(Circulation. 1995;92:2855-2862.)
© 1995 American Heart Association, Inc.
Articles |
N-Acetylcysteine in Combination With Nitroglycerin and Streptokinase for the Treatment of Evolving Acute Myocardial Infarction
Safety and Biochemical Effects
From the Cardiology Unit (M.A.A., J.Y., I.S., J.D.H.) and the Rheumatology Unit (W.H.B.), The Queen Elizabeth Hospital, University of Adelaide, South Australia, Australia.
Correspondence to Prof J.D. Horowitz, Senior Director, Cardiology Unit, The Queen Elizabeth Hospital, 28 Woodville Rd, Woodville South, South Australia 5011, Australia.
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Abstract |
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Background N-acetylcysteine (NAC) has been shown to potentiate the effects of nitroglycerin (NTG) and to have antioxidant activity. This is the first study to assess the safety and effect of NAC in the treatment of evolving acute myocardial infarction (AMI).
Methods and Results Patients with AMI received either 15 g NAC infused over 24 hours (n=20) or no NAC (n=7), combined with intravenous NTG and streptokinase. Peripheral venous plasma malondialdehyde (MDA), reduced (GSH) and oxidized (GSSG) glutathione concentrations, and rate of reperfusion (using continuous ST-segment analysis) were measured. Cardiac catheterization was performed between days 2 and 5. No significant adverse events occurred. Less oxidative stress occurred in patients treated with NAC than in patients not receiving NAC (GSH to GSSG ratio 44±25 versus 19±13 at 4 hours, P<.05). NAC concentration (mean 172±79 µmol/L at 4 hours) was correlated to GSH concentration (P=.006). MDA concentrations were lower (P=.001) over the first 8 hours of treatment with NAC. There was a trend toward more rapid reperfusion (median 58 minutes, 95% confidence interval [CI] 48 to 98 minutes versus median 95 minutes, 95% CI 59 to 106 minutes; P=.17) and better preservation of left ventricular function (cardiac index 3.4±0.8 versus 2.6±0.27 L · min · m2, P=.009) with NAC treatment.
Conclusions NAC in combination with NTG and streptokinase appeared to be safe for the treatment of evolving AMI and was associated with significantly less oxidative stress, a trend toward more rapid reperfusion, and better preservation of left ventricular function.
Key Words: free radicals • reperfusion • myocardial infarction
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Introduction |
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Rapid restoration of coronary artery patency and salvage of threatened myocardium at the time of evolving AMI are key aims in the management of AMI. Treatment with intravenous thrombolytic agents has been shown to result in improvement in both systolic function1 2 3 and survival.4 5 With the reperfusion of previously ischemic myocardium, there is a concurrent rapid and sustained release of oxygen-derived free radicals6 7 8 leading to peroxidation of lipids9 10 11 12 13 and depletion of endogenous antioxidants.14 15 16 These factors contribute to the development of reperfusion injury, characterized by temporary impairment of systolic function (myocardial stunning),14 15 arrhythmias,17 and possibly further necrosis.15 18 The full clinical significance of reperfusion injury has been difficult to assess in the absence of specific effective maneuvers for its prevention.19
A variety of antioxidants and scavengers of oxygen-derived free radicals have been shown to diminish the extent of reperfusion injury in animal models of myocardial ischemia followed by reperfusion. One such agent is NAC, which is in clinical use as a potentiator of the hemodynamic and antiaggregative effects of NTG.20 21 22 Previous studies have shown that the addition of NAC to intravenously infused NTG decreases the incidence of AMI in patients with severe unstable angina pectoris23 and limits the development of nitrate tolerance.24 25 In vitro, NAC has been found to scavenge several oxygen-derived free radicals and oxidants26 27 28 and to ameliorate the extent of reperfusion injury in animal models, resulting in reduced myocardial stunning,29 30 decreased infarct size, and reduced severity of ventricular arrhythmias during reperfusion.31 Despite these promising results and a low incidence of adverse effects, NAC has not yet undergone clinical evaluation in evolving AMI treated with thrombolytics. The aim of the current study was to assess the safety and biochemical effects of NAC in this setting and secondarily to make a preliminary assessment of the effect of NAC on rate of reperfusion and hemodynamic status after AMI.
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Methods |
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Inclusion and Exclusion Criteria
This study was approved by the Ethics Committee on Human Research of The Queen Elizabeth Hospital, and informed consent was obtained from all patients before entry into the trial. Inclusion criteria were age
75 years, admission to the coronary care
unit with chest pain of 4 hours' duration, and ECG evidence of
transmural ischemia (
1 mm ST-segment elevation in 2 limb
leads and/or 2 mm ST-segment elevation in 2 precordial
leads). Exclusion criteria were past Q-wave myocardial infarction;
previous severe (New York Heart Association class III to IV) cardiac
failure; admission systolic blood pressure <90 mm Hg; AMI
within the preceding 7 days; hemodynamically
significant valvular heart disease; ingestion of allopurinol,
penicillamine, gold salts, ethacrynic acid, or captopril within the
previous 7 days; known allergy to any of the protocol medications; and
contraindications to the use of streptokinase. The contraindications to
streptokinase were streptokinase administration within the previous 6
months, allergy to the drug, surgery or cerebrovascular accident within
the previous 6 weeks, warfarin therapy, active peptic ulcer disease,
bleeding disorders, uncontrolled hypertension, or diabetic
proliferative retinopathy.
