Myocardial contraction-relaxation coupling

Abstract

Since the pioneering work of Henry Pickering Bowditch in the late 1800s to early 1900s, cardiac muscle contraction has remained an intensely studied topic for several reasons. The heart is located centrally in our body, and its pumping motion demands the attention of the observer. The contraction of the heart encompasses a complex interplay of mechanical, chemical, and electrical properties, and its function can thus be studied from any of these viewpoints. In addition, diseases of the heart are currently killing more people in the Westernized world than any other disease. When combined with the increasing emphasis of research to be clinically relevant, this contributes to the heart remaining a topic of continued basic and clinical investigation. Yet, there are significant aspects of cardiac muscle contraction that are still not well understood. A big complication of the study of cardiac muscle contraction is that there exists no equilibrium among many of the important governing parameters, which include pre- and afterload, intracellular ion concentrations, membrane potential, and velocity and direction of movement. Thus the classic approach of perturbing an equilibrium or a steady state to learn about the role of the perturbing factor in the system cannot be unambiguously interpreted, since each of the parameters that govern contraction are constantly changing, as well as constantly changing their interaction with each other. In this review, presented as the 54th Bowditch Lecture at Experimental Biology meeting in Anaheim in April 2010, I will revisit several governing factors of cardiac muscle relaxation by applying newly developed tools and protocols to isolated cardiac muscle tissue in which the dynamic interactions between the governing factors of contraction and relaxation can be studied.

Fig. 1.

A: active force development increases in isolated rabbit cardiac trabeculae when frequency of stimulation is increased, resulting in a positive force-frequency relationship. Both diastolic and systolic calcium concentrations increase when frequency increases, whereas the calcium transient amplitude (systolic minus diastolic values) also increases. B: time from peak force to 50% relaxation (RT₅₀) declined when frequency of stimulation is increased, whereas myofilament calcium sensitivity decreases with frequency. Data were recorded at optimal length and at 37°C and modified from Varian and Janssen (54).

Fig. 2.

A: active force development increases in isolated rabbit cardiac trabeculae when length of the muscle is increased. The amplitude of the intracellular calcium transient also increases but is less pronounced. B: RT₅₀ of the force transient is slowed when muscle length is increased, whereas the 50% decline in the intracellular calcium transient is slightly accelerated. C: assessment of calcium sensitivity shows that at higher length, the muscle becomes more sensitive to calcium, whereas maximal force production is increased. Data were recorded at a stimulation frequency of 2 Hz at 37°C and modified from Monasky et al. (39) and Monasky et al. (37).

Fig. 3.

A: correlation of the maximal speeds of contraction and relaxation in an isolated murine trabecula (wild-type C57 mouse), assessed under conditions where length, frequency, or concentration of the β-adrenergic agonist isoproterenol was varied. Data recorded at 37°C. dF/dt_max and dF/dt_min, maximum positive and negative derivatives of force, respectively. B: correlation of speed of relaxation and speed of contraction in rat trabeculae (average data of n = 10 trabeculae) at various conditions. FS, Frank-Starling relationship, muscle contracted at 4 different lengths (0.5, 1, or 2 stimulation frequency); RT, room temperature (held at 22.5°C); BT, body temperature (held at 37.5°C); Temp, 1 Hz, optimal length at various temperature (in 2.5°C steps) between RT and BT; Iso, various concentrations of isoproterenol; Temp Up ISO, maximal isoproterenol concentration at different temperatures; FFR, force-frequency relationship. Because the slowest data (low dF/dt) are bundled and to convey that the correlation holds true for timing parameters in general rather than only dF/dt, we plotted the same data now correlating time from stimulation to peak tension to time from peak tension to RT₅₀. All data except for those at low preload, 0.5 Hz, and at the lowest temperature (●) deviated significantly (P < 0.05, analysis of variance) from the mean correlation. Data modified from Janssen (22).

Fig. 4.

A: trabeculae isolated from pulmonary artery-banded rabbits show a blunted FFR, whereas the systolic (Syst) calcium concentration increases less pronounced with increasing frequency compared with muscles isolated from sham-operated rabbits. Diastolic (Diast) calcium concentration rose with frequency in both groups. B: myofilament calcium sensitivity significantly (*P < 0.05) decreased in muscles from sham-operated rabbits but remained unchanged in pulmonary artery-banded muscles when frequency of stimulation was increased from 1 to 4 Hz. All data were obtained at steady state and at optimal length at 37°C. Data modified from Varian et al. (55).