Determinants of frequency-dependent contraction and relaxation of mammalian myocardium

Abstract

An increase in heart rate is the primary mechanism that up-regulates cardiac output during conditions such as exercise and stress. When the heart rate increases, cardiac output increases due to (1) an increased number of beats per time period, and (2) the fact that myocardium generates a higher level of force. In this review, we focus on the underlying mechanisms that are at the basis of frequency-dependent activation of the heart. In addition to increased force development, the kinetics of both cardiac activation and relaxation are faster. This is crucial, as in between successive beats there is less time, and cardiac output can only be maintained if the ventricle can fill adequately. We will discuss the cellular mechanisms that are involved in the regulation of rate-dependent changes in kinetics, with a focus on changes that occur in regulation of the intracellular calcium transient, and the changes in the myofilament responsiveness that occur when the heart rate changes.

Figure 1

Comparison of the force frequency relationships in various species. All data are representative averages obtained in isometric contractions of small and thin ventricular trabeculae at 37 °C under near identical conditions (n=4–12/species). Within their respective in vivo frequency range (solid lines), the force frequency relationship is positive in all species, but the enhancement of force upon increase in frequency is much more pronounced in larger mammals compared to small rodents. Outside the in vivo frequency range, a flat or negative relationship can be obtained depending on the frequency range studied. In human, dog, and rabbit, the relative increases in force within the in vivo range are similar (nearly 100%) so contractile force generally doubles between resting and exercise heart rate, whereas in the rat the increase is only about 50%, and in the mouse only about 10%.

Figure 2

Comparison of frequency dependent acceleration of relaxation in various species. All data are representative averages obtained in isometric contraction/relaxations of small and thin ventricular trabeculae at 37 °C under near identical conditions (n=4–12/species). Over the entire frequency range, encompassing the in vivo frequency range (solid lines), relaxation (indicated by time form peak tension to 50% relaxation) was accelerated when frequency increased. Both in absolute times as well as relative to the lowest rate, within the in vivo range of the species, FDAR is most pronounced in the larger mammals, but can clearly be observed even in small rodents.