Insight into the Mode of Action of ACE Inhibition in Coronary Artery Disease
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- Ferrari, R. & Fox, K. Drugs (2009) 69: 265. doi:10.2165/00003495-200969030-00003
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ACE inhibition is now recognized as superior to placebo on outcomes in stable coronary artery disease (CAD), including total and cardiovascular mortality, fatal and nonfatal myocardial infarction, heart failure, revascularization and stroke. This review examines clinical evidence for the mode of action of ACE inhibitors in CAD, which is dominated by the results of a single trial, EUROPA, and its substudies.
The generally accepted mode of action for ACE inhibitors in CAD is blood pressure reduction. However, the EUROPA data demonstrate that endothelial protection, with the effect of arresting or reducing the processes of atherosclerosis is also important. Chronic overexpression of tissue ACE in CAD disrupts the angiotensin II/bradykinin balance with a net result of endothelial dysfunction. ACE inhibitors reduce production of angiotensin II, which prevents vasoconstriction, reduces adhesion molecules and growth factors, decreases oxidative stress and prevents apoptosis. A concomitant decrease in the degradation of bradykinin as a result of ACE inhibition raises levels of this kinin, leading to vasodilation and an antiapoptotic action, as well as opposition of the negative actions of angiotensin II.
We now have clinical trial evidence of these processes in CAD patients participating in the EUROPA study by measurement of markers of endothelial function, including nitric oxide synthase (eNOS), the rate of apoptosis and levels of von Willebrand factor (vWf ). Serum from CAD patients was found to significantly downregulate eNOS protein expression and activity versus that of healthy controls (p <0.01), most probably as a result of upregulation of tissue ACE. One year of treatment with perindopril upregulated eNOS protein expression and activity (19% and 27% vs placebo; p < 0.05). Similarly, vWf was elevated at baseline and significantly reduced after 1 year of treatment with perindopril (p< 0.001). Increased endothelial apoptosis by serum of CAD patients was accompanied by excess angiotensin II and tumour necrosis factor-α and a reduction in bradykinin; all of these parameters were reversed by treatment. We therefore have clinical results showing that perindopril normalizes the angiotensin II/bradykinin balance, reduces inflammation and prevents endothelial apoptosis. Accumulating preclinical evidence for the absence of a class effect for ACE inhibitors includes differences in terms of effect on eNOS and rate of endothelial apoptosis. These differences appear to be related to tissue affinity, penetration of atherosclerotic plaque and affinity for the target enzyme. Consideration of these features is important when administering ACE inhibition as secondary prevention in CAD patients. In this context, current European guidelines for stable angina pectoris recommend prescription of agents and doses with proven efficacy in secondary prevention.
Building on these results, three trials tested the effect of administration of an ACE inhibitor 2 weeks after acute myocardial infarction (MI) in patients selected for the presence of left ventricular (LV) dysfunction (LV ejection fraction <40%). These trials, AIRE, SAVE and TRACE, showed that ramipril, captopril and trandolapril could reduce mortality and morbidity in acute MI survivors with reduced LV function. Finally, three mega trials, CONSENSUS II, ISIS-4 and GISSI-3, investigated the administration of ACE inhibitors to unselected patients just 24 hours post-MI. The results of GISSI-3 and ISIS-4 showed small, but significant, reduction in mortality with lisinopril and captopril, respectively, but no improvement of survival with enalapril was found in CONSENSUS II. In the latter trial, enalapril was given intravenously and with rapid uptitration to target dose (enalaprilat 1 mg followed by oral doses of enalapril titrated up to 20 mg/day over 5 days), which might have caused hypotension with consequent further deleterious neuroendocrine activation.
This progression shows a trend towards prescription of ACE inhibitors as early as possible after MI, and to an unselected patient population. As the risk levels of the populations decreased, larger trials were required to achieve the power to show clinical efficacy ranging from 253 patients in CONSENSUS I to 19 394 and 58 050 patients in GISSI-3 and ISIS-4, respectively (figure 1).
Some of these trials produced unexpected results, such as the observation from SOLVD and SAVE that long-term treatment with ACE inhibitors significantly reduced the incidence of MI. This implied that ACE inhibitors could not only be considered to treat MI and its consequences, but also to prevent it from occurring. Trials were therefore set up to investigate the efficacy of ACE inhibition in patients with stable CAD,[10–14] i.e. secondary prevention, and, more recently, in hypertensive patients, i.e. primary prevention (figure 1). Positive advantages in terms of secondary prevention of cardiac outcomes have been reported for ramipril in HOPE and perindopril in EUROPA, while other trials have failed to find such an advantage, for example, PEACE and QUIET. Efficacy of ACE inhibition in conjunction with indapamide and amlodipine in broader populations has been demonstrated in trials such as ADVANCE  and ASCOT.
