A number of endogenous systems exist to counter the effects of vasoconstricting neurohormones that are increased in congestive heart failure (CHF). These include natriuretic peptides, nitric oxide, and prostaglandins. A major pathway for the clearance of these endogenous vasodilator substances is through the enzyme neutral endopeptidase. The development of vasopeptidase inhibitors (VPIs), which inhibit both neutral endopeptidase and angiotensin-converting enzyme (ACE), may allow for enhanced natriuretic peptide and bradykinin effects. However, bradykinin in supraphysiologic doses is a potent stimulant for inﬂammation. Alternatively, by stimulating nitric oxide in more physiologic doses, bradykinin may prove to be anti-inﬂammatory. In addition, neutral endopeptidase is involved in the degradation of endothelin-1, a vasoconstrictor neurohormone that is elevated in patients with heart failure and has been associated with a poor outcome. Overall, if an improvement in the balance between endogenous vasoconstrictor and vasodilator substances can be achieved, VPIs may prove to be superior to ACE inhibitors alone in treating patients with CHF. We randomized patients with stable chronic CHF, a left ventricular ejection fraction＜40%, and who were currently receiving an ACE inhibitor to either the VPI, omapatrilat, or the ACE inhibitor, lisinopril. Baseline, 12-, and 24-week circulating neurohormone and cytokine levels were measured and the effects of the 2 treatments on neurohormones and cytokines were compared.
This investigation is a substudy of the Inhibition of Metalloproteinase in a Randomized Exercise and Symptoms Study in Heart Failure (IMPRESS) trial, which was a prospective, double-blind trial of 573 patients with heart failure randomized to either the ACE inhibitor, lisinopril 20 mg/day or the VPI, omapatrilat 40 mg/day. The methods of the study have been previously reported. The trial enrolled patients＞18 years of age with New York Heart Association functional class II to IV and left ventricular ejection fraction ≤40%. Background therapy with an ACE inhibitor for ≥4 weeks before entry was required; these medications were discontinued upon study randomization (no washout period). Patients were as- sessed at baseline, and at 12 and 24 weeks of follow-up. The primary outcome in the study was change in exercise tolerance at 12 weeks. The secondary outcome was the combined end point of mortality, emergency room visit, hospitalization, discontinuation of study medication for worsening heart failure, or addition of supplemental diuretic. The IMPRESS study and the neurohormone substudy were approved by the institutional review boards of each of the participating centers.
Baseline characteristics: The mean left ventricular ejection fraction was 29% and most of the patients had New York Heart Association class II symptoms. Eighty percent of the patients had ischemic cardiomyopathy and 20% had dilated cardiomyopathy. All patients were on background therapy with an ACE inhibitor. The most striking differences between heart failure patients and normal controls were seen in the levels of BNP, N-ANP, and C-ANP. Patients with heart failure also had an increase in markers of adrenergic tone, including norepinephrine, epinephrine, and dopamine. Similar levels of neurohormonal activation were seen in patients randomized to omapatrilat and lisinopril, with no signiﬁcant differences between groups.
Baseline neurohormone and cytokine proﬁles and clinical outcomes: The relation of baseline neurohormone and cytokine status and clinical variables to clinical outcomes (mortality, emergency room visit, hospitalization, discontinuation of study medication for worsening heart failure, or addition of supplemental diuretic) demonstrated that the most important predictor of clinical outcomes was C-ANP level above the median. BNP and N-ANP above the median also tended to be associated with a moderately increased relative risk of adverse outcome. Cytokines or other neurohormones were not correlated with adverse outcome. Among clinical variables, increased age was associated with a worse outcome. New York Heart Association class showed a trend toward worse outcome, although this was not statistically signiﬁcant.
Tej Sheth, The American Journal of Cardiology Vol. 90 September 1, 2002