Relative risks for heart failure: Framingham Study Content Points: This slide summarizes the multivariate adjusted risks of heart failure in the Framingham Heart Study (N = 5143). Hypertension, MI, angina pectoris, diabetes, LVH, and valvular heart disease were identified as independent risk factors for heart failure.63 Hypertension increased the risk for heart failure by two-fold in men and by more than three-fold in women. It was the most common risk factor for heart failure, and found in 91% of cases. LVH increased the risk for heart failure independently from hypertension, by nearly two-fold in men and by nearly three-fold in women. LVH was about equal to diabetes or valvular heart disease as a risk for heart failure.64

Progression of hypertension to LVH and heart failure Content Points: The two principal factors contributing to heart failure are hypertension and coronary artery disease, but 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.65 LVH and associated left ventricular dysfunction are among the most common cardiac sequelae of hypertension. LVH leads to heart failure through various mechanisms. Initially, mild LVH allows the heart to compensate for increases in vascular resistance. Ultimately, 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 begins the downward spiral of ventricular dilatation and symptomatic disease. 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.

Effect of ACE inhibition on mortality and morbidity 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, SOLVD, SAVE, and others conducted over more than a decade.66-68 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 or hospitalization for heart failure.69 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 increases exercise tolerance. The use of ACE inhibition benefits patients with symptomatic heart failure,66 asymptomatic left ventricular dysfunction,67 or those who are at risk for developing heart failure following myocardial infarction.68

LVH regression: Changes in left ventricular mass index with 4 drug classes Content Points: This study was a meta-analysis of 50 double-blind, randomized, controlled clinical trials that evaluated reduction of left ventricular mass by antihypertensive therapy with placebo, diuretics, b-blockers, calcium channel blockers, or ACE inhibitors.70 Left ventricular mass index was decreased by 12% with ACE inhibitors (95% confidence interval (CI): 9.0%-14.5%), by 11% with calcium channel blockers (95% CI: 7.8%-13.7%), by 5% with b-blockers (95% CI: 1.2%-7.3%) and by 8% with diuretics (95% CI: 3.9%-11.1%) (overall P < .01). ACE inhibitors and calcium channel blockers were more effective than b-blockers in reducing left ventricular mass index, with diuretics in the intermediate range. Similar differences between drug classes were found with regard to effect on left ventricular wall thickness (P < .05).

LVH is normalized in most patients with long-term quinapril treatment Content Points: Reversal of LVH and of other cardiac adaptations to increased afterload is 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.71 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 HCTZ. None of the patients had previously received treatment for hypertension. 90.5% of the patients who underwent long-term treatment with quinapril had a complete regression of LVH, as shown in this graph. Their left ventricular mass index was restored to normal values (<125 g/m2 for men and <110 g/m2 for women). 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.

Effect of ACE inhibition on FMD in patients with heart failure 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.72 Patients were given arterial infusions of either quinaprilat (1.6 mg/min, N = 15), enalaprilat (5 mg/min, N = 15), or placebo (N =10). Flow-dependent endothelium-mediated 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. 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 < .01) whereas enalaprilat had no effect. Since the two ACE inhibitors doses were equivalent for inhibiting conversion of Ang I to Ang 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 effect of increasing enalaprilat doses will be shown on the next slide.

Increasing dosages of enalaprilat did not affect FMD Content Points: The effect of increasing enalaprilat doses on FMD was evaluated in 5 patients from the study discussed in the previous slide.72 Even at infused doses of 30 g/min, enalaprilat did not significantly increase FMD relative to saline (control) infusion. On the basis of the study findings, Hornig and coworkers concluded that ACE inhibitors work by differing mechanisms. ACE inhibitors with high tissue affinity appear to have stronger effects on endothelial-mediated vasodilation.

