1. Section VI: The endothelium:
New target for antihypertensive therapy
Content Points:
Hypertension is integrally related to diabetes, dyslipidemia and obesity. It is also a cause of endothelial dysfunction.

2. Cardiovascular dysmetabolic syndrome
Content Points:
Elevated blood pressure is part of the cardiovascular dysmetabolic syndrome and contributes to CHD. The following slides will address ways in which hypertension leads to endothelial dysfunction and effective treatments.64

3. Risk of cardiovascular disease
Content Points:
Hypertension increases the risk of CVD. The greater the level of hypertension, the greater the risk.101,102
Data from the Framingham Study illustrates how hypertension interacts with other risk factors such as elevated cholesterol levels, glucose intolerance, smoking, left ventricular dysfunction (as indicated by ECG abnormalities) and elevated HDL-C.
As blood pressure increases, there is an accompanying increase in the probability of developing CVD. Each additional risk factor compounds this risk, escalating to a probability of 299 per 1000 of developing CVD in 8 years for individuals with severe hypertension combined with 5 other risk factors.
This graphic depiction of the Framingham data illustrates why people with CDS, a condition with multiple risk factors, experience a high incidence of adverse outcomes.

4. Impaired endothelium-dependent vasodilation in essential hypertension
Content Points:
This study by Panza et al demonstrates impairment of endothelial function in people with hypertension.103
As shown in the graphs, both blood flow and vascular resistance responses to acetylcholine were abnormal in untreated hypertensive patients as compared to responses from normotensive controls (P < for both groups).

5. Consequences of endothelial dysfunction: Hypertension
Content Points:
The endothelium in hypertensive individuals is characterized by morphological and physiological changes. The endothelial cells tend to have an increased volume and bulge into the lumen. The subintimal space becomes a site where cells and fibrin are deposited. Increased adhesiveness of the endothelium encourages monocytes and platelets to settle. The extracellular matrix increases and the media thickens. As a result of these numerous changes, the vessel’s lumen size decreases.3,104
Experimental models of hypertension indicate that NO formation and release appear to be reduced and that endothelium derived contracting factor (EDCF) or prostaglandin H2 may be increased. Diabetes also reduces NO release.104
In addition to NO and EDCF, secretion of other vasoactive substances— such as growth factors, A II and matrix proteins and proteinases—is altered.3
This constellation of changes leads to vascular disorders such as atherosclerosis, myocardial ischemia, stroke and renal failure.3

6. Risk of cardiovascular events by hypertensive status
Content Points:
Both men and women who are hypertensive have an elevated risk of cardiovascular events including CHD, stroke, peripheral artery disease and congestive heart failure (CHF). As shown in earlier slides, the endothelial dysfunction that occurs with hypertension is probably responsible for this increase in cardiovascular events.105

7. Hypertension awareness, treatment and control
Content Points:
Awareness and treatment of hypertension has waxed and waned over the past several decades. But, as indicated by the graph, there remains substantial room for improvement.106
Since, as previously shown, hypertension puts people at significant risk for cardiovascular events, early diagnosis and appropriate treatment is crucial.

8. Goal of hypertension prevention and management
Content Points:
To reduce morbidity and mortality in people with hypertension, they should be treated to goal.106
It is particularly important to maintain acceptable blood pressure levels in people with diabetes since they are at high risk for morbidity and mortality from CVD.107
Current guidelines from the JNC and ADA specify that systolic blood pressure should be maintained below 140 mm Hg and diastolic blood pressure should be kept below 90 mm Hg, except for patients in the highest risk group who have several complications.
Additionally, other cardiovascular risk factors such as diabetes and dyslipidemia should be kept in check.

9. Classification of blood pressure for adults
Content Points:
According to the JNC VI guidelines, for adults aged at least 18 years, normal systolic pressure is less than 120 mm Hg and diastolic pressure is less than 85 mm Hg. However, a slightly lower diastolic pressure is optimal.106
The upper limit of normal is 139 mm Hg for systolic pressure and 89 mm Hg for diastolic pressure. Any blood pressure above these limits is considered to be in the hypertension category.
Stage 1 hypertension is characterized by a systolic pressure of mm Hg or a diastolic pressure of mm Hg.
When systolic pressure increases to mm Hg or diastolic pressure reaches mm Hg, this is considered stage 2 hypertension.
Any systolic pressure of 180 mm Hg or above or any diastolic pressure of or above is classified as stage 3 hypertension.