The consequence of this impressive research activity is a clear change in clinical practice, moving from the use of a pharmacological class for treatment to the use of the same class for the prevention of the events they were previously used to treat. This is partly due to the unexpected clinical trial data from SOLVD and SAVE, but can also be traced to a shift in perception of the action of ACE inhibitors from a pure pharmacological action, i.e. blood pressure (BP) lowering, to a more biological action, i.e. an antiatherosclerotic and endothelial protective effect. A large majority of this shift is due to several investigations suggesting that ACE inhibition can have an anti-inflammatory effect, and counteract atherosclerotic progression and plaque rupture.[17–20] Confirmation of this came from the substudies of the EUROPA trial, which were designed to shed light on a number of mechanistic issues. Further evidence that blocking the renin-angiotensin system (RAS) can exert a useful systemic anti-inflammatory and antiaggregant effect comes from head-to-head comparisons between angiotensin AT1 receptor antagonists (blockers) [ARBs] and ACE inhibitors.[22,23] It was suggested by Schieffer et al. that ARBs exerted a stronger effect than ACE inhibitors. However, this did not result in a greater clinical benefit in ONTARGET. In this article, we review the evidence from clinical trials, particularly EUROPA, and preclinical studies for the antiatherosclerotic effect of ACE inhibitors.
1. Clinical Trial Evidence for ACE Inhibition in Stable Coronary Artery Disease (CAD)
A recent meta-analysis of HOPE, EUROPA and PEACE included data from nearly 30 000 patients. ACE inhibition was found to be systematically better than placebo, and significantly reduced risk of total and cardiovascular mortality, fatal and nonfatal MI, HF, revascularization and stroke in patients with atherosclerosis without existing evidence for HF or LV dysfunction. The results of this meta-analysis left no doubt that CAD patients should receive ACE inhibitors. The question now is why ACE inhibitors work so well and how they act.
2. The Role of the Endothelium in CAD
Another possible mechanism for the action of ACE inhibition on coronary atherosclerosis is a beneficial effect on the endothelium. In this context, we should note that the primary endpoint of the EUROPA trial (i.e. cardiovascular death, nonfatal MI or resuscitated cardiac arrest) is a composite of acute coronary syndromes (ACSs). The most common cause of ACSs is progression and subsequent disruption of atherosclerotic plaque, which is directly related to damage of the endothelium. This implies that, if the endothelium was somehow protected by ACE inhibition, atherosclerosis would not progress or would progress to a lesser extent, and thus ACSs would be prevented.
The endothelium is the lining of the vessel, which is made up of a continuous layer of cells, rather like tiles on a floor. The average human endothelium weighs around 1.5 kg, with a surface area of more than 800 m2. The human endothelium is capable of producing more than 250 biologically active substances that help regulate vascular structure and function. ACE is primarily a tissue enzyme (80–90%) and indeed it is present, among many other tissues, in the endothelium and smooth muscle. ACE promotes the formation of angiotensin II from angiotensin I in the RAS, as well as the degradation of bradykinin, leading to the regulation of BP. Chronic overexpression of tissue ACE results in the overproduction of angiotensin II, a potent vasoconstrictor and growth factor, which, among several other actions, causes vasoconstriction, inflammation, vascular remodelling, thrombosis, apoptosis, and eventually plaque rupture. The concomitant decrease in bradykinin reduces the vasodilatory, antioxidant, profibrinolytic and antiapoptotic effects of this kinin, i.e. protective effects against angiotensin II. Experiments in genetically modified mice with no tissue ACE found that they developed hypotension as a result of inactivation of the RAS. This shows just how vital tissue ACE is to BP regulation, even in the presence of plasma ACE.
Another important, and often forgotten, feature of the endothelium is that, like almost every cell of the body, it undergoes a life/death cycle, which includes the process of programmed cell suicide or apoptosis,[32,33] matched by a consequent regeneration. Apoptosis should be distinguished from necrosis, such as happens in myocytes during an infarct because apoptosis is a ‘physiological’ form of cell death, which originates in the nuclei, occurs in one cell at a time and does not evoke an immunological response. It is accompanied by renewal and regeneration. Necrosis, on the contrary, is not physiological, as it occurs as a response to an external inducer, for example, in the case of MI, the occluding thrombus in the coronary arteries. Necrosis involves millions of cells at the same time and causes an immunological reaction.
