensive treatment regimens reduce morbidity and mortality, patients are often noncompliant, and medications may not completely normalize blood pressure. As a result, current therapy frequently does not prevent or reverse the cardiovascular remodeling that often occurs when blood pressure is chronically elevated. Blockade of the renin-angiotensin system (RAS) is effective in controlling hypertension and treating congestive heart failure. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) inhibit the activity of the RAS, but these two classes of antihypertensive medications have different mechanisms of action and different pharmacologic profiles. Angiotensin-converting enzyme inhibitors block a single pathway in the production of angiotensin II (Ang II). In addition, angiotensin I is not the only substrate for ACE. The ACE inhibitors also block the degradation of bradykinin that may have potential benefits in cardiovascular disease. Bradykinin is, however, the presumed cause of cough associated with ACE inhibitor therapy. Data from clinical trials on ACE inhibitors serve to support the involvement of the RAS in the development of cardiovascular disease. Angiotensin receptor blockers act distally in the RAS to block the Ang II type 1 (AT1) receptor selectively. Thus, ARBs are more specific agents and avoid many side effects. Experimental and clinical trials have documented the efficacy of ARBs in preserving target-organ function and reversing cardiovascular remodeling. In some instances, maximal benefit may be obtained with Ang II blockade using both ARBs and ACE inhibitors. This review describes clinical trials that document the efficacy of ARBs in protecting the myocardium, blood vessels, and renal vasculature.     

Identification and management of albuminuria in the primary care setting

Albuminuria is an important risk marker for adverse cardiovascular (CV) and renal outcomes and mortality. The relationship between albuminuria and risk is continuous and linear, like that of blood pressure and cardiovascular risk. Evidence now supports increased risk even at levels traditionally considered within normal limits. In high-risk patients, routine annual screening can detect changes in urine albumin excretion and improve the timely identification of albuminuria, and therefore should be considered in patients with diabetes, hypertension, and chronic kidney disease. Preferred simple screening methods appropriate for use in the primary care setting include microalbumin-specific dipsticks and urinary albumin:creatinine ratio determination (from a spot urine sample). Cornerstones of albuminuria treatment include risk factor management, ongoing monitoring, and, in patients with hypertension, chronic kidney disease, or diabetes, the use of renin-angiotensin-aldosterone system (RAAS)-blocking agents. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have demonstrated utility in this regard; data from studies of direct renin inhibition are promising. The combined use of an ACE inhibitor and ARB was once considered a viable option for the treatment of albuminuria; however, results of the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) raised important questions regarding the benefits and limitations of dual RAAS blockade. Ongoing studies should provide important insight into the effects of this approach on renal outcomes.     

Novel therapies blocking the renin-angiotensin-aldosterone system in the management of hypertension and related disorders

Although significant advances have been made in the therapeutic blockade of the renin-angiotensin-aldosterone system (RAAS) using angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers and non-selective aldosterone receptor antagonists, there is a clear need for both additional blocking strategies and enhancements of current therapeutic approaches. Vasopeptidase inhibition may still find a role despite the small incremental value of this approach and the obvious issue of kinin-mediated adverse effects still to be fully addressed. Blockade of the RAAS upstream using renin inhibitors as well as the greater selectivity of aldosterone blockade using selective aldosterone blockers such as eplerenone are also novel approaches. Not yet in clinical use but certainly an attractive therapeutic target is angiotensin II growth factor receptor transactivation, with selective inhibitors having been developed for various specific kinase pathways. Finally, ACE2 augmentation, antisense gene strategies, and vaccination against the renin-angiotensin system should still be considered experimental, but have significant appeal as additional approaches to the blockade of this system.     

Endothelial Damage and Regeneration: The Role of the Renin-Angiotensin-Aldosterone System

The renin-angiotensin-aldosterone system (RAAS) is part of the blood pressure regulating system. Its main effector peptide is angiotensin II (Ang II). Although it may induce hypertension, the proinflammatory, profibrotic, and prothrombotic effects are mainly mediated by effects of Ang II on the cellular and molecular level that are independent of blood pressure. Therefore, pharmacotherapeutic intervention within the RAAS is an important treatment modality for patients suffering from cardiovascular diseases, even those who are not hypertensive. In addition to the blood pressure lowering and vasculoprotective (pleiotropic) effects of angiotensin II type 1 (AT₁) receptor blockers (ARBs), and angiotensin-converting enzyme (ACE) inhibitors, regenerative progenitor cell therapy emerges as an auxiliary therapy to improve regeneration of the vascular endothelium. This review focuses on the growing knowledge about regenerating vascular cells, their response to RAAS effectors, and RAAS-modulating pharmacotherapy in the context of endothelial cell damage and regeneration.     

Clinical Implications of SARS-CoV-2 Interaction With Renin Angiotensin System: JACC Review Topic of the Week

Severe acute respiratory-syndrome coronavirus-2 (SARS-CoV-2) host cell infection is mediated by binding to angiotensin-converting enzyme 2 (ACE2). Systemic dysregulation observed in SARS-CoV was previously postulated to be due to ACE2/angiotensin 1-7 (Ang1-7)/Mas axis downregulation; increased ACE2 activity was shown to mediate disease protection. Because angiotensin II receptor blockers, ACE inhibitors, and mineralocorticoid receptor antagonists increase ACE2 receptor expression, it has been tacitly believed that the use of these agents may facilitate viral disease; thus, they should not be used in high-risk patients with cardiovascular disease. Based on the anti-inflammatory benefits of the upregulation of the ACE2/Ang1-7/Mas axis and previously demonstrated benefits of lung function improvement in SARS-CoV infections, it has been hypothesized that the benefits of treatment with renin-angiotensin system inhibitors in SARS-CoV-2 may outweigh the risks and at the very least should not be withheld.