Proarrhythmia mechanism

Another mechanism to maintain CO when contractility is low is to increase heart rate. This is achieved through sympathetic nervous system (SNS) activation and the agonist effect of norepinephrine on P-adrenergic receptors in the heart. Sympathetic activation also enhances contractility by increasing cytosolic calcium concentrations. SV is relatively fixed in HF, thus HR becomes the major determinant of CO. Although this mechanism increases CO acutely, the chronotropic and inotropic responses to sympathetic activation increase myocardial oxygen demand, worsen underlying ischemia, contribute to proarrhythmia, and further impair both systolic and diastolic function. 

Proarrhythmia refers to development of a significant new arrhythmia (such as VT, ventricular fibrillation [VF], or TdP) or worsening of an existing arrhythmia. Proarrhythmia results from the same mechanisms that cause other arrhythmias or from an alteration in the underlying substrate due to the antiarrhythmic agent. TdP is a rapid form of polymorphic VT associated with evidence of delayed ventricular repolarization due to blockade of potassium conductance. TdP may be hereditary or acquired. Acquired forms are associated with many clinical conditions and drugs, especially type la and type III IKr blockers. 

Digitalis glycosides enhance the inotropic state by increasing the intracellular calcium concentration. Intracellular calcium overload is also the mechanism for proarrhythmia associated with digitalis intoxication. The direct effect of digitalis on the electrophysiology of the myocytes is to increase the slope of phase 4 depolarization, an effect that enhances automaticity. 

Inhibitors of the renal cation secretion mechanism, eg, cimetidine, prolong the half-life of dofetilide. Since the QT-prolonging effects and risks of ventricular proarrhythmia are directly related to plasma concentration, dofetilide dosage must be based on the estimated creatinine clearance. Treatment with dofetilide should be initiated in hospital after baseline measurement of the rate-corrected QT interval (QTC) and serum electrolytes. A baseline QTC of > 450 ms (500 ms in the presence of an intraventricular conduction delay), bradycardia of < 50 bpm and hypokalemia are relative contraindications to its use. 

Krishnan SC, Josephson ME. ST segment elevation induced by class Ic antiar-rhythmic agents underlying electrophysiologic mechanisms and insights into drug-induced proarrhythmia. J Cardiovasc Electrophysiol 1998 9 1167-1172. 

Frommeyer G, Eckardt L (2016) Drug-induced proarrhythmia risk factors and electrophysiologi-cal mechanisms. Nat Rev Cardiol 13 36-47... 

The anticipated outcome from this change in paradigm is the development of a non-clinical, standardised in vitro assay that determines the effects of drugs on the major cardiac ion channels and provide an assessment of the potential to precipitate clinical proarrhythmia, obviate conduct of the clinical TQT study and facilitate more efficient drug discovery efforts. In order to understand the fundamentals of this novel paradigm, it is important to review fundamental cardiac electrophysiology including basic ion channel biophysics as well as review some fundamental cardiac arrhythmia mechanisms to achieve this alternate approach. 

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