Study Protocol
The major objective of this study was to determine the safety of
NAC in combination with NTG and streptokinase in the treatment of
evolving AMI. A small control group was included to permit a
preliminary assessment of the effect of NAC on the rate of reperfusion,
hemodynamics, and myocardial oxidative stress by use of
two biochemical markers: plasma MDA concentration and plasma ratios of
reduced GSH to oxidized GSSG concentration. For these reasons, a
randomization protocol was chosen to result in a ratio of 3:1 for NAC
to no NAC treatment.
All potentially eligible patients received NTG infused at 5 µg/min IV before trial entry. NAC infusion was commenced at 20 mg/min IV for the first hour, then 10 mg/min for the subsequent 23 hours, to give a total dose of 15 g over 24 hours. Fifteen minutes after commencement of NAC infusion, a bolus of 100 mg IV hydrocortisone was administered, immediately followed by 1.5 MU streptokinase IV over 30 minutes.
Additional therapy thereafter consisted of intravenous NTG infusion for 48±12 hours followed by oral isosorbide dinitrate 10 mg three times daily for at least 7 days. The NTG infusion rate was limited to a maximum of 10 µg/min in an attempt to limit development of nitrate tolerance32 33 and reduce the risk of development of hypotension due to the potentiation of NTG effect by NAC.23 Heparin infusion immediately followed streptokinase, as did oral verapamil (80 mg every 8 hours) unless contraindicated.34 Aspirin was not administered during the first 12 hours of the study.
Criteria for withdrawal of trial medications included the onset of cardiogenic shock, complications of myocardial infarction requiring emergency cardiac surgery, persistent ischemic chest pain requiring emergency coronary revascularization, or severe adverse reactions to NTG, NAC, or streptokinase.
Investigations
A number of clinical and biochemical investigations were
performed in all cases. Twelve-lead continuous ST-segment
monitoring was performed for 12 to 24 hours from the time of admission
to the coronary care unit by use of a MAC 15 ST Guard
(Marquette Electronics), with measurement of ST deviation every 30
seconds from baseline 60 milliseconds after the J-point and 12-lead ECG
stored every 15 minutes. Data were stored on computer disk and printed
as hard copy for each patient. The lead with the maximum ST elevation
was used as the reference lead. The time to reperfusion of the
infarct-related artery was defined as time from trial entry to that
at which the ST segment elevation had declined to 50% of the maximum
level in the reference lead.35 Left
ventricular systolic function was assessed at day 1
and day 7 by gated heart pool scanning by use of 900 mBq
technetium-99m IV and a General Electric 300 mobile gamma
camera on day 1 and a Triad triple-headed gamma camera (Trionics)
on day 7. Right and left cardiac catheterization with
estimation of cardiac index via the Fick method36 and
coronary angiography was performed between days 2 and 5.
Infarct-related coronary artery patency was graded
according to the TIMI-1 criteria.37
Peripheral venous blood was serially sampled to measure several biochemical parameters. Plasma creatine kinase concentration was measured at 0, 1, 2, 4, 8, 12, 16, 20, 24, and 48 hours after trial onset.
Plasma MDA was measured at 0, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours
after trial onset. Venous blood samples were anticoagulated with
potassium EDTA, centrifuged, and resultant plasma frozen with
long-term storage at -70°C. A modified TBA test was used to
estimate plasma MDA concentration.38 39 40 To maximize the
specificity of this assay, interfering proteins and lipids were first
removed to preclude in vitro generation of MDA and MDA-like substances.
Proteins were precipitated with perchloric acid and lipids were
extracted with chloroform.41 The resultant supernatant and
added TBA was boiled for 1 hour in the presence of orthophosphoric
acid. Further extraction was carried out with 70:30
chloroform:methanol (vol/vol). The fluorescence intensity
of the TBA–MDA adduct was measured at excitation 
of 530 nm and
emission of 547 nm by use of a Perkin Elmer LS 50B luminescence
spectrometer with correction for an aqueous blank sample. Homogeneity
of source fluorescence material as MDA was confirmed by
detection of a single peak on HPLC with fluorescence
detection.38 40 The intra-assay coefficient of
variance was 9% for the blank standard and 2% for 0.5 µmol/L MDA.
