Molecular determinants and therapeutic potential of focal ec
Putative molecular mechanisms of focal ectopic (triggered) activity. Inherited [e.g. catecholaminergic polymorphic ventricular tachycardia (CPVT)], acquired [atrial fibrillation (AF) or heart failure (HF)], or drug-induced cardiovascular diseases promote sarcoplasmic reticulum (SR) calcium leak, mainly via dysregulation of the ryanodine receptor type-2 (RyR2) channel or SR calcium-ATPase type-2a (SERCA2a). This SR calcium leak can give rise to calcium overload and calcium waves. Subsequent calcium-dependent activation of the sodium/calcium-exchange current (INCX) and calcium-activated chloride current [ICl(Ca)] produces a transient inward current that determines the amplitude of the delayed afterdepolarization (DAD). In parallel, direct or indirect calcium-dependent modulation of several ion channels can depolarize [INCX, late sodium current (INa, L), or transient receptor potential subfamily-M member-4 current (ITRPM4)] or hyperpolarize [basal inward-rectifier potassium current (IK1) or small-conductance calcium-activated potassium current (ISK)] the resting membrane potential (RMP). Simultaneously, calcium-dependent regulation of the peak sodium current (INa) determines cellular excitability. The balance between these processes determines whether the DADs remain subthreshold or whether the threshold for action potential (AP) generation is reached, eliciting a triggered AP that promotes ectopic firing. Meclofenamate is a TRPM4 inhibitor that reduces the depolarizing background current and decreases the likelihood of focal ectopic activity.