(Circulation. 1995;91:1619-1623.)
© 1995 American Heart Association, Inc.
Articles |
Evaluation of Myocardial Cell Damage by In-111-Monoclonal Antimyosin Antibodies in Patients Under Chronic Tricyclic Antidepressant Drug Treatment
From the Department of Cardiology (V.M., M.B., D.O., G.P.-L.), Service of Psychiatry (C.U., E.A.) and Unit of Nuclear Medicine (I.C.), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
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Abstract |
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Background The capability of chronic tricyclic antidepressant drug (TAD) treatment to elicit myocardial damage has been a subject of debate. Lack of an adequate noninvasive method to detect such damage has prevented an in-depth study.
Methods and Results A prospective study with In-111-monoclonal antimyosin antibodies was undertaken in a series of 21 young patients with major depression on TADs and a control group of 19 healthy subjects. A heart-to-lung ratio (HLR) of antimyosin uptake was used to discriminate normal from abnormal scans. HLR in healthy subjects was 1.39±0.08. Patients on imipramine (HLR, 1.41±0.09) or clomipramine (HLR, 1.44±0.06) showed normal studies. Those under amitriptyline had a higher HLR (1.58±0.12) compared with nonamitriptyline or normal groups (P<.05). None of the 15 patients on imipramine or clomipramine showed abnormal HLR, while 3 of 6 on amitriptyline did (P<.01). In these 3 patients, uptake decreased or disappeared after drug withdrawal. Ejection fraction was normal in every patient.
Conclusions Monoclonal antimyosin antibody studies are normal in imipramine- and clomipramine-treated patients. Antibody uptake in those under amitriptyline treatment, which disappears after drug withdrawal, would suggest early evidence of myocardial toxicity.
Key Words: drug interactions • nuclear medicine • cardiomyopathy • clomipramine • imipramine • amitriptyline • antibodies
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Introduction |
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Myocardial injury due to long-term exposure of tricyclic antidepressant drugs (TADs) has been a subject of debate since the clinical description of reversible heart failure induced by treatment with these drugs.1 2 That TADs can induce myocardial damage was suggested experimentally by Acosta and Ramos3 who showed in cell cultures that lactate dehydrogenase (LDH) release was present and cell viability was limited when these drugs were added to the culture media. Demonstration of such cardiotoxic effects of TADs in humans has not been possible. Endomyocardial biopsy, which allows detection of active myocardial damage, has rarely been used.
Recently, Khaw et al4 5 have shown that In-111-labeled monoclonal antimyosin antibodies specifically bind to cardiac myosin when sarcolemmal disruption and irreversible myocyte damage have occurred. This method has been used in the detection of active myocardial damage occurring in several conditions: acute myocardial infarction,6 7 8 acute myocarditis,9 10 cardiac rejection after heart transplantation,11 12 13 14 chronic idiopathic dilated cardiomyopathy,15 16 alcohol-induced cardiomyopathy,17 and during doxorubicin therapy for cancer.18 19 20
To study if long-term treatment with TADs is associated with the presence of active myocardial damage, a series of young patients with a history of major depression under long-term treatment with TADs were prospectively evaluated with In-111-monoclonal antimyosin antibodies.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Patients
Patients were selected from those regularly attending the depression unit at our institution. A series of consecutive patients were selected who met the following criteria: (1) <40 years of age; (2) diagnosis of major depression (see below) on long-term TAD therapy; (3) exclusion of the following conditions: heart disease, hypertension, diabetes, renal or thyroid disease, hypercholesterolemia, chest pain, alcoholism, treatment with cardiovascular drugs, and patients with a history of past oscillations of their tricyclic antidepressant drug blood concentrations suggesting lack of compliance.
In the resulting group, a full cardiac and psychiatric assessment was undertaken, drug blood concentrations were determined at the time of inclusion, and ECG, M-mode, two-dimensional (2D) echocardiograms, and an antimyosin study were performed. Therefore, the selected group comprised young patients with a history of major depression on chronic TAD therapy, with a low probability of coronary heart disease, and who complied with TAD treatment.
