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Journal of Human (2004) 18, 599–606 & 2004 Nature Publishing Group All rights reserved 0950-9240/04 $30.00 www.nature.com/jhh REVIEW ARTICLE Effect of the – system on the vessel wall: using ACE inhibition to improve endothelial function

JM Neutel Orange County Institute, Orange, CA, USA

Plasma renin activity and (CVD) hibitors produce significant improvements in arterial incidence correlate closely in people with hypertension. compliance, which may yield a reduction in cardiovas- The effects of angiotensin II (Ang II) on pressure cular events. Blockade of the neurohormonal system (BP) are important in hypertensive patients; accumulat- may be a critical first-line approach to management of ing data suggest that the growth effects of Ang II in the hypertension in an effort to prevent or reverse endothe- cardiovascular system play a critical role in the devel- lial dysfunction. Moreover, the effects of ACE inhibition, opment of . Atherosclerosis develop- in addition to its effect on BP, suggest that this ment in hypertensive patients requires fundamental therapeutic approach may be appropriate for managing changes in endothelial structure and function. Key patients at risk of CVD who do not yet have hyperten- among the factors that may affect the endothelium is sion. The ideal antihypertensive agent should yield the renin–angiotensin– system. Ang II, inde- smooth, consistent BP control over the entire 24-hour pendent of other environmental and neurohormonal period, both to avoid BP variability that places patients factors, mediates the vessel wall changes critical for at increased risk of cardiovascular events and to offer the development of atherosclerotic disease. A strong protection during the vulnerable early morning hours correlation appears to exist between Ang II and CVD. when patients are well known to be at high risk. Blockade of the renin–angiotensin system has a major Journal of Human Hypertension (2004) 18, 599–606. impact on arterial structure and function independent of doi:10.1038/sj.jhh.1001714 BP. Certain angiotensin-converting enzyme (ACE) in- Published online 10 June 2004

Keywords: atherosclerosis; angiotensin-converting-enzyme inhibition; endothelium; renin–angiotensin; trough:peak ratio