The interassay coefficient of variance was 8%. Recovery of MDA after
extractions was >80% within the normal plasma range. With this
methodology, plasma concentration of MDA in normal subjects (n=21) was
0.16±0.03 (mean±SD) µmol/L in men and 0.17±0.04 µmol/L in women,
equivalent to that assayed by others using an assay without preceding
TBA–MDA adduct formation.41
Plasma NAC, GSH, and GSSG were each assayed at 0, 4, and 24 hours after trial entry. Plasma was obtained as for MDA measurement, but protein was immediately precipitated with perchloric acid and dithiothreitol.42 The supernatant was then immediately frozen and stored at -70°C. Before HPLC assay, penicillamine was added as an internal standard and excess dithiothreitol was removed by extraction with ethyl acetate. Nitrogen was then used to evaporate traces of ethyl acetate from the sample. Separation of NAC, GSH, and GSSG by HPLC was carried out by use of a modification of a previously described method.43 The column was a 220x4.6-mm, 5-µm C18 Brownlee with a 3-cm precolumn (Applied Biosystems), with a mobile phase consisting of 96% 50 mmol/L chloroacetic acid, 4% methanol, and 3 mmol/L sodium heptanesulfonate, adjusted to pH 3 with fresh, concentrated sodium hydroxide. An electrochemical detector (ESA Coulochem II) equipped with a dual high-sensitivity analytical cell and guard cell (applied electrode potentials were +0.75 V, +0.9 V, and +0.95 V, respectively) was used for detection by a method described previously.44 Typical retention times for NAC, GSH, GSSG, and penicillamine were 5.8, 7, 25, and 14 minutes, respectively. GSH and GSSG concentrations and GSH-to-GSSG ratios at 4 and 24 hours were expressed both as absolute values and as percentages of baseline levels, to minimize the potential effects of any losses during prolonged storage. Thresholds for the detection in plasma of GSH, GSSG, and NAC were 0.5 µmol/L, 0.05 µmol/L, and 12.5 µmol/L, respectively. For purposes of calculation of a GSH to GSSG ratio, a value of 0.04 µmol/L was arbitrarily assigned to all GSSG plasma concentrations <0.05 µmol/L. Intra-assay coefficient of variance was 2.2% for 2.4 µmol/L GSH, 3.5% for 95 µmol/L NAC, and 7.3% for 0.28 µmol/L GSSG.
Statistical Analysis
Sample sizing was prospectively determined in regard to the
biochemical end points of plasma MDA concentrations. With a 3:1
randomization protocol, 20 patients in the treatment group were
required to detect a 50% difference in peak MDA plasma concentration
with a power of 87%. Normally distributed data were analyzed
by use of Student's t test and skewed data via the
Mann-Whitney U test. Variance within and between groups was
assessed by use of two-way ANOVA followed by Dunnett's test for
multiple comparisons. Correlations were sought between different
measured values by use of linear regression. All normally distributed
data are expressed as mean±SD unless otherwise stated. Median values
with 95% confidence intervals are used to describe skewed data. All
analysis was two-tailed, and a value of P<.05
was considered statistically significant.
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Results |
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Patient Characteristics
Of 29 consecutive eligible patients, 28 patients were enrolled in the study. One patient was not included in further analysis because his final diagnosis was acute viral pericarditis with ST segment elevation in the precordial ECG leads. The two groups were well matched for age, sex, previous myocardial infarction, site of infarction, and length of time from onset of symptoms to trial entry as outlined in Table 1
. Two patients had been taking
aspirin before trial entry.
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Safety of NAC
No deaths occurred during hospital admission, and there were no
allergic reactions to trial medication. Among the 20 patients receiving
NAC, 3 had minor episodes of hemorrhage (two Mallory-Weiss
tears and one spontaneous hemarthrosis); none of these 3 patients had
been taking aspirin. These complications were not associated with
hemodynamic compromise, nor did they result in a need
for transfusion. Four patients developed headache. Before the
streptokinase infusion, there was no symptomatic
hypotension related to the infusion of NTG and/or NAC. Furthermore, no
patient developed sustained hypotension at any time. One patient had a
transient episode of extreme sinus bradycardia. No patients treated
with streptokinase and NTG alone had any adverse effects.
Clinical Follow-up
No one within the NAC group developed reinfarction within 7 days
of trial entry, but one patient developed symptomatic and
persistent left ventricular failure on day 6 after trial
entry. One patient in the control group was withdrawn from the trial at
18 hours due to reinfarction and continued unstable angina pectoris
requiring urgent revascularization with
coronary artery bypass grafting.
Clinical Investigations
Results of the clinical investigations are summarized in Tables 2 and 3. Consistent with the
small sample size of the control group and anticipated extensive
interindividual variability, there were no significant differences
between groups for the majority of parameters measured.
However, median time to reperfusion on ECG criteria tended to be
shorter (59 minutes, 95% CI 48 to 98 minutes versus 95 minutes, 95%
CI 59 to 106 minutes; P=.17) in patients receiving NAC, with
somewhat more rapid time to peak plasma creatine kinase concentrations.
Patients receiving NAC had significantly greater cardiac indexes
(median 3.3, 95% CI 3.0 to 3.8 versus 2.5, 95% CI 2.3 to 2.9;
P=.009), with trends toward lower mean pulmonary
capillary wedge pressure and greater left ventricular
ejection fraction (Table 3). Left ventricular
systolic function was generally well preserved.
Infarct-related artery patency at day 2 to day 5 was 90% in
NAC-treated patients and 100% in the control group.
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Biochemical Investigations
The extent of lipid peroxidation in this setting was estimated by
measurement of peripheral plasma MDA. Plasma MDA
concentrations (Fig 1) peaked at a median of 1 hour
(95% CI 0.9 to 8.0 hours) in the NAC-treated patients and 2 hours
(95% CI 0.7 to 3.9 hours) in the control patients (P=NS).
