Antiepileptic Drugs Impair Shortening of Isolated Cardiomyocytes

Abstract

BackgroundMost antiepileptic drugs (AEDs) inhibit seizure generation by acting on voltage-dependent ion channels. Voltage-dependent sodium and calcium channels are commonly expressed in brain and heart, suggesting that AEDs may have considerable cardiodepressive effects, thereby facilitating sudden cardiac death as a potential cause of sudden unexpected death in epilepsy. Here, we investigated the effects of carbamazepine (CBZ), lamotrigine (LTG), and levetiracetam (LEV) alone and in combination on the shortening properties of isolated ventricular cardiomyocytes of wild-type mice.MethodsProperties of murine cardiomyocytes were determined by recording the sarcomere shortening with a video imaging system before, during, and after administration of AEDs in different concentrations and combinations. We assessed (i) the number of successful shortenings during continuous electrical stimulation (electromechanical coupling) and (ii) the shortening amplitude as well as other shortening-related properties upon repetitive electrical stimulation at 4 Hz. Data are given as mean ± SEM.ResultsAt 100 μM, CBZ (10 cells), LTG (11 cells), and LEV (11 cells) alone had no effect on the electromechanical coupling but reversibly reduced shortening amplitudes by 15 ± 4, 24 ± 3, and 11 ± 3%, respectively. Increasing the LTG concentration to 250 (21 cells) and 500 μM (4 cells) reversibly inhibited the electromechanical coupling in 62 and 100% of the experiments. Importantly, simultaneous application of CBZ, LTG, and LEV at 100 μM also impaired the electromechanical coupling in 8 of 19 cardiomyocytes (42%) and reduced the shortening amplitude by 21 ± 4%.ConclusionOur data show that AEDs reversibly impair cardiac excitation and contraction. Importantly, the blocking effect on electromechanical coupling appears to be additive when different AEDs are simultaneously applied. The translational value of these experimental findings into clinical practice is limited. Our results, however, suggest that rationale AED therapy may be important with respect to cardiac side effects and potential facilitation of serious cardiac dysfunction especially when AEDs are used in combination or at very high doses.

Identifying patients with epilepsy at high risk of cardiac death: signs, risk factors and initial management of high risk of cardiac death

“…Importantly, at very high doses, after ingestion ("overdose'') or in combination with other sodium channel blocking agents or ASMs at higher daily doses, sodium channel inhibitors were reported to cause cardiac arrhythmias, independently of pre-existing cardiac diseases. The use of carbamazepine, lacosamide, lamotrigine and phenytoin was mostly associated with bradyarrhythmias (such as sinus node dysfunction and AV block), but also with ventricular tachyarrhythmia and atrial fibrillation [126][127][128][129][130][131]. The reports on ASM-induced alterations of cardiac autonomic control and HRV are controversial, but according to a meta-analysis including six original studies, there is no apparent effect of ASM on HRV [132].…”

Blood Pressure in Seizures and Epilepsy

“…For instance, rapid intravenous application of phenytoin and sedatives such as barbiturates, benzodiazepines, and anesthetic agents are known to lower BP or to induce hypotension (94). These acute effects are likely to be induced by inhibition of voltage-gated sodium and calcium channels with subsequent decrease of cardiac contractility and SV [for review see e.g., (95)]. Probably the most common effects of anti-seizure agents on BP are of indirect nature and related to weight gain [e.g., upon intake of valproic acid, gabapentin, and pregabalin (6)] and detrimental effects on circulating cardiovascular risk factors such as dyslipidemia and hyperhomocysteinemia mostly caused by enzyme-inducing anti-seizure drugs (e.g., carbamazepine, phenobarbital, phenytoin) which in turn may lead to atherosclerosis with decreased blood vessel flexibility and reactivity (96–98).…”

Epilepsy and ultra-structural heart changes: The role of catecholaminergic toxicity and myocardial fibrosis. What can we learn from cardiology?

“…These drugs increase the risk of arrhythmias (proarrhythmic effect) such as ventricular tachycardia and death in individual with structural heart disease and thus should not be use is theses patients [32]. In murine models, Hubert et al found that carbamazepine, lamotrigine and levetiracetam use were associated to a reduction in cardiac myocyte contraction and excitability compromising electromechanical coupling which was more intense with association of drugs [33].…”