CONTRACTILITY IN THE MODERN CONTEXT

The use of the term contractility goes back well over a 125 years, and was used to simply describe a property of assorted tissues to shorten. The term has something to do with the ability of heart tissue to shorten, but has taken on new connotations in current thinking. Moreover, with the state of detailed knowledge of molecular and cellular control of the level of activity and dynamics of the heart, assigning a strict definition does not seem appropriate inasmuch as the relative performance of the heart may take on different dimensions including the relative peak pressure in the cardiac chambers at relatively constant volume (peak tension in an isometric contraction of muscle fibers), changes in the rate of pressure (tension) development, and the slope of the relation between chamber volume and chamber end systolic pressure. There has also been the designation of changes in contractility as promoted by extrinsic control mechanisms such as neuro-humoral signaling in contrast to those promoted by intrinsic control mechanisms such as the end diastolic fiber length (Frank-Starling relation). As will be evident here, consideration of the mechanism by which contractility is controlled indicates that this is an artificial separation. Whatever the case, it is apparent that the term contractility remains useful to permit succinct written and oral communication between and among scientists and clinicians. However, as described here, detailed understanding of the control mechanisms altering contractility in health and disease demands flexibility in the interpretation of the meaning of a statement regarding the relative contractility of the heart. In approaching this detailed understanding, we first consider the pressure and volume dynamics of the heart beat and how these change with changes in contractility. These altered dynamics constrain theories as to the mechanisms accounting for altered contractility at the molecular and cellular levels. We then discuss current understanding of these molecular and cellular mechanisms. In considering these mechanisms, we focus on the left ventricle (LV). Chapters in monographs (Page et al., 2001; Bers, 2001; Opie, 2004, and Katz, 2010) provide more details and extended discussions of contractility.

CONTROL OF CARDIAC CONTRACTILITY IS CRITICAL TO THE MATCHING OF CARDIAC OUTPUT TO VENOUS RETURN DURING EXERCISE WITH LITTLE CHANGE IN END DIASTOLIC VOLUME AND WITH TUNING OF THE DYNAMICS OF CONTRACTION AND RELAXATION TO HEART RATE

Revelations on the state of contractility of the left ventricle come from measures of the changes in the LV volume and pressure in the transition from rest to exercise, a short term modification in cardiac performance, Straight forward and useful expressions related to cardiac performance are the following equations:

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Figure 1

Schematic illustrating the cardiac cycle. Illustrations at the top and middle represent the heart at end diastolic volume (EDV) and end systolic volume (ESV) emphasizing circumferential shortening of the ventricular chambers responsible for ejection. (more...)

Figure 2

Changes in heart rate, cardiac output, and left ventricular volumes during increasing work load during exercise. Data (courtesy of Dr. Edward Lakatta) were collected on a normal young healthy male exercising on a stationary bicycle. During a repeat of (more...)

Figure 2 provides an illustration of the interplay of HR, SV and CO during an episode of exercise. The data were determined for a healthy young adult before and after administration of the beta-adrenergic blocking agent, propranolol. Comparison of the changes in the ventricular volumes and HR before and after blockage of adrenergic input to the heart provides a measure of how modifications in contractility and HR affect the functional readouts. Comparisons shown in Figure 2 also provide insights into the effects of physiological aging on the heart, which resemble the effects of beta-blockade. The data in Figure 2 reveal important aspects of the control of cardiac output during the most common physiological stress on the cardiovascular system. There are several important revelations provided by the data in Figure 2. Note that CO is essentially a linear function of the work load, and does not change with blockade of beta receptors. This result reflects the necessity and capability of the cardiovascular system to meet the demands of the tissues. A critical driving force is tissue oxygen needs, which in the case demonstrated in Figure 2 changed many fold in a relatively short time. Oxygen extraction as blood flows through the tissues is about 20% of the arterial concentration, making oxygen among the most flow limited components of the blood together with carbon dioxide and heat. Other components of blood have extraction ratios much less than oxygen and are much less flow limited. Thus, meeting tissue oxygen demands automatically provides all of the needs of the cell for exchange of other nutrients and wastes. The coupling of tissue oxygen needs to CO involves neural, mechanical, and chemical control mechanisms, which will be elucidated as we take up the theme of control of cardiac contractility.