Of the 22 patients initially evaluated, 1 on amitriptyline treatment showed a dilated cardiomyopathy at echocardiography. As such disease has been associated with ongoing myocardial cell damage,15 this patient was excluded. Therefore, a total of 21 consecutive patients (5 men, 16 women) 19 to 40 years old (mean, 31±5 years) were finally included. They were on treatment with imipramine (5 patients), clomipramine (10 patients), or amitriptyline (6 patients).
Control Group
19 healthy individuals, 10 men and 9 women, 20
to 43 years old
(mean, 29±6 years) with no history of cardiac disease, normal physical
examination, and normal ECG and 2D echocardiogram were studied with
monoclonal antimyosin antibodies and used as a control group.
Psychiatric Evaluation
Patients fulfilled the DSM III
criteria for the diagnosis of
major depression.21 Objective assessment of the severity
of depression and response to therapy was undertaken through the
Hamilton score22 ; with this method, scores >18 before
treatment suggest moderate depression, while scores <9 after therapy
indicate total remission.
TAD Treatment and Drug and Metabolite Plasma
Concentrations
Patients had been treated in the depression unit in a
standardized manner: at the beginning of treatment and during the first
6 months after the diagnosis of depression, daily doses of TADs
administered were 250 mg in imipramine-treated patients, 100 mg for
clomipramine, or 225 mg for amitriptyline. Heparinized venous blood
samples were taken frequently after initiation of treatment and every 3
months; drug dosage was modified according to the clinical response or
blood concentrations.
At the time of the antimyosin study, blood samples were drawn to determine blood concentrations of each one of the TADs. Plasma concentrations were performed by high-performance liquid chromatography with a normal phase and ultraviolet detection. A Kontrom Instruments chromatograph and a Shimadzu C-R3A Chromatopac integrator were used. The plasma concentration of the three drugs (imipramine, clomipramine, and amitriptyline) and its corresponding secondary demethylated metabolites (demethylimipramine, demethylclomipramine, and nortriptyline, respectively) were determined for each patient. Calculation of the total plasma concentration for each drug was based on the addition of the concentration drug and its metabolite.
On the basis of the daily doses taken since the beginning of treatment and the length of therapy, a cumulative drug dose was calculated for each patient.
Electrocardiographic Assessment
Standard 12-lead ECGs were
recorded at 25 mm/s speed with a
three-channel electrocardiograph. PR, QRS, and QT intervals were
measured. The QT interval was corrected for heart rate according to
Bazett's formula.
Echocardiographic Assessment
The echocardiographic study was
performed with a cardiac
ultrasound imaging unit (Vigmed CFM-700) equipped with a 3.5-MHz
transducer. The apical or parasternal approaches were used. From the
M-mode tracing taken from a 2D echocardiogram, end-systolic and
end-diastolic left ventricular (LV) diameters and septal
and posterior wall thickness were measured and LV mass and ejection
fraction calculated.23 24 Left end-diastolic
ventricular diameter and mass were indexed by dividing results by body
surface area.
Monoclonal Antimyosin Antibody Studies
After giving their
consent, patients and control subjects were
injected intradermally with 0.1 mL of labeled antibody; skin tests were
negative in all subjects. R11D10-Fab-DTPA (0.5 mg IV) labeled with 2
mCi of In-111 (Centocor) were administered 30 minutes later. Planar
scintigraphic images were obtained 48 hours after antimyosin
injection.10 Imaging was undertaken in anterior projection
with a conventional large field of view camera with a high-resolution
medium-energy collimator and 20% window centered on 247- and 173-kev
peaks. A minimum of 500 000 counts between 5 and 10 minutes were
collected. Analog and digital images were stored in a 128x128 matrix
for subsequent analysis. Interpretation of antimyosin studies was
performed by an independent observer, unaware of the cardiovascular and
psychiatric assessment, through a heart-to-lung ratio (HLR) of
antimyosin uptake, calculated by dividing average counts per pixel in a
cardiac region of interest by average counts per pixel in a pulmonary
area as previously reported in our laboratory.10 Mean HLR
in the control group was 1.39±0.08; therefore, HLR
1.55 (mean+2
SD)
was used to define abnormal antimyosin studies.