Peak plasma MDA concentrations within 24 hours were 0.22±0.07 µmol/L
and 0.30±0.14 µmol/L in NAC-treated and control patients,
respectively (P=.097). Plasma concentrations of MDA were
significantly lower over the first 8 hours of the study in NAC-treated
patients (P<.001, ANOVA).
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) or not receiving (
)
NAC (mean±SEM).
Effects of NAC on plasma concentrations of GSH and on the ratio of GSH
to GSSG are summarized in Table 4 and Fig 2. GSH concentrations were significantly higher in
NAC-treated patients than in control patients (mean 87±119% increase
versus 19±47% decrease at 24 hours, P<.002, ANOVA).
Furthermore, there was a significantly lower concentration of GSSG in
the NAC-treated groups (P=.012, ANOVA), with significant
changes over time in both groups (P=.001, ANOVA). Therefore,
the GSH to GSSG ratios were significantly higher for NAC-treated
patients (P<.001, ANOVA), with a significant increment of
effect in NAC-treated patients with time compared with control patients
(P=.01, ANOVA).
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) or
not receiving (
) NAC.
In the NAC-treated patients, plasma NAC concentrations were
172±79 µmol/L at 4 hours and 151±78 µmol/L at 24 hours,
suggesting attainment of steady state plasma NAC concentrations within
4 hours. Plasma concentrations of NAC were correlated with plasma GSH
concentrations at 4 and 24 hours
(r2=.298, P=.006; Fig 3) and percentage change of GSH at 4 hours
(r2=.235, P=.042). No other
statistically significant correlations between biochemical and/or
clinical parameters were found.
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Additional Clinical Data
After completion of the randomized study, further data regarding
safety of NAC/NTG/streptokinase were collected in consecutive patients
in whom evolving AMI was treated with this combination. All patients
received NAC within 6 hours of administration of NTG/streptokinase. Of
these 17 patients, 8 were treated concurrently with aspirin. The only
significant adverse event was minor upper gastrointestinal
hemorrhage in 1 patient.
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Discussion |
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Rationale for the Use of NAC in AMI
Despite evidence of the antioxidant effects of NAC in animal29 30 and in vitro studies26 27 28 and its established clinical role in limiting tolerance to24 25 and potentiating the effect of20 21 22 NTG, this is the first study to assess the clinical and biochemical effects of NAC in evolving AMI in humans. Only one previous case report45 exists regarding its use in this situation. Nevertheless, the use of NAC in patients with evolving AMI is theoretically attractive both because of its antioxidant activity and because of its interactions with NTG.
Early reperfusion during evolution of AMI in humans has been shown to be associated with a rapid and sustained release of oxygen-derived free radicals8 and is likely to be related causally to the associated increased peroxidation of lipids,11 12 13 resulting in temporary disruption of physiological function13 and possibly in further necrosis of cells. The antioxidant and free radical scavenging effects of NAC are demonstrable in vitro. NAC is a scavenger of several free radical species26 27 28 and has been shown to inhibit the release of superoxide from activated neutrophils.28 In vivo, there is additional potential for repletion of endogenous antioxidant mechanisms such as the GSH redox pathway.30 46 NAC has been shown to decrease the extent of temporary myocardial dysfunction29 30 and infarction31 in animal models of ischemia followed by reperfusion.
However, it is possible that beneficial effects might result from interactions between NAC and NTG, as previously demonstrated in patients with severe unstable angina pectoris.23 NAC would be expected to potentiate the beneficial effects of NTG on systemic20 and coronary22 hemodynamics, as well as its effects in inhibiting21 and reversing47 platelet aggregation. It is likely that in spite of the low infusion rate of NTG used in this study, appreciable tolerance would have occurred within 24 hours in the control group that would have been prevented by NAC in the NAC-treated patients32 33
Safety of NAC in AMI
The results of this study suggest that NAC can be coadministered
safely in combination with NTG and streptokinase in the treatment of
uncomplicated AMI. Prospectively, we anticipated several potential
hazards related to the potentiation of both the vasodilator and
antiplatelet effects of NTG by NAC, namely sustained
hypotension,23 headache,48 and
hemorrhage. Although 3 patients had minor hemorrhages,
the most common problem was that of headache. This was controllable
with simple analgesia, and no patient needed to be withdrawn from the
study as a consequence of this problem.
Hemodynamic Effects
The size of the study was not adequate for reliable
analysis of the clinical and hemodynamic
effects of NAC; rather, the study was designed to permit limited
assessment of the biochemical effects of NAC. Therefore, the lack of
statistically significant differences between treatment groups may
reflect type II error. Despite this, two trends were noted. First,
reperfusion tended to occur more rapidly in the NAC-treated patients.
Although the mechanism for this was not assessed during this study, it
is possible that this reflects either a potentiation of effects of NTG
or even an antiaggregative effect of NAC per se.49 Mean
plasma concentration of NAC at 4 hours (172±79 µmol/L) was similar
to that at which NAC had been shown to inhibit platelet aggregation
in vitro.49 Second, hemodynamics tended to
be better preserved in the NAC-treated patients. Although only cardiac
index showed a statistically significant difference between treatment
groups, all measured parameters suggested a beneficial
effect of NAC treatment.