10. A treatment approach: Hypertension and diabetes
Content Points:
The JNC VI guidelines specify treatment approaches for patients with hypertension and for those who have additional, complicating disorders such as diabetes.106
For individuals in the high normal range with either zero or one complicating risk factor, lifestyle modification is an appropriate treatment.
However, individuals with diabetes who have blood pressure in the high normal range or above require pharmacological treatment.
Pharmacological therapy is necessary when appropriate trials of lifestyle modification do not lower blood pressure in individuals with stage 2 hypertension and zero or one complicating factor. Drug therapy is also necessary for individuals with stage 2 hypertension and complicating factors such as target organ disease or clinical CVD.
All individuals with stage 3 hypertension require drug therapy.

11. Compelling indications Content Points:
Specific classes of pharmacological agents are identified in the JNC VI guidelines as appropriate treatments for hypertension combined with complicating factors.106
For people with hypertension and diabetes, appropriate drug classes include ACE inhibitors, alpha-blockers, calcium antagonists and diuretics given in a low dose.
The guidelines specify, however, that for people with type 1 diabetes, proteinuria and hypertension, ACE inhibitors are the preferred treatment.
Individuals with hypertension and heart failure should be treated with ACE inhibitors or diuretics.
Elderly patients with isolated systolic hypertension should preferentially be treated with diuretics but may also be treated with calcium channel blockers such as long- acting dihydropyridine (DHP).
Individuals who have experienced an MI and have hypertension should be treated with ACE inhibitors if they have systolic dysfunction or, if their systolic function is satisfactory, with beta-blockers.

12. Likely mechanisms of ACE inhibition: Beneficial effects in hypertensive patients with diabetes
Content Points:
ACE inhibition appears to have an impact on endothelial function via 2 separate pathways; it interferes with the conversion of A I to A II and it reduces degradation of bradykinin.108
Both of these actions increase vasodilatation. Since A II is a vasoconstrictor, reducing levels of this compound tips the balance toward vessel relaxation. Bradykinin facilitates production of NO, a vasodilator.
ACE inhibition plays a critical role in restoring the balance within the endothelium between constriction and dilation and between growth promotion and inhibition.

13. Vasculoprotective effects of tissue ACE inhibition
Content Points:
The mechanisms by which ACE inhibitors work appear to be vasculoprotective.
Inhibition of ACE results in a decrease in A II levels and an increase in bradykinin levels. Elevation of bradykinin levels facilitates release of NO, which leads to relaxation of smooth muscle around blood vessels.109
ACE inhibition appears to improve endothelial function by a variety of mechanisms including: reducing vascular smooth muscle growth and cell migration, decreasing platelet aggregation and PAI-1 levels, inhibiting matrix synthesis and increasing t-PA levels.

14. Potency of ACE inhibitors in plasma and tissue (RIB studies)
Content Points:
Radioligand inhibitor binding (RIB) studies demonstrate a wide range of ACE binding affinity among the available ACE inhibitors.12,110,111
Quinaprilat, the active metabolite of quinapril, possesses the highest ACE binding affinity in both tissue and plasma.
Tissue ACE appears to play an important role in the development of atherosclerosis. It is plausible that differences in ACE binding affinity could translate into differential clinical responses.

15. Endothelial function and ACE inhibition: TREND results Content Points:
Several recent studies have assessed the efficacy of ACE inhibition at improving endothelial function. The first of these studies to be discussed is TREND.
TREND was a 6-month, randomized, double-blind, placebo-controlled study in normotensive adults with coronary artery disease. Serial intracoronary acetylcholine and quantitative coronary angiography (QCA) assessed the effect of quinapril on endothelial dysfunction in epicardial coronary arteries.112
This slide summarizes the results for the primary end point of the study: net change in mean diameter of the target segment after 6 months of treatment. Target segment was defined as the segment with the greatest initial constriction in response to acetylcholine challenge.
Subjects randomized to quinapril treatment showed a net increase in the mean diameter of target segments of 4.5 ± 3.0 for the 10-6 mol/L acetylcholine infusion and 12.1 ± 3.0 for the 10-4 mol/L acetylcholine infusion after 6 months of treatment. In contrast, the responses in the placebo group did not improve at either dose of acetylcholine.
There was a highly significant difference between quinapril and placebo (a net change of ± 3.0 for quinapril and -0.8 ± 2.9 for placebo; P < ) with the larger dose of acetylcholine.

