1. From hypertension to LVH and heart failure
Content Points:
A growing body of experimental and clinical research has identified the endothelium as a major contributor to the pathophysiology of hypertension and its progression to left ventricular hypertrophy (LVH) and heart failure.
This presentation examines the relation of hypertension to the development of LVH and heart failure, including the role of the renin-angiotensin system and endothelial dysfunction in pathophysiology. It also emphasizes the clinical impact of these findings on current therapeutic trends and the role of ACE inhibition in the current treatment of heart failure, LVH, and hypertension.

2. Content outline
Content Points:
This program will discuss the following:
The pathophysiologic progression of disease from hypertension to LVH and heart failure
Modern therapeutic trends in hypertension management that address the underlying pathology: JNC-VI guidelines
Regression of LVH as an important therapeutic target
Impact of hypertension and heart failure on endothelial function and the role of the renin-angiotensin system
Improving endothelial dysfunction with ACE inhibition
The efficacy of tissue ACE inhibition in patients with heart failure

3. Progression of hypertension to LVH and heart failure
Content Points:
The 2 principal factors contributing to heart failure are hypertension and coronary artery disease. Of the 2, hypertension is the more common. Hypertension is very frequently the initial step in pathophysiologic progression to heart failure, which is a complex syndrome that involves a variety of linked hemodynamic and metabolic changes.1
LVH and associated left ventricular dysfunction are among the most common cardiac sequelae of hypertension.
LVH leads to CHF through a variety of mechanisms. At first, mild LVH allows the heart to compensate for increases in vascular resistance. In time, however, the increase in left ventricular wall thickness and left ventricular remodeling lead to diastolic dysfunction and subsequently to systolic dysfunction.
In addition to pressure-related mechanical strain, pathologic changes that are a direct result of stimulation of the renin-angiotensin system also contribute to LVH.
Clinically overt heart failure develops when the hypertrophied left ventricle can no longer maintain its output and the downward spiral of ventricular dilatation and symptomatic disease begins.
The structural and functional changes associated with hypertension and the development of LVH and heart failure occur over decades and are preventable with effective antihypertensive treatment.

4. JNC-VI guidelines: Compelling indications and treatment choices
Content Points:
The JNC-VI hypertension treatment algorithm represents a dramatic departure from the past. In the new system, initial drug choices are individualized according to the severity of hypertension as well as on the basis of an assessment of the pattern of comorbidities and complications of hypertension.2
Thus, in JNC-VI, the presence of heart failure, diabetes, or renal failure in the hypertensive patient offers compelling indication for the use ACE inhibitors.
Emerging data suggest that choosing an antihypertensive therapy aimed at ameliorating the underlying pathophysiologic process may optimize treatment outcomes.
Although early intervention is extremely important to prevent cardiovascular complications of hypertension, it is never too late to institute effective targeted treatment.

5. Relative risks for heart failure: Framingham Heart Study
Content Points:
This slide summarizes the multivariate adjusted risks of heart failure in 5,143 Framingham Heart Study participants based on a mean 14-year follow-up. The analysis identified hypertension, myocardial infarction, angina pectoris, diabetes mellitus, LVH, and valvular heart disease as independent risk factors for heart failure.3,4
Hypertension increased the risk for heart failure from 2-fold in men and over 3-fold in women. It was the most common risk factor for heart failure, found in 91% of all cases.3
LVH increased the risk for heart failure independently from hypertension, from 2-fold in men to nearly 3-fold in women. LVH was about as much of a risk for heart failure as diabetes or valvular heart disease.

6. LVH regression: Changes in left ventricular mass index with 4 drug classes
Content Points:
LVH is a powerful independent cardiovascular risk factor, and therefore prevention or regression of LVH is an important goal in the treatment of hypertension.
A meta-analysis of 39 randomized double-blind studies showed that ACE inhibitors were more effective than the other first-line antihypertensive therapies in reducing LVH. The analysis compared ACE inhibitors with ß-blockers, calcium channel blockers, and diuretics.5
Patients who took ACE inhibitors had a 13% decrease in left ventricular mass as contrasted with 9% with calcium channel blockers, 6% with ß-blockers and 7% with diuretics. ACE inhibitors and, to a lesser extent, calcium channel blockers produced a statistically significant regression in LVH (P < .01). There was a trend for improvement with diuretics, but it was not statistically significant.
The proposed mechanism for additional reduction in LV mass seen with ACE inhibitors is complex. In addition to favorable effects on cardiac preload and afterload, ACE inhibitors probably diminish the growth stimulating actions of angiotensin on cardiac myocytes. As such, ACE inhibitors may help reverse LVH independently of their impact on blood pressure.5

