Can angiotensin-converting enzyme inhibitors reverse atherosclerosis? (Review Article).

Abstract

Angiotensin II, a potent vasoconstrictor, is mainly present in the vascular endothelium. Multiple studies have confirmed that angiotensin-converting enzyme (ACE) inhibitors, which block the formation of angiotensin II, lower blood pressure and also improve heart failure. These agents not only have beneficial hemodynamic effects but also bestow additional benefits on vascular function and prevent clinical cardiovascular events in patients at risk for coronary artery disease. These latter benefits may represent effects of ACE inhibitors on local endocrine pathways, inflammatory processes, and atherosclerosis taking place within the arterial wall. Current evidence suggests that, although ACE inhibitors may not substantially reverse atherosclerotic plaque already present, they may slow the progression of such atherosclerotic lesions, In addition, by modulating inflammatory pathways within and adjacent to the atherosclerotic lesion, they may stabilize an unstable plaque and therefore decrease the risk of plaque rupture and its complications.

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About 90% of angiotensin II is present in tissues, whereas only 10% is found in the circulation. (1) Angiotensin-converting enzyme (ACE) inhibitors, which block angiotensin II formation, potentially bind to ACE within tissues to exert their effect. ACE inhibitors with improved ability to bind to, penetrate, and traverse vascular membranes are said to have tissue ACE effects. (2) Recent studies have shown a benefit of ACE inhibitors that seems to be related to their nonhemodynamic effects. (3-8) After a brief discussion of ACE pathways, this article examines the evidence that ACE inhibitors may differ in their ability to bind to tissue ACE and possible mechanisms by which they exert their nonhemodynamic effects. Finally, a summary of recent and ongoing trials will help to show how these beneficial effects translate into the promotion of vascular health by way of improvement in atherosclerosis and thus the prevention of cardiovascular events.

Angiotensin-converting Enzyme

ACE, also known as kininase II, is a bivalent dipeptidyl carboxyl zinc metalloproteinase that catalyzes the conversion of angiotensin I to the potent vasoconstrictor, angiotensin II. Most of the vascular effects of angiotensin II are mediated by way of its binding to the angiotensin II type I receptor, which is located primarily in the vascular smooth muscle cells, heart, kidney, and adrenal gland. (9,10) Some angiotensin II binds to the angiotensin II type 2 receptor and may help counteract some of the undesirable effects mediated through its binding to the type I receptor. (11-14) Importantly, ACE also cleaves the C-terminal dipeptide of bradykinin, resulting in inactive peptides. (15) Most of the effects of bradykinin are mediated through the endothelial B2 kinin receptor. (16) These two pathways and the central role of ACE are shown in Figure 1. In addition, ACE has other potential substrates, including tachykinins, neurotensin substance P, and others. (18)

Most ACE is located in the vascular endothelium (expressed in endothelial cells) and the adventitia of the vessel wall. A smaller amount is found in the vessel wall media, as well as in smooth muscle cells and macrophages. (20) Also, ACE is found in neuroepithelial cells, monocytes, renal tubular cells, and epididymal cells. (21,22) ACE is attached to the endothelial surface membrane by an anchor peptide, which, when cleaved, releases a small amount of soluble ACE into the circulation (about 10% of the total body ACE). (21) Evidence suggests that local production of angiotensins I and II takes place in the peripheral tissues.23 ACE present within vascular tissue (tissue ACE) is responsible for converting nearby angiotensin I to angiotensin II, which can then exert local effects (paracrine and autocrine) on vascular function. (24)

Immunohistochemical studies of atherosclerotic lesions within human coronary arteries have confirmed that significant sources of tissue ACE and angiotensin II are within regions of inflammatory cells, especially areas of clustered macrophages, as well as microvessel endothelial cells. (19) Thus, ACE accumulation within the plaque may contribute to an increased production of local angiotensin II, an important ingredient in the pathobiology of coronary artery disease (CAD). (25)

Some studies have demonstrated that the potent inhibition in angiotensin II generation early on with ACE inhibitors may wear off within weeks; angiotensin II may be generated by non-ACE pathways directly or indirectly. (17) This phenomenon is referred to as angiotensin II escape. (26-28)

Are All ACE Inhibitors Created Equal?

