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Original Article

Neurohumoral Changes in Patients With Left Ventricular Dysfunction Following Acute Myocardial Infarction and the Effect of Nitrate Therapy: A Randomized, Double-Blind, Placebo-Controlled Long-Term Study

Tingberg, Erik MD; Roijer, Anders MD, PhD; Thilen, Ulf MD; Öhlin, Hans MD, PhD

Author Information
Journal of Cardiovascular Pharmacology: October 2006 - Volume 48 - Issue 4 - p 166-172
doi: 10.1097/01.fjc.0000246149.92535.59
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Abstract

INTRODUCTION

The predominant use of organic nitrates has been in the treatment of angina pectoris. But clinical studies also suggest beneficial long-term effects in patients with congestive heart failure (CHF). In the Veterans Administration Heart Failure Trial I (V-HeFT),1 the combination of nitrate and hydralazine added to standard therapy reduced the mortality rate.

In the African-American Heart Failure Trial (A-HeFT),2 African American patients in New York Heart Association (NYHA) class III or IV heart failure with dilated ventricles were randomized to receive a fixed dose of isosorbide dinitrate plus hydralazine or placebo in addition to standard therapy for heart failure that included neurohumoral-inhibitor drugs. The study demonstrated a significantly higher mortality and hospitalization rate in the placebo group than in the group given isosorbide dinitrate plus hydralazine.

The sole effect of nitrates can not be judged by the results of these studies. We have previously reported that long-term treatment with nitrates does not affect hemodynamics in patients with left ventricular (LV) dysfunction after acute myocardial infarction (AMI).3 Nitrate tolerance resulting from neurohumoral activation is one hypothetical explanation to these results.

In the present analysis, a substudy of a previously published investigation,3 we aimed to study whether long-term treatment with a moderate dose of the sustained-release formula of isosorbide-5-mononitrate (IS-5-MN) influences the neurohumoral response in patients with LV dysfunction following AMI, already treated with standard CHF therapy including angiotensin-converting enzyme (ACE) inhibitors and mostly β-blockers and diuretics. We also intended to study long-term changes in neurohormones and their relationship with the NYHA class categories and ventricular function assessed using echocardiography and right-heart catheterization.

MATERIAL AND METHODS

In brief, the present study formed part of a single-center, randomized, double-blind, placebo-controlled long-term investigation of IS-5-MN therapy in patients with LV dysfunction following AMI. The local ethics committee approved the study design, and patients gave their consent to participate. Inclusion and exclusion criteria of the study, hemodynamic measurements, titration, and dosage of IS-5-MN have been previously published.3

The primary objective of the larger study was to investigate whether long-term treatment with a moderate dose of IS-5-MN reduces pulmonary artery wedge pressure (PAWP).

Patients included in the study were aged 18 to 80 years, hospitalized for an AMI, and with evidence of LV dysfunction during hospitalization, the latter defined by at least 1 of the following features: clinical criteria (bilateral posttussive crackles extending at least one third of the way up the lungs in the absence of chronic pulmonary disease); radiographic criteria of pulmonary congestion; and/or left ventricular ejection fraction (LVEF) ≤ 40% assessed by echocardiography during hospitalization for the initial AMI.

In patients who met the inclusion criteria, treatment with an ACE inhibitor (ramipril) was initiated in the hospital between day 2 and the day of discharge. The dose was adjusted if necessary after discharge from the hospital. If patients had previously been treated with an ACE inhibitor other than ramipril, that treatment was discontinued and replaced with ramipril.

Concomitant diuretics, beta blockers, digoxin, and aspirin were accepted.

Five weeks after the initial AMI, the patients were randomized to 1 of 2 arms of the study. At baseline, a complete medical history was taken and a physical examination was performed.

Blood samples were collected for biochemical analyses and hemodynamic evaluation was performed using echocardiography and right-side heart catheterization. An electrocardiogram was recorded and a chest radiogram was performed.

The patients were randomly assigned to receive either oral IS-5-MN or a placebo. The initial dose of IS-5-MN was 30 mg daily for 7 days, titrated to 60 mg daily.

One year after the initial AMI, patients were reassessed using the same measurements at randomization/baseline.