16. TREND: Endothelium-dependent microvascular response
Content Points:
In this study, a subgroup of the TREND patients (29 subjects) had coronary blood flow (CBF) measurements taken using a Doppler flow wire.113
The acetylcholine/adenosine ratio is an indicator of maximal blood flow in a given arterial bed. An increase in this ratio denotes improved endothelial function.
At baseline, placebo and quinapril groups had similar endothelium- dependent flow responses.
After therapy, the endothelium-dependent flow response of the group receiving quinapril increased while that of the placebo group was unchanged.
The results show a trend for improvement of endothelial function with quinapril. Because this trial was small, significance could not be demonstrated, however, the results indicate that a larger trial is warranted.

17. TREND—Predictors of improved endothelial function: Multivariate analysis
Content Points:
A logistical regression model was used to identify predictors of improvements in endothelial function, defined as a greater than 5% net improvement during the 6-month follow-up. Variables associated with a value of P < 0.1 were subjected to a stepwise regression model.112
The only independent predictor of improvement was assignment to quinapril treatment (P = 0.022).
The factors examined were age, gender, smoking history, history of MI, diabetes, hypertension, number of CAD risk factors, blood pressure, severity of baseline diameter stenosis, number of diseased vessels, mean vessel diameter, serum cholesterol and triglyceride levels and baseline response to acetylcholine.

18. BANFF trial: Study design
Content Points:
The BANFF trial was an open label, randomized, partial block, crossover design study.114
Patients with documented CAD were included in the study. However, patients were excluded if they had previous CABG, left ventricular fraction of < 40%, total cholesterol > 6.0 mmol/L, uncontrolled hypertension, cigarette smoking or lipid-lowering therapy.
There were 3 8-week treatment periods with a 2-week washout. Four treatment arms were included. Two ACE inhibitors were included: quinapril (20 mg/day) was given to 56 patients and enalapril (10 mg/day) was given to 55 patients. The angiotensin receptor antagonist, losartan, was given to 38 patients (50 mg/day). In the last treatment arm, the calcium channel antagonist, amlodipine, was given to 45 patients (5 mg/day).

19. BANFF trial: Absolute changes in flow-mediated vasodilation
Content Points:
Endothelial function was assessed by measuring reactive hyperemia to determine flow-mediated dilation of the brachial artery.114
The quinapril group had significantly improved flow-mediated vasodilation. None of the other treatment groups showed significant improvement, although some improvement was seen with losartan and amlodipine.

20. BANFF trial: Summary and conclusions
Content Points:
The BANFF trial was one of the largest and most comprehensive studies to compare treatments to improve endothelial function.114
The study results demonstrate significant impairment of flow-mediated dilation in patients with CAD.
This investigation was a direct comparison of the effectiveness of quinapril, enalapril, losartan and amlodipine at ameliorating endothelial dysfunction and results showed significant improvement of flow-mediated dilation only with quinapril.
The results suggest that ACE inhibitors and other vasoactive agents differ in their effectiveness at reducing endothelial dysfunction.

21. Low-dose diuretics vs placebo: Meta-analysis of long-term trials
Content Points:
This meta-analysis examined 18 placebo controlled, randomized trials of anti-hypertensive treatments that assessed major disease end points over a long time period.115
Evaluation of studies of low-dose diuretic therapy, mostly in older adults, revealed that this type of therapy was associated with important reductions in the incidence of stroke, CHD, CHF and death.
This study concludes that appropriate treatment of hypertension is important to reduce morbidity and mortality from CVD. Diuretics offer one option for treatment.

22. Atherosclerotic lesion area reduced with ACE inhibition
Content Points:
The primary focus of this investigation was the determination of the effects of chronic ACE inhibition on infarct size and leukocyte accumulation in ischemic myocardium.116
A rabbit model of atherosclerosis was studied. Four treatment groups were followed up for 10 weeks: – Normal diet, quinapril therapy (n = 9) – Normal diet, placebo (n = 8) – High cholesterol diet, quinapril therapy (n = 9) – High cholesterol diet, placebo (n = 8)
Aortic atherosclerosis was assessed by dissecting the arteries and determining vasomotor responsiveness to acetylcholine and norepinephrine.
As shown on the left-hand side of the graph, cholesterol-fed rabbits had substantially greater atherosclerotic lesion areas than did normally fed controls. Treating cholesterol-fed rabbits with quinapril resulted in significantly smaller lesion areas (P < 0.05 vs cholesterol fed, placebo).
Aortic ACE activity was determined spectrophotometrically. As shown in the right-hand side of the figure, cholesterol-fed rabbits had significantly higher aortic ACE activity than normally fed rabbits (P < 0.05). Quinapril significantly suppressed ACE activity in both the normally fed and cholesterol- fed rabbits (P < 0.05).
These data show that quinapril therapy reduces the severity of myocardial injury produced by coronary occlusion/reperfusion in a rabbit model of atherosclerosis.