The three major classes of ACE inhibitors are based on their predominant chemical side groups: the sulfhydryl- (captopril), phosphorus- (fosinopril), and dicarboxyl-containing (all others) ACE inhibitors. Most ACE inhibitors are prodrugs and are converted into their active forms, designated by the addition of the suffix -at to their names (eg, the prodrug quinapril is converted into its active form, quinaprilat). The ability of an ACE inhibitor to penetrate biologic membranes and tissues is probably related to its lipophilicity (22,29) and molecular size. (30) Other factors that may influence tissue bioavailability of ACE inhibitors include plasma concentration, active transport systems, the blood-tissue barrier, and tissue esterase activity. (31)

After traversing the cell membrane, the ACE inhibitor can proceed to inhibit tissue ACE and thus block its local (paracrine and autocrine) functions (19,30) The degree of inhibition of tissue ACE activity in vascular tissue has been shown to correlate better with blood pressure reductions than inhibition of plasma ACE activity. (32,33)

Key differences among various approved ACE inhibitors are presented in Table 1. By shifting the balance between angiotensin II and bradykinin, ACE inhibitors may modulate their various vascular effects (Fig. 2). These main effects are detailed in Table 2, and their consequences are briefly discussed here.

Vascular Tone. Angiotensin II causes vasoconstriction directly by way of stimulation of vascular smooth muscle cells and indirectly by way of increased endothelin-l production, sympathetic nervous system activity, and decreased nitric oxide production. (35) Bradykinin, in contrast, results in vasodilation by increasing production of nitric oxide (probably by stimulating nitric oxide synthetase) as well as the vasodilating prostaglandins. (22,39,44,74) Thus, ACE inhibition results in net reduction in vascular tone.

Sodium and Water. Angiotensin II promotes sodium and fluid retention as well as aldosterone production. (36,46) Bradykinin does the opposite, promoting a natriuresis. (47) ACE inhibition thus results in a net sodium excretion and diuresis.

Fibrinolysis Thrombosis. Angiotensin 11 and its hexapeptide metabolite, angiotensin IV, have been shown to increase levels of the circulating plasminogen-activator inhibitor (PAI)-1, known to promote thrombosis as well as inhibit the body's natural thrombolytic agent, tissue plasminogen activator (tPA). (48,49) In contrast, bradykinin increases tPA. (54) By reducing angiotensins II and IV, ACE inhibitors improve the ratio of PAI-1 to tPA in favor of fibrinolysis and thus reduce the risk of atherothrombotic events. (75) Angiotensin II type 1 receptor antagonists may not produce this effect to the same extent as ACE inhibitors. (76,77) In addition, ACE inhibitors inhibit platelet aggregation and the release of platelet-derived growth factor, which stimulates endothelial PAI-1 synthesis. (52) Also, attenuation of the increase in plasma PAI activity within the acute phase following myocardial infarction has been shown to occur with AGE inhibitors. (54,78) The net effect of ACE inhibitors thus promotes the lytic s tate.

Endothelial Function. The endothelium consists of a monolayer of cells lining the inner vascular wall, positioned between the circulating blood and the vascular smooth muscle cells of the media. More than a barrier, it is a highly active endocrine organ that responds to mechanical and hormonal signals from the blood and from within the vessel wall. (57) This organ is considered to be of fundamental importance in maintaining vascular integrity and is sensitive to and adversely affected by cardiovascular risk factors. Maintaining a balance between the vasorelaxor atheroprotective factors (prostacydin and nitric oxide) and vasoconstrictor pro-atherogenic factors (endothelin-1 and angiotensin II) is the basis of endothelial (79) When this balance is altered, the endothelium becomes dysfunctional and no longer able to prevent noxious stimuli, such as oxidized low-density lipoprotein (LDL) cholesterol, from breaching it, thus inciting inflammation and damaging underlying vascular architecture. (80) Endothelial dysf unction is now believed to be a prerequisite to atherosclerosis, and all major cardiovascular risk factors cause it (eg, hypertensive patients manifest endothelial dysfunction). (81) Even in patients with mild CAD, endothelial dysfunction significantly increases the risk of cardiac events. (82) Much research is focusing on measuring and modifying endothelial function to understand and better manage the vascular disorders associated with it.

