Pacing staircase phenomenon in the heart: from Bodwitch to the XXI century

Abstract

The frequency of pacing is a fundamental physiological modulator of myocardial function. When the pacing rate increases there is normally an increase in contractility (a positive force-frequency relationship). However in small rodents, fish and end-stage failing myocardium, the force-frequency response has been found to be flat or even negative. The positive staircase is understood to be related with the increase in the intracellular Ca(2+) transient, mainly due to an enhanced sarcoplasmic reticulum Ca(2+) content at higher stimulation frequencies, resulting from an increase in Ca(2+) influx per unit time and reduced Ca(2+) efflux between beats. However, additional mechanisms, such as increased activity of Ca(2+)/calmodulin-dependent protein kinase or enhanced myofilament responsiveness to Ca(2+) may also play a role. Although an increase in contraction frequency has been shown to be associated with an increase in intracellular Na(+), several studies have shown a temporal dissociation between the increase in Na(i)(+) and the increase in force evoked by changes in pacing frequency. The way in which the Na(+)/Ca(2+) exchanger contributes to contraction frequency inotropy is still not well understood. The aim of this review is to examine the contribution of the fundamental components of cardiac excitation-contraction coupling to frequency inotropy in healthy and failing hearts.