7. LVH reversed in most patients with long-term quinapril treatment
Content Points:
Reversal of LVH and of other cardiac adaptations to increased afterload are an important therapeutic goal in hypertension treatment. In a long-term study by Franz and colleagues, LVH regressed to normal over the course of 3 years of treatment with the ACE inhibitor quinapril.19
The study included 23 patients with electrocardiographic evidence of LVH who were treated with either 10-mg or 20-mg doses of quinapril daily. Five patients also took 25-mg doses of hydrochlorothiazide. None of the patients had previously received treatment for hypertension.
In 90.5% of the patients who underwent long-term treatment with quinapril, there was complete regression of LVH, as shown in this graph. Left ventricular mass index was restored to normal values of < 125 grams for men and < 110 grams for women.19
Atrial fibrillation is another major complication of hypertension and an important contributor to cardiovascular morbidity and mortality. This study also showed that left atrial enlargement is reduced as LVH regresses. The most important decrease occurred after only 7.5 months of treatment.

8. Mechanisms of cardiac RAS activation in cardiac remodeling
Content Points:
This diagram by Dzau summarizes the mechanisms that precipitate activation of the renin-angiotensin system (RAS) in the heart and lead to cardiac remodeling.7
It is now known that there are two RAS, the circulatory and tissue RAS. The tissue RAS is present in cardiac tissue, vascular walls, the CNS, and lungs, etc. and produces more than 90% of all ACE. The tissue RAS exerts long-term effects on cardiovascular structure and function.
In the heart, the increase in pressure overload associated with LVH and hypertension results in an adaptive ventricular response in which gene expression of ACE is increased. This results in intracardiac activation of angiotensin II that contributes to myocardial remodeling, to an adaptive response to overload, and subsequently to increased diastolic stiffness that is characteristic of LVH.
Long-term treatment with ACE inhibitors blocks angiotensin II production and thereby inhibits the progression of cardiac remodeling. This explains the well-documented beneficial effects of ACE inhibition in preventing or regressing LVH.
The next slides discuss the role of the endothelium in heart failure.

9. Hypothesized role of vascular endothelial dysfunction in chronic heart failure pathogenesis
Content Points:
This diagram by Drexler depicts the hypothetical role of vascular endothelial dysfunction in heart failure.8 An expanding body of evidence indicates that endothelial dysfunction with impaired flow-dependent dilation (FDD) is important in the pathogenesis of hypertension and heart failure.
As the complexity of this slide suggests, the causes and consequences of endothelial dysfunction in heart failure are multifactorial. The pathogenesis of endothelial dysfunction in heart failure may be related to cytokine and neurohormonal activation, increased oxidative stress, and abnormal regional flow conditions.8
More information about the mechanisms of endothelial dysfunction in heart failure and appropriate potential therapeutic interventions will be discussed in the slides that follow.

10. Possible mechanisms of endothelial dysfunction in heart failure
Content Points:
Not one, but several, mechanisms are involved in the pathophysiology of endothelial dysfunction in patients with chronic heart failure.9,10
Among these, a reduced release of NO in response to receptor- or flow-mediated conditions appears to play a central role.
Reduction of L-arginine, a precursor of NO, is potentially a rate-limiting step in NO synthesis.
Decreased expression of NO synthase, the enzyme that generates NO from L-arginine, leads to decreased NO availability.
Increased ACE activation causes bradykinin destruction, leading to decreased NO production.
Increases in angiotensin II stimulate formation of oxygen-free radicals which inactivate NO.

11. Effects of ACE inhibition on flow-dependent vasodilation
Content Points:
ACE inhibitors have become a cornerstone in the treatment of heart failure.11
The benefits of ACE inhibitors have frequently been attributed to a reduction in angiotensin II and norepinephrine levels. But ACE inhibition is also associated with an increase in bradykinin.9,10
Thus, ACE inhibitors decrease levels of the potent vasoconstrictor angiotensin II and they also stimulate the endothelium to release potent vasodilators, including NO and prostacyclin, by a bradykinin-dependent mechanism.