Angiotensin II induces production of superoxide radicals that scavenge nitric oxide; it also increases expression of endothelin-1. (57) By counteracting angiotensin II, ACE inhibitors may improve endothelial function. (83)

In a small study of hypertensive patients with endothelial dysfunction, perindopril, an ACE inhibitor with high tissue-binding affinity, normalized endothelial response to a cold pressor test in coronary arteries. (84) The Brachial Artery Normalization of Forearm Flow study evaluated the effectiveness of quinapril, enalapril, losartan, and amlodipine on brachial endothelial function (by flow-mediated dilation) over an 8-week period in patients with CAD. Endothelial function improved only in those receiving quinapril, an ACE inhibitor with strong tissue effects. (85) Neither enalapril nor losartan (an angiotensin II type I receptor antagonist) improved endothelial function, suggesting that a tissue effect by bradykinin, and thus locally induced nitric oxide, may explain these findings. Furthermore, after determining the ACE genotype, the authors noted that these benefits were confined to patients with DI and DII ACE genotypes, with no effect in the DD genotype.

In a study of congestive heart failure, patients with endothelial dysfunction manifested by impaired flow-dependent, endothelium-mediated dilation, quinaprilat (having high tissue-ACE affinity) was compared with enalaprilat (which has low tissue-ACE affinity). Taking quinaprilat improved flow-dependent, endothelium-mediated dilation by increasing nitric oxide production, whereas taking enalaprilat did not, suggesting that high tissue-ACE affinity may be an important factor in improving endothelial function. (86) Again, this is probably secondary to increased production of bradykinin, which has been shown to induce up-regulation of endothelial nitric oxide synthase, the enzyme responsible for converting L-arginine into nitric oxide. (40,67) Nitric oxide not only retards vasoconstriction but has been shown to decrease inflammation, platelet aggregation, and thrombosis (ie, actions opposite those of angiotensin II). (87) A further trial echoed these findings. The Trial on Reversing Endothelial Dysfunction random ized normotensive patients with endothelial dysfunction (without heart failure or hyperlipidemia) to treatment with quinapril (40 mg/d) or placebo. (88) After 6 months, endothelial function of epicardial coronary arteries improved in the group assigned quinapril, most likely because of increased nitric oxide and decreased angiotensin II production. Also, smokers derived an even greater improvement in endothelial function from quinapril than nonsmokers. (89) In summary, ACE inhibitors, especially those with high tissue-ACE affinity, improve endothelial function.

Atherosclerosis, Inflammation, and Cellular Effects. Studies involving animal and human subjects, in vitro and in vivo, have demonstrated effects of ACE inhibitors on angiotensin II and bradykinin at the cellular level, which may alter the initiation and progression of atherosclerosis. Local ACE synthesis occurs following ACE gene expression, which in turn is induced by hypertension, ischemia, cardiac pressure overload, and heart failure. (90) This ACE appears to be activated long term, even in compensated phases of these conditions; thus unchecked, local angiotensin II production is sustained and bradykinin degradation is prolonged. (60)

Angiotensin II causes endothelial cell and vascular smooth muscle cell migration, growth, and proliferation; (39,61) it also stimulates cardiac fibroblast growth and hypertrophy. (91,92) By inducing various proto-oncogenes and growth factor genes, angiotensin II causes vascular smooth muscle cell growth; (60) it also leads to release of chemoattractants that lead to neutrophil accumulation in the vascular wall. (73) Also, angiotensin II promotes expression of cell adhesion molecules (by way of nuclear factor-kappa B) and facilitates monocyte recruitment into the vessel wall to form atherosclerotic foam cells (by way of monocyte chemoattractant protein-1 and vascular cell-adhesion molecule-1). (20) Collectively, this leads to intimal and medial thickening seen in early atherosclerosis. (34) In addition, inflammatory cells release enzymes (including ACE) that generate angiotensin II. (58) Some studies examining these effects are summarized here. In a study involving smooth muscle cells cultured from leftover hu man saphenous-vein grafts harvested for bypass surgery, Kranzhofer et al (71) demonstrated that angiotensin II stimulated vascular smooth muscle cells, as measured by an increase in the inflammatory signals interleukin-6 and nuclear factor-kappa B. Furthermore, increases in interleukin-6 occurred in a concentration-dependent manner by way of activation of the angiotensin II type 1 receptor; this effect was inhibited by captopril, ramipril, and losartan (an angiotensin type 1 receptor antagonist). Interleukin-6 mRNA was augmented by angiotensin II, suggesting regulation at the pretranslational level.

Angiotensin II, the angiotensin II type 1 receptor, and ACE colocalize within human coronary plaques, especially at the vulnerable shoulder region. (93) ACE is also expressed near macrophages in plaques. These findings suggest that the renin-angiotensin system contributes to inflammatory processes within the coronary artery wall, which may presage development of unstable atherosclerotic plaques and their complications such as acute coronary syndromes. Can modulation of these cellular effects by ACE inhibitors translate into favorable effects on the structure and function of atherosclerotic plaque? Several trials have sought to answer this question.