Effect of quinapril on b-receptor function in heart failure Content Points: Townend and colleagues conducted a study evaluating the effects of ACE inhibition with quinapril on b-receptor function in 12 patients with severe heart failure (NYHA class II or IV).73 At the outset, b-receptor function was significantly lower in patients with heart failure than in controls, indicating substantial b-cell downregulation. Therapy was started with a dose of quinapril 2.5 mg twice daily. Following 16 weeks of treatment, lymphocyte b-adrenoceptor function as measured by cAMP production in response to isoprenaline, was restored to almost normal levels. Changes in b-receptor density will be discussed on the next slide.

Effect of quinapril on b -receptor density Content Points: Another way of assessing b-receptor function is to determine b-receptor density. Down-regulation of receptors is evident by a decrease in the number of receptors per cell. Whole blood samples from healthy controls had about 1000 b-receptors per lymphocyte. Samples from patients with severe heart failure had only about 25% of that number. Townend and colleagues demonstrated that after 16 weeks of quinapril therapy, b-receptor density in patients with heart failure increased significantly, from approximately 240 receptors per cell to just under 900 receptors per cell (P < .05).73 To confirm the linkage beween these changes and clinical effects, Townend and Davis showed that improved b-cell density was accompanied by improved hemodynamic responses. Following 16-weeks of quinapril, the same 12 patients had significant improvements in cardiac index, stroke volume, and cardiac output during sub-maximal exercise testing and dobutamine infusion. They concluded that ACE inhibitors cause lymphocyte b-receptor upregulation in heart failure. This is associated with an improved cardiac pumping capacity in response to b-agonist stimulation. They also concluded that b-receptor upregulation may be an important mechanism for the therapeutic effects of ACE inhibition in patients with chronic heart failure.

ATLAS: High- vs low-dose ACE inhibition in heart failure—study design Content Points: The Assessment of Treatment with Lisinopril and Survival (ATLAS) trial was designed to compare the effectiveness of high- versus low-dose ACE inhibition in patients with depressed LV ejection fractions.74 The trial was double-blind and randomized, with 3164 patients enrolled. All patients had Class II to Class IV heart failure with LV ejection fractions of 30% or less. After a two-week open label treatment period, patients were randomized to lisinopril in a low dose (2.5-5.0 mg/day) (N = 1596) or a high dose (32.5-35 mg/day) (N = 1568). The median follow-up period was 46 months.

ATLAS: High-dose ACE-I reduces adverse outcomes in heart failure Content Points: In the group receiving high-dose ACE inhibitor therapy, there was a significant decline of 10% in cardiovascular mortality (P = .07).74 The group receiving high-dose ACE inhibition also had a significant 12% decrease in death or hospitalization for any reason (P = .002). High dose therapy was also associated with a significant 16% decline in cardiovascular hospitalizations (P = .05) and a 24% decline in hospitalizations for heart failure (P = .002). There was an 8% difference between the groups in death from all causes, but this did not reach statistical significance. The results support the use of high-dose ACE inhibitor therapy in patients with heart failure. The study also demonstrated that this type of therapy is safe and well-tolerated.

ACE inhibitors in CHF: Are maximally recommended doses sufficient? Content Points: This study by Jorde and colleagues measured the level of ACE inhibition in patients with CHF who were receiving maximally recommended doses of ACE inhibitors to find out whether these doses completely prevent ACE-mediated formation of Ang II.75 The response to increasing doses of Ang I was measured in 42 patients with congestive heart failure who had been treated with either 40 mg/day of a long-acting ACE inhibitor or 150 mg of captopril for periods ranging from 3 months to 120 months. As shown in the slide, the increase in radial artery systolic pressure in response to increasing doses of Ang I was significantly blunted in 11 patients who were given twice the maximally recommended dose of ACE inhibitor for 1 week. Doubling the dose of ACE inhibitor completely blocked the response to Ang I, as did the administration of the ARB valsartan. These observations support the conclusion that the maximally recommended doses of ACE inhibitors do not completely inhibit ACE in patients with chronic heart failure and that this is due to inadequate medication. Greater ACE inhibition is achieved at twice the recommended dose of ACE inhibitors.