Nitrates and Left Ventricular Dysfunction
Abstract: Use of beta-blockers and inhibitors of the renin angiotensin system (RAS) is established practice in the treatment of chronic heart failure (CHF). Clinical studies also suggest beneficial long-term effects of nitrates in CHF. In the Veterans Administration Heart Failure Trial (V-HeFT) I, the combined use of a nitrate and hydralazine reduced the mortality rate. However, it is not possible to determine the relative importance of nitrate therapy in that study. The main objective of this thesis was to study the long-term effects of nitrate therapy in patients with evidence of left ventricular (LV) dysfunction after acute myocardial infarction (AMI) already treated with standard heart failure (HF) therapy. Paper I. In a randomized, double-blind, placebo controlled trial, we evaluated the effects of a 60 mg dose of isosorbide-5-mononitrate (IS-5-MN) given daily to 47 patients with clinical or echocardiographic evidence of LV dysfunction after AMI. Forty-five patients received a placebo. No significant haemodynamic effects of IS-5-MN therapy were observed. We found that nitrate therapy resulted in lower plasma atrial natriuretic peptide (P ANP) levels and reduced the need for additional diuretics. Less LV dilatation was observed in patients with more severe LV dysfunction at baseline, indicating clinically beneficial effects, especially in patients with more reduced LV function after AMI. Paper II. The main finding of this study was that lipid peroxidation measured by plasma malondialdehyde (MDA) and 8-isoprostane were not increased in patients with LV dysfunction treated with standard HF therapy. No positive correlations to the markers of severity of HF were found. Long-term IS-5-MN therapy did not influence P-MDA concentrations. Results from many studies suggest that oxidative stress is increased in HF, but this may not be true for patients treated with beta-blockers and inhibitors of the RAS. Paper III. Chronic nitrate therapy did not significantly affect the neurohumoral status in patients with LV dysfunction after AMI, apart from a decrease in P-ANP. Some hormones were seen to be more closely associated with diastolic dysfunction/increased volume load, viz ANP and brain natriuretic peptide (BNP), while others were found to be more closely associated with systolic dysfunction, namely plasma renin activity (PRA), norepinephrine (NEPI) and aldosterone (Aldo). A temporal dissociation between these two groups of hormones occurred 1 year after the infarction: ANP and BNP decreased, while NEPI and Aldo showed slight increases. Paper IV. Isosorbide-5-mononitrate treatment and diastolic function were evaluated in patients with LV dysfunction after AMI. Chronic nitrate therapy did not significantly affect diastolic function evaluated by echocardiography. Changes in diastolic parameters during 1 year after AMI indicated improved diastolic function and/or reduced pre-load. Fewer factors indicating worse prognosis were demonstrated in patients with normal or slightly reduced LV ejection fraction (LVEF) 1 month after AMI, compared with patients with moderately or severely depressed LVEF.
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