CLINICAL STUDY: HEART FAILURE: EDITORIAL COMMENT
Activation of vascular tissue angiotensin-converting enzyme (ACE) in heart failure
Effects of ACE inhibitors*
Nathalie Lapointe, RN, MSc* and
Jean-Lucien Rouleau, MD, FACCa,*
* Division of Cardiology, University Health Network/Mount Sinai Hospital, Toronto, Ontario, Canada
* Reprint requests and correspondence: Dr. Jean L. Rouleau, Toronto General Hospital, Division of Cardiology, 13EN-212-200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.
Jean.rouleau{at}UHN.on.ca
The seminal event in the discovery of the renin system was an experiment in 1898 by Tigerstedt and Bergman (1), who produced a pressor response by injecting crude rabbit kidney extracts into anesthetized animals. Angiotensin-converting enzyme (ACE), a dicarboxy peptidase, was first described in 1956 by Skeggs et al. (2) while trying to purify angiotensin (ANG). The description of insertion/deletion polymorphism for the ACE gene and its role in determining variations in the physiologic activity of ACE was first described by Rigat et al. (3) in 1990. The critical role of ACE in the production of ANG II led to the development of specific inhibitors of ACE. In 1968, Bakhle (4) reported that the bradykinin (BK) potentiating factor of snake venom inhibited the conversion of ANG I to ANG II. Work by Vane (5) led to the synthesis of the nonapeptide, teprotide, by Ondetti et al. (6) and eventually to the synthesis of captopril.
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Overview of ACE and ACE inhibitors
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The ACE is a 150–180-kDa ectoenzyme that is expressed in many tissues, including vascular endothelium, renal proximal tubular endothelium, the heart, the lung, activated macrophages and several regions of the brain (7). Studies of recombinant full-length ACE have shown that the apparent Km of ACE for BK is substantially lower than it is for ANG I (8), indicating more favorable kinetics for the hydrolysis of BK than for the conversion of ANG I to ANG II. In most tissues, including the heart, the messenger ribonucleic acids for the production of all components of the renin–angiotensin system (RAS) have been demonstrated, and the rate-limiting step in the ANG II cascade is plasma renin activity (9). It would appear from studies in ACE knockout mice that essentially all the important physiologic effects of ACE are the result of tissue rather than circulating ACE activity (10). Other enzyme systems that can convert ANG I to ANG II, such as chymase, are present in some tissues (11) and may be an important source of ANG II. However, in vitro studies have generally overestimated the potential importance of these alternate pathways, particularly in vascular tissues. Generally, ACE is bound to the sarcolemma, the site of most of the conversion of ANG I to ANG II (12), while chymase is distributed throughout the cell and in the interstitial space (11), physiologically less important sites in vivo.
In nearly all cardiovascular diseases, there is an increase in ACE activity, particularly in tissues involved in the disease process. This includes an increase in vascular ACE activity in hypertension (13), in plaque ACE activity in atherosclerosis (14), in cardiac ACE activity in heart failure (15,16) and in vascular and cardiac ACE activity in diabetes (17). This upregulation of the activity of ACE can be accompanied by an increase in ANG II type 1 (AT-1) receptor density (18). Evidence from clinical studies would suggest that patients with the D/D ACE polymorphism have increased plasma ACE activity and that this is associated with an increased risk of myocardial infarction (MI) and numerous other cardiovascular diseases, such as hypertrophic and dilated cardiomyopathies (19,20). However, other large studies do not support a relationship between polymorphisms of the ACE gene and increased cardiovascular risk (21), such that at this time, the clinical importance of ACE polymorphisms has been called into question. Polymorphisms of other components of the RAS have also been described (22), and it may be that a combination of these polymorphisms rather than a single polymorphism will ultimately prove clinically important.
The ACE inhibitors have been shown to be beneficial in a wide range of cardiovascular diseases, whether it be acute MI, chronic heart failure (CHF), hypertension, atherosclerosis or diabetes (23–26). Evidence from experimental and clinical studies would suggest that the beneficial cardiovascular effects of ACE inhibitors are the result of their effects on both BK metabolism and the conversion of ANG I to ANG II (27). In many disease processes, the effects of ACE inhibitors are only clinically evident after months to years of therapy (23,26), suggesting that these medications exert their effects by altering the underlying pathophysiologic process involved in the disease.
Evidence of gradual reactivation of ACE activity over time with the use of ACE inhibitors.
Several studies would suggest that plasma ANG II levels do not remain suppressed during chronic ACE inhibitor therapy (28,29). Cross-sectional clinical studies also show that human tissues can sometimes generate ANG II from ANG I during chronic ACE inhibitor therapy (28). Although intriguing, these reports did not initially elicit the interest they should have because of uncertainty as to the clinical importance of these findings. After all, the clinical benefits of ACE inhibitors often took one to two years to be expressed, and even when their benefits were expressed early, they were maintained over time (23–26). However, more recently a number of potentially important clinical reports have helped us refocus on this issue.
First, studies such as the Valsartan Heart Failure Trial (ValHeft) (30) clearly indicated that the addition of an AT-1 receptor blocker (ARB) to an ACE inhibitor in patients with CHF resulted in both a marked decrease in systolic arterial pressure (8 mm Hg) and in some clinical benefit. Also, studies such as the Assessment of Treatment with Lisinopril And Survival (ATLAS) in patients with CHF (31), and studies indicating beneficial effects with the addition of an ARB in patients with proteinuria (32), would suggest that further clinical benefit can be obtained by increasing the dose of these medications. This has helped refocus the research community on the adequacy of ARB and the degree of inhibition of the conversion of ANG I to ANG II in order to obtain maximal beneficial effect.