Data concerning the peptides atrial natriuretic peptide (P-ANP) and brain natriuretic peptide (P-BNP) in relation to the severity of CHF and IS-5-MN therapy have been published before3,4 but it is presented together with other, new measurements for overall clarity.

LABORATORY EVALUATION

Blood samples were collected after 60 minutes of rest in a supine position, by venipuncture into evacuated tubes containing EDTA (ethylenediamine tetraacetic acid). Routine blood tests were analyzed at the local hospital laboratory. For determination of plasma epinephrine (EPI) and norepinephrine (NEPI), antidiuretic hormone (ADH-LI), aldosterone (Aldo), renin activity (PRA), substance P (SP-LI), neuropeptide Y-like immunoreactivity (NPY-LI), calcitonin gene-related peptide (CGRP-LI), and vasoactive intestinal peptide (VIP-LI), BNP and ANP were separated from plasma after centrifugation at +4°C and stored at −70 °C until analyzed (within 1 month).

Plasma levels of SP-LI, NPY-LI, CGRP-LI,and VIP-LI were measured by high-performance liquid chromatography (HPLC) with a method and procedure described by Kraiczi et al,5 and ADH-LI was determined by radioimmunoassay.6 Plasma EPI and NEPI were both determined by radioenzymatic assay.7 Plasma PRA was assessed by radioimmunoassay measurement of angiotensin I generation.8 P-Aldo was measured using competitive radioimmunoassay (Aldosterone II RIA Diagnostic Kit, ABBOTT Laboratories, Diagnostics Division, Abbott Park, IL,USA). P-ANP9 and P-BNP10 were assayed with a direct and specific monoclonal antibody radioimmunoassay kit.

STATISTICAL ANALYSIS

As a result of the skewness of most of the variables included in this study, the sample median or the geometric mean was chosen as measures of location and interquartile range (IQR) was chosen as a measure of spread. Spearman's rank correlation coefficient was used as a measure of correlation between variables. In Table 4, the Wilcoxon matched pairs signed rank sum test was used to evaluate if the distribution of intra individual differences between 2 measurement times had changed from 0. The same method could have been used to calculate the P-values for 12 months vs. randomization in Table 1, but the standard paired t-test using log-transformed variables was chosen instead because it directly tests for shift differences between 2 groups using the linear model. The P-values presented have not been adjusted for multiple testing, but a note on conservative Bonferroni adjustment is presented in the legend to Table 2. The statistical calculations were carried out using Stata 9.1 (StataCorp LP, College Station, TX, USA). All tests were 2-sided, and P-values of less than 0.05 were considered to be significant.

TABLE 1
TABLE 1:
Patient characteristics at randomisation.
TABLE 2
TABLE 2:
Neurohumoral changes during study (Randomisation/baseline - 12 Month visit) and the effect of treatment.

RESULTS

Patients

Ninety-two nonconsecutive patients fulfilled the inclusion criteria, 47 of whom were assigned to IS-5-MN. Forty-five received the placebo. Table 1 describes patient characteristics at randomization.

Concomitant Medication

Details concerning medication have been described previously.3 In summary, there was an increase in ramipril dose in both treatment groups (IS-5-MN/Placebo) during the study.

The proportion of patients taking diuretics was significantly reduced with IS-5-MN therapy (from 68% to 45%) but not with the placebo (63% at both occasions).

The number of patients taking beta blockers and digoxin was not different between the 2 groups, and the doses of digoxin and metoprolol did not change significantly during the study.

IS-5-MN Treatment and Hormonal Responses

Only P-ANP was statistically significantly reduced in the nitrate group compared with the placebo group (Table 2).

Neurohumoral Activation in Relation to the Severity of Congestive Heart Failure

Table 3 shows the correlations at randomization between neurohormones and different markers for the severity of LV dysfunction.

TABLE 3
TABLE 3:
Relationship at randomisation/baseline between different markers of the severity of heart failure and plasma neurohumoral factors.

Changes in Neurohumoral Activation From Baseline to End of Treatment After Acute Myocardial Infarction in the Total Study Population

We found small but significant increases in EPI, NEPI, Aldo, and VIP-LI and decreases in ADH-LI, NPY-LI, BNP, and ANP. Data are presented in Table 4A. In Table 4B the percentage of measurements, at randomization, above and below the local laboratory reference ranges are shown.

