Intrinsic Control Systems

The most obvious is the length-dependent activation underlying the Frank-Starling relation. This allows heart muscle to adjust its performance on a beat-to-beat basis, e.g., with respiration and changes in body position, and is discussed further under ventricular function.

Another important intrinsic control mechanism is the force-frequency relation (FFR)73-75 (Fig. 3-14). At a basal rate of 60 per minute, the duration of the myocardial twitch contraction is such that relaxation would be incomplete at rates achieved during exercise and cause impaired diastolic filling. Therefore, the myocardium must have mechanisms that automatically speed contraction and relaxation at rapid rates. In conjunction with this abbreviation of contraction, the strength of contraction is markedly enhanced, allowing maintenance of SV even though less time is available for filling and emptying. The mechanism of the positive FFR involves increased and more rapid Ca cycling per beat as frequency increases.8,59,76-79 Factors contributing to this include the direct effect of a greater number of APs per unit time, causing intracellular accumulation of Ca ions, as well as increases in SR Ca pumping. Thus Ca entry increases directly with more frequent opening of L-type Ca channels and indirectly when the Na-Ca exchanger extrudes excess Na ions arising from the increased frequency of sarcolemmal Na channel opening. Operating in isolation, these factors would risk elevation of diastolic Ca concentration. However, SR Ca pump speed increases concomitantly, increasing relaxation rate and abbreviating the contraction. In addition to PLB, SERCA2 activity is under the control of another protein, Ca-activated calmodulin kinase, which increases SERCA2 activity in response to increased Ca concentration and has built-in frequency sensitivity. Slight, transient increases in Ca ions, even if insufficient to directly activate the kinase, are held in binding sites long enough so that repeated increases are summated. This averaging process results in increased speed of the SERCA2 pump in response to increased average and instantaneous Ca concentration.

Plb Coronary Artery

Figure 3-14: Example of average relation between developed force and stimulation frequency in strips of human myocardium obtained by epicardial biopsy from a group of patients undergoing coronary bypass surgery, all with normal LV contraction patterns. Note the marked increase in force as contraction frequency increases from typical basal level of 60 per minute to a value of 170 to 180 per minute, at which force is maximal (see text).

Figure 3-14: Example of average relation between developed force and stimulation frequency in strips of human myocardium obtained by epicardial biopsy from a group of patients undergoing coronary bypass surgery, all with normal LV contraction patterns. Note the marked increase in force as contraction frequency increases from typical basal level of 60 per minute to a value of 170 to 180 per minute, at which force is maximal (see text).

The FFR appears to depend on the intactness of multiple elements of Ca handling, as evidenced by the fact that it is depressed in a number of conditions in which the myocardium is diseased and/or subjected to chronic stress.73-74'76'80 The ratio of SERCA2 pumps to PLB protein has been proposed as an important determinant of its magnitude.77 Moreover, the FFR is markedly amplified by increased ^-adrenergic stimulation.75 Thus, during stress, increased adrenergic stimulation not only increases HR but also increases the magnitude of FFR occurring in response to the increase. This amplification appears to be related to cyclic AMP-mediated phosphorylation of PLB.30

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