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Cardiovascular protection by angiotensin-converting enzyme inhibition

Roberto Ferrari
DOI: http://dx.doi.org/10.1093/eurheartj/sup023 E1-E3 First published online: 29 August 2009

One of the most important health achievements during the twentieth century was the unravelling of the causes of the cardiovascular diseases (CVDs). Since the 1980s, coronary artery disease (CAD) mortality rates have been reduced in many developed countries and have fallen by 75% in countries such as Finland.1 Modern cardiovascular treatment has played an important role. The explosion in evidence-based treatments since the 1980s has provided us with the tools to increase life expectancy in those affected by the disease. The discovery of angiotensin-converting enzyme (ACE) inhibitors is one of these important tools. Ironically, ACE inhibitors come from the veins of poisonous snakes and yet their widespread use has saved millions of patients. Again, ironically, ACEs and the renin–angiotensin system have been and still are phylogenetically pivotal for the preservation of the species and for our daily life. The endpoint of the system is the production of angiotensin II, a potent vasoconstrictor and a growth factor essential to counteract bleeding and to repair the eventual hole in the vessel wall. Indeed, bleeding is a threat to mammalian survival and was a threat to primitive man, who was obliged to hunt to survive and therefore exposed to the risk of massive bleeding. Things have, however, changed. With evolution, hunting is often criticized as a sport rather than a necessity and bleeding is no longer a problem during our daily life. Once again, ironically, it is our very high standard of living and lifestyle that is the problem. Several attitudes, generally recognized as risk factors, through several complicated pathways, lead to hypertension and atherosclerosis and start a pernicious continuum of cardiovascular diseases. The primum movens of all of this is a percentage increase in endothelial apoptosis which is recognized by our ‘bodyguard’ system as a hole, although small, in the vessel wall and therefore the renin–angiotensin system is activated to repair it. So, again, ironically, the activation of tissue ACE in CAD is a response to our evolution. The problem is that the activation is chronic and not temporary as in the case of bleeding. Chronic activation of the renin–angiotensin system is dangerous and can even start a vicious cycle, as angiotensin II is pro-apoptotic and bradykinin is anti-apoptotic.2 Thus, chronic activation favours further endothelial apoptosis, further activation of the system and eventually the progression of atherosclerosis. In addition, excess angiotensin II and a sub-optimal concentration of bradykinin can aggravate hypertension and indeed ACE inhibition has been proved to be very effective in treating hypertension.

However, the last 20 years have also witnessed a progressive change in the therapeutic role of ACE inhibitors ranging from the treatment of hypertension to the management of CAD through the entire cardiovascular continuum.

This evolution in clinical practice can be appreciated by considering the major ACE inhibitor trials, the types of patients they included, and the natural tendency to build on previous trial evidence. The first major trials in CAD were CONSENSUS (Cooperative New Scandinavian Enalapril Survival Study)3 and SOLVD (Studies of Left Ventricular Dysfunction),4 in which enalapril was given several months after an acute event to patients with New York Heart Association functional class II to IV heart failure (HF). Both trials concluded that ACE inhibition with enalapril could reduce mortality and improve symptoms in HF patients.

Building on these results, other trials tested the effect of administration of ACE inhibitor 2 weeks after acute myocardial infarction (MI) in patients selected for the presence of left ventricular (LV) dysfunction (LV ejection fraction <40%). Subsequently, three mega-trials, CONSENSUS II,5 ISIS-4 (the Fourth International Study of Infarct Survival),6 and GISSI-3 (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico)7 investigated the administration of ACE inhibitors to unselected patients just 24 h post-MI. The results of GISSI-3 and ISIS-4 showed small, but significant, reductions in mortality.

This progression shows a trend towards prescription of ACE inhibitors as early as possible after MI, and in an unselected patient population.

Some of these trials threw up unexpected results, such as the observation that long-term treatment with ACE inhibitors significantly reduced the incidence of MI.8 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,913 i.e. secondary prevention and, more recently, in hypertensive patients,14 i.e. primary prevention (Figure 1). Positive advantages in terms of secondary prevention of cardiac outcomes have been reported for ramipril in HOPE (Heart Outcomes Prevention Evaluation study)9 and perindopril in EUROPA (European trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease),10 while other trials have failed to find such an advantage. Efficacy of ACE inhibition in conjunction with indapamide and amlodipine in primary prevention has been demonstrated in trials such as ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation)11 and ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial).14

Figure 1

ACE inhibition trials in CAD.

The consequence of this impressive research activity is a clear change in clinical practice, moving from the use of a pharmacological class for treatment of hypertension first and myocardial infarction and heart failure afterwards to the use of the same class for the prevention of the events they were previously used to treat. This is traced to a shift in perception of the action of ACE inhibitors from a pure pharmacological action, i.e. blood pressure lowering, to a more biological action, i.e. an antiatherosclerotic and endothelial protective effect.

A large majority of this shift is due to the data from EUROPA and its substudies, which were designed to shed light on a number of mechanistic issues,15 and in general by the 50 000 patients, half being randomized in different trials to perindopril and placebo.

This supplement reviews the evidence for the effectiveness of perindopril in clinical trials, with particular emphasis on preclinical studies showing the latest evidence of the antiatherosclerotic effect of perindopril in the delicate balance between reduction of endothelial apoptosis and increase of endothelial regeneration (Figure 2). It is clear today that perindopril not only reduces the abnormally increased rate of endothelial apoptosis of CAD patients (due to maintaining the correct balance between angiotensin II and bradykinin and to a reduction of TNF-α, which is pro-apoptotic) but also increases the generation of endothelial progenitor cells from the bone marrow.

Figure 2

ACE inhibition reduces death and improves life of the endothelium.

Then the supplement illustrates that ACE inhibition with perindopril has a central role to play in secondary prevention in patients with stable CAD. The most convincing evidence for this comes from large-scale, placebo-controlled trials of perindopril in relatively low-risk patients. Differences between EUROPA and similar trials with other agents have produced different results and stimulated much discussion and debate, confirming perindopril as the ultimate choice for these patients.

The PERTINENT study2 demonstrated that perindopril upregulates eNOS—and therefore the NO pathways—and reduces endothelial apoptosis, which has a direct effect on clinical outcomes like ACS, cardiovascular events, and mortality. These effects are observed concomitant to maintenance of the angiotensin I/bradykinin balance and an attenuation of the increase in the pro-apoptotic TNF-α. These effects have all been confirmed in laboratory animals and in the clinical arena and this is summarized in the articles by Prof. Simoons and Prof. Tardif. Later, data illustrated in the article by Prof. Levi suggest that ACE inhibition with perindopril increases the production of EPC from bone marrow, suggesting further protection of the endothelium.

Finally, the advantage of combining perindopril with amlodipine for cardiac protection is highlighted in the article by Prof. Bertrand and also shown in the intimate mechanism of the synergism (Figure 3), from which it is obvious that the Ca2+ antagonist prevents further contraction of the vessel smooth muscle cells, while ACE inhibition by increasing NO production via a bradykinin-mediated effect improves relaxation and, at the same time, counteracts further vasoconstriction by reducing angiotensin II.

Figure 3

Antihypertensive mode of action of ACE inhibition and calcium channel blockade.


  • The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal Supplement or of the European Society of Cardiology.


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