Section III: The renin-angiotensin system and ACE inhibition Circulating and local (tissue) RAS influence on the cardiovascular system Content points: • The far-reaching effects of the renin-angiotensin system (RAS) make it an ideal target to antagonize therapeutically. Not only is the RAS an important regulator of blood-pressure homeostasis, but it also has a critical influence on cardiovascular remodeling. • The circulating RAS has both long- and short-term effects on the cardiovascular system.1 Short-term effects include facilitating sodium and water reabsorption, blood vessel constriction, positive chronotropic effects, and antiarrhythmogenic effects. The circulating RAS is activated during states of cardiovascular compensation, including dehydration, hemorrhage, and heart failure. This system can raise blood pressure through multiple efferent pathways, but primarily by increasing vasoconstriction and extracellular fluid volume. • Long-term changes in vascular tone are accomplished by the local or tissue RAS and they cause changes in vascular structure and function. Although the peripheral or systemic RAS as we classically understand it may be involved in this process, it is the autocrine or paracrine production of angiotensin II by the local RAS that is most important in promoting cardiovascular restructuring and remodeling.

Influence of the RAS: Circulating vs local ACE Content points: • Only about 10% of the angiotensin-converting enzyme (ACE) in the body circulates in the plasma where it exerts an endocrine effect. Circulating ACE is responsible for acute changes in blood pressure.1 • Approximately 90% of the ACE occurs locally in the tissues, such as blood vessels, myocardium, and central nervous system. • The local production of angiotensin II by tissue ACE exerts a paracrine or autocrine effect and is thought be involved in vascular and cardiac structure and function over the long term.

Links between angiotensin and atherogenesis Content points: • Angiotensin II is an important factor in the pathophysiology of atherosclerosis and coronary ischemic events. It is linked to atherogenesis through its role in inflammatory and remodeling processes.2 • When vascular cells are exposed to angiotensin II there is a significant increase in superoxide anion. The resulting oxidative stress is associated with an increase in monocyte adhesion molecules and release of cytokines by these monocytes. • Factors that contribute to endothelial dysfunction, such as imbalance between NO and reactive oxygen species, are mediated by increased angiotensin II. The molecules stimulated by endothelial dysfunction, oxidative stress, and diminished NO activity (transcription factors, such as vascular cell adhesion molecule-1 [VCAM-1], monocyte chemoattractant protein-1 [MCP-1], and cytokines), activate genes for various pro-inflammatory mediators. Data are emerging to show that atherosclerosis is actually an inflammatory disease. • Angiotensin II may participate in a local positive feedback loop that contributes to the development of atherosclerosis as follows: Angiotensin II promotes the transformation of monocytes to lipid-laden macrophages in the presence of oxidized LDL-cholesterol (C). The activation of macrophages stimulates cellular expression of ACE, and thus, increases synthesis of angiotensin II. In this manner, this potential feedback loop may lead to increased ACE and angiotensin II levels in atherosclerosis lesions. • Increases in local ACE activity are associated with vascular proliferation. ACE has been demonstrated in vascular smooth muscle in intimal lesions and in macrophages and vascular smooth muscle cells in fibroproliferative lesions of human atherosclerotic plaques. • Furthermore, angiotensin II may contribute acutely to ischemic events by affecting hemostasis. Angiotensin stimulates the release of plasminogen activator inhibitor 1 (PAI-1) and it may therefore attenuate thrombolysis. • Angiotensin appears to be involved in platelet activation and aggregation and it contributes to plaque instability through its effects on hemostasis.

Influence of angiotensin II on the blood vessel Content points: • Angiotensin II exerts substantial influence on the blood vessel wall, and in particular, vascular smooth muscle, through a variety of effects that lead to growth, remodeling, and restructuring.3 • Blood pressure itself is an important instigator of this process, through mechanical stress, stretch, and turbulence. However, in addition, vascular injury may stimulate local angiotensin II production through various local mechanisms and result in a proliferative process and progressive atherosclerotic changes. • Thus angiotensin II synthesis is excellent target for pharmacologic blockade.

Influence of angiotensin II on the heart Content points: • The cardiac response to mechanical stretch, stress, tension and turbulence is similar to that of the blood vessel. As shown here, various clinical scenarios lead to left-ventricular overload, including hypertension, particularly systolic hypertension. Aortic stenosis and coarctation of the aorta have similar outcomes.3 • With cardiovascular aging, the aorta loses much of its elastic recoil. This produces a marked increase in left ventricular pressure with each systolic contraction of the heart, resulting in substantial left ventricular wall tension. • Volume overload also increases left ventricular work and wall tension. Immediately after myocardial infarction (MI) or after acute valvular insufficiency, left ventricular volume increases cause an increase in left ventricular diameter. • Whatever the clinical situation, either left ventricular pressure overload or left ventricular volume overload, or both, the result is an increase in wall tension and size and increased induction of angiotensin II pathways at the local tissue level that leads to myocardial hypertrophy, and ultimately, systolic dysfunction. • Therapeutic strategies geared toward aggressive blood pressure reduction or that antagonize the effect of angiotensin II may be optimal in protecting vascular structure and function.

ACE activity is increased in coronary artery specimens from patients with ACS Content points: • Hoshida et al demonstrated an increase in ACE activity in culprit lesions in studies of coronary artery specimens from patients with acute coronary syndromes.4 • ACE activity was measured in vascular tissue obtained on directional coronary atherectomy in patients with acute coronary syndromes and in patients with stable ischemic heart disease with and without restenosis.4 • Patients with acute coronary syndromes had a significant increase in ACE activity of the culprit coronary lesions (P < 0.01). In contrast, ACE activity was not increased in patients with ischemic heart disease, including those with and without restenosis. • Serum ACE activity did not differ significantly between the two groups of patients. • These findings indicate enhanced ACE activity is related to the causative mechanisms of active coronary lesions.