In the study by Farquharson et al. (33) published in this issue of the Journal, strong evidence is provided for incomplete blockade of the vascular conversion of ANG I to ANG II by frequently used doses of ACE inhibitors. The investigators employed a clinical bioassay to assess the vascular conversion of ANG I to ANG II in patients with varying degrees of CHF using cross-sectional and longitudinal studies; and they assessed the effects of increasing doses of ACE inhibitors on this process. One of the advantages of their methodology is that it assesses not only the vascular conversion of ANG I to ANG II, but also assesses the integrity of the whole of the ANG I signaling pathway. Importantly, the investigators also verified the effects of ANG II and found that the abnormalities in their patients were essentially limited to differences in the conversion of ANG I to ANG II and not to deregulation of other parts of the pathway or to other potentially important systems activated in CHF and that are modified by ACE inhibitors. Farquharson et al. (33) did not assess the effects of other pathways involved in the generation of ANG II; however, this in no way invalidates or diminishes the importance of their results. The one weakness of this methodology is that it employs pharmacologic doses of ANG I, such that the applicability of their findings to clinical practice is a bit complex. The investigators essentially come to four different conclusions.
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Increasing vascular ACE activity with increasing CHF severity and over time
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In a cross-sectional study of patients with varying degrees of CHF, the investigators (33) demonstrate that patients with more severe heart failure have less suppression of the conversion of ANG I to ANG II by ACE inhibitors than patients with less severe CHF. This very important observation suggests that larger dose of ACE inhibitors should perhaps be used to treat patients with more severe CHF. The findings of Farquharson et al. (33) are compatible with animal studies indicating that tissue ACE activity increases in heart failure, whether the heart failure be due to volume overload (34) or post-MI (16). This observation is particularly important in clinical practice, where lower doses of ACE inhibitors are frequently used for fear of adversely effecting systemic arterial pressure or renal function. Although the investigators (33) did not evaluate the interaction of ACE activity and severity of disease with ACE polymorphism, the effects of severity of the disease appear to overwhelm any effect directly related to specific ACE polymorphisms. Of course, clustering of ACE polymorphisms according to disease severity cannot be ruled out, as this was not evaluated in the study (33).
The second set of studies was a longitudinal evaluation of vascular ACE activity over an 18-month period. The investigators (33) found that vascular ACE inhibition by lisinopril was significantly reduced over time despite apparent clinical stability of their patients. It is probable that their results reflected upregulation of ACE activity due to a progression of the disease rather than upregulation of ACE activity over time due to ACE inhibitor use. First, prior to entering the study, these patients were on a higher dose of an ACE inhibitor (16 to 17 mg) than during the study, and this for an average of 3.6 years such that any upregulation that would have resulted from ACE inhibitor use should have long been complete. Rather, their findings likely result from the progression of CHF over time that has previously been described in patients with CHF, despite the use of an ACE inhibitor (35).
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Further suppression of vascular ACE activity with increasing doses of ACE inhibitor: importance of tissue ACE
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The third set of studies helps complete the first two and clearly indicates that patients that had the least inhibition of vascular ACE activity with lisinopril in the first set of studies could have further suppression of vascular ACE activity by increasing the dose of the ACE inhibitor. This finding, coupled with the first and second set of studies, would suggest that larger doses of ACE inhibitors may be more effective than lower doses, and should be used in patients with more severe heart failure. The investigators (33) also suggest that consideration should be given to increasing the dose of the ACE inhibitor used over time, even if patients appear stable.
Results from the first three sets of studies by Farquharson et al. (33) clearly provide an explanation of the results of the ATLAS study (31) indicating a clinical benefit with the use of larger doses of an ACE inhibitor. It is nevertheless important to remember that the doses of ACE inhibitors proven beneficial in clinical studies are superior to the highest dose used in the Farquharson et al. (33) study, such that simply using the dose of an ACE inhibitor proven to be beneficial in clinical studies may obviate the need to increase doses over time.
The fourth and final finding from this study would suggest that circulating ACE activity and the effects of ACE inhibitors on circulating ACE activity have very little correlation with what happens at the tissue level. These results are compatible with studies in ACE knockout mice indicating that all of the physiologic effects of ACE result from tissue ACE (10) and from studies done in volume-overloaded rats where suppression of tissue and not circulating ACE activity resulted in beneficial ventricular remodeling (34). That tissue ACE activity is more important than circulating ACE activity raises the question as to whether ACE inhibitors with greater tissue affinity may prove to be superior to those with less tissue affinity. Clearly, acute studies of vascular reactivity by Hornig et al. (36) would suggest that such a difference might exist. However, in large clinical studies, benefit has been found with ACE inhibitors regardless of tissue affinity and, unless a clinical trial indicating superiority of one ACE inhibitor over another is performed, any differences in ACE inhibitors related to tissue affinity remain purely speculative. In any case, from the study of Farquharson et al. (33), it would appear that lack of tissue affinity can be overcome by increasing the dose.
Thus, this study provides more information to support the use of doses of ACE inhibitors proven to be beneficial in clinical trials, particularly in patients with more severe heart failure, and that increasing the dose over time may prove beneficial, particularly if there are any signs of progression of the disease.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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Overview of ACE and...
Increasing vascular ACE activity...