Clinical Trials of ACE Inhibitors and Atherosclerosis. The Prevention of Atherosclerosis with Ramipril (PART-2) Collaborative Research Group examined the use of ramipril (5-10 mg/d) or placebo in patients with coronary or other occlusive arterial disease. In assessing carotid atherosclerosis by B-mode ultrasonography, no difference was found between groups in the changes in common carotid artery-wall thickness or in carotid plaque. (94) A trend toward benefit was observed, however, in death from cardiovascular events, suggesting that a functional effect, possibly improved vascular function and plaque stability, rather than a structural effect, may be occurring.

A substudy of the Heart Outcomes Prevention Evaluation trial, the Study to Evaluate Carotid Ultrasound changes with Ramipril and Vitamin E (SECURE), used B-mode carotid ultrasonography to monitor atherosclerotic lesions in patients aged 55 years or older with vascular disease or diabetes and at least one other risk factor. Ramipril reduced carotid artery atherosclerosis progression rates, as measured by intimal medial thickness. (95)

Why did SECURE find a significant decrease in atherosclerotic progression when PART-2 did not? First, the populations studied were different. Patients in SECURE were a higher-risk group, and thus more likely to manifest atherosclerotic progression. At baseline they were 5 years older, had four times the prevalence of diabetes, double the prevalence of peripheral arterial disease, and were more likely to have sustained a myocardial infarction. In addition, lipid profiles in PART-2 patients appeared more favorable overall, including a lower LDL to high-density lipoprotein ratio (3.5 versus 3.8), and lower triglyceride levels (1.8 mmol/L or 159 mg/dl versus 2.2 mmol/L or 195 mg/dl). Similar percentages (29%) of patients in each study were taking lipid-lowering medication. Another possible explanation is the measuring instrument and diagnostic criteria used, namely, carotid ultrasound measurement of intimal medial thickness. The SECURE study used an aggregate measurement across 12 carotid arterial segments (inte rnal, bifurcation, and common left and right carotid arteries), which appears to be more sensitive to detecting change. The PART-2 study, however, only evaluated changes in mean far-wall intimal medial thickness of the common carotid arteries. (95)

The Quinapril Ischemic Event Trial (QUIET) reported no significant decrease at 3-year follow-up in time to first ischemic event in patients who had undergone percutaneous transluminal coronary angioplasty (PTCA) and were randomized to taking either quinapril (20 mg/d) or placebo. (96) In a quantitative coronary angiography substudy of 450 randomly selected QUIET patients, those assigned to quinapril did not differ from placebo patients in progression of coronary atherosclerosis. (97)

One possible reason for the lack of effect in QUIET is that the dose of quinapril (20 mg/d) was low. (96) Dose may be important in enabling the active drug to penetrate the vascular wall. Also, one must remember that angiography provides a luminogram and does not give measurements of early, preatherosclerotic changes in the arterial wall. Even so, in a subgroup analysis of QUIET, patients with elevated LDL cholesterol did have a reduction in atherosclerotic progression. (95) Oxidized LDL is a potent stimulant to angiotensin II production, smooth muscle cell activation, and endothelial dysfunction. Thus, in the QUIET and Trial on Reversing Endothelial Dysfunction studies, it is not surprising that the benefits of ACE inhibitors on endothelial function were more pronounced when patients' LDL cholesterol levels were higher (ie, more baseline dysfunction to be improved upon).

The Simvastatin/Enalapril Coronary Atherosclerosis Trial evaluated the effects of cholesterol reduction and ACE inhibition on coronary atherosclerosis in normocholesterolemic patients over 4 years. By using quantitative coronary angiography, patients taking simvastatin had less progression in their atherosclerotic lesions and less often required PTCA. Enalapril-treated patients did not manifest any beneficial angiographic effects; however, they did have a significantly lower combined endpoint of death/myocardial infarction! stroke (16 versus 30; P = 0.043) than patients receiving placebo. (98)

In the two studies involving angiograms (QUIET and Simvastatin/Enalapril Coronary Atherosclerosis Trial), no effects of ACE inhibitors on angiographic progression were noted. Again, both studies measured lumen size. Endothelial or medial wall thickness, which is thought to be an early change in the atherosclerotic process, may be present before any change in lumen size. (99) These later abnormalities were not measured.