Effects of NAC on Oxidative Stress
A primary consideration was the determination of effects of NAC on
oxidant stress, with use of both measurement of the redox state of the
endogenous antioxidant GSH and assay of a product of
lipid peroxidation, MDA. Because these biochemical indexes are more
likely to represent the consequences rather than the cause of
oxidative stress, two parameters were used to minimize the
potential for nonspecific results and/or disparate effects of
ischemia followed by reperfusion on individual biochemical
indexes.
Both MDA and GSH redox status indicated less oxidative stress in NAC-treated patients. With regard to MDA, the effect of NAC appeared to be limited to approximately 25% reduction of plasma MDA concentrations during the first 8 hours of treatment; thereafter, there was no difference between treatment groups. This lack of difference in MDA concentrations over the 8- to 24-hour period is not explained on the basis of current investigations. On the other hand, the effects of NAC on GSH, GSSG, and GSH to GSSG ratio were apparent both at 4 and at 24 hours and were more marked than changes in MDA concentrations. Similar biochemical effects of NAC in patients undergoing coronary revascularization have been described.46 The lower GSSG concentration at 24 hours in the NAC-treated patients supports the role of NAC as an antioxidant per se, thereby decreasing oxidative stress. Furthermore, the correlation between GSH and NAC concentrations in plasma supports the hypothesis that NAC is in part metabolized to GSH,30 46 another potential indirect mechanism for the antioxidant effects of NAC in vivo.
In previous studies measuring oxidative stress associated with AMI, reported plasma concentrations of MDA vary widely,11 12 13 50 51 52 53 54 probably reflecting different and sometimes very nonspecific assay methodology, thereby making direct comparisons difficult. However, the study of Giardina et al41 is of particular interest; in that study, the MDA assay used actually quantified MDA,55 and the reported normal range for plasma MDA concentrations was comparable to that found in our laboratory by use of the method described here. However, mean peak plasma MDA concentrations in their patients who reperfused were considerably higher than those in either of our treatment groups. This suggests a greater degree of reperfusion injury, perhaps due to later reperfusion. Alternatively, NTG (not routinely administered in the above-mentioned study) may have also exerted anti-ischemic and antioxidant effects.56
Study Limitations
There were several limitations to this study. The small size of
the study, and of the control group in particular, limited
determination of NAC effects on the measured clinical
parameters, such as time to reperfusion and postinfarction
hemodynamic status. Therefore, the results in general
show only trends, and no firm conclusions can be made at this stage.
Nevertheless, these encouraging results would justify the
performance of a larger controlled study with primary
hemodynamic end points. Regarding the biochemical
parameters, changes in the GSH redox pathway were profound,
which allowed us to confidently discern a limitation in redox stress by
NAC. Plasma MDA concentration differences were less marked between
groups, although NAC prevented the initial rise in MDA concentration
(P<.001, ANOVA). However, differences in peak MDA
concentrations were not statistically significant.
Although coadministration of NAC, NTG, and streptokinase appeared to be relatively safe in this study, a much larger investigation would be required to detect a small incremental risk of adverse effect, such as hemorrhage. Furthermore, it must be noted that aspirin therapy was not routinely initiated until after the first 48 hours of treatment in these patients. Hence, it remains possible that concomitant aspirin therapy may increase hemorrhagic risk in the presence of NAC/NTG/streptokinase. However, it appears that the extent of potentiation of the antiplatelet effects of NTG by NAC is similar in normal subjects, patients not receiving aspirin, and those taking aspirin (Y. Chirkov, PhD, and J.D. Horowitz, MD, unpublished data, 1995).
In the assessment of time to reperfusion, we did not perform early coronary angiography, instead using the more indirect but potentially more dynamically sensitive method of continuous ECG monitoring. This method of continuous monitoring for the extent of abnormalities of ST segments on 12-lead ECG, to assess fluctuations of ST-segment elevation during AMI, has been shown previously to be a useful noninvasive assessment of infarct-related artery patency in individual patients.57 Rapid resolution of ST-segment elevation has been shown to correlate with restoration of patency of the infarct-related artery in patients receiving thrombolytic therapy.35 57 58 59 60 Similar to methods used in other studies,35 we chose to monitor (as a surrogate of reperfusion time) time to halving of the maximum ST-segment elevation in the lead with maximum ST-segment elevation in any individual patient.
The precise mechanism of biochemical and hemodynamic effects of the NAC/NTG/streptokinase treatment regimen cannot be deduced from the present study. Indeed, it is uncertain that NAC must be administered before reperfusion to exert a beneficial effect, although the current regimen and previous animal models of myocardial ischemia/reperfusion30 are concordant with the hypothesized major mechanism of effect. The timing of therapy and the examination of components of NAC/NTG or NAC/streptokinase interaction versus direct NAC effect would require future larger studies comparing NAC/NTG, NAC, and NTG with streptokinase monotherapy both before and after reperfusion with streptokinase. Furthermore, the safety and effect of other thrombolytic agents with NAC/NTG cannot be determined.61
Summary
In summary, administration of NAC in combination with
streptokinase and NTG limits oxidant stress without obvious major
adverse effects in patients with evolving AMI. The potential clinical
benefits of this treatment regimen are uncertain, as it remains unclear
to what extent reperfusion injury is a determinant of outcome after
AMI, either overall or in particular subgroups. However, it appears
that a clinically applicable strategy for evaluating the putative
benefit of the limitation of reperfusion injury is now available.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Dr Arstall is supported by a National Heart Foundation of Australia postgraduate medical research scholarship. This study was financially supported in part by Zambon S.P.M., Milan, Italy. We wish to acknowledge the large contribution made to this study by the staff of the Coronary Care Unit and the Cardiac Catheterization Laboratory of The Queen Elizabeth Hospital, and assistance and advice of Dr G. Lazzarino and Dr B. Giardina of II Universitá Degli Studi di Roma, Italy, in regard to the MDA assay.