23. ACE inhibition: Effect on angiogenesis
Content Points:
In addition to quinapril's favorable effect on endothelial function, a beneficial effect on angiogenesis has recently been shown.
As illustrated in the slide, blood pressure index (BPI), measurements of flow reserve recovery, angiographic score and capillary density all significantly improved (P < 0.01) with both quinapril and vascular endothelial growth factor (VEGF) as compared with captopril or placebo.117
The growth of new blood vessels may improve tissue function following ischemia. Treatments that facilitate angiogenesis could therefore have a beneficial effect in some forms of cardiovascular or coronary diseases.

24. Probability of death from CHD in diabetic and nondiabetic people with and without prior MI
Content Points:
As discussed earlier, hypertension is often found in conjunction with diabetes.
People with diabetes need to receive appropriate treatment to reduce risk of CVD because they have a marked increase in risk. A person with diabetes has a 2- to 4-fold greater risk of developing CHD than a nondiabetic individual.118
This high risk translates into increased mortality. As shown in the graph, chance of survival for a person with diabetes who has not had an MI is similar to that of a person without diabetes who has already experienced an MI.
Adjustment for LDL-C, HDL-C, triglyceride, smoking and hypertension do not change these results significantly.
Chances of survival drop substantially once an individual with diabetes experiences an MI.

25. Survival of diabetic patients after acute MI is increased with ACE inhibition
Content Points:
One group of drugs that has been used to treat people with diabetes, hypertension and/or MI is ACE inhibitors.
In this study by Zuanetti et al, patients with acute MI were randomized to 4 treatment arms: lisinopril with and without nitroglycerin, nitroglycerin alone and no trial therapy. Of the total patient population, 2790 patients had either type 1 or type 2 diabetes.119
As shown in the graph, survival of nondiabetic patients increased slightly with lisinopril treatment. The lisinopril group experienced a 5% reduction in mortality which equated to about 3 (± 4) lives saved per 1000.
The diabetic patient population, on the other hand, had a significant increase in survival. The reduction in mortality was 30% which translates to about 37 (± 12) lives saved (P = 0.002).
Although treatment with the ACE inhibitor lasted only 6 weeks, most of the survival gain was maintained at 6 months.
Overall, the study results indicated that ACE inhibition has a favorable risk/benefit ratio when used during the acute phase of MI in diabetic patients.

26. UKPDS: Tight blood pressure control decreases CVD risk in people with type 2 diabetes
Content Points:
The UKPDS study investigated the effect of blood pressure control on macrovascular and microvascular complications in patients with type 2 diabetes.120
A total of 1148 hypertensive patients with type 2 diabetes were allocated to a tight control group that tried to maintain a blood pressure of < 150/85 mm Hg with use of captopril or atenolol or to a group that maintained less tight control with blood pressure kept at < 180/105 mm Hg.
Patients in the tight control group experienced a 24% reduction in risk of developing any end point related to diabetes compared with the moderate control group (P = ).
A 32% reduction in risk of mortality related to diabetes occurred in the tight control group compared with the moderate control group (P = 0.019).
Risk of MI was reduced by 21% in the tight control group; however, this reduction did not reach significance. All-cause mortality and peripheral vascular disease were not significantly reduced.

27. FACET: Probability of remaining free of stroke, acute MI or hospitalized angina
Content Points:
Another recent study, FACET, examined the effectiveness of ACE inhibition as a treatment for patients with diabetes and high blood pressure.121
In this study 380 patients with type 2 diabetes and hypertension were randomized to treatment with fosinopril or the calcium antagonist, amlodipine, and were followed up for 3.5 years.
Patients treated with ACE inhibition had a significantly greater probability of remaining free of stroke, acute MI, or angina severe enough to require hospitalization (P = 0.03 log rank). In the fosinopril group, major cardiovascular events were reduced by 50%.
Since both ACE inhibitors and calcium antagonists substantially lower blood pressure, the authors conclude that a mechanistic difference, such as the effect of ACE inhibition on the fibrinolytic system, must account for the difference in outcomes with the 2 treatments.