Genetics may play a role in how effective ACE inhibitors are in slowing the atherosclerotic process. One small study of 345 consecutive patients undergoing PTCA selected out 115 who had the DD genotype for the angiotensin-I-converting enzyme deletion allele polymorphism, thought to be a genetic risk factor for restenosis after coronary stent implantation. Of these, 91 went on to be assigned to treatment with 40 mg/d of quinapril (n = 46) or placebo (n = 45). Treatment was started within 48 hours after stent implantation and continued for 6 months; 79 patients complied with the protocol and underwent follow-up angiography at 6 months. In patients with the DD genotype, ACE-inhibitor treatment was associated with an exaggerated restenotic process when compared with administration of placebo. (100) An explanation other than ACE-inhibitor accelerating restenosis may include the fact that the significance of the restenosis is questionable (mm), the standard deviation large, and only 79 of 115 (69%) with the DD gen otype had treatment and were followed up at 6 months time, introducing a possible selection bias.

Another study, the Angiotensin-converting Enzyme Inhibition Post-Revascularization Study, evaluated treatment with ramipril following PTCA or coronary artery bypass grafting in 159 normotensive patients with reduced ejection fraction (0.30-0.50) but no clinical evidence of congestive heart failure. The group receiving ramipril had a significant reduction in all-cause mortality and the composite of cardiac death! myocardial infarction/congestive heart failure. (101) At least one small study has shown that both ACE inhibitors and angiotensin II type 1 receptor antagonists increase bioavailability of nitric oxide by reducing oxidative stress in the vessel wall, possibly by increasing the activity of extracellular superoxide dismutase, the major antioxidative enzyme of the arterial wall (which is impaired in patients with CAD). (83) A summary of some of the larger recently completed and ongoing clinical trials of ACE inhibitors can be found in Table 3.

Conclusions

ACE inhibitors have had an unprecedented effect on morbidity and mortality from CAD. Both the hemodynamic effects (vasodilation and cardiac unloading) and the vascular effects (stabilization of atherosclerotic lesions and improved endothelial function) may be complementary in reducing acute and chronic coronary atherosclerotic events.

Clearly, ACE inhibitors play a novel role in atherosclerosis. ACE inhibitors, rather than having significant angiographic effect on regression of plaque size, have demonstrated improvement in endothelial function or intimal medial-wall thickness. In addition, ACE inhibitors appear to modulate the deleterious effects of angiotensin II, including vasoconstriction, thrombosis, inflammation, cell growth, and atherosclerosis. These effects at the molecular level have so far translated into decreased risk of cardiovascular events in several large, randomized clinical trials, with confirmatory trials ongoing.

As more evidence confirms that atherosclerosis is an inflammatory process, future work may delve further into the relationship between the vascular health as measured by surrogates of inflammation (such as C-reactive protein and other inflammatory mediators) and vascular function (endothelial function).

Future research on patients at high risk for vascular disease may help to determine if ACE inhibitors, which appear to have anti-inflammatory, antithrombotic, and anti-atherogenic properties, may prevent progression of disease and events related to unstable lesions within these distributions.

One large question that still remains unanswered is the importance of ACE escape (ie, other enzymes may convert angiotensin I to angiotensin II and bypass ACE). (27) Theoretically, a combination ACE inhibitor and angiotensin II type 1 receptor antagonist might help prevent angiotensin II (produced by these other pathways) from having its effect. At least one pilot study has shown that such a combination resulted in lower levels of neurohormones (aldosterone) and natriuretic peptides (B-type natriuretic peptide) being produced. (111) Further research is ongoing in this area.

ACE inhibitors, especially those with activity inside vascular tissues, are poised to become a strong link to attenuating inflammation, slowing atherogenesis, stabilizing lesions, and ultimately preventing vascular morbidity and mortality.

Table 1

Various angiotensin-converting enzyme inhibitors approved for use in the
United States

                                     Dose range    Lipophilicity (22,34)
ACE inhibitor    Half-life (h)     studied (mg/d)   (lipid solubility)

Benazepril             11               5-80             Mild
Captopril              2              6.25-300           Mild
Enalapril              11              2.5-40            Mild
Fosinopril           12-15             10-80             High
Lisinopril             13               5-40             None
Moexipril             2-9              7.5-30            Moderate
Perindopril           8-10              4-16             Moderate
Quinapril         2-5, 25 (a)           5-80             Moderate
Ramipril       2-4, 9-18, >50 (b)     1.25-20            Moderate
Trandolapril      2, 15-24 (a)          1-8              Moderate

               Significantly binds
ACE inhibitor      tissue ACE       Prodrug

Benazepril             No             Yes
Captopril              No             No
Enalapril              No             Yes
Fosinopril             No             Yes
Lisinopril             No             No
Moexipril              Yes            Yes
Perindopril            Yes            Yes
Quinapril              Yes            Yes
Ramipril               Yes            Yes
Trandolapril           Yes            Yes

(a)Biphasic; pharmacokinetically has two peaks associated with two
different half-lives. ACE, angiotensin-converting enzyme.