TABLE 4A
TABLE 4A:
Plasma neurohumoral measurements in total study population at randomisation/baseline and at 12 month visit.
TABLE 4B
TABLE 4B:
Plasma neurohumoral measurements at randomisation/baseline.

Changes in New York Heart Association, Hemodynamic, and Echocardiographic Measurements in the Total Study Population

Echocardiographic and invasive hemodynamic measurements were unchanged during the study period, whereas 46 patients (53%) fell into a less severe NYHA class, 33 patients (38%) remained stable, and 8 patients changed into a more severe NYHA class, P < 0.0001 (Table 5).

TABLE 5
TABLE 5:
Haemodynamic measurements, echocardiographic measurements and NYHA at randomisation/baseline and at the 12 month visit in the total study-population.

DISCUSSION

Nitrates and Hormonal Responses

The primary objective of the present study was to evaluate the neurohumoral responses to orally administrated IS-5-MN in patients with LV dysfunction following AMI.

We have previously reported the results concerning P-BNP and P-ANP.3 We observed a significant decrease in P-ANP in the nitrate group compared with the placebo group, whereas P-BNP was reduced similarly in both groups. However, P-BNP was only analyzed in a small subgroup of patients, which may have influenced the result. We now report a more comprehensive analysis of neurohumoral activation and we did not observe any effect of IS-5-MN on plasma levels of EPI, NEPI, Aldo, ADH-LI, PRA, SP-LI, NPY-LI, CGRP-LI, or VIP-LI.

The possible associations between nitrate therapy and neurohumoral activation have been evaluated in previous studies, but to our knowledge the effects of nitrates on peptides such as SP, NPY, CGRP, and VIP have not been previously investigated.

The hemodynamic and hormonal responses to 24 hours of therapy with transdermal nitroglycerin were studied in 9 patients with severe CHF and in 9 normal subjects.11 In the patients with CHF, right and left ventricular filling pressures were decreased, but plasma levels of NEPI and PRA were unchanged.

In normal subjects, peripheral vasodilatation was accompanied by sympathetic activation reflected by an increase in heart rate and plasma NEPI.

Similar results have been reported using transdermal nitroglycerin (90 mg) for 24 hours12 and by using a single dose of isosorbide dinitrate (40 mg).13

In the Nitrates in Congestive Heart Failure (NICE) study,14 IS-5-MN (50 mg once daily) or placebo were administered to patients with CHF (n = 136) in NYHA class II-III for 12 weeks, all of whom received captopril; the majority received furosemide in addition. No IS-5-MN effect was seen on plasma NEPI and ANP.

In summary, previous studies with different patient characteristics, type of administration, and duration of therapy have not been able to demonstrate any effect of nitrate therapy on NEPI or PRA levels. We obtained concordant results in our study with a longer duration of treatment. Our finding of reduced P-ANP levels as a result of nitrate therapy is inconsistent with the NICE outcomes.

Neurohumoral Activation and Its Relationship to Congestive Heart Failure Severity

The levels of neurohormones and peptides were not compared with those of controls, which precluded a formal statistical analysis. However, if the medians and IQR are compared with the laboratory reference values, it is apparent that a substantial proportion of the patients have raised plasma levels of BNP, NEPI, PRA, and NPY, whereas the levels of the other analyzed substances were within the reference ranges in most patients.

The inclusion criteria were similar to those in the Acute Infarction Ramipril Efficacy (AIRE) study,15 including patients with low LVEF, clinical evidence of heart failure, or both, regardless of LVEF values. We found that the correlation between LVEF and PAWP was weak (−0.27)4 and statistically insignificant. Therefore it seemed essential to relate neurohumoral activation to echocardiographic measurements of systolic dysfunction and remodeling to invasive measurements of filling pressures.

Numerous studies have demonstrated that NEPI is increased in heart failure16,17 and that elevated levels signal a worse prognosis.18 In our study it was significantly correlated with LVEF and NYHA class but not with PAWP.

When studying the effect of beta-receptor antagonists on neurohumoral activation in patients with CHF following AMI,19 a significant association was found of NEPI to LVEF but not to NYHA class.

