EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Corticosteroids have a wide range of uses. The most common adverse side effects of high-dose pulse steroids are hyperglycemia, gastrointestinal intolerance, and psychiatric symptoms. Cardiac arrhythmias have been reported in patients who receive high-dose steroid therapy. Bradycardia is a rare adverse side effect of pulse steroid therapy. We present the case of a 57-year-old male patient who developed symptomatic sinus bradycardia after he received pulse methyl-prednisolone therapy as treatment for graft-versus-host disease. The patient’s pulse steroid therapy was discontinued, and the dose of methylprednisolone was reduced to 100 mg/day. He was treated conservatively and with close observation; the patient’s heart rate increased to 68 beats/min after 1 day, and then to 78 beats/min. The diagnosis of methylprednisolone-induced bradycardia was made after exclusion of other common etiologies of sinus bradycardia. This case report demonstrates the importance of careful cardiovascular monitoring in patients who receive high-dose methylprednisolone because of dose-related cardiovascular risks.

Key words : Cardiovascular risk, Graft-versus-host disease, High-dose steroid therapy, Pulse therapy

Corticosteroids have a wide range of uses due to the anti-inflammatory and immune modulatory pro-perties of these agents. Because of these properties, corticosteroids are used in the treatment of various hematologic conditions, as well as the treatment of many diseases. Acute graft-versus-host disease (aGVHD) is a complication of allogeneic hemato-poietic stem cell transplant that occurs early after transplant.

The skin, gastrointestinal tract, and liver are the main target organs in patients with aGVHD. For the treatment of aGVHD at grade ?2, treatment with systemic glucocorticoids (eg, methylprednisolone) has been widely adopted. Treatment is usually started with 2 mg/kg/d methylprednisolone in divided doses.¹ Studies of high-dose intravenous methylprednisolone (eg, 10-20 mg/kg/d) have shown a high response rate.^2,3 Our patient had extensive skin and gastrointestinal and liver involvement, so we planned a regimen of high-dose methylprednisolone for 3 days followed by methyl-prednisolone at a dose of 2 mg/kg. The most common adverse side effects of high-dose pulse steroids are hyperglycemia, gastrointestinal intolerance, minor infections, and psychiatric symptoms. Overall, cardiac arrhythmias have been reported in 1% to 82% of patients given high-dose corticosteroid therapy.^4,5

Bradycardia is a rare side effect of pulse steroid therapy and is usually asymptomatic. In this case report, we present an episode of severe asymp-tomatic sinus bradycardia detected during routine follow-up of vital functions, which developed 3 days after pulse steroid therapy in a 57-year-old male patient with aGVHD.

Bone marrow biopsy was performed in a 57-year-old male patient due to pancytopenia in July 2021. In the patient’s bone marrow, cellularity was 80%, myeloid/erythroid ratio was 15/1, and blast ratio was 15%. The patient was diagnosed with myelodysplastic syndrome and was given 4 cycles of hypomethylation therapy. However, allogeneic stem cell transplant was performed from an unrelated 9/10 matched male donor in June 2022, to treat the increased need for transfusion and high risk of complications according to the International Prognostic Scoring System in this patient who did not respond to the treatment.

Echocardiogram results were unremarkable, and contractility and valve function were within reference limits, both after the diagnosis of myelodysplastic syndrome and before the allogeneic stem cell transplant. In September 2022, chimerism was 100%. After taper of the cyclosporine dose was initiated, widespread erythema and skin dryness was observed on the head, neck, trunk, and extremities of the patient. The patient’s cyclosporine dose was increased, and he received steroid therapy for a short time. Skin lesions regressed with treatment, but desquamation and postinflammatory hyperpigmen-tation remained present in some areas.

In January 2023, thrombocytopenia was detected. Bone marrow biopsy showed increased myeloid series, 70% cellularity, and sufficient multilobular megakaryocytes. The patient’s cyclosporine dose was reduced. In the control physical examination, there was widespread erythema, dry skin, and hyperpig-mentation. Liver was palpable in deep inspiration, and the Traube space was open. A skin biopsy was taken from the right scapula. In the complete blood count, white blood cell count was 9.81 × 10⁹ cells/L, neutrophils 7.97 × 10⁹ cells/L, hemoglobin 9.6 g/dL, hematocrit 28.1%, and platelet count 26 × 10⁹ cells/L. The platelet count in the peripheral smear was consistent with the results from whole blood.

The patient, who also had an increase in liver and cholestasis enzymes (Table 1), was hospitalized with a prediagnosis of liver and skin GVHD. His biopsy was reported as skin GVHD. Mycophenolate mofetil (2 doses of 1000 mg) and intravenous methylpred-nisolone (1 g/d) were planned for 3 days. On day 3 of treatment, heart rate was 55 beats/min, and sinus bradycardia was observed on elec-trocardiography in the routine follow-up of vital functions. We obser-ved that the patient was asymptomatic at this time.