Introduction treatment; that for coronary heart disease is reduced by only 14%.3 Hypertension is the most common risk factor for However, even in hypertensive patients in whom development of cardiovascular disease (CVD) and BP is controlled, the relative risk of dying is about remains a major health-care problem, with one in 4 1 30% higher than in normotensive patients. This five Americans (one in four adults) afflicted. Nearly suggests that in hypertensive patients there are a third are not even aware that they have high blood factors beyond elevated BP that are responsible for pressure (BP). Abundant data indicate that as BP this increased risk. increases, so does the incidence of CVD. A meta- The greater risk may be explained in part by the analysis of nearly half a million patients illustrated 2 coexistence of dyslipidemia, insulin resistance, that this increase is nearly linear. glucose intolerance, and obesity. Hypertension The goal of antihypertensive therapy is to reduce occurs in isolation in fewer than 20% of patients.5 the incidence of CVD, including myocardial infarc- This has led researchers to focus on hypertension tion and stroke. Therapy has yielded far greater not just as a ‘disease of numbers,’ but as a much success in reducing the incidence of stroke than more complex syndrome of cardiovascular risk of coronary heart disease. The incidence of stroke factors (Figure 1).6–13 All of these contribute is reduced by nearly half with antihypertensive to the development of CVD and should receive attention in the hypertensive patient. The greater the number of risk factors present, the greater Correspondence: Dr JM Neutel, Orange County Heart Institute, the risk of a cardiovascular event. In particular, 505 South Main Street, Suite 300, Orange, CA 92868, USA. E-mail: [email protected] hypertension, hypercholesterolaemia, and altered Received 31 March 2003; revised 09 January 2004; accepted 22 glucose metabolism interact closely in accelerating January 2004; published online 10 June 2004 atherogenesis.7 Effect of RAS on the vessel wall JM Neutel 600 Role of the renin–angiotensin system be protected from CVD. Those with higher renin levels appeared to be at greater risk of CVD. This A delicate balance exists between haemodynamic study was one of the first to recognize the renin– factors, serum , , and the 7 angiotensin system as an important risk indicator for wall. The renin–angiotensin system plays a crucial CVD. Then, a study by Alderman et al16 showed that role in this cardiovascular . It acts as a in patients matched for BP but with other risk circulating hormonal system, a local endogenous factors such as smoking, dyslipidaemia, and dia- hormonal system, and a neurotransmitter and 14 betes, those with elevated renin levels are at much neuromodulator. The functions include control of greater risk of CVD (Figure 2).16 electrolyte balance, fluid volume, and systemic BP via the circulating endocrine system.11 The kidneys produce renin in response to changes in renal perfusion or blood flow. Angiotensin-converting Development of enzyme (ACE) catalyses the conversion of angioten- The work of Laragh et al,17 examining the associa- sin I to angiotensin II (ANG II), a potent vasocon- tion between the renin–angiotensin–aldosterone strictor that elevates BP and stimulates secretion of system and the development of hypertension and aldosterone, a salt-retention hormone. 15 cardiovascular disease, has been supported by More than 30 years ago, Brunner showed that subsequent work by Dzau,18 Gibbons,19 and others patients with low circulating renin levels appear to that has focused on the role of increased levels of tissue Ang II in . Ang II has a profound effect on the endothelium, and these effects appear to have an impact on the development of CVD. The endothelium may be the that bridges various cardiovascular risk factors— hypertension, , congestive heart failure, elevated cholesterol—and the development of ather- osclerotic disease. Perhaps the two most important effects of excessive Ang II on the endothelium are (1) endothelial dysfunction and (2) vascular hypertro- phy, resulting in decreased compliance (Figure 3).20 A well-functioning endothelium acts as a barrier between circulating blood and the subendothelial space. Endothelial dysfunction occurs when there is an upset in the balance of vasoactive substances and growth factors and inhibitors in the endothelium; this balance regulates the structure and function of the vessel wall. When the endothelium is injured, low-density- cholesterol can enter the vessel wall.21–23 There, it becomes oxidized and acts as an irritant, causing . This is the earliest form of atherosclerosis. Figure 1 The ‘syndrome’ of hypertension. BP ¼ ; The injury also induces the endothelium to have LVH ¼ left ventricular hypertrophy. procoagulant instead of anticoagulant properties

Figure 2 Incidence of myocardial infarction per 1000 person-years in smokers and nonsmokers, patients with and without hypercholesterolaemia, and with and without diabetes according to renin level. Regardless of the presence of other risk factors, those with high renin levels were much more likely to have an infarction. From Alderman et al.16

Journal of Human Hypertension Effect of RAS on the vessel wall JM Neutel 601

Figure 3 The role of the renin–angiotensin system in the circulation and in tissue. The circulating renin–angiotensin system exerts short- term regulation on cardiovascular homeostasis and the tissue renin–angiotensin system influences the cardiovascular system through long-term structural changes. Reproduced with permission from Dzau.20

Figure 4 Atherogenic effects of angiotensin II (AII). NO ¼ ; PAI-1 ¼ plasminogen activator inhibitor; t-PA ¼ tissue plasminogen activator; VCAMs ¼ vascular molecules. and to form vasoactive molecules, , and and less compliant, the progression of atherosclero- growth factors.7,11,21 The inflammatory response sis increases.24 Normal vascular homeostasis is stimulates migration and proliferation of smooth maintained by a balance between vasoconstrictors, muscle cells, which become intermixed with the such as Ang II, and vasodilators, such as nitric area of inflammation to form an intermediate oxide.11 The characteristics of these local vasoactive lesion.11 These effects are schematized in Figure 4. mediators are listed in Table 1.11 The balance The other important effect of an imbalance in Ang between Ang II and nitric oxide is crucial to a II involves stiffening of the blood vessel wall, or healthy endothelium. When Ang II is elevated, decreased compliance. Arterial stiffening is the endothelial dysfunction begins. The imbalance principal cause of increasing systolic pressure in toward Ang II by itself can cause many of the ageing and in patients with arterial hypertension. changes in the endothelium that set the athero- Moreover, it appears that as a vessel becomes stiffer sclerotic process in motion. By stimulating growth,

