Proarrhythmia

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. 

PVCs often cause no symptoms or only mild palpitations. The presentation of VT may vary from totally asymptomatic to pulseless hemodynamic collapse. Consequences of proarrhythmia range from no symptoms to worsening of symptoms to sudden death. VF results in hemodynamic collapse, syncope, and cardiac arrest. 

Proarrhythmia can be difficult to diagnose because of the variable nature of underlying arrhythmias. 

The use of antiarrhythmic drugs in the United States is declining because of major trials that showed increased mortality with their use in several clinical situations, the realization of proarrhythmia as a significant side effect, and the advancing technology of nondrug therapies such as ablation and the implantable cardioverter-defibrillator (ICD). 

Type Ic drugs profoundly slow conduction velocity while leaving refractoriness relatively unaltered. Although effective for both ventricular and supraventricular arrhythmias, their use for ventricular arrhythmias has been limited by the risk of proarrhythmia. 

AF often recurs after initial cardioversion because most patients have irreversible underlying heart or lung disease. A metaanalysis confirmed that quinidine maintained sinus rhythm better than placebo however, 50% of patients had recurrent AF within 1 year, and more importantly, quinidine increased mortality, presumably due in part to proarrhythmia. Type Ic (e.g., flecainide, propafenone) and type III (e.g., amiodarone, sotalol, dofetilide) antiarrhythmic agents may be alternatives to quinidine however, these agents are also associated with proarrhythmia. Consequently, chronic antiarrhythmic drugs should be reserved for patients with recurrent paroxysmal AF associated with intolerable symptoms during episodes of AF. 

The typical form of proarrhythmia caused by the type Ic antiarrhythmic drugs is a rapid, sustained, monomorphic VT with a characteristic sinusoidal QRS pattern that is often resistant to resuscitation with cardioversion or overdrive pacing. Some clinicians have had success with IV lidocaine (competes for the sodium channel receptor) or sodium bicarbonate (reverses the excessive sodium channel blockade). 

Focused preclinical studies for proarrhythmia if altered repolarization is seen in preclinical screening or in patients. 

APD prolongation per se does not necessarily indicate proarrhythmia (the TRIaD concept should be considered see text)... 

Karagueuzian, H.S. (2000) Acquired long QT syndromes and the risk of proarrhythmia. Journal of Cardiovascular Electrophysiology, 11, 1298. 

The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. European Heart Journal, 21, 1216-1231. 

Hondeghem, L.M., Carlsson, L. and Duker, G. (2001) Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhyfhmic. Circulation, 103, 2004-2013. 

Shah, R.R. and Hondeghem, L.M. (2005) Refining detection of drug-induced proarrhythmia QT interval and TRIaD. Heart Rhythm, 2, 758-772. 

MAP, ECG parameters, proarrhythmia Isolated intact hearts (Langendorff) Hondeghem et al. 92 Eckardt et al93 94... 

Lawrence, C.L., Pollard, C.E., Hammond, T.G., and Valentin, J.P., Nonclinical proarrhythmia models predicting Torsades de Pointes, /. Pharmacol. Toxicol. Methods, 52, 46-59, 2005. 

Adverse reactions occurring in at least 3% of patients include angina first-degree AV block CHF intraventricular conduction delay palpitations proarrhythmia ventricular tachycardia dizziness fatigue headache constipation dyspepsia nausea/vomiting unusual taste blurred vision dyspnea. About 20% of patients discontinued treatment due to adverse reactions. 

Proarrhythmia Mexiletine can worsen arrhythmias it is uncommon in patients with less serious arrhythmias (freguent premature beats or nonsustained ventricular tachycardia) but is of greater concern in patients with life-threatening arrhythmias, such as sustained ventricular tachycardia. 

Proarrhythmias- Amo6aror e can cause serious exacerbation of the presenting arrhythmia, a risk that may be enhanced by concomitant antiarrhythmics. In addition, amiodarone has caused symptomatic bradycardia. 

Proarrhythmia Like other antiarrhythmic agents, sotalol can provoke new or worsened ventricular arrhythmias in some patients, including sustained ventricular tachycardia or ventricular fibrillation, with potentially fatal consequences. Because of its effect on cardiac repolarization, is the most common form of proarrhythmia associated with sotalol, occurring in approximately 4% of high-risk patients. 

Ahmad, K. and Dorian, P. (2007) Drug-induced QT prolongation and proarrhythmia an inevitable link Europace, 9, 16-22. 

IC Flecainide Propafenone Markedly decrease V, of phase 0, profoundly decrease ventricular conduction velocity, markedly inhibit inward sodium current. High potential for proarrhythmia. 

III Amiodarone Bretylium Sotalol Prolong ventricular action potential, prolong refractoriness, inhibit potassium repolarization currents. Prolong QTc interval. Potential for proarrhythmia (torsades de pointes tachyarrhythmia). 

Quinidine Quinidex) was one of the first clinically used antiarrhythmic agents. Because of the high incidence of ventricular proarrhythmia associated with its use and numerous other equally efficacious agents, quinidine is now used sparingly. Quinidine shares all of the pharmacological properties of quinine, including an-timalarial, antipyretic, oxytocic, and skeletal muscle relaxant actions. 

Worsening of heart failure and prolongation of the PR and QRS intervals are likely to occur with flecainide, and an increased risk of proarrhythmia has been reported. 

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. 

Hohnloser SH. Proarrhythmia with class III antiarrhythmic drugs Types, risks, and management. Am J Cardiol 1997 80(8A) 82G-89G. 

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