The lifespan of the endothelium is about 1–3 months, which means that the entire endothelium of the human body is continuously regenerated throughout our life. If there is an imbalance between the endothelial life/death cycle, and apoptosis outweighs regeneration, then there is a loss of continuity of the layer of the vessel, thus favouring the occurrence and progression of atherosclerosis. Furthermore, if the imbalance occurs at the level of endothelium already covering an existing atherosclerotic plaque, then thrombus formation is likely to occur leading to an ACS.
Tissue ACE is known to be upregulated in ACS patients, which implies an alteration in the balance between angiotensin II and bradykinin. The increase in angiotensin II and reduction in bradykinin has a net negative effect on endothelial function, including the rate of its life/death cycle, which is another central feature of atherosclerosis. All of this points towards the endothelium as another possible target, in addition to hypertension, for the prevention of ACS via ACE inhibition.
3. ACE Inhibition and Endothelial Function
The dual nature of the action of tissue ACE leads to a dual pharmacological effect for ACE inhibitors within the endothelium.[35,36] On the one hand, they reduce the endothelial production of angiotensin II and prevent its vasoconstrictive effect. Lowering angiotensin II levels also reduces levels of adhesion molecules and growth factors, decreases oxidative stress and prevents apoptosis. On the other hand, ACE inhibitors decrease degradation of endothelial bradykinin, which leads to vasodilation by stimulating the production of nitric oxide (NO) and other relaxing factors. Bradykinin also counteracts all the negative actions of angiotensin II and exerts an antiapoptotic action.
Interestingly, the PERTINENT investigators demonstrated that the increased apoptosis in the endothelium of CAD patients was accompanied by excesses of angiotensin II and tumour necrosis factor (TNF)-α (both of which are proapoptotic since they augment oxidative stress), and also by a lack of bradykinin, which is an antiapoptic substance. Treatment with perindopril for 1 year reduced the rate of endothelial cell apoptosis by 31% (p < 0.05) [figure 6], whereas in the placebo group, it remained elevated throughout. In parallel, treatment returned angiotensin II and TNFα levels towards normal (−27% and −13%, respectively, both p < 0.05 vs baseline) and increased bradykinin exactly to the level of healthy volunteers (+17%, p < 0.05 vs baseline). Therefore, treatment with perindopril restores the balance between angiotensin II and bradykinin levels towards normal, reduces indices of inflammation (TNFα) and, in doing so, prevents endothelial apoptosis from occurring.
In parallel to PERTINENT, another EUROPA substudy, PERFECT, assessed change in ischaemia-induced FMD over 3 years in patients (n = 333) receiving perindopril or placebo. Perindopril produced a greater reduction in FMD (2.6–3.3% over 3 years) than placebo (2.8–3.0%), although these results did not reach significance. However, the prespecified endpoint of the 6-monthly change in FMD from baseline was significant for perindopril (0.14%; p < 0.05), but not for placebo (0.02%; p = 0.74). Together with the results of PERTINENT, this substudy supports a positive effect of perindopril on endothelial function.
The PERSPECTIVE substudy[39,40] was set up within EUROPA to collect data on the effect of ACE inhibition on the progression of atherosclerosis using quantitative coronary angiogram and intravascular ultrasound. In the relatively small number of patients (n = 194) enrolled in PERSPECTIVE, there was no progression of atherosclerotic plaque in the placebo group and, as a consequence, it was impossible to determine the impact of treatment with perindopril on plaque size in general. However, treatment with perindopril was linked to a beneficial pattern of coronary remodelling, which is associated with more stable plaque. Further analysis also detected a reduction in plaque with little or no calcification with perindopril treatment. These effects may act in parallel to the improvement of endothelial function with perindopril, contributing to its antiatherosclerotic action.
In conclusion, it is possible to postulate a series of events, which could be summarized in simple terms as follows:
CAD itself causes an upregulation of tissue ACE, particularly that in the vascular tissue.
As a consequence, these autocrinal changes alter the balance of angiotensin II/bradykinin with an increase in angiotensin II, which is proapoptotic, and a decrease in bradykinin, which is antiapoptotic.
CAD also causes an increase in blood TNFα levels, which is a strongly proapoptotic.
The cycle between endothelial life and death is altered, with an excess of apoptosis, leading to a loss of endothelial continuity.
This facilitates the origin and progression of the atherosclerotic process and, in the case of endothelium covering an atherosclerotic plaque, of acute thrombosis.
Effective ACE inhibition slows down and/or prevents this series of events.
