Negative Chronotropic Effects and Coronary Ischaemic Abnormalities Following Thalidomide Therapy

Abstract

The severe teratogenic side effects of thalidomide led to its well-publicized withdrawal in the 1970s, but as it is cautiously being reintroduced into clinical use, new adverse effects are being described. A 65-year-old male with multiple myeloma received chemotherapy which included cyclophosphamide, thalidomide and dexamethasone. Whilst on this treatment he experienced severe chest pain leading to an acute hospital admission complicated by significant bradycardia with sinus pauses of 7 s, necessitating temporary right ventricular pacing. Despite correction of the bradycardia with temporary pacing, he experienced further episodes of chest pain, during which an ECG (with the pacemaker briefly switched off) showed ST elevation in the inferior leads along with runs of non-sustained ventricular tachycardia. Emergency coronary angiography demonstrated unobstructed coronary arteries. Due to ST elevation in the absence of flow-limiting coronary disease his presentation was presumed to be due to intermittent coronary artery spasm. He was started on sustained-release nifedipine without any beta-blockers and further thalidomide therapy was omitted. On this pharmacological therapy, over a period of 24 months, there were no further recurrences of any cardiac symptoms. To our knowledge there have been no previous reports of coronary artery spasm associated with the use of thalidomide. The precise mechanism remains undefined, with several plausible hypothetical pathways which we discuss. We discuss various mechanisms including autonomic, autocoid and paracrine modes of action that may underlie cardiac side effects of thalidomide. We report coronary spasm in addition to bradycardia as cardiac side effects that cardiologists and oncologists need to be alert to.

Myocardial infarction, symptomatic third degree atrioventricular block and pulmonary embolism caused by thalidomide: a case report

“…Because no right-left shunt was found in heart, paradoxical embolism of coronary artery from venous thrombi was not likely. Because coronary angiography demonstrated no flow-limiting lesions or thrombus in major coronary arteries, it probably was the coronary spasm that caused myocardial infarction [ 9 ], which had been reported as a rare complication of thalidomide therapy (only one case in the past) [ 2 ] and maybe further ergonovine provocation test was needed to ensure the existence of it. The precise mechanism that caused spasm remains undefined, and someone believed thalidomide could cause vasoconstriction through endothelial disruption [ 2 ].…”

“…Because coronary angiography demonstrated no flow-limiting lesions or thrombus in major coronary arteries, it probably was the coronary spasm that caused myocardial infarction [ 9 ], which had been reported as a rare complication of thalidomide therapy (only one case in the past) [ 2 ] and maybe further ergonovine provocation test was needed to ensure the existence of it. The precise mechanism that caused spasm remains undefined, and someone believed thalidomide could cause vasoconstriction through endothelial disruption [ 2 ]. And the ST segment elevation was persistent even though no obvious coronary spasm observed during angiography, probably because of acute myocardial infarction (likely ST elevated myocardial infarction) caused by coronary spasm.…”

“…Cardiac adverse effects associated with thalidomide also include bradycardia [ 2 – 4 ]. The mechanism for this remains unclear although interference with autonomic nervous system has been suggested, with parasympathetic over activity caused by inhibition of TNF-α by thalidomide in the dorsal motor neurons of valgus nerve [ 4 ].…”

“…As it is cautiously being reintroduced into clinical use, new adverse effects are being described. Trials have reported numerous thromboembolic events attributed to thalidomide therapy, especially in multiple myeloma patients; deep vein thrombosis (DVT) and pulmonary embolism (PE) are more common, but occasional arterial thrombotic events have also been reported [ 1 ]; it also can cause bradycardia [ 2 – 4 ] and even total atrioventricular block (AVB) (the only case ever reported) [ 5 ]. Even Rarely, thalidomide can caused coronary artery spasm [ 5 ] and myocardial infarction (MI).…”

Chemotherapeutic agents for the treatment of hepatocellular carcinoma: efficacy and mode of action

“…Ten years later, thalidomide was banned due to its teratogenic action which was related to the inhibition of new blood vessel formation. 38 , 39 Once more, thalidomide attracted the attention of oncologist due to its effects in certain multiple myelomas. 40 , 41 …”