28. ABCD trial: Ca2+ blockade vs ACE inhibition in diabetic hypertensives
Content Points:
The ABCD trial, like FACET, compared the effectiveness of an ACE inhibitor with that of a calcium channel antagonist at reducing cardiovascular events in patients with diabetes and hypertension.
In the trial, 470 patients were randomized to treatment with nisoldipine or enalapril and were followed up for 5 years.122
Cardiovascular outcomes in the group receiving ACE inhibition were superior to outcomes with the calcium channel antagonist. In the group receiving enalapril, there were 5 deaths due to CVD as compared with 10 deaths in the nisoldipine group.
In the group given the ACE inhibitor, there were significantly fewer fatal and nonfatal MIs (P = 0.001) and nonfatal MIs (P = 0.001).

29. Interpretation of the findings of FACET and ABCD
Content Points:
Both ACE inhibitors and calcium antagonists (CAs) lower blood pressure. However, based on the results of the FACET and ABCD trials, ACE inhibitors are more effective at reducing CVD morbidity and mortality in hypertensive patients with type 2 diabetes.
The reduction in CVD events observed with ACE inhibitors in the FACET and ABCD trials could be due either to a special beneficial effect of ACE inhibitors or to a harmful effect of calcium antagonists.
The differences in outcomes with use of the 2 types of drugs likely results from differences in their mechanisms of action and not simply to reduction of blood pressure since both drug classes are effective at reducing hypertension.
There is a need for more comparative clinical trials of antihypertensive agents. Since hypertension is a common and often deadly disorder, clear understanding of the risks and benefits of each agent is vital.
Placebo-controlled trials do not provide the necessary information on relative drug benefits. Comparative trials are needed.

30. Hazard ratio for CV events in isradipine/HCTZ treated patients with high or low glucose levels
Content Points:
This substudy of the MIDAS trial examined the effect of glucose levels on outcomes with isradipine or hydrochlorothiazide.123
A total of 30 individuals with previously undiagnosed diabetes were included in the study.
The incidence of CV events, including MI, stroke, CHF, hospital admission with angina and fatal vascular events, was 5.7% in the isradipine group compared with 3.2% in the controls. The hazard ratio (HR) was 1.81, 95% CI,
In comparing the isradipine and hydrochlorothiazide groups, the adjusted HR for experiencing a major vascular event among patients below the median HbA1c level or 6.7% was 1.11 (95% CI, ). But among patients above the median HbA1c level, the HR for major vascular events was much higher, 2.81 (95% CI, ).
The results suggest that among hypertensive patients with impaired glucose metabolism, calcium antagonists such as isradipine may lead to higher levels of CV events, therefore, other therapies, such as diuretics, may be preferable.

31. Relative risk of CV events in hypertensive patients with diabetes or IGM in randomized controlled trials
Content Points:
The 3 trials just reviewed, FACET, ABCD and MIDAS, all reveal a trend toward increased CV events with calcium antagonists.124
In the FACET trial, the group receiving the calcium antagonist, amlodipine, had a relative risk of 2.0.
In the ABCD trial, the nisoldipine group had an unadjusted relative risk of
Isradipine therapy, in the MIDAS trial, resulted in an adjusted relative risk of 2.7.
Analysis of these trials indicates that calcium antagonists in any formulation, short-, intermediate-, or long-acting, are inferior to other antihypertensive agents in terms of protection from major cardiovascular complications.
At this time, it is not known whether this lack of protection from CV events is due to a negative effect of the drug class or due to lack of a positive effect that occurs with other drug classes such as ACE inhibitors.

32. Clinical decisions based on clinical trial data
Content Points:
Based on the results of the 3 investigations just reviewed, it seems prudent to use ACE inhibitors, low-dose diuretics, and probably beta-blockers as preferred first-line agents in patients with hypertension and diabetes.
Future clinical trials may provide more evidence on which to base therapeutic decisions.

33. Summary: Tissue ACE inhibition in hypertension
Content Points:
In this presentation, evidence has been presented that tissue ACE inhibition may provide therapeutic benefits to individuals with hypertension and diabetes, both components of the CDS.
These benefits of tissue ACE inhibition are derived by mechanisms separate from those of plasma ACE inhibition or from simple reduction of blood pressure.
The dosage of ACE inhibitors needed to reduce endothelial dysfunction may be higher than the dose needed to achieve blood pressure reduction.
ACE inhibitors have been shown to differ in their effectiveness at tissue ACE inhibition. These differences may translate into differences in improvement of endothelial function.
Evidence has been presented from recent clinical trials that indicates improved clinical outcome and cardiovascular event reduction in patients with hypertension and/or diabetes following treatment with ACE inhibitors.