Few patients in our study demonstrated increased EPI values and we found no correlations between EPI and markers of heart failure severity, which is consistent with results reported previously,19 showing no increase in EPI in patients with CHF following AMI.

The majority of patients had elevated levels of PRA, which may be explained somewhat by the use of ramipril and diuretics. PRA is well known to be influenced by medical treatment. Diuretics20 and ACE inhibitors21 are known to increase PRA levels, whereas beta blockers19 decrease PRA levels. Therefore, the effect of medication may partially account for the significant correlation between PRA, LVEF, and NYHA class in our study.

Elevated Aldo is associated with a reduced ejection fraction22 and with an increased mortality24 in patients with chronic systolic heart failure, but it is also influenced by medical treatment. It is increased by activation of the renin-angiotensin system; consequently, inhibitors of that system such as ACE inhibitors,21 angiotensin II receptor blockers, and beta blockers19 reduce plasma levels of the hormone. Few patients in our study had elevated levels that may reflect the use of ramipril in particular and beta blockers.

ADH/Vasopressin is increased in severe heart failure.24 In our study, moderate heart failure was predominant and may explain the low ADH levels generally detected. Nevertheless, ADH was significantly associated with LVEF and NYHA class like NEPI and PRA.

Neuropeptide Y exhibits a wide spectrum of central and peripheral activities and is the most abundant peptide present in the mammalian brain. In the periphery, NPY is generally found costored and coreleased with NEPI,25 and in the cardiovascular system it acts as a potent vasoconstrictor.26

Nearly half of the patients in our study had increased levels of NPY-LI, which is consistent with previously published reports on increased levels in CHF.19,27,28 However, we did not observe any significant correlations with markers of heart failure severity. A similar lack of correlations with ejection fraction and cardiac index is reported by other investigators.27 However, Persson et al19 found significant correlations with wall motion index and fractional shortening.

In a CHF study28 increased catecholamine levels were accompanied by NPY release already in mild heart failure, without a further increase in cardiac failure classified as III-IV according to NYHA.

The majority of the circulating level of substance P is generally considered to be derived from perivascular nerves, where it may participate in the regulation of vascular tone1 and might act as a vasodilator, counteracting vasoconstrictive factors in CHF.28 Few patients in our study had elevated levels, and it is surprising that we demonstrated that levels of substance P correlated positively with cardiac index. These findings do not support previously published results showing increased plasma levels in moderate and severe CHF.28 In patients with heart failure undergoing ACE inhibitor therapy, SP-LI levels were higher than in patients not treated with ACE inhibitors.29

CGRP is a potent vasodilator synthesized and released from small, capsaicin-sensitive sensory nerves. It has potentially beneficial effects in CHF by virtue of its potential inotropic action and vasodilation.30 Taquet et al31 found decreased levels of CGRP in patients with CHF compared with healthy controls, whereas Edvinsson et al28 reported unchanged levels. Our laboratory did not provide any lower reference limits that precluded any evaluation of decreased plasma levels in our study. However, a significant negative correlation with LVEF was found, suggesting that CGRP is released in severe failure, possibly as a compensatory measure for vasoconstriction.

VIP was originally isolated from intestinal extracts and has been shown to be a potent vasodilator. It is widely distributed in the peripheral and central nervous systems and counteracts the vasoconstrictive effects of the sympathetic and renin-angiotensin systems. It has a positive inotropic effect and increases the heart rate, and it also may play a role in the regulation of coronary artery flow.32

In humans,33 it has been reported that the plasma concentration of VIP was not higher than normal in a whole group of patients with CHF and did not correlate with the echocardiographic data. Moreover, other investigators28 found no change in VIP-LI levels in patients with CHF. Few patients in our study had increased levels, and without a lower reference limit we were unable to judge if a tendency to decreased values exists in patients with CHF. However, no correlation to markers of CHF severity was found in our study.