Figure 1 shows the electrocardiography results before the pulse steroid treatment, during the bradycardia, and after the dose reduction of the steroid treatment. Troponin T and creatinine kinase were within reference limits. The dose of methylprednisolone was reduced to 100 mg/d, and 1 day later the patient’s heart rate increased to 68 beats/min, and then subsequently to 78 beats/min.

Due to the absence of bradycardia among the adverse side effects of other drugs and because the heart rate recovered after corticosteroid dose reduction, bradycardia was associated with pulse steroid therapy.

Corticosteroids are widely used for many pathologic conditions in clinical practice. High-dose corticos-teroid therapy (known as pulse corticosteroid therapy) is used for the treatment of hematologic, ophthalmic, neurologic, nephrologic, dermatologic, and rheumatologic diseases, as well as some neoplastic diseases.⁶ Although the adverse side effects of chronic corticosteroid use are well known (eg, increased appetite, hyperglycemia, hypertension, depression, osteoporosis, and Cushing syndrome), awareness remains low regarding the adverse side effects that occur with short-term high doses of corticosteroid.

In recent years, rhythm changes due to corti-costeroid treatments have been reported, mostly in adults. These rhythm changes can be seen as tachyarrhythmias or bradyarrhythmias.⁷ These arrhythmias include atrial fibrillation, sinus tachy-cardia or bradycardia, premature atrial contractions, and premature ventricular contractions.⁸ Although arrhythmias are usually asymptomatic and mitigated with simple treatment, symptoms such as palpitations, chest pain, unconsciousness, and cardiac arrest may occur in some patients.⁹

Steroids are known to cause arrhythmias, but the mechanism of action remains controversial. Animal studies have shown that high-dose methyl-prednisolone has various effects on the cardiovascular system, particularly blunting the chronotropic response to catecholamines through ?1 receptor sensitivity.^10-12 These effects may result from (1) a direct effect on electron exchange in the myocardial cell membrane and (2) changes in the sensitivity of the sinoatrial node to catecholamines.

Many factors may contribute to the development of bradycardia after pulse corticosteroid therapy. These predisposing factors include rapid intravenous infusion of corticosteroids (typically less than 30 minutes) and underlying heart disease or kidney disease.^13,14 Electrolytes, especially potassium, should be monitored prior to treatment, and any deficiencies should be corrected. In patients without comorbidities, corticosteroids are less likely to cause bradycardia, but such a complication was seen in our patient, despite the absence of a renal or cardiac comorbid disease. In our case, bradycardia was detected 3 days after initiation of pulse corticosteroid therapy.

In the literature, sinus bradycardia has generally been reported between 1 and 7 days after the initiation of pulse corticosteroid therapy.^15,16 Late onset may make it difficult to consider corticos-teroids as the cause of bradycardia. Cardiac arrhythmias at varying rates have been reported in patients receiving high-dose corticosteroids.^4,5 These undesirable effects are usually associated with the intravenous route of administration. As in our case, bradycardia is usually associated with high-dose intravenous corticosteroid administration, but some cases of bradycardia have been reported after low-dose intravenous and oral corticosteroid therapy.7,8,16-18 As in our case, methylprednisolone or prednisone has been reported as the cause of steroid-related bradycardia.^7,8,15,16 However, intravenous dexamet-hasone has also been identified as a causative agent.^5,19

Corticosteroid-induced bradycardia is generally well tolerated in the absence of underlying heart or kidney disease or electrolyte disturbances.^7,14,16 Dizziness and chest pressure/pain are often reported as symptoms.^8,20 Our patient was asymptomatic and had a medical history of normal cardiac functions; no sudden cardiac pathology was detected in the re-evaluation with echocardiography after the incidental detection of bradycardia. Generally, bradycardia resolves within 3 to 10 days after corticosteroid cessation or dose reduction.^16,19,21 In accordance with the literature, bradycardia completely resolved without any other intervention after the steroid dose was reduced in our patient.

Steroids are frequently used in the treatment of many diseases. Our report provides evidence to suggest that pulse steroid therapy may be complicated by adverse side effects that are different from the effects observed in long-term corticosteroid therapy. Patients with an underlying heart or kidney disease who receive high-dose steroids are at particularly high risk to develop bradycardia, although it is rare. These patients should be followed closely in terms of electrolyte disturbance and heart rate. Cardiac complications should be considered in patients with chest pressure, pain, or shortness of breath, and symptomatic patients should seek immediate medical attention.

Volume: 21 Issue: 11 November 2023

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