Neurohormones and Oxidative Stress in Nonischemic Cardiomyopathy
Neurohormones and Oxidative Stress in Nonischemic Cardiomyopathy
Objectives: The purpose of this study was to assess the effects of amlodipine on neurohormones and oxidative stress in nonischemic cardiomyopathy, and determine the relationship between baseline and posttreatment levels of these markers with survival.
Background: Neurohormones and oxidative stress are important in the pathophysiology of heart failure. Calcium-channel blockers are associated with poor outcomes in patients with heart failure, in part due to neurohormonal activation. In contrast, amlodipine, a second-generation dihydropyridine, has a more favorable clinical profile.
Methods: In the Prospective Randomized Amlodipine Survival Evaluation 2 (PRAISE-2) trial, a subset of 181 patients with nonischemic cardiomyopathy were randomized to amlodipine (10 mg/day) or placebo. Blood samples were evaluated at baseline, 2 weeks and 26 weeks for norepinephrine, epinephrine, angiotensin II, dopamine, N-terminal pro-atrial natriuretic peptide (Nt-pro-ANP), brain natriuretic peptide (BNP), adrenolutin and malondialdehyde.
Results: There was no difference in levels of neurohormones or oxidative stress markers between the amlodipine and placebo groups at the different times. Both Nt-pro-ANP and BNP decreased at 2 weeks and at 26 weeks. Baseline Nt-pro-ANP correlated with survival in multivariate analysis (P = .001). A strong relationship was found between a reduction in BNP at 26 weeks and survival, with a hazard ratio of 0.153 (95% CI 0.051-0.461, P = .017). No relationship was found between markers of oxidative stress and survival.
Conclusions: We conclude that amlodipine does not affect circulating neurohormones and oxidative stress markers in patients with nonischemic cardiomyopathy treated with angiotensin-converting enzyme inhibitors, digoxin and diuretics. In addition, low circulating Nt-pro-ANP and a reduction in BNP over time confers a good prognosis.
Chronic heart failure is characterized by the activation of the sympathetic nervous system and the renin-angiotensin system, and the release of neurohormones such as atrial-natriuretic peptide, brain natriuretic peptide (BNP) and endothelin. Elevations of these neurohormones have been correlated with poor outcome in heart failure. Moreover, there is extensive data from animal studies suggesting that oxidative stress is involved in the progression of heart failure. In support of this, elevations of markers of oxidative stress, such as malondialdehyde, have been documented in humans with congestive heart failure (CHF), and increased levels of the oxidized product of adrenalin, adrenolutin, has been correlated with a poor outcome.
Calcium-channel blockers such as nifedipine, nisoldipine, verapamil, and diltiazem cause clinical deterioration and increased mortality with long-term use in patients with chronic heart failure. The detrimental effects of these drugs have been at least partially attributed to neurohormonal activation. Some of this neurohumoral activation probably results from hypotension-mediated baroreceptor activation, but it also results from specific actions of calcium-channel blockers, such as interference with calcium-mediated inhibition of renin-release, thereby directly increasing renin activity.
The Prospective Randomized Amlodipine Survival Evaluation study (PRAISE) demonstrated that amlodipine, a second-generation dihydropyridine calcium-channel blocker, did not cause a similar deterioration in chronic heart failure, and the PRAISE-2 study confirmed these findings (unpublished results). The second-generation dihydropyridine calcium-channel blockers are hypothesized to have less neurohormonal activation compared with older calcium-channel blockers, which possibly explains their more favorable profile in heart failure.
Amlodipine has been shown to have potent antioxidant properties in multiple in-vitro studies, and it has been postulated that this may be one of the mechanisms by which it exerts its beneficial effects. In heart failure, the antioxidant effect of amlodipine may be the reason amlodipine appears to set itself apart from most other calcium-entry blockers by being safe. However, at this time, little long-term information is available on the interaction between amlodipine, neurohormones and oxidative stress and survival, and none exists in nonischemic cardiomyopathy.
Thus, the purpose of this study was to assess the effects of short (2 weeks) and long-term (26 weeks) therapy with amlodipine on neurohormonal activation and markers of oxidative stress, and to determine the correlation of these with survival. Our hypotheses were that this second-generation dihydropyridine calcium-entry blocker would cause less neurohumoral activation and would reduce oxidative stress. We also hypothesized that patients with a reduction in neurohumoral activation would have better survival.