Changes in Neurohumoral Activation From Pretreatment to Posttreatment Following Acute Myocardial Infarction

ANP and BNP correlated significantly with LVEF and PAWP, and both natriuretic peptides decreased during follow-up. Iwanaga et al34 showed that BNP levels reflect left ventricular end-diastolic wall stress (EDWS) more than ejection fraction, left ventricular end-diastolic pressure (LVEDP), or end-systolic pressure. The main determinants of EDWS are LVDEP, ventricular internal dimension, and wall thickness. PAWP reflects LVEDP, but no significant change in PAWP was observed in the present study. However, we cannot exclude a small change in PAWP not detected by catheterization. That explanation is supported by the fact that the change in P-BNP correlated significantly with the change in PAWP. A decrease in left ventricular internal dimension could be another possible explanation of our results, but that is not supported by echocardiographic findings of unchanged left ventricular end-diastolic volumes. Finally, reduced EDWS could also be the effect of remodeling resulting in increased wall thickness or reduced myocardial ischemia.

In contrast NEPI and Aldo, which both correlated with markers of systolic dysfunction but not with PAWP, showed slight but statistically significant increases during the study. The increase in EPI was of borderline significance. The stimuli responsible for activation of the sympathetic nervous system in heart failure are yet to be determined. However, sympathetic activation appears to be linked to the structural and functional changes by the heart during cardiac remodeling.35 Thus, our finding of slight increases in EPI, NEPI, and Aldo might represent a small, slow, but continuous impairment of the LV function and an ongoing remodeling that the echocardiographic studies were not sensitive enough to detect.

BNP levels predict morbidity and mortality in patients with heart failure. Troughton et al36 demonstrated that therapy guided by BNP levels reduces cardiovascular events compared with intensive clinically guided therapy. Consequently, there is a strong trend to use BNP for monitoring of heart failure therapy. However, our results suggest that BNP levels do not reflect all important pathophysiologic mechanisms in heart failure: decreased EDWS might coexist with a continuous remodeling and impairment of left ventricular function.

Consequently, the use of other neurohormones than BNP for monitoring of heart failure therapy should be explored.

NPY is generally found costored and coreleased with NEPI.25 Nevertheless, we found a temporal dissociation of these 2 hormones: NEPI increased after 11 months and NPY-LI decreased. Persson et al19 also reported a temporal dissociation of NEPI and NPY-LI but the converse to our results: NEPI decreased and NPY-LI increased. NEPI is mainly released during low-frequency nerve stimulation, whereas NPY release requires nerve activation at a higher frequency.37 Thus, our results may indicate a change in mode of sympathetic activation during the study. However, an improved clearance of NPY via hepatomesenteric circulation is an alternative explanation for the decrease in NPY-LI.19

VIP in our study increased slightly, but the rise was highly significant. A transient increase of VIP at the time of an AMI has been reported.38 It was followed by an abrupt decrease below normal values after 24 hours. In that study, VIP reached its lowest concentration 48 hours after the onset of symptoms of AMI and it gradually returned to the normal concentration by day 14.

Explanations for the increase in VIP in our study are purely speculative. The increase may indicate an improvement in myocardial function with less ischemia and reduced filling pressure or it may represent a counterregulatory mechanism against reduced systolic function or a vasoconstriction.

Study Limitations

The study was designed to detect hemodynamic changes (PAWP) and not changes in hormonal or echocardiographic measurements.

Some features also constitute limitations for the generalizability of our results to the total population of patients with heart failure following AMI. We studied a small number of nonconsecutive patients, and it is possible that our data are not representative of the total population of patients with LV dysfunction following AMI. The included patients were a mix of LV diastolic and systolic dysfunction.

All patients received ramipril and the majority were already receiving beta blockers, but few received spironolactone. Thus, the therapy was fairly, but not completely, up to date with respect to present therapeutic guidelines.

CONCLUSION

Chronic nitrate therapy does not significantly affect the neurohumoral status in patients with LV dysfunction after AMI, apart from a decrease in ANP.

Some neurohumoral factors are more closely associated with diastolic dysfunction/increased volume load (ANP and BNP) and others with systolic dysfunction (PRA, NEPI, Aldo). A temporal dissociation of these 2 groups of hormones occurs 1 year after the infarction: ANP and BNP decrease, whereas NEPI and Aldo show slight increases.

ACKNOWLEDGMENTS

The study was supported by grants from the Swedish Heart and Lung Foundation; AstraZeneca; Hoechst Marion Roussel; and Merck, Sharp & Dohme.

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Keywords:

myocardial infarction; heart failure; neurohumoral activation; nitrates

© 2006 Lippincott Williams & Wilkins, Inc.