1. Section IV: The interaction of the RAS and lipids
Prevalence of dyslipidemia increases with BP level
Content points:
• The association of hypertension and dyslipidemia has been noted in several population studies. Recently, Lloyd-Jones and colleagues analyzed data on 4962 subjects from the Framingham Heart Study and the Framingham Offspring Study who were examined between 1990 and
• They found that the prevalence of dyslipidemia (defined as total cholesterol >240 mg/dL, HDL-C 35 mg/dL, or currently receiving lipid-lowering medication) increased with increasing blood pressure in men and women.
• In men, the proportion with dyslipidemia rose from 37% with normal blood pressure to 53% with stages 2 and 3 blood pressure. The proportion of women with dyslipidemia rose from 20% of women with optimal blood pressure to 43% of women with stage 2 and 3 blood pressure. On average, over 40% of men and 33% of women with blood pressure 140/90 mm Hg were dyslipidemic.
• The data demonstrate that hypertension and hypercholesterolemia are frequently associated. The data also suggest that individuals with hypertension may be more likely to become dyslipidemic over time.

2. Cholesterol lowering reduces blood pressure response to mental stress
Content points:
• Sung et al examined the blood pressure response to a standard mental arithmetic test in 37 healthy normotensive subjects with hypercholesterolemia (mean total cholesterol 263 mg/dL) and 33 normotensive subjects with normal cholesterol levels.2 None of the hypercholesterolemic group were receiving lipid-lowering therapy prior to study entry.
• In the first part of the study, the blood pressure response to the arithmetic test was determined. The blood pressure response during the arithmetic test was significantly higher in the hypercholesterolemic group compared with the normocholesterolemic group (18  8 versus 10  5 mm Hg, respectively, P < 0.05).
• To confirm that blood pressure reactivity was dependent on cholesterol, in the second part of the study, the hypercholesterolemic group was divided into 2 subgroups that received either 6 weeks of lovastatin or 6 weeks of placebo. There were 26 evaluable patients in this part of the study.
• As shown on the slide, statin treatment resulted in significant reductions from baseline in total cholesterol and LDL-C (P = 0.001). Compared with placebo, statin treatment was associated with lower mean systolic blood pressure prior to (119  11 versus 122  9 mm Hg, P = 0.07) and during the arithmetic test (133  12 versus 141  10 mm Hg, P < 0.05).
• Diastolic blood pressure changes were not significantly correlated with lipid lowering.
• These findings demonstrate that individuals with hypercholesterolemia have exaggerated systolic blood pressure responses to mental stress and that lipid lowering improves the systolic response to stress.

3. Angiotensin II induces LOX-1, an endothelial receptor for oxidized LDL
Content points:
• Activation of oxidatively modified LDL (ox-LDL) plays a key role in the initiation and progression of atherosclerosis. Certain effects of ox-LDL are mediated by the endothelial ox-LDL receptor, LOX-1, or lectinlike ox-LDL receptor.
• In this study, Morawietz and colleagues showed that LOX-1 expression is regulated by Ang II and that induction of LOX-1 is mediated by the AT1 receptor.3 They treated cultured human umbilical vein endothelial cells with Ang II for 3 hours, which induced expression of the LOX-1 protein, as shown on the slide. As also shown, the induction of LOX-1 by Ang II could be prevented by AT1 receptor blockade.
• Angiotensin II-mediated expression of LOX-1 augmented oxLDL uptake in human endothelial cells. This also could be prevented by AT1 receptor blockade.
• These findings suggest a new mechanism to explain how hypertension might promote early initiation and progression of atherosclerosis: Hypertension is associated with activation of the RAS, leading to increased expression of angiotensin II. Increased angiotensin II levels would lead to stimulated uptake of proatherogenic ox-LDL in endothelial cells. Therefore angiotensin II-stimulated ox-LDL uptake into endothelial cells would accelerate early proatherosclerotic processes.
• The induction of LOX-1 was completely prevented by AT1 receptor blockade, which suggests that pharmacologic interventions that block the RAS have the ability to prevent atherosclerosis.
• More about the therapeutic potential for agents that block the RAS is shown on the next slide.

4. ACE inhibition downregulates LOX-1 in mammary artery segments of
patients with CAD
Content points:
• Morawietz and colleagues also showed that long-term ACE inhibition downregulates LOX-1 expression in internal mammary arteries of patients with CAD.3 This observation provides further support for the antiatherosclerotic potential of pharmacologic intervention with the RAS.
• In this part of the study, they obtained biopsy samples from internal mammary arteries of 24 patients undergoing elective coronary artery bypass graft (CABG) surgery. The cohort included 12 patients who had been receiving long-term ACE inhibitor therapy and a matched group of 12 patients who had not been taking ACE inhibitors. The groups were similar in every other respect, including the use of concomitant therapies.
• Long-term ACE inhibition was associated with a significant decrease in LOX-1 expression. The effect seemed to be specific for the RAS, because no significant correlation of LOX-1 expression with other medications could be found in either group.
• This downregulation of LOX-1 expression by long-term ACE inhibition might represent an antiatherosclerotic mechanism that contributes to their vasculoprotective potential and the improved survival of patients in recent ACE inhibitor trials.