(b)Triphasic.

Table 2

Effects of angiotensin II and bradykinin in the cardiovascular system

Effect                          Angiotensin II

Vascular tone                   Vasoconstriction
                                 Direct effect (angiotensin II type 1
                                  receptor stimulation) (10)
                                 Activates sympathetic nervous
                                  system (35)
                                 Augments peripheral nonadrenergic
                                  activity (10)
                                 Increases endothelin-l (20,35,36)
                                 Reduces nitric oxide (37,38)

Sodium and water                Sodium and water retention
                                 Increases aldosterone synthesis and
                                  secretion (46)
                                 Increases antidiuretic hormone
                                  (arginine vasopressin) (36)
                                 Decreases renal blood flow (10)

Fibrinolysis thrombosis         Prothrombotic
                                 Increases plasma activator inhibitor
                                  type 1 (PAI-1) (48-51)
                                 Increases platelet aggregation and
                                  adhesion (52,53)
                                 Increases tissue factor (10)

Endothelial function            Promotes endothelial dysfunction
                                 Increases superoxide radicals that
                                  deplete nitric oxide (57)
                                 Reduces nitric oxide (37,38)
                                 Increases endothelin-l (20,35,57)
                                 Inhibits endothelial cell
                                  migration (10)
                                 Promotes uptake of oxidized
                                  low-density lipoprotein
                                  cholesterol (34)
                                 Increases reactive oxygen species
                                  (superoxide anion, hydrogen
                                  peroxide, peroxynitrite) that
                                  deplete nitric oxide, oxidizes
                                  low-density lipoprotein
                                  cholesterol, expresses
                                  chemoattractant proteins,
                                  increases cytokine production,
                                  and expresses proinflammatory
                                  markers (34,58,59)

Atherosclerosis, inflammation,  Promotes atherosclerosis and
and cellular effects             vascular damage
                                 Vascular smooth muscle activation,
                                  hypertrophy, and migration (39,60,61)
                                 Stimulates production of extracellular
                                  matrix, matrix glycoprotein, and
                                  metalloproteinases (type IV
                                  collagenases and elastases)
                                  (10,34,62-65)
                                 Collagen synthesis in vascular smooth
                                  muscle cells (66)
                                 Increases adhesion molecules vascular
                                  cell adhesion molecule-l (allows
                                  monocytes, after rolling, to adhere
                                  and transmigrate through the
                                  endothelium and invade the
                                  subendothelial space to form
                                  atherosclerotic foam cells)
                                  and intracellular adhesion molecule
                                  (20,67)
                                 Activates mitogen-activated protein
                                  kinases (67)
                                 Induces growth-factor expression
                                  (platelet-derived, basic
                                  fibroblast, insulin-like, and
                                  transforming growth factor-[beta])
                                  (52,67-69)
                                 Generates superoxide anions
                                  (increasing oxidative stress) (70)
                                 Increases interleukin-6 (20,69)
                                 Increase inflammatory mediators
                                  (eg, phopholipase A2) (71,72)
                                 Activates transcription factor
                                  nuclear factor-kappa B (causes
                                  expression of molecules for cell
                                  adhesion and proliferation) (20,69)
                                 Increases monocyte chemoattractant
                                  protein-1 (recruits monocytes to
                                  the vessel wall) (20)
                                 Monocyte and macrophage activation
                                  (monocyte colony-stimulating
                                  factor) (73)

Effect                          Bradykinin

Vascular tone                   Vasodilation
                                 Increases nitric oxide
                                  production (20,22,38-43)
                                 Increases prostacyclin and
                                  prostaglandin E2
                                 (prostaglandins) (44,45)




Sodium and water                Natriuresis and diuresis
                                 Direct tubular effect (47)





Fibrinolysis thrombosis         Enhances fibrinolytic function
                                 Increases tissue-type
                                  plasminogen activator
                                 (tPA) (53-56)



Endothelial function            Improves endothelial function
                                 Increases nitric oxide
                                  production (20,22,38-43)


