Journal of Human Hypertension Effect of RAS on the vessel wall JM Neutel 602 Table 1 Characteristics of local vasoactive mediators

Nitric oxide Angiotensin II

Vasodilator Vasoconstrictor Antithrombotic Prothrombotic Anti-inflammatory Proinflammatory Growth inhibitor Growth promotor Antioxidant Pro-oxidant Antiatherogenic Proatherogenic

Reproduced with permission from Gibbons.19

it stimulates smooth muscle cell hypertrophy, which decreases compliance. Compliance refers to the means by which the structure and function of the arterial wall influence the relation between volume and pressure, such that in stiff, noncompliant vessels, a greater rise in BP is yielded by a smaller change in volume as compared with the same change in volume in a normally compliant system.25 The vessel has the capacity to alter its geometry to accommodate these changes; this is termed vascular remodelling.11 Figure 5 Measurements of distal and proximal compliance in There appears to be a correlation between circu- normal volunteers (diastolic blood pressure (DBP) o90 mmHg), and patients with borderline (DBP 90–99 mmHg), or established lating angiotensin levels and development of ather- 7 17,26 (DBP X100 mmHg) hypertension. Values are mean standard osclerosis. However, other factors can also error of the mean. Adapted with permission from Weber et al.30 influence this balance. For example, insulin appears to be very important in the formation and release of nitric oxide at the level of the endothelium.27–29 When, as in the case of a person with insulin treated before the development of overt hyperten- resistance, insulin interaction with the endothelium sion—is the subject of much scrutiny. is reduced, insulin flow into endothelial cells is lessened, and nitric oxide activity is compromised, once again driving the balance in favour of Ang II Cardioprotective effects of ACE inhibition and decreasing compliance. As the renin–angiotensin system plays such a large role in the development of hypertension and, Measuring arterial compliance subsequently, atherosclerosis, studies have exam- ined whether blocking this system can prevent the We assessed the changes in arterial compliance from onset of endothelial changes. In the tissue renin– the normotensive to hypertensive state.30 This was angiotensin system, Ang II causes the degradation of done using the Windkessel model, a technique that bradykinin, which stimulates nitric oxide produc- analyses the arterial pulse wave contour to quantify tion and release. ACE, which is proximal compliance ( and large vessels) and identical to kininase II, also causes bradykinin distal, or reflective, compliance (small and degradation. Thus, ACE inhibition’s benefits appear ). Proximal compliance was 24% lower to be due to the resulting bradykinin accumulation. among subjects with borderline hypertension com- There is abundant information suggesting a role for pared with those with normal BP and 33% lower in ACE-inhibitor therapy in reducing myocardial hy- those with established hypertension compared with pertrophy, vascular hypertrophy, atherosclerosis those with normal BP; distal compliance was 58 and progression, plaque rupture, and after 61% lower, respectively (Figure 5). plaque rupture.14,31–34 These effects may be expected This study indicates that changes in vessel to reduce the incidence of major cardiovascular compliance occur primarily at the initiation of events (Table 2).14 hypertension. As one moves from borderline to In an experimental study, Clozel et al31 studied established hypertension, there is little further spontaneously hypertensive rats given the long- change in compliance in the small vessels and an acting ACE inhibitor cilazapril compared with even smaller change in compliance of the larger spontaneously hypertensive rats given placebo; a vessels. Thus, decreased compliance may be an reference group of Wistar-Kyoto rats was also given early marker of hypertension and may be a determi- placebo. At 14 weeks, the arteries were examined. nant of cardiovascular prognosis.25 The implica- The researchers found that cilazapril normalized tion—that perhaps high-risk patients should be the media thickness:diameter ratio in all types of

Journal of Human Hypertension Effect of RAS on the vessel wall JM Neutel 603 Table 2 Potential beneficial effects of angiotensin-converting normalizes both resistance structure and left enzyme inhibition ventricular hypertrophy in patients with hyperten- sion within 1 year of treatment. Cardioprotective effects