5. Antiatherosclerotic effect of ACE inhibition and AT1 receptor blockade
Content points:
• Miyazaki and colleagues studied the relationship between angiotensin II formation and the development of atherosclerotic lesions in the aorta of monkeys fed a high cholesterol diet for 6 months.4 They also studied the effects of the ACE inhibitor trandolapril and the angiotensin receptor blocker (ARB) HR 720.
• The level of LDL-C was significantly increased by the cholesterol diet, whereas that of HDL-C was significantly decreased. The relative areas of the atherosclerotic lesions in the thoracic aorta in the normal and cholesterol-diet groups were 1.3+/-0.3 and 64+/-10%, respectively.
• ACE activity and angiotensin II concentration were significantly increased in the aorta of the cholesterol-fed monkeys.
• As shown on the slide, both the ACE inhibitor and the ARB decreased significantly the area of the atherosclerotic lesions in the thoracic aorta of cholesterol-fed monkeys.
• In plasma and aorta, trandolapril, but not HR 720, decreased significantly the ACE activities in the cholesterol-fed monkeys, while both of these drugs decreased significantly the angiotensin II levels.
• This study shows that blockade of angiotensin II in vascular tissues by ACE inhibition or ARB may play an important role in preventing the development of atherosclerosis.

6. AT1 receptor density is upregulated in hypercholesterolemia and
downregulated by statin therapy
Content points:
• Nickenig and colleagues examined AT1 receptor overexpression in hypercholesterolemic vs normal men (N = 19 and 20, respectively) and therapeutic interventions to lower cholesterol levels with HMG CoA reductase inhibitors (statins).5 Hypercholesterolemia has been shown to regulate vascular angiotensin type 1 (AT1) receptor expression in cell culture and animal models.
• The effects of hypercholesterolemia were determined by measuring changes in blood pressure after Ang II infusion in men with normal cholesterol or hypercholesterolemia. The men with hypercholesterolemia had an exaggerated elevation in blood pressure in response to angiotensin II.
• As shown on the slide, AT1 receptor expression was significantly greater in hypercholesterolemic individuals. Cholesterol-lowering treatment with statins downregulated AT1 receptor density and reversed the exaggerated blood pressure response to angiotensin II.
• The data show that hypercholesterolemia stimulates AT1 receptor overexpression and enhances the biological effects of angiotensin II. These findings provide novel insights into the pathogenesis of hypertension and atherosclerosis and may initiate rational and new therapeutic concepts.

7. Combined and distinct vascular effects of ACE-I and statins:
Effects on blood pressure
Content points:
• As discussed on the previous slide, hypercholesterolemia induces AT1 receptor overexpression and enhances the biological effects of angiotensin II.
• Nazzaro and coworkers studied the effects of ACE inhibitors and statins in 30 subjects with hypercholesterolemia and hypertension at rest and during stress.6 Participants were given either enalapril or simvastatin for 14 weeks and the combined medications for an additional 14 weeks.
• This slide shows the effect on systolic blood pressure of one medication and combination therapy under stressful conditions.
• As you would expect, the ACE inhibitor lowers blood pressure. But there is also a lowering of blood pressure with the statin. However, the combination achieves a much better lowering of blood pressure. Similar results were achieved for diastolic blood pressure.
• The results suggest that both medications have vasodilatory properties, conceivably second to the effects on the arterial wall.

8. Combined and distinct vascular effects of ACE-I and statins:
Effects on hemodynamic reactivity
Content points:
• Nazzaro and colleagues also studied hemodynamic reactivity in response to stress (reactive hyperemia).6
• Forearm blood flow increased more with ACE inhibition than with the statin, and forearm vascular resistance was decreased more with ACE inhibition than with the statin. But in both cases, the effect was greater with combination therapy.
• The findings suggest that as monotherapy, ACE inhibition induces a larger reduction than HMG-CoA reductase blockade in vascular reactivity and structural damage in hypercholesterolemic hypertensive subjects.
• The clinical data support the notion of a strong pathophysiologic link between hypercholesterolemia, specifically LDL-C, and blood pressure response. They suggest that structural and functional vascular impairments in hypercholesterolemic hypertensive subjects may be attributed primarily to high blood pressure.
• They also suggest that the RAS, the AT1 receptor, and LDL-C are linked and that ACE inhibitors and statins reduce angiotensin II and AT1-receptor activation to modify this exaggerated response.

9. Hypertension and hypercholesterolemia: Interactions and potential
mechanisms
Content points:
• In summary, hypertension and hypercholesterolemia, the major risk factors for atherosclerotic disease, are frequently associated.1,2
• Data from laboratory studies suggest that the vascular RAS may be involved via LDL-mediated AT1 receptor upregulation, which leads to production of ox-LDL. Adverse effects of ox-LDL on the vascular wall may be mediated by the LOX-1 receptor.3-6
• These findings are extending our understanding of the interplay among risk factors that increases cardiovascular risk and the antiatherosclerotic effects of local ACE inhibition to reduce cardiovascular risk.