Atherosclerosis, inflammation,   Antiatherosclerotic and
and cellular effects              vasculoprotective
                                  Inhibits cell growth (67)

Table 3

Large clinical trail involving angiotensin-converting enzyme inhibitors
and their vascular effects (a)

Study, year  No. of
(ref. no.)   patients          Patient population

EUROPA,      10,500    Patients with CAD (no clinical heart
1998 (103)              failure) or positive stress test
                        (treadmill, stress echo, or nuclear)




PEACE,        8,100    Patients with CAD with preserved left
1998 (106)              ventricular function (ejection
                        fraction >0.40)

HOPE,         9,297    High-risk patients with evidence of
2000 (8)                vascular diseases or diabetes plus
                        one other cardiovascular risk factor

PART-2,         617    Patients with clinical atherosclerotic
2000 (94)               disease within 5 years



QUO VADIS       187    Patient scheduled for CABG
Part 1,
2000 (109)







SCAT,           468    Patients with documented CAD, total
2000 (98)               cholesterol of 160-180 mg/dl



DREAM,        4,000    Patients without diabetes, >30 years
2003 (102)              of age, not pregnant or planning to
                        become pregnant for the next 5 years

IMAGINE,      2,204    Patients immediately post-CABG
2002 (104)



PROGRESS,     6,105    Patients with TIA or ischemic or
2001 (107)              hemorrhagic stroke within 5 years



QUASAR,         400    Patients with CAD and transient
2001 (108)              ischemia (silent ischemia and
                        effort-induced angina)

QUO VADIS       149    CABG patients from QUO VADIS Part 1
Part 2,                 assigned to quinapril or placebo who
2001 (110)              continued those medications for 1 yr








Q-WISE,          78    Women with microvascular angina
2001 (108)


SECURE,         732    Patients at high risk for major
2001 (95)               cardiovascular event (substudy of HOPE)



ONTARGET,    23,400    Patients with CAD, stroke, PVD, or
2002 (105)              diabetes with end-organ damage
                        (microalbuminuria, ankle-brachial index
                        less than 0.8, or left ventricular
                        hypertrophy)

TRANSCEND,    5,000    Parallel study with ONTARGET, enrolling
2002 (105)              patients who cannot tolerate ACE
                        inhibitors



Study, year
(ref. no.)   ACE inhibitor           Duration

EUROPA,      Perindopril             3 yr
1998 (103)





PEACE,       Trandolapril            5 yr
1998 (106)


HOPE,        Ramipril                5 yr
2000 (8)


PART-2,      Ramipril                4 yr
2000 (94)



QUO VADIS    Captopril vs            1 mo
Part 1,      quinapril               (before
2000 (109)                           surgery)







SCAT,        Enalapril               5 yr
2000 (98)



DREAM,       Ramipril                4 yr
2003 (102)


IMAGINE,     Quinapril               1-2 yr
2002 (104)



PROGRESS,    Perindopril             5 yr
2001 (107)



QUASAR,      Quinapril               6 mo
2001 (108)


QUO VADIS    Quinapril               1 yr
Part 2,
2001 (110)








Q-WISE,      Quinapril               1 yr
2001 (108)


SECURE,      Ramipril                4 yr
2001 (95)



ONTARGET,    [Telmisartan.sup.c]     5.5 yr
2002 (105)    vs ramipril vs
              [telmisartan.sup.c] +
              ramipril


TRANSCEND,   [Telmisartan.sup.c]     5.5 yr
2002 (105)




Study, year
(ref. no.)   Outcome

EUROPA,      Primary end point is a
1998 (103)    composite  of total mortality,
              nonfatal acute MI, unstable
              angina pectoris, and cardiac
              arrest with successful
              [resuscitation.sup.b]

PEACE,       Cardiovascular mortality,
1998 (106)    [MI.sup.b]


HOPE,        22% reduction in combined
2000 (8)      end point of  cardiovascular
              death, MI, and stroke

PART-2,      No difference in intimal
2000 (94)     medial thickness of carotid
              atherosclerotic lesions
              (by B-mode ultrasonography)

QUO VADIS    Quinapril, but not captopril,
Part 1,       was able  to significantly
2000 (109)    reduce vascular angiotensin
              II formation in internal
              mammary arteries (blood
              pressure levels  were similar
              in all three groups,
              suggesting a nonhemodynamic
              effect)

SCAT,        No effect of enalapril on
2000 (98)     coronary artery  progression
              by quantitative coronary
              angiography

DREAM,       Diabetes mellitus or death
2003 (102)    [(any cause).sup.b]