Objectives: The purpose of this study was to assess the effects of amlodipine on neurohormones and oxidative stress in nonischemic cardiomyopathy, and determine the relationship between baseline and posttreatment levels of these markers with survival.
Background: Neurohormones and oxidative stress are important in the pathophysiology of heart failure. Calcium-channel blockers are associated with poor outcomes in patients with heart failure, in part due to neurohormonal activation. In contrast, amlodipine, a second-generation dihydropyridine, has a more favorable clinical profile.
Methods: In the Prospective Randomized Amlodipine Survival Evaluation 2 (PRAISE-2) trial, a subset of 181 patients with nonischemic cardiomyopathy were randomized to amlodipine (10 mg/day) or placebo. Blood samples were evaluated at baseline, 2 weeks and 26 weeks for norepinephrine, epinephrine, angiotensin II, dopamine, N-terminal pro-atrial natriuretic peptide (Nt-pro-ANP), brain natriuretic peptide (BNP), adrenolutin and malondialdehyde.
Results: There was no difference in levels of neurohormones or oxidative stress markers between the amlodipine and placebo groups at the different times. Both Nt-pro-ANP and BNP decreased at 2 weeks and at 26 weeks. Baseline Nt-pro-ANP correlated with survival in multivariate analysis (P = .001). A strong relationship was found between a reduction in BNP at 26 weeks and survival, with a hazard ratio of 0.153 (95% CI 0.051-0.461, P = .017). No relationship was found between markers of oxidative stress and survival.
Conclusions: We conclude that amlodipine does not affect circulating neurohormones and oxidative stress markers in patients with nonischemic cardiomyopathy treated with angiotensin-converting enzyme inhibitors, digoxin and diuretics. In addition, low circulating Nt-pro-ANP and a reduction in BNP over time confers a good prognosis.
Chronic heart failure is characterized by the activation of the sympathetic nervous system and the renin-angiotensin system, and the release of neurohormones such as atrial-natriuretic peptide, brain natriuretic peptide (BNP) and endothelin. Elevations of these neurohormones have been correlated with poor outcome in heart failure. Moreover, there is extensive data from animal studies suggesting that oxidative stress is involved in the progression of heart failure. In support of this, elevations of markers of oxidative stress, such as malondialdehyde, have been documented in humans with congestive heart failure (CHF), and increased levels of the oxidized product of adrenalin, adrenolutin, has been correlated with a poor outcome.
Calcium-channel blockers such as nifedipine, nisoldipine, verapamil, and diltiazem cause clinical deterioration and increased mortality with long-term use in patients with chronic heart failure. The detrimental effects of these drugs have been at least partially attributed to neurohormonal activation. Some of this neurohumoral activation probably results from hypotension-mediated baroreceptor activation, but it also results from specific actions of calcium-channel blockers, such as interference with calcium-mediated inhibition of renin-release, thereby directly increasing renin activity.
The Prospective Randomized Amlodipine Survival Evaluation study (PRAISE) demonstrated that amlodipine, a second-generation dihydropyridine calcium-channel blocker, did not cause a similar deterioration in chronic heart failure, and the PRAISE-2 study confirmed these findings (unpublished results). The second-generation dihydropyridine calcium-channel blockers are hypothesized to have less neurohormonal activation compared with older calcium-channel blockers, which possibly explains their more favorable profile in heart failure.
Amlodipine has been shown to have potent antioxidant properties in multiple in-vitro studies, and it has been postulated that this may be one of the mechanisms by which it exerts its beneficial effects. In heart failure, the antioxidant effect of amlodipine may be the reason amlodipine appears to set itself apart from most other calcium-entry blockers by being safe. However, at this time, little long-term information is available on the interaction between amlodipine, neurohormones and oxidative stress and survival, and none exists in nonischemic cardiomyopathy.
Thus, the purpose of this study was to assess the effects of short (2 weeks) and long-term (26 weeks) therapy with amlodipine on neurohormonal activation and markers of oxidative stress, and to determine the correlation of these with survival. Our hypotheses were that this second-generation dihydropyridine calcium-entry blocker would cause less neurohumoral activation and would reduce oxidative stress. We also hypothesized that patients with a reduction in neurohumoral activation would have better survival.
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