Restoring balance between myocardial oxygen supply and Mechanism of improvement demand The decrease in BP alone does not appear to be the Reduction in left ventricular preload and afterload reason for the improvement in endothelial function. Reduction in left ventricular mass Reduction in sympathetic stimulation Studies that have compared ACE-inhibitor therapy Beneficial effects on (demonstrated in animals) with other classes of antihypertensive therapy suggest that ACE inhibition is the reason. Thybo Vasculoprotective effects et al34 compared the effects of antihypertensive Direct antiatherogenic effects (demonstrated in animals) treatment on small arteries of patients with pre- Antiproliferatory and antimigratory effects on smooth muscle cells, and mononuclear cells viously untreated hypertension. These investigators Improvement and/or restoration of endothelial function compared the effects of the b-blocker atenolol vs Protection from plaque rupture (demonstrated in animals) perindopril. While the decrease in BP yielded by the Antiplatelet effects two agents was approximately the same, patients Enhancement of fibrinolysis (demonstrated in animals) antihypertensive effects treated with atenolol showed no change in arterial Improvement in arterial compliance and tone compliance, whereas those treated with perindopril showed an increase in small-artery diameter and a Reproduced with permission from Lonn et al.14 reduction in the media: ratio (Figure 6).34 The change in small-artery morphology caused by perindopril was not accompanied by any change in media cross-sectional area, suggesting that the arteries examined (carotid, mesenteric, renal, and change was due to remodelling—and suggesting coronary). Cross-sections of the arteries of the that ACE inhibition was responsible for this normal- placebo-treated rats showed a stiffened vessel with ization. Angiotensin-receptor blockers (ARBs) have many inflammatory cells—atherosclerosis at work. BP-lowering effects similar to those of other anti- Thus, changes in the arterial wall were decreased or hypertensives, and recent studies, including the prevented with ACE inhibition. Irbesartan Diabetic Nephropathy Trial (IDNT), the Studies in humans are consistent with these Reduction of Endpoints in NIDDM with the Ang II 32 findings. Asmar et al studied 16 patients with Antagonist Losartan Study (RENAAL), and the sustained hypertension before and 3 months after Irbesartan Microalbuminuria Type 2 (IRMA 2) trial therapy with the ACE inhibitor perindopril. There suggest that these agents also confer benefits beyond was an impressive improvement in arterial compli- BP lowering.35 Trials are under way that may further ance after 3 months. ACE inhibition also induced clarify this. The use of ARBs is accompanied by regression of left ventricular hypertrophy. At that lower rates of cough and angioedema than seen with point, the investigators started treating the patients ACE inhibitors, presumably due to the ARBs’ lack of with placebo. After 4 weeks, compliance returned effect on bradykinin levels. toward baseline levels, demonstrating a reversal of the changes in the vessel wall achieved with ACE inhibition. Also, after discontinuing treatment, end- Blood pressure variability and arterial compliance diastolic volume returned toward basal values. Thus, the disease process is reversible—as is the Although many benefits of ACE inhibition in the benefit when ACE-inhibitor therapy is discontin- hypertensive patient are now established, it should ued. be noted that not all ACE inhibitors are created Sihm et al33 examined the effects of the ACE equal. Most desirable is an agent that provides inhibitor perindopril on peripheral vascular struc- smooth BP control over 24 h to avoid lability of BP. ture and cardiac hypertrophy in patients with newly Variability in BP appears to be very important in diagnosed hypertension and sought to determine the development of atherosclerotic disease and in whether there are any parallels between cardiac and changes in arterial compliance. Studies show that vascular structural normalization. Gluteal subcuta- the greater the diastolic load—the amount of time neous biopsy specimens were examined at baseline during the day that one is hypertensive—the greater and after 9 months of treatment with perindopril. the left ventricular mass index. Using ambulatory Media:lumen ratio was measured in two small BP monitoring, White et al36 showed that if more resistance arteries, and left ventricular mass was than 40% of ambulatory BP values were elevated determined by echocardiography at baseline and over a 24-h period, the incidence of increased mass after 12 months of treatment with perindopril. or decreased filling was 461%; if o40% of the Mean media:lumen ratio decreased significantly ambulatory values were elevated, the incidence of and left ventricular mass decreased significantly, these findings was o17%. both indicating improvement with perindopril treat- In another study conducted using ambulatory BP ment. The researchers concluded that perindopril monitoring, Frattola et al37 separated patients into