4. ACE Inhibitors and Secondary Prevention: Absence of a Class Effect
The EUROPA and HOPE trials demonstrated that ACE inhibitors have a role to play in secondary prevention in CAD, while QUIET and PEACE did not. There has been much debate and comment on why these trials failed, with arguments including too low dose of ACE inhibitors in QUIET and PEACE; too low compliance in PEACE; not enough patients in QUIET; and a higher number lost to follow-up in PEACE. Another possibility relates to the ancillary differences between the ACE inhibitors tested.[44–46] A series of experimental studies in our laboratories has now gone some way to answering these questions by producing strong evidence that these effects are not class specific. However, we should note that there are no clinical data for the comparative effects of ACE inhibitors on endothelial function, NO or apoptosis, making it difficult to compare within the class.
In another in vivo study in rats, the rate of endothelial cell apoptosis was evaluated after 1 week of treatment with the same ACE inhibitors at the same dosages as in the eNOS study described previously. Apoptosis was induced in the isolated rat aortic endothelial cells by endotoxic shock with bacterial lipopolysaccharides. All the ACE inhibitors reduced the rate of endothelial apoptosis compared with vehicle, but this reached significance only for perindopril (4.3% vs 10.7% for vehicle; p < 0.001). The order of potency was perindopril > ramipril >> quinapril ≈ trandolapril ≈ enalapril, which is similar, but not identical to the order for the magnitude of the effect on eNOS protein expression.
These differing effects on eNOS and the rates of apoptosis are clearly linked to the agents themselves. One possible difference between the agents is tissue affinity, which is determined by liposolubility. More liposoluble agents such as perindoprilat and ramiprilat have much better tissue penetration than hydrosoluble ACE inhibitors such as enalaprilat and captopril. In this context, in binding studies, perindopril has one of the highest levels of radioligand displacement. Liposolubility and therefore tissue affinity are understood to increase penetration of atherosclerotic plaque, increasing antiatherosclerotic activity.
Affinity for the target enzyme itself is also another important factor in determining activity. ACE is a type I membrane protein with two homologous extracellular catalytic domains, each of which contains an active site. Because ACE has a dual action, it can be regarded as either an angiotensin I-converting enzyme (for its action producing angiotensin II) or as a kininase (for its action in the degradation of bradykinin). Experiments in our laboratories have shown that ACE inhibitors generally have a higher affinity for the bradykinin binding sites than the angiotensin I binding sites on ACE, implying that these agents are primarily inhibitors of the degradation of bradykinin, and only secondarily inhibitors of angiotensin II production. Furthermore, binding assays showed that the ACE inhibitors differed in their selectivity for the bradykinin site over the angiotensin I site, with a surprisingly similar order of potency as found in the apoptosis experiments described previously: perindopril > ramipril > quinapril ≈ trandolapril > enalapril. The implication of this result is that perindopril has the most powerful effect on bradykinin levels among the ACE inhibitor class. This observation is strongly supported by the observed increase in bradykinin to normal levels and a relative decrease in angiotensin II in PERTINENT patients treated with perindopril, as described in section 3.
ACE inhibition has a central role to play in secondary prevention in patients with stable CAD. Convincing evidence for this comes from large-scale, placebo-controlled trials of perindopril in relatively low-risk patients.
The PERTINENT substudy demonstrated that perindopril upregulated eNOS — and therefore the NO pathways — and reduces endothelial apoptosis, which has a direct effect on clinical outcomes such as ACSs, cardiovascular events and mortality. These effects are observed concomitant to maintenance of the angiotensin II/bradykinin balance and attenuation of the increase in the proapoptotic TNFα. This has been confirmed in laboratory animals. Although these effects may be shared by the other members of the ACE inhibitor class, they do not always occur at clinically relevant concentrations. Other differences between ACE inhibitors may also determine their efficacy in secondary prevention, for example, affinity for tissue ACE and penetration of atherosclerotic plaque. There is strong evidence for a substantial role for the bradykinin pathway on endothelial function. The fact that this pathway is affected differently by ACE inhibitors and ARBs could explain the results of certain head-to-head studies in which ACE inhibitors improved conduit artery endothelium-dependent vasodilation versus ARBs.[52,53]
We believe that these features should be considered when administering ACE inhibitors as secondary prevention in patients with stable CAD. In this context, current European guidelines in stable angina pectoris recommend prescription of agents and doses with proven efficacy in secondary prevention.
The preparation of this article was supported by the University of Ferrara and an unconditional grant from Servier International. The authors have both received grants and honoraria from Servier Laboratories.