Received May 3, 1994; revision received May 22, 1995; accepted July 5, 1995.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. White HD, Norris RM, Brown MA, Takayama M, Maslowski A, Bass NM, Ormiston JA, Whitlock T. Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med. 1987;317:850-855. [Abstract]
2.
O'Rourke M, Baron D, Keogh A, Kelly R, Nelson G,
Barnes C, Raftos J, Graham K, Hillman K, Newman H, Healey J, Woolridge
J, Rivers J, White H, Whitlock R, Norris R. Limitation of
myocardial infarction by early infusion of recombinant tissue-type
plasminogen activator.
Circulation. 1988;77:1311-1315.
3. Sheehan FH, Doerr R, Schmidt WG, Bulson EL, Uebis R, Von Essen R, Effert S, Dodge HT. Early recovery of left ventricular function after thrombolytic therapy for acute myocardial infarction: an important determinant of survival. J Am Coll Cardiol. 1988;12:289-300. [Abstract]
4. Gruppo Italiano Per Lo Studio Della Streptochinasi Nell'infarto miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet. 1986;327:397-401.
5. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction. Lancet. 1988;332:349-360.
6. Bolli R, Patel BS, Jeroudi MO, Lai EK, McCay PB. Demonstration of free radical generation in `stunned' myocardium of intact dogs with the use of the spin trap alpha-phenyl N-tert-butyl nitrone. J Clin Invest. 1988;82:476-485.
7.
Garlick PB, Davies MJ, Hearse DJ, Slater TF.
Direct detection of free radicals in the reperfused rat heart
using electron spin resonance spectroscopy.
Circ Res. 1987;61:757-760.
8. Grech ED, Dodd NJF, Bellamy CM, Perry RA, Morrison WL, Ramsdale DR. Free-radical generation during angioplasty reperfusion for acute myocardial infarction. Lancet. 1993;341:990-991. [Medline] [Order article via Infotrieve]
9. Kirshenbaum LA, Thomas TP, Randhawa AK, Singal PK. Time-course of cardiac myocyte injury due to oxidative stress. Mol Cell Biochem. 1992;111:25-31. [Medline] [Order article via Infotrieve]
10. Parinandi NL, Weis BK, Natarajan V, Schmid HHO. Peroxidative modification of phospholipids in myocardial membranes. Arch Biochem Biophys. 1990;280:45-52. [Medline] [Order article via Infotrieve]
11. Davies SW, Ranjadayalan K, Wickens DG, Dormandy TL, Timmis AD. Lipid peroxidation associated with successful thrombolysis. Lancet. 1990;335:741-743. [Medline] [Order article via Infotrieve]
12.
Young IS, Purvis JA, Lightbody JH, Adgey AAJ, Trimble
ER. Lipid peroxidation and antioxidant status following
thrombolytic therapy for acute myocardial
infarction. Eur Heart J. 1993;14:1027-1033.
13.
Davies SW, Ranjadayalan K, Wickens DG, Dormandy TL,
Umachandran V, Timmis AD. Free radical activity and left
ventricular function after thrombolysis for
acute myocardial infarction. Br Heart J. 1993;69:114-120.
14.
Ferrari R, Alfieri O, Curello S, Ceconi C, Cargnoni A,
Marzollo P, Pardini A, Caradonna E, Visioli O. Occurrence of
oxidative stress during reperfusion of the human heart.
Circulation. 1990;81:201-211.
15.
Blaustein A, Deneke SM, Stolz RI, Baxter D, Healey N,
Fanburg BL. Myocardial glutathione depletion impairs recovery
after short periods of ischemia.
Circulation. 1989;80:1449-1457.
16.
Singh A, Lee KJ, Lee CY, Goldfarb RD, Tsan MF.
Relation between myocardial glutathione content and extent of
ischemia-reperfusion injury.
Circulation. 1989;80:1795-1804.
17. Goldberg S, Greenspon AJ, Urban PL, Muza B, Berger B, Walinsky P, Maroko PR. Reperfusion arrhythmia: a marker of restoration of antegrade flow during intracoronary thrombolysis for acute myocardial infarction. Am Heart J. 1983;105:26-32. [Medline] [Order article via Infotrieve]
18. Farb A, Kolodgie FD, Jenkins M, Virmani R. Myocardial infarct extension during reperfusion after coronary artery occlusion: pathological evidence. J Am Coll Cardiol. 1993;21:1245-1253. [Abstract]
19.
Nayler WG, Elz JS. Reperfusion injury:
laboratory artifact or clinical dilemma?
Circulation. 1986;74:215-221.
20.
Horowitz JD, Antman EM, Lorell BH, Barry WH, Smith TW.