12. Bradykinin and ACE inhibition
Content Points:
This study by Hornig and coworkers showed that ACE inhibition improves endothelial function by a bradykinin-dependent mechanism.11 In 10 healthy volunteers, they examined the effects of quinapril and the selective bradykinin antagonist icatibant and the 2 agents combined on resting tone and on flow-dependent, endothelium-mediated dilation of the radial artery.
Quinapril improved flow-dependent dilation of the radial artery by 46% over baseline compared with a 33% reduction with icatibant. This benefit was totally eliminated during infusion with both icatibant and with a quinapril/icatibant combination. The bar graphs represent the percent change in radial artery diameter during reactive hyperemia after 8 minutes of wrist occlusion.
Hornig et al concluded that ACE inhibition increases flow-dependent dilation by a mechanism that involves the accumulation of endogenous bradykinin.

13. Effect of ACE inhibition on FDD in patients with CHF
Content Points:
Hornig and coworkers compared the effects of enalaprilat and quinaprilat on endothelium-mediated vasodilation in 40 patients with NYHA class III heart failure.12 Patients were given arterial infusions of either quinaprilat (1.6 mg/min, n = 15), enalaprilat (5 mg/min, n = 15), or placebo (n =10).
Endothelium-mediated flow-dependent dilation (FDD) of the radial artery was evaluated at rest and following reactive hyperemia, both before and after administration of N-monomethyl-L-arginine (L-NMMA), which inhibits NO synthesis.
It was found that radial artery diameter and blood flow at rest and after inhibition of NO was improved by quinapril but not enalapril. Quinaprilat acutely improved FDD of peripheral conduit arteries by > 40% (P < 0.01) whereas enalaprilat had no effect.
Since the 2 ACE inhibitor doses were equivalent for inhibiting conversion of angiotensin I to angiotensin II, the authors attributed the observed difference to the fact that quinapril has a higher affinity for tissue ACE than enalapril. They suggested that high tissue ACE affinity may be necessary to improve FDD with short-term ACE inhibition.
The differences between ACE inhibitors in tissue-binding will be presented on the next slide.

14. Relative potency of ACE inhibitors in plasma and tissue (RIB studies)
Content Points:
ACE inhibitors exhibit a wide range of ACE-binding capabilities in tissue and plasma. The differences have been measured in radioligand inhibition-binding (RIB) studies.
Second-generation ACE inhibitors demonstrate considerably more tissue and plasma activity than first-generation agents Quinaprilat, the active metabolite of quinapril, demonstrates the highest ACE-binding capability in both tissue and plasma.
Since 90% of ACE is present in tissue, including the vessel walls, the heart, brain, and lungs, differences in tissue ACE-binding affinity among ACE inhibitors may translate into differences in clinical responses. This was seen in the work by Horning and Drexler, as well as in the TREND and BANFF studies.

15. Effect of ACE inhibition on morbidity and mortality in heart failure patients —an analysis of 32 trials
Content Points:
The benefits of ACE inhibition in patients with heart failure have been demonstrated in a number of large clinical trials including CONSENSUS,16 SOLVD,17 SAVE,18 among others conducted over more than a decade.
A meta-analysis of 32 trials of ACE inhibition in patients with symptomatic heart failure (NYHA functional class II or III) demonstrated a significant 23% reduction in total mortality and a 35% reduction in mortality and hospitalizations for heart failure.19
There were also trends toward fewer myocardial infarctions, strokes, and pulmonary emboli. Patients with the lowest ejection fractions had the greatest reduction in deaths and hospitalizations for heart failure.
The trials involved several different ACE inhibitors and the results showed that they each produced similar benefits. Effects were consistent across various subgroups based on age, gender, heart failure etiology, and NYHA functional class.
ACE inhibition reduces total mortality, heart failure mortality, hospitalization rates, progression of left ventricular dysfunction, and symptom severity and also increases exercise tolerance.20 The use of ACE inhibition is of benefit to patients with symptomatic heart failure16 and asymptomatic left ventricular dysfunction17 or at risk for developing heart failure following myocardial infarction.18