Statistical Analysis
Unpaired t test was used to
evaluate differences
between variables in the control group and patients on TAD treatment.
ANOVA was performed to assess differences between different drug groups
(imipramine, clomipramine, and amitriptyline). Statistical significance
was set at a P value of .05. Results are expressed as
mean±SD.
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Results |
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Of the 21 patients, 6 had presented with a single episode of major depression, and the remaining 15 had had more than one episode; the number of depressive episodes ranged from 1 to 10 (3.1±2.5). The first episode of major depression had been detected 10 to 164 months (mean, 44±42 months) before the study. Interval between the present episode of depression and the antimyosin study was 8 to 72 months (20±16 months). At the beginning of treatment of the current episode of depression, the Hamilton score was >18 in all patients; at the time of antimyosin study, it was <9 in all but 2, thus showing complete remission of the depression episode in 19 patients; in the remaining 2, a score of 12 was obtained, suggesting partial remission.
Table 1
shows the results in patients on tricyclic
antidepressant treatment compared with the control group. There were no
significant differences between both groups in terms of age, PR and QRS
intervals, LV size, ejection fraction, and indexed mass.
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Differences between the healthy subjects and patients on TAD treatment involved heart rate, which was higher in patients treated with TADs than in the control group (P<.005), and the QTc interval, longer in the former group (P<.001). In addition, mean HLR in the patients on TAD treatment (1.47±0.11) significantly differed from that obtained in healthy individuals (1.39±0.08) (P<.02).
Table 2 shows the clinical, echocardiographic, and
antimyosin results in the 21 consecutive patients according to the type
of antidepressive drug. When different drug groups were analyzed, it
was found that only patients with amitriptyline had abnormal HLR
(Figure). In fact, 3 of 6 patients with amitriptyline
showed abnormal HLR compared with none of the 15 patients treated with
imipramine or clomipramine (P<.01). Mean HLR in patients on
amitriptyline was significantly higher (1.58±0.12) than in those
treated with imipramine (1.41±0.09) or clomipramine (1.44±0.06)
(P<.05).
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In view of the positive antimyosin studies obtained in patients under amitriptyline treatment, it was decided to restudy this particular group after withdrawal of the drug. Five of the 6 patients in this group were restudied 5 to 12 months (mean, 6.2 months) after changing to clomipramine therapy (3 patients) and fluoxetine (2 patients). Results showed that in the 3 patients with antimyosin uptake, HLR decreased from 1.60 in 2 patients and 1.80 in the remaining patient to 1.40, 1.44, and 1.70, respectively. No changes in mean LV diameter, mass, or ejection fraction were noted between the two antimyosin studies. Interestingly, the patient excluded from the present study with dilated cardiomyopathy under amitriptyline treatment had an abnormal antimyosin uptake (HLR, 1.73), which normalized after drug withdrawal (HLR, 1.40) without functional changes.
No correlation was found between the HLR and total plasma concentration of TADs, cumulative drug doses, or ECG or echocardiographic parameters.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The main side effects of TADs on the cardiovascular system are hypotension, tachycardia, and ECG changes. These have been well documented and are thought to be due to the pharmacological features of these drugs (anticholinergic activity,
-receptor blocking
properties).25 26 In the present study, the high
ejection fraction (>75%) seen in 7 of the patients studied and the
increased heart rate and longer QTc in patients compared
with control subjects probably reflect these effects.
