Cardiac arrhythmia as a side effect of ketanserin therapy in a patient with systemic scleroderma.
ABSTRACT INTRODUCTION Systemic scleroderma (SS) is a systemic disorder of the connective tissue, of obscure etiology and characterized by fibrosis of the skin, visceral organs and vascular walls. Clinically, it is a heterogeneous disorder characterized by high collagen deposition into the connective tissue, microcirculation abnormalities, and immune system impairment (1). It may be localized to the skin and show a mild clinical course, or may involve visceral organs, kidneys, lungs, heart and gastrointestinal organs, assuming a malignant course (1). The pathophysiology of SS is complex. Environmental, genetic, vascular and immune factors, fibroblasts and matrix substances seem to be implicated in the pathogenesis of the disease, thus SS is classified in autoimmune diseases, or generally in connective tissue disorders (2). Immune fibroblast stimulation occurs due to some unknown reason, which is followed by an enhanced collagen production, vascular endothelial lesions and fibrosis (2). Raynaud's phenomenon is pronounced in SS, found in 90%-98% of cases (1,2); however, pulmonary and renal vessels may frequently be involved, resulting in considerably more severe sequels. Some observations imply serotonin as the possible pathogenetic factor in the development of microvascular disease (2,3). Serotonin may lead to digital ischemia or constriction of digital arteries alone. In patients with Raynaud's phenomenon, serotonin infusion leads to abnormally long vasoconstriction. Serotonin antagonists alleviate these symptoms and improve blood flow in digital arteries as well as clinical signs of SS. Nearly all circulating serotonin is found in specific platelet granules and is released on platelet aggregation. Platelet activation has been clearly demonstrated in SS. Besides kidneys and lungs, SS may also involve the heart. Cardiac involvement in SS may frequently be underestimated because the symptoms are attributed to pulmonary, musculoskeletal or esophageal lesions. Cardiac manifestations in SS may vary, may be primary or secondary, due to pulmonary hypertension or renal crisis (4). Systemic scleroderma may involve the myocardium, coronary arteries, conduction system, or pericardium (4). Clinically, it may present with left heart failure, cardiac congestion, chest pain due to myocardial ischemia, syncope, and sudden death due to arrhythmia. Recent studies indicate that clinical signs of myocardial lesion are present in 20%-25% of SS patients (4,5). In a study that included 54 patients, electrocardiogram abnormalities, pericardial effusion, elevated systolic pressure in the right ventricle, or left atrial dilatation were recorded in 69% of patients (4). Besides structural changes, arrhythmias and conduction system abnormalities were verified by 24-h ambulatory monitoring (4). Heart involvement is an adverse prognostic sign in SS (6,7). Medsger and Masi demonstrated the clinically present heart involvement in SS to be associated with 70% 5-year mortality (6). Myocardial fibrosis and pericardial disease are the most common and typical autopsy findings. Arrhythmias and conduction impairments are relatively frequent in SS patients and are considered consequential to cardiac conduction system fibrosis or ischemia. The treatment of SS is focused on the prevention and alleviation of endothelial lesions, collagen overproduction, and suppression of immune reaction. Many agents have been tried in the treatment and prevention of vascular manifestations, however, mostly with disappointing results (1,2). Patients are advised to avoid cold and stress exposure, and to quit smoking. Calcium antagonists, e.g., nifedipine in a dose of 30-60 mg/day, are used with limited success and frequently have to be discontinued due to side effects. Angiotensin II receptor antagonists have proved more efficient than calcium antagonists in Raynaud's phenomenon, losartan 50 mg/day led to reduction of body weight and frequency of vasospasms. Prostaglandins, e.g., iloprost and cisaprost, as potent vasodilators, were not superior to placebo in a controlled study (8). Prasosine proved only partially efficient, whereas ketanserin and cyclophenyl were inefficient. Ketanserin is a serotonin receptor blocker. Serotonin can cause peripheral vasoconstriction, especially in SS, platelet aggregation and pulmonary hypertension (3). In some studies, the use of ketanserin led to inhibition of platelet aggregation and of vasoconstriction (3,9,10). CASE REPORT A female patient N. M., born in 1959, was diagnosed with SS according to the American College of Rheumatology criteria (1). Clinical picture was predominated by the symptoms and signs of Raynaud's syndrome, and therapy with nifedipine, a calcium antagonist, aspirin and ketanserin was prescribed. The patient was followed-up at regular intervals, with complete work-up every 6 months to verify the possible changes involving parenchymal organs. Despite therapy, hand and foot lesions progressed, with the occurrence of ulcerations, necrosis and contractures. The patient had difficulties with food mastication and deglutition. In 2000, she was treated for pneumonia; in 2004, she was diagnosed with cryoglobulinemia and a corticosteroid was introduced in therapy. In 2007, ultrasonography of the heart revealed frequent extrasystoles (ES), which were not noticed by the patient; therefore, ambulatory ECG monitoring (Holter) was used to record an array of cardiac rhythm abnormalities (supraventricular or ventricular ectopic beats, sinus bradycardia, sinus tachycardia, sinus pauses, paroxysmal supraventricular tachycardia, and ventricular tachycardia, fortunately without hemodynamic and subjective discomforts). The conduction system impairments due to the underlying disease were considered to be the cause of these abnormalities. As the patient reported no subjective discomforts and no hemodynamic sequels were recorded, we decided to postpone additional cardiologic examinations and therapy for some time. Instead, we reconsidered the medicamentous therapy she had taken by then and raised doubts about side effects of the drugs taken by the patient, first of all ketanserin. Indeed, all heart rhythm abnormalities disappeared upon discontinuation of ketanserin therapy. The follow up Holter finding was normal. CONCLUSION Systemic scleroderma may involve almost every parenchymal organ or system, including cardiovascular, myocardium, pericardium, and conduction system of the heart. Although the impact of SS on cardiac function has long been known, its prevalence and prognosis have only recently been more extensively investigated and better understood. In most patients, cardiac involvement is subclinical; however, the prognosis is very poor in those that develop overt symptoms and complications. Development of a number of novel noninvasive and invasive techniques in cardiology has certainly contributed to these new insights. Of the currently available screening methods, annual echocardiographic examination and assessment of the N-terminal segment of the pro-B natriuretic peptide (NT-pro-BNP) concentration is recommended to anticipate the development of cardiac symptoms (5). The true cause of SS remains unknown, and thus the treatment remains quite inefficient. Therefore, the aim of therapy is to prevent and reduce vascular lesions, fibrosis and/or immune response suppression. Numerous agents, including ketanserin, have been tried to prevent and reduce vascular lesions. Ketanserin proved efficient in some studies, but not in others. However, all these drugs are associated with potential side effects. Therefore, in case of complications in SS patients, differential diagnosis is very broad; yet, prior to introducing extensive diagnostic work-up with both noninvasive and invasive examinations, therapy taken by the patient should be carefully explored, with special reference to its possible side effects. In our patient, drug side effects were the main culprit, fortunately without clinical sequels, and recognizing it we obviated the use of invasive procedures.