IMAGINE,     Cardiovascular death or arrest,
2002 (104)    MI, coronary revascularization,
              hospitalization for unstable
              angina, and [angina.sup.b]

PROGRESS,    28% risk reduction in stroke
2001 (107)    (primary end point) and major
              vascular events (secondary
              outcomes)

QUASAR,      Isehemia on ambulatory
2001 (108)    electrocardiogram and
              treadmill exercise [test.sup.b]

QUO VADIS    77% reduction in clinical
Part 2,       ischemic events (death,
2001 (110)    revascularization, MI,
              angina pectoris, isehemic
              stroke, or TIA) in the group
              receiving ACE inhibitors
              (4% quinapril vs 15% placebo;
              P 0.02); isehemia at exercise
              testing and Holter monitoring
              were unchanged

Q-WISE,      Myocardial isehemia secondary
2001 (108)    to coronary microvascular
              [dysfunction.sup.b]

SECURE,      Decreased intimal medial
2001 (95)     thickness of carotid
              atherosclerotic lesions
             (by B-mode ultrasonography)

ONTARGET,    Cardiovascular events,
2002 (105)    endothelial [function.sup.b]




TRANSCEND,   Same as ONTARGET; in addition,
2002 (105)    will explore the ACE
              tolerance or "escape" noted
              by some with long-term
              use of ACE inhibitors


(a)DREAM, Diabetes Reduction Approaches With Ramipril and Rosiglitazone
Medications study; EUROPA, European Trial on Reduction of Cardiac
Events With Perindopril in Stable Coronary Artery Disease: HOPE, Heart
Outcomes Prevention Evaluation Trial; IMAGINE, Ischemic Management with
Accupril Post-bypass Graft via Inhibition of Converting Enzyme;
ONTARGET, Ongoing Telmisartan Alone and in Combination with Ramipril
Global Endpoint Trial; PAR T-2, Prevention of Atherosclerosis with
Ramipril Collaborative Research Group; PEACE, Prevention of Events with
Angiotensin-converting Enzyme Inhibition; PROGRESS, Perindopril
Protection Against Recurrent Stroke Study; QUASAR, Quinapril
Anti-ischemia and Symptoms of Angina Reduction; QUO VADIS, The Effects
of Quinapril on Vascular ACE and Determinants of Ischemia; Q-WISE,
Quinapril--Women 's Ischemic Syndrome Evaluation Ancillary Study;
SCAT, Simvastatin/Enalapril Coronary Atherosclerosis Trial; SECURE,
Study to Evaluate Carotid Ultrasound Changes with Ramipril and Vitamin
E; TRANSCEND, Telmisartan Randomized Assessment Study in ACE-I
Intolerant Patients with Cardiovascular Disease; ACE,
angiotensin-converting enzyme; CABG, coronary artery bypass grafting;
CAD, coronary artery disease; ML myocardial infarction; PVD, peripheral
vascular disease; TIA, transient ischemic attack.

(b)Results unavailable; trial ongoing.

(c)Angiotensin II type I receptor antagonist.

Accepted May 24, 2002.

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RELATED ARTICLE: Key Points

* Approximately 90% of angiotensin II is present in tissues, whereas only 10% is found in the circulation.

* Most of the vascular effects of angiotensin are mediated by way of its binding to the angiotensin II type 1 receptor, which is located primarily in the vascular smooth muscle cells, heart, kidney, and adrenal gland.

* The weight of evidence favors using angiotensin-converting enzyme inhibitors to decrease the risk of vascular events, whether they involve the cerebrovasenlar or coronary vessels.

* The hemodynamic effects (vasodilation and cardiac unloading) and the vascular effects (stabilization of atherosclerotic lesions and improved endothelial function) of angiotensin-converting enzyme inhibitors may be complementary in reducing acute and chronic coronary atherosclerotic events.

* Angiotensin-converting enzyme inhibitors, especially those with activity inside vascular tissues, are poised to become a strong link to attenuating inflammation, slowing atherogenesis, stabilizing lesions, and, ultimately, preventing vascular morbidity and mortality.

From the Muskogee Heart Center, Inc., Muskogec, OK, and the Department of Cardiovascular Medicine and Surgery, University of Oklahoma, St. John's Hospital, Tulsa, OK.

Reprint requests to John P. Higgins, MD, MPhil, Muskogee Heart Center, Inc., 3340 W. Okmulgee Street, Muskogee, OK 74401.

Copyright [c] 2003 by The Southern Medical Association