Potentiation of the cardiovascular effects of
nitroglycerin by N-acetylcysteine.
Circulation. 1983;68:1247-1253.
21. Loscalzo J. N-acetylcysteine potentiates inhibition of platelet aggregation by nitroglycerin. J Clin Invest. 1985;76:703-708.
22.
Winniford MD, Kennedy PL, Wells PJ, Hillis LD.
Potentiation of nitroglycerin-induced
coronary dilatation by N-acetylcysteine.
Circulation. 1986;73:138-142.
23.
Horowitz JD, Henry CA, Syrjanen ML, Louis WJ,
Fish RD, Smith TW, Antman EM. Combined use of
nitroglycerin and N-acetylcysteine in the
management of unstable angina pectoris.
Circulation. 1988;77:787-794.
24. Packer M, Lee WH, Kessler PD, Gottlieb SS, Medina N, Yushak M. Prevention and reversal of nitrate tolerance in patients with congestive heart failure. N Engl J Med. 1987;317:799-804. [Abstract]
25. May DC, Popma JJ, Black WH, Schaefer S, Lee HR, Levine BD, Hillis LD. In vivo induction and reversal of nitroglycerin tolerance in human coronary arteries. N Engl J Med. 1987;317:805-809. [Abstract]
26. Westlin W, Mullane KM. Does captopril attenuate reperfusion-induced myocardial dysfunction by scavenging free radicals? Circulation. 1988;77(suppl I):I-30-I-39.
27. Aruoma OI, Halliwell B, Hoey BM, Butler J. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med. 1989;6:593-597. [Medline] [Order article via Infotrieve]
28. Betts WH, Zhang Y, Rokicinski M, Horowitz JD. N-acetylcysteine and captopril inhibit but S-nitroso-N-acetylcysteine stimulates human neutrophil free radical production. Circulation. 1993;88(suppl I):I-90. Abstract.
29.
Forman MB, Puett DW, Cates CU, McCroskey DE, Beckman
JK, Greene HL, Virmani R. Glutathione redox pathway and
reperfusion injury: effect of N-acetylcysteine on infarct
size and ventricular function.
Circulation. 1988;78:202-213.
30. Ceconi C, Curello S, Cargnoni A, Ferrari R, Albertini A, Visioli O. The role of glutathione status in the protection against ischaemic and reperfusion damage: effects of N-acetylcysteine. J Mol Cell Cardiol. 1988;20:5-13. [Medline] [Order article via Infotrieve]
31. Sochman J, Kolc J, Vrana M, Fabian J. Cardioprotective effects of N-acetylcysteine: the reduction in the extent of infarction and occurrence of reperfusion arrhythmias in the dog. Int J Cardiol. 1990;28:191-196. [Medline] [Order article via Infotrieve]
32. Boesgaard S, Iversen HK, Wroblewski H, Poulsen HE, Frandsen H, Kastrup J, Aldershvile J. Altered peripheral vasodilator profile of nitroglycerin during long-term infusion of N-acetylcysteine. J Am Coll Cardiol. 1994;23:163-169. [Abstract]
33. Meredith IT, Alison JF, Zhang FM, Horowitz JD, Harper RW. Captopril potentiates the effects of nitroglycerin in the coronary vascular bed. J Am Coll Cardiol. 1993;22:581-587. [Abstract]
34. Arstall MA, Beltrame JF, Mohan P, Wuttke RD, Esterman AJ, Horowitz JD. Incidence of adverse events during treatment with verapamil for suspected acute myocardial infarction. Am J Cardiol. 1992;70:1611-1612. [Medline] [Order article via Infotrieve]
35. Krucoff MW, Croll MA, Pope JE, Pieper KS, Kanini PM, Granger CB, Veldkamp RF, Wagner BL, Sawchak ST, Califf RM. Continuously updated 12-lead ST-segment recovery analysis for myocardial infarct artery patency assessment and its correlation with simultaneous early angiographic observations. Am J Cardiol. 1993;71:145-151. [Medline] [Order article via Infotrieve]
36. Grossman W. Blood flow measurement: the cardiac output. In: Grossman W, ed. Cardiac Catheterization and Angiography. Philadelphia, Pa: Lea & Febiger; 1986:101-117.
37. The TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial: phase I findings. N Engl J Med. 1985;312:932-936. [Medline] [Order article via Infotrieve]
38. Bird RP, Draper HH. Comparative studies on different methods of malonaldehyde determination. Methods Enzymol. 1984;105:299-305. [Medline] [Order article via Infotrieve]
39. Yagi K. Assay for blood plasma or serum. Methods Enzymol. 1984;105:328-331. [Medline] [Order article via Infotrieve]
40.
Wong SH, Kjight JA, Hopfer SM, Zaharia O, Leach CN,
Sunderman FW. Lipoperoxides in plasma as measured by
liquid-chromatographic separation of
malondialdehyde-thiobarbituric acid adduct. Clin
Chem. 1987;33:214-220.
