Cardiotoxicity of high-dose methylprednisolone in patients with chronic lymphocytic leukemia – a case report

Introduction: Several classes of drugs can cause atrial fibrillation (AF) in patients without heart disease, as well as the occurrence of AF in pre-existing heart disease. Drug-induced AF is most often clinically manifested in the form of paroxysms. High doses of intravenous methylprednisolone (HDMP) in the treatment of chronic lymphocytic leukemia (CLL) have been associated with the occurrence of various adverse effects, including AF. The exact mechanism of HDMP-induced AF is unknown.

Case presentation: We present the case of a patient with CLL in whom AF occurred after the administration of a high dose of intravenous methylprednisolone.

Conclusion: Physicians should be aware of the special circumstances in the treatment of CLL, because drug-induced AF can be a side effect that limits further therapy.

INTRODUCTION

Atrial fibrillation (AF) is the most frequent cardiac rhythm disturbance in clinical practice and is most commonly associated with coronary disease and hypertension. It is known, from relevant literature, that several classes of drugs (sympathomimetics, parasympathomimetics, and their inhibitors) may cause atrial fibrillation in patients who do not suffer from heart disease [1],[2],[3]. Drug-induced AF increases the number of hospitalizations and the incidence of ischemic stroke.

High-dose intravenous methylprednisolone therapy (HDMT) is the standard therapy in a large number of autoimmune and hematological diseases (autoimmune thrombocytopenia, chronic lymphocytic leukemia (CLL), and other diseases) [4],[5],[6],[7].

The occurrence of methylprednisolone-induced atrial fibrillation has been described in literature in several different diseases (multiple sclerosis, rheumatoid arthritis, membranoproliferative glomerulonephritis). The use of corticosteroids is associated with different adverse effects. Cases of atrial fibrillation have also been documented [8],[9],[10],[11],[12],[13],[14]. The following have been registered as the most frequently occurring adverse effects of high doses of corticosteroids: altered sense of taste (61%), facial redness (61%), insomnia (44%), and mood disorders (36%) [15].

Electrophysiological effects in the atrium, leading to atrial fibrillation, may be induced or triggered by physiological processes, such as adrenergic or vagus nerve stimulation, by metabolic or electrolyte disorders, as well as by the effects of certain drugs or agents [16]. Pathophysiologically, drugs increasing or decreasing adrenergic or vagal activity, such as sympathomimetics, parasympathomimetics, and their inhibitors, may cause atrial fibrillation, especially in cardiovascular patients (the disease is the substrate, the drug is the trigger), but also in seemingly healthy patients. [3]. The mechanism of drug-induced atrial fibrillation is not precisely known. Fujimoto et al. found that the efflux of potassium from the cell, caused by the direct action of methylprednisolone on the cell membrane, may lead to cardiac rhythm disturbance [12].

We present the case of a patient with CLL, in whom, after the administering of high-dose intravenous methylprednisolone, AF occurred.

CASE REPORT

A 69-year-old patient had the diagnosis of chronic lymphocytic leukemia, established in 1992 – clinical stage (CS) 0. Anamnesis showed no other chronic diseases. The patient had regular follow-up; he received no treatment until February 2019, when the disease started to progress and general symptoms, as well as splenomegaly, developed. Laboratory blood test results showed the following: leukocytosis (47.1 x 10⁹/l) with 80% of lymphocytes, anemia with a hemoglobin level of 115 g/l, thrombocytopenia (132 x 10⁹/l), as well as normal levels of lactate dehydrogenase (194 IJ/L), renal function parameters, and hepatogram. Cytogenetic analysis – fluorescence in situ hybridization (FISH) discovered 3q deletion in 80% of nuclei and 17p deletion in 20% of nuclei.

Treatment started with the application of HDMP (1,500 mg per day, IV, for 5 days, in four-week cycles). On the third day of the second cycle, after the application of HDMP, the patient reported feeling palpitations. The electrocardiogram (ECG) registered individual extrasystoles, and then the occurrence of atrial fibrillation, with a ventricular frequency of around 140/min, without changes in the ST segment. The patient was normotensive. Troponin (high sensitivity troponin I assay – hsTnI), creatine kinase (CK), creatine kinase isoenzyme (CK-MB), pro b-type natriuretic peptide (proBNP) (100 pg/ml), and thyroid status (thyroid stimulating hormone – TSH) (1.66 mU/l) were within the reference range (hsTnI < 34 ng/L; CK = 29 - 168 IJ/L; CK-MB = 7 – 25 IJ/L: proBNP < 450 pg/ml; TSH = 0.35 – 4.94 mU/L). Echocardiographically, the left atrium had normal dimensions, without spontaneous echo contrast or thrombotic masses; normal systolic and diastolic function of the left ventricle (ejection fraction = 55%) was registered. Coronarography did not establish the presence of coronary heart disease.