Journal of Human Hypertension Effect of RAS on the vessel wall JM Neutel 604

Figure 6 Comparison of the effect of the ACE inhibitor perindopril and the beta-blocker atenolol on media-to-lumen ratio. Values are mean7standard error of the mean. *Po0.05; wpo0.01. Adapted with permission from Thybo et al.34

quartiles (mean arterial pressure o95, 95–108, 109– 50% of the BP reduction effect achieved at peak is in 120, and 4120 mmHg) and then divided each of effect 24-h postdose (Figure 7). The higher the T:P, these groups into patients with variable BP and the more constant the effect of the drug through those with less variability. The mean variability over the 24-h dosing period. In addition, a high T:P 24 h was similar between the subgroups in each insures that a drug does not lose efficacy immedi- level of BP; but those with more variable BP had an ately before the next dose administration, which increased left ventricular mass index, suggesting typically occurs in the morning, when cardiovascu- that the vascular system does not tolerate changes in lar risk is high. BP well. A X50% T:P is required by the FDA for a once- Deedwania and Nelson38 showed yet another daily drug. Agents with higher T:Ps are lisinopril problem with BP variability. Using simultaneous (30–70%), trandolapril (50–90%), and perindopril Holter (ambulatory electrocardiographic) and ambu- (75–100%) (Figure 8).40–46 The half-life of an agent latory BP monitoring, they found that changes in BP should also be considered; a once-daily agent with a at any time of the day were clearly associated with shorter half-life that is given at a lower dosage may periods of silent myocardial ischemia. Thus, smooth not, in effect, be a once-daily drug. For example, the control of BP is essential, a finding that takes on T:P of lisinopril is 24% at 2.5 mg and 55% at even more importance in view of the knowledge that 80 mg.47 While the significance of the T:Ps of ACE the peak incidences of cardiovascular events is in inhibitors have not been evaluated in clinical out- the early morning.3 An effective 24-h control is come studies, consistent, effective control over the crucial. entire 24-h period is desirable. A once-daily drug is preferred because it facil- itates patient adherence. In addition to this, if an agent indeed provides sustained and smooth BP Summary control, it averts the intermittent BP surges that Hypertension comprises a complex syndrome of occur with the multiple doses of a shorter- cardiovascular risk factors. The interaction of these acting drug. Administration of multiple doses of risk factors compound the risk of a cardiovascular a shorter-acting drug to effect coverage over a event. Therefore, if physicians are truly to make an 24-h period would yield a ‘sawtooth’ pattern of impact in reducing the risk of a cardiovascular decreased/elevated BP surges, surges similar to the event, they must treat more than simply the elevated early morning surge known to increase the risk BP. The physician should consider the presence of of coronary events and stroke. The choice of these risk factors and attempt to treat as many ACE inhibitor may be particularly important be- aspects of the syndrome as is possible. Use of cause within the ACE-inhibitor class, agents vary an ACE inhibitor will have a beneficial effect not dramatically in duration of action. only on hypertension, but on vascular homeostasis, The trough-to-peak ratio (T:P) is the parameter by which is a pivotal factor in the initiation and which the US Food and Drug Administration (FDA) progression of atherosclerosis. The ideal antihyper- evaluates a drug for once-daily status. The T:P tensive agent should yield smooth, constant BP measures the percentage of BP-lowering effect control over the entire 24-hour period, both to avoid achieved at peak that is still in effect at trough the variability in BP that places patients at increased (24 h after dosing). Thus, a 50% T:P indicates that risk of cardiovascular events and to offer protection

Journal of Human Hypertension Effect of RAS on the vessel wall JM Neutel 605

Figure 7 A 48-h comparison of two agents with trough-to-peak ratios of 50 and 100%, respectively.

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