Verapamil as an antiarrhythmic agent in congestive heart failure: hopping from rabbit to human?

摘要: In cardiac ventricular myocytes, an imbalance between inward and outward currents may prolong action potential duration. This makes the heart vulnerable to occurrence of so-called torsade de pointes (TdP) arrhythmias, which are life-threatening tachycardias that create rapid fluctuations QRS complexes around isoelectric line on human ECG. patients, there several independent risk factors or ‘challenges’ for TdP including hypokalaemia, bradycardia, genetic drug-induced long QT syndromes chronic congestive failure (CHF) (Roden, 2004). A single ‘challenge’ repolarization, example, reduction a membrane ion current, usually does not result in repolarization-dependent arrhythmias. Apparently, has reserve, commonly referred as ‘repolarization reserve’ (Varro Baczko, 2011), multiple challenges therefore required order provoke arrhythmia. Often, QT-prolonging drugs associated with arrhythmias final challenge exceeds resulting proarrhythmia. Quantification repolarization however, remains difficult. Although number surrogate parameters have been suggested (Thomsen et al., 2006), such temporal spatial dispersion duration, optimal quantification reserve still requires testing susceptibility where cumulative severity exceed then provides estimation reserve. Interestingly, some drugs, those block L-type calcium current (ICa-L), shown be effective against by counteracting one more predisposing (Oros 2010). Only few experimental large animal models mimicking CHF developed. Currently, efficacy ICa-L inhibition prevents suppresses early after depolarizations (EAD) polymorphic tachycardia is clear difficult predict since calcium-handling disturbances apparent this disease (Janse, Moreover, setting CHF, simple antiarrhythmic approach deal conflicting imperatives versus haemodynamic tolerance. issue BJP, Milberg al. (2012a) report outcome verapamil, well established compound, arrhythmic end points rabbit model non-ischemic long-QT characteristics (Milberg 2012a). was generated continuous right pacing and, subsequently, Langendorff-perfused sham hearts were subjected additional arrhythmias: ectopic activation, severe hypokalaemia erythromycin-mediated IKr block. Repolarization prolonged extent but affected at baseline. Only block, especially transmural increased larger CHF. Arrhythmias observed, their from animals (four 11 hearts; 36%) significantly different (eight 11; 73%; P = NS). Unfortunately, only reported normokalemic circumstances, when challenged less severely thus could directly point. Remarkably, findings same group published recently (Frommeyer used analyse proarrhythmic effect blocker sotalol favour here. group, induced EADs (as estimated monophasic morphology) 16 18 (89%) compared seven 14 (50%) group. When we solely compare arrhythmia incidence based these numbers, P-value 0.023 obtained (two-tailed Fisher exact test). However, both studies, yet another [seven 2012b], pronounced represents limitation. Nevertheless, verapamil demonstrated efficient drug setting, importantly, conclude effectiveness treatment persists isolated added. The next hurdle will reach similar conclusions vivo prominent factor. Mechanisms ascribed shortening interval decreases beat-to-beat variability duration 2010; Bourgonje now show it counteracts too. Promising seems, contraindicated cases systolic dysfunction reduced fractional (Chew 1981). As inhibits flux consequently, contractility, negatively inotropic, probably poor choice clinic; certainly, considering concentration (0.75 µM) unable suppress completely. complete atrial-ventricular dog model, plasma levels 0.5 µM clearly also lowered left pressure 2010). Upon titrating activity observed without drop (Bourgonje 2011). Other channel antagonists might better option, authors themselves advocate second-generation blockers. Take, instance, nifedipine strongly affects smooth than striated muscle (Millard 1983), lowering peripheral resistance would compensate negative inotropy. major drawback because, preserve blood contractility vessels dilated, rate must increase, unfavourable already weakened heart. Obviously, hard individual effects vasodilatation they counterbalance each other haemodynamically under neurohumoral influence. should approached experimentally. Furthermore, while inhibiting worrisome, case diastolic dysfunction, antagonism beneficial improving coronary flow relaxation. answering questions beyond opportunities offered (2012a), employed address intriguing possibilities. In conclusion, study demonstrates agent basic science insights into its mechanism reducing dispersion. Further studies pinpoint contribution arrhythmogenesis recapitulate validate demonstrate clinical feasibility,