16. ACE inhibition reduces hospitalizations for heart failure: Effect of dosing
Content Points:
Studies have demonstrated that ACE inhibition lowers the rate of hospitalization in patients with heart failure. However, several studies have shown that ACE inhibitors remain under-used in patients with heart failure.21-25
Luzier and coworkers conducted a retrospective analysis of 314 patients readmitted for heart failure over a 36-month period.25 Most patients received combination therapy. Digoxin was used in 72%, diuretic in 86%, and 67% received an ACE inhibitor.
An ACE inhibitor was the principal determinant of hospitalization (P < .05) with a clear dose-response relation. Doses of 5 mg of enalapril or less (or an equivalent ACE inhibitor), which comprise the majority of prescriptions written in the United States, failed to reduce hospitalization rates.
Doses of > 10 mg enalapril (or an equivalent) reduced 90-day readmission rates by 28% compared with digoxin or diuretic (P < .05):     - 10 mg doses reduced the RR to 0.55 (95% CI 0.24 to 0.86)     - 20 mg doses reduced the RR to 0.44 (95% CI 0.6 to 0.72).
Only 22% of patients received the recommended ACE inhibitor dose of 20-mg enalapril daily or an equivalent ACE inhibitor.

17. ACE inhibitors and angiotensin II receptor blockers compared for heart failure treatment: RESOLVD
Content Points:
The Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial compared the efficacy of ACE inhibition enalapril and the angiotensin II receptor blocker (ARB) candesartan in patients with heart failure.26
The study included 769 patients with NYHA class II (64%) or class III (31%) heart failure, ejection fractions of < 40%, and a 6-minute walk distance of 500 meters or less. They were randomly assigned to one of the therapies.
After 46 weeks of treatment, patients treated with enalapril had a greater improvement in left ventricular ejection fraction and left ventricular systolic volume and fewer deaths (P = .14) and hospitalizations (P = .136).
The results of ELITE 2, which are discussed on the next slide, are further clarifying the relative superiority of ACE inhibitors as compared with ARBs in heart failure.

18. Angiotensin II blockade vs ACE inhibition: Comparable outcomes in heart failure (ELITE-2)
Content Points:
Results of ELITE-2 (Evaluation of Losartan In The Elderly) comparing losartan with captopril show that the angiotensin receptor blocker (ARB) confers no survival advantage over the ACE inhibitor.27
The double-blind randomized parallel study enrolled 3152 patients mean age 71.4 years with NYHA class II-IV heart failure. They were randomized to losartan 50 mg qd (n = 1578) or captopril 50 mg tid (n = 1574).
The trial, started in June 1997, was statistically powered to detect a 25% treatment difference in all-cause mortality. The endpoint was 510 deaths.
The results showed no significant difference in mortality (P = .16). The secondary endpoint of sudden death/resuscitated cardiac arrest trended strongly in favor of captopril (P = .08). Significantly more patients in the captopril group discontinued treatment because of adverse events (14.5% vs 9.4%, P = .001).
The ELITE-2 results differed markedly from the ELITE heart failure study which indicated a survival benefit with losartan, primarily due to a reduction in sudden deaths.28 The difference was attributed to the fact that ELITE was a much smaller (n = 722) study and of shorter duration (48 weeks).
ELITE-2 led to the conclusion that ACE inhibitors should remain the preferred treatment for heart failure, owing to the large body of data documenting their significant benefit on morbidity and mortality. For patients who cannot tolerate this class of drugs, ARBs can be considered an alternative.

19. Evolving cardiovascular goals in hypertension therapy
Content Points:
LVH is now recognized as a powerful, pressure-independent, risk factor for cardiovascular morbidity.2 Therefore antihypertensive therapy includes multiple cardiovascular goals: 28      - To lower BP by reducing TPR      - To enhance the regression of LVH      - To restore elasticity of the stiff left ventricle      - To reduce ventricular ectopy that is associated with LVH      - To maintain or improve          - coronary perfusion          - left ventricular contractility.

20. Summary
Content Points:
Hypertension is the most common risk factor for heart failure. Hypertension leads to LVH, which is an independent risk factor for heart failure.
Aggressive treatment, even in the early stages of hypertension, is essential to prevent the progression of hypertension to LVH and heart failure.
Emerging data on the role of the vascular endothelium in hypertension and heart failure suggest that choosing an antihypertensive therapy aimed at not only lowering blood pressure but also at correcting the underlying pathophysiologic process may optimize treatment outcomes.
ACE inhibitors have been shown to regress LVH and improve endothelial function. According to new JNC-VI guidelines they are the preferred first-line agents in the treatment of heart failure.