ACE inhibition: Two critical pathways Content points: • ACE regulates the balance between the vasodilatory and natriuretic properties of bradykinin and the vasoconstrictive and salt-retentive properties of angiotensin II. As seen in this schematic illustration, locally produced ACE is strategically poised to regulate the balance between angiotensin II and bradykinin by actions in two critical pathways.5 • In the RAS, ACE catalyzes the change of angiotensin I to angiotensin II. Acutely, angiotensin II has potent vasoconstrictive and salt-retentive properties. Acting locally, through a variety of direct or indirect mechanisms, angiotensin II can influence structure, function, and atherosclerotic progression in the vascular tree. • In the kallikrein-kinin system, ACE catalyzes the degradation of bradykinin. Among its most important actions, bradykinin promotes vasodilation and influences vascular structure and function. In the kidney, bradykinin causes natriuresis through direct tubular effects. • ACE inhibition has a two-pronged approach: 1) it interferes with the conversion of angiotensin I to angiotensin II and 2) it inhibits the degradation of bradykinin. • By inhibition of these two important vasoactive substances, ACE inhibitors can restore the balance between vasoconstriction and growth promotion and vasodilation and growth inhibition. Thus ACE inhibitors are able to modify vascular disease progression.

Vasculoprotective effects of local ACE inhibition Content points: • By blocking the RAS, ACE inhibitors interfere with the progression of cardiovascular disease by a number of antiatherogenic and antithrombotic effects that protect the vascular wall.6 • ACE inhibition decreases locally generated angiotensin II, which contributes to structural changes in cardiovascular vascular disorders in various important ways. ACE inhibition increases bradykinin levels, facilitating the release of NO, which is probably the most important vasodilator in the body. • ACE inhibition leads to beneficial remodeling of the left ventricle and arteries by reducing vascular smooth muscle cell contraction, growth, and migration, and by preventing cardiac myocyte growth and matrix synthesis. • ACE inhibition also decreases oxidative stress and inflammation, and enhances myocardial angiogenesis. • ACE inhibitors improve fibrinolytic balance by reducing platelet aggregation and by decreasing plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (tPA) levels. • The next slide briefly describes actions of tPA and PAI-1.

The fibrinolytic system: tPA and PAI-1 Content points: • The fibrinolytic system is a balance between tissue plasminogen activator (tPA) and plasminogen activator inhibitors, mainly plasminogen activator inhibitor-1 (PAI-1).7-9 • tPA converts plasmin to plasminogen, which acts on fibrin to disrupt the thrombus. • PAI-1 inhibits tPA and fibrinolysis, and promotes clot progression. • Elevated PAI-1 levels correlate with increased risk of thrombosis and reinfarction.10

Systolic blood pressure predicts plasma PAI-1 Content points: • The Framingham study data show that PAI-1 levels increase significantly with increasing systolic blood pressures in men and women.11 Similarly, tPA levels also increase as blood pressure rises. • These changes in fibrinolytic potential are also associated with increases in diastolic blood pressure. • Elevations in PAI-1 cause fibrinolytic disruption and predict increased CVD risk. Elevations in PAI-1 predispose to thrombosis, increasing the risk of acute coronary events and possibly restenosis potentiated by clot-associated mitogens.

PAI-1 is increased in atheroma from diabetic subjects Content points: • Sobel and colleagues found an increase in total PAI-1 (free plus plasminogen activator–complexed PAI-1) and a decrease in total u-PA (free and receptor bound) in the atheroma from the diabetic patients.12 Thus, even if some of the PAI-1 detected is complexed with some of the u-PA (an interaction possible with the two-chain species), the amount of free PAI-1 appears to be increased. This increase in PAI-1 may contribute to an acceleration in restenosis following angioplasty in individuals with diabetes, and to accelerated macrovascular disease. • The results of this study are consistent with the hypothesis that one of the contributors to the development of accelerated macrovascular disease in patients with diabetes is an alteration in tissue expression of components of the fibrinolytic system within atheroma and presumably therefore within the arterial walls. • The results also support the hypothesis that a disproportionate elevation of PAI-1 not only in blood but also in extracted atheroma and presumably vessel walls is characteristic of and perhaps a direct consequence of hyperinsulinemia and hyperproinsulinemia typical of insulin-resistant states, including type 2 diabetes mellitus.

ACE inhibition favorably alters fibrinolytic balance Content points: • Vaughan and colleagues studied the effects of the ACE inhibitor ramipril on fibrinolytic balance in 120 subjects with anterior MI who were participants in the Healing and Early Afterload Reduction (HEART) study.8 Within 24 hours of the onset of symptoms patients were randomly assigned to receive ramipril (0.625 or 1.25 mg daily) or placebo for 14 days. • At day 14 of the post-acute MI recovery phase, in the group treated with ramipril, PAI-1 antigen was 44% lower (P = 0.004) and PAI-1 activity was 22% lower (P = 0.02) compared with the placebo group. There was a trend toward a reduction in tPA. Overall ramipril appears to shift the fibrinolytic balance toward lysis in patients after MI. • In two other studies, not shown here, captopril was shown to significantly decrease PAI-1 and tPA levels in post AMI patients.13,14 • These observations suggest that the RAS appears to play an important role in the regulation of vascular fibrinolytic balance after MI. Interruption of this regulatory pathway may contribute to the ability of ACE inhibitors to reduce ischemic coronary events in patients. Use of ACE inhibitor therapy post-MI may reduce the frequency of recurrent thrombosis by increasing fibrinolytic capacity.