The effects of TADs on the myocardium are far from clear. Since the
first descriptions of reversible heart failure ascribed to TAD
therapy,1 2 several attempts to find a causal
relationship
between TAD administration and myocardial disease through controlled
studies have failed (Table 3). Noninvasive assessment of
LV function through calculation of systolic time intervals revealed a
mild, concentration-dependent, negative inotropic
effect,29 30 31 but doubts arose on
changes of such intervals
being specific indicators of LV dysfunction. Lack of detectable effects
on LV function in a series of 35 patients with acute intoxication with
TADs further questioned TAD-induced myocardial toxicity.33
More recently, two prospective series using multiple gated isotopic
studies have failed to demonstrate any effects of TAD treatment on LV
performance in depressive patients with heart
disease.34 35
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The present work provides the first prospective study to evaluate the presence of active myocardial damage in a selected group of young patients under long-term treatment with TADs through the myocardial uptake of In-111–labeled monoclonal antimyosin antibodies. The presence and intensity of antimyosin uptake assessed by HLR was equated with the presence and degree of active myocardial damage, as validated in two human models of diffuse myocardial damage.12 13 14 18 19
Results showed that patients under treatment with imipramine and clomipramine do not have antibody uptake. Therefore, long-term treatment with these two drugs does not appear to be associated with myocardial cell damage. However, antibody uptake was detected in 3 patients under amitriptyline treatment; cessation of the drug significantly decreased such uptake, and in 2 patients a second antimyosin study was normal.
The presence of antibody uptake in the face of normal ventricular function raises the issue of possible early myocardial toxicity due to amitriptyline detected by monoclonal antimyosin antibodies. In this respect, earlier than the conventional evidence of myocardial damage has been documented by In-111–monoclonal antimyosin antibodies in other types of diffuse myocardial disease, such as in rejection after heart transplantation36 and in patients under doxorubicin treatment.20 In the former instance, long-term coexistence of antimyosin uptake and normal ventricular function has been described.37 The rare occurrence of myocardial dysfunction in patients on TADs has been ascribed to the usual short duration of these treatments, and the few reports dealing with patients on long-term treatment with TADs showed a negative inotropic effect reversible after drug withdrawal.30 31
The mechanism of myocardial cell damage is uncertain. Experimentally, Acosta and Ramos,3 using LDH release of cultured myocardial cells as a criterion for cell damage, showed that amitriptyline induced severe abnormalities of the sarcolemmal integrity that were more important than those induced by imipramine. Mattila and Saarnivaara38 reported that rabbits injected with amitriptyline showed myocardial dysfunction and death, findings not seen with imipramine or other antidepressant drugs. Sarcolemmal disruption would explain the permeability of cell membrane to Fab fragments of antimyosin antibodies, a finding which heralds irreversible cell death.5
Study Limitations
The present study was designed to assess
the possible presence
of myocardial damage detected in a very select group of young
individuals under long-term TAD treatment. No previous hypothesis
regarding the differential effect of various TADs on the myocardium was
considered. Although the statistical power of the comparative
analysis between the three TADs and the significant reduction of
antimyosin uptake after amitriptyline withdrawal provide strong
evidence of a causal relationship between amitriptyline treatment and
myocardial damage, the present data should be interpreted with
caution in relation to the long-term clinical implications of this
toxicity, especially in terms of the uncertain evolution to more severe
forms of myocardial disease.
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Acknowledgments |
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This work was supported by the Fondo de Investigaciones Sanitarias de la Seguridad Social (FISS), grant no. 0723/89, and Premio Banco de Santander de la Sociedad Española de Cardiología 1990. We are grateful to Carme Casanovas for her efficient and dedicated secretarial work and to Ferran Sanz, PhD, and Jaume Marrugat, MD, PhD, for statistical advice.
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Footnotes |
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Reprint requests to Vicens Martí, MD, PhD, Department of Cardiology, Hospital de la Santa Creu i Sant Pau, Sant Antoni M. Claret 167, 08025 Barcelona, Spain.
Received October 20, 1994; accepted January 14, 1995.
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