After 48 hours of treatment with a class III antiarrhythmic (amiodarone), conversion into normal sinus rhythm occurred; the normal sinus rhythm persisted, which was confirmed with 24-hour Holter ECG. In addition to amiodarone, the patient was also on a low dose of beta-blockers when the next cycle of HDMP was administered, upon whose completion, after 48-hour Holter monitoring, paroxysmal atrial fibrillation was not registered.

DISCUSSION

Drug-induced atrial fibrillation occurs in patients without previous episodes of atrial fibrillation or structural heart disease. The expected risk of drug-induced atrial fibrillation is increased in elderly patients and patients with cardiovascular comorbidities [3],[17]. The mechanism of the development of arrythmias after high doses of corticosteroids is not clear. Several possible mechanisms have been proposed: direct increase in the efflux of potassium, the effect of mineralocorticoids, which leads to the retention of sodium and fluids, increase of the left atrium and congestive heart failure, as well as the development of late potentials and pronounced peripheral vasodilator response [3],[12],[18],[19].

Several cases of atrial fibrillation developing after high-dose corticosteroid treatment have been described in literature [10],[11],[13],[19],[20],[21],[22]. A study by van der Hooft et al. has shown that the application of high doses of corticosteroids is connected with increased risk of atrial fibrillation development [18].

In some studies, corticosteroids have been connected to the occurrence of atrial fibrillation, independently of the method of drug administration. The occurrence of atrial fibrillation was recorded during the application of high-dose methylprednisolone pulse therapy [5],[6],[7],[8],[9],[14], in the application of lower doses of intravenous methylprednisolone therapy, as well as after the application of inhalation corticosteroids [5],[23],[24].

Reports of atrial fibrillation occurring during or soon after IV administration of HDMP [11] or within 24 – 48 hours of the completion of HDMP therapy [5],[21],[22] can be found in literature. Also, several published cases have shown that the occurrence of atrial fibrillation was registered within 24 to 48 hours since the completion of HDMP therapy. In our patient, the time of atrial fibrillation occurrence was in keeping with previous reports.

Moretti et al. described the case of a fifty-nine-yearold man diagnosed with primary progressive multiple sclerosis, who was treated with high doses of methylprednisolone. After the third dose of methylprednisolone (1 g, IV, for 2 hours) ECG showed AF. After being treated for two days with digoxin and propafenone, AF was converted to normal sinus rhythm with medication [9].

The onset of drug-induced atrial fibrillation is rather variable, depending on the drug, ranging from several seconds/minutes after intravenous application of a drug with a short half-life, to several days after application, in the case of some chemotherapeutic agents. Sometimes, drug-induced AF occurs, not during the first, but after repeated exposure to a drug. The duration of drug-induced atrial fibrillation is also variable – the duration of several seconds to several hours has been described [25].

Our patient did not have a history of previous stroke, or a history of hyperthyreosis, coronary disease, nor implanted cardiac devices, previous open-heart surgeries or previously registered episodes of atrial fibrillation. The ECG, before HDMP application, showed normal cardiac rhythm. As in most cases, in the case of our patient as well, AF was paroxysmal and ended after a few hours.

To date, no factors have been identified that would help predict the occurrence of atrial fibrillation. In previously published studies, the so-called global strain and strain rate of the left atrium were significantly decreased in patients with paroxysmal atrial fibrillation, as compared to the normal values found in the control group [26],[27],[28],[29].

It is interesting that P-wave duration and P-wave dispersion are also connected with the increased risk of atrial fibrillation occurrence, and they can be used as electrocardiographic markers [30]. Also, natriuretic peptides are statistically significantly connected with incident AF [31]. In our patient, proBNP was within the reference range.

The occurrence of atrial fibrillation has also been reported in the application of tyrosine kinase inhibitors (ibrutinib) in patients with CLL, in 6 – 16% cases [32],[33].

CONCLUSION

Drug-induced atrial fibrillation is a side effect of treatment, which may be a limiting factor for the continuation of underlying disease treatment. Clinical examination and electrocardiographic monitoring, during and after high-dose corticosteroid treatment, may increase the chances of earlier diagnosis of atrial fibrillation. Further research and investigation are necessary in order to discover the predictive factors for the occurrence of atrial fibrillation, before the administration of specific therapy.