41. Giardina B, Penco M, Lazzarino G, Romano S, Tavazzi B, Fedele F, Di Pierro D, Dagianti A. Effectiveness of thrombolysis is associated with a time-dependent increase of malondialdehyde in peripheral blood of patients with acute myocardial infarction. Am J Cardiol. 1993;71:788-793. [Medline] [Order article via Infotrieve]
42. Johansson M, Lenngren S. Determination of cysteine, glutathione and N-acetylcysteine in plasma by ion-pair reversed-phase liquid chromatography and post-column derivatization. J Chromatogr. 1988;432:65-74. [Medline] [Order article via Infotrieve]
43. Richie JP Jr, Lang CA. The determination of glutathione, cysteine, and other thiols and disulfides in biological samples using high-performance liquid chromatography with dual electrochemical detection. Anal Biochem. 1987;163:9-15. [Medline] [Order article via Infotrieve]
44. Krien PM, Margou V, Kermici M. Electrochemical determination of femtomole amounts of free reduced and oxidized glutathione: application to human hair follicles. J Chromatogr. 1992;576:255-261. [Medline] [Order article via Infotrieve]
45. Sochman J, Peregrin JH. Total recovery of left ventricular function after acute myocardial infarction: comprehensive therapy with streptokinase, N-acetylcysteine and percutaneous transluminal coronary angioplasty. Int J Cardiol. 1992;35:116-118. [Medline] [Order article via Infotrieve]
46. Ferrari R, Ceconi C, Curello S, Cargnoni A, Alfieri O, Pardini A, Marzollo P, Visioli O. Oxygen free radicals and myocardial damage: protective role of thiol-containing agents. Am J Med. 1991;91(suppl 3C):95S-105S.
47. Chirkov YY, Gee DJ, Naujalis JI, Sage RE, Horowitz JD. Reversal of ADP-induced platelet aggregation by S-nitrosothiols, nitroglycerin and nitroglycerin/N-acetylcysteine. Pharm Com. 1993;3:97-105.
48. Iversen HK. N-acetylcysteine enhances nitroglycerin-induced headache and cranial arterial responses. Clin Pharmacol Ther. 1992;52:125-133. [Medline] [Order article via Infotrieve]
49. del Principe D, Menichelli A, de Matteis W, di Giulio S, Giordani M, Savini I, Finazzi-Agro A. The effect of cyst(e)ine on human platelets is mediated by hydrogen peroxide. Clin Chem Enzym Com. 1990;3:9-17.
50. Rao PS, Mueller HS. Lipid peroxidation and acute myocardial infarction. Adv Exp Med Biol. 1983;161:347-363. [Medline] [Order article via Infotrieve]
51. Dousset JC, Trouilh M, Foglietti MJ. Plasma malondialdehyde levels during myocardial infarction. Clin Chim Acta. 1983;129:319-322. [Medline] [Order article via Infotrieve]
52.
Aznar J, Santos MT, Valles J, Sala J. Serum
malondialdehyde-like material in acute myocardial
infarction. J Clin Pathol. 1983;36:712-715.
53. Loeper J, Goy J, Rozensztajn L, Bedu O, Moisson P. Lipid peroxidation and protective enzymes during myocardial infarction. Clin Chim Acta. 1991;196:119-126. [Medline] [Order article via Infotrieve]
54. Loeper J, Goy J, Klein JM, Dufour M, Bedu O, Loeper S, Emerit J. The evolution of oxidative stress indicators in the course of myocardial ischemia. Free Radic Res Com. 1991;12-13:675-680.
55. Lazzarino G, Di Pierro D, Tavazzi B, Cerroni L, Giardina B. Simultaneous separation of malondialdehyde, ascorbic acid, and adenine nucleotide derivatives from biological samples by ion-pairing high-performance liquid chromatography. Anal Biochem. 1991;197:191-196. [Medline] [Order article via Infotrieve]
56.
Cooke JP, Tsao PS. Cytoprotective effects of
nitric oxide. Circulation. 1993;88:2451-2453.
57. Krucoff MW, Green CE, Satler LF, Miller FC, Pallas RS, Kent KM, Del Negro AA, Pearle DL, Fletcher RD, Rackley CE. Noninvasive detection of coronary artery patency using continuous ST-segment monitoring. Am J Cardiol. 1986;57:916-922. [Medline] [Order article via Infotrieve]
58. Shah PK, Cercek B, Lew AS, Ganz W. Angiographic validation of bedside markers of reperfusion. J Am Coll Cardiol. 1993;21:55-61. [Abstract]
59. Kwon K, Freedman SB, Wilcox I, Allman K, Madden A, Carter GS, Harris PJ. The unstable ST segment early after thrombolysis for acute myocardial infarction and its usefulness as a marker of recurrent coronary occlusion. Am J Cardiol. 1991;67:109-115. [Medline] [Order article via Infotrieve]
60. Hackett D, Davies G, Chierchia S, Maseri A. Intermittent coronary occlusion in acute myocardial infarction: value of combined thrombolytic and vasodilator therapy. N Engl J Med. 1987;317:1055-1059. [Abstract]
61. Nicolini FA, Ferrini D, Ottani F, Galvani M, Ronchi A, Behrens PH, Rusticali F, Mehta JL. Concurrent nitroglycerin therapy impairs tissue-type plasminogen activator-induced thrombolysis in patients with acute myocardial infarction. Am J Cardiol. 1994;74:662-666.[Medline] [Order article via Infotrieve]
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