Although not extensively discussed here an important variable providing the tissue oxygen needs is venous return (VR). Inasmuch as the cardiovascular circuit is closed, it is difficult to separate CO from VR since they must be the same in the steady state. Certainly the increase in CO noted in Figure 2 came about not only because the heart rate is increased but because return flow to the heart, the VR, has increased as the contraction and relaxation of the muscles squeeze blood vessels holding large volumes of blood (capacitance vessels), and because of neural inputs to the resistors in the circuit and the walls of the capacitance vessels. This return of blood is critical to the increase in flow out of the heart to the lungs and eventually to the body. Yet, imagine what would happen to the ventricular volumes in Figure 2 if the return of the volume of blood added to the chambers of the heart from the veins during diastole was not completely transferred to the arteries. This might happen over a few transitional beats, but cannot be sustained for very long. Thus, an important function of the heart in which altered contractility comes into play is the matching of CO to VR, while maintaining an overall economy of oxygen use by the pump. As we consider the molecular and cellular mechanisms of control of contractility, we will emphasize how alterations at the level of heart are integrated into the overall homeostasis of blood flow. Failure of these mechanisms to provide a robust response to exercise induces alterations in the ventricular volumes that will limit exercise capacity and promote compensatory alterations in contractility that are adaptive for a time, but in the long term become maladaptive and fatal. These long term adaptive and maladaptive responses to stresses affect contractility and induce significant disorders of the heart.

A second revelation of the data in Figure 1 is that in the control conditions (no beta-blocker) the nearly 3 fold increase in CO occurred not by increasing the loading volume i.e. elevated EDV, but with a drop in both EDV and ESV. SV increased with the work load of exercise indicating that the ESV fell a bit more than the EDV. As we will see, the fall in ESV reflects molecular mechanisms promoting the ventricle to reduce the volume at end systole. The ratio of SV/EDV provides a measure to the relative ability of the ventricle to eject. This ratio is called the ejection fraction and is commonly employed to assess relative cardiac function i.e. contractility. Activation of the sympathetic nervous system (SNS) is an inevitable consequence of exercise either by conscious activity of the cerebral cortex affecting the brainstem or by involuntary neural mechanisms typical of the autonomic nervous system. An important aspect is that the ability of the heart to match an increase in VR to an increase in CO with a reduction in EDV and ESV is energetically favorable. The favorable energetic profile of the heart in the control condition in the data illustrated in Figure 2 is couched in the law of LaPlace. This law, which is illustrated in Figure 3, states that wall tension is related to the pressure in the ventricular chamber times the radius of curvature of the chamber (equation 3),

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Figure 3

Schematic illustrating the law of Laplace. The Laplace relation emphases the favorable economy of cardiac ejection at relatively small EDV compared to relative big EDV. See text for further discussion.

The increase in CO occurred in the control condition largely because of an increase in HR and a fall in ESV. Both of these major control mechanisms are subject to regulation by the autonomic nervous system (ANS). This role of the ANS is emphasized by data in Figure 2 following blockade of adrenergic beta receptors with propranolol in which there is inhibition of the adrenergic signaling to the heart. Note that the increase in CO associated with the increased work load is not affected by propranolol. Matching of CO to the increase in VR was not compromised, but there was a trade off in making sure the system supplies the tissue oxygen needs. The fractional increase in HR was less in the presence of beta blockade, and thus according to equation (1) with the constant CO, SV must be increased. With out beta-receptor stimulation the increase in SV occurred largely due to an increase in EDV, and this result indicates the significance of the ANS in matching CO to VR while maintaining hemeostatic control over the EDV.

The values presented in Figure 2, which are steady state values of HR, CO and ventricular volumes, do not emphasize the alterations in cardiac dynamics that occur during increased work load and activity of the ANS. Changes and levels of contractility are often assessed and understood in terms of these dynamics. The data in Figure 4 illustrate these dynamics of cardiac function as the time dependence of left ventricular volume before and after an episode of exercise. This view of cardiac function not only emphasizes the decrease in ESV with little change in EDV that occurred with exercise, but indicates the abbreviation of the contraction/relaxation cycle. The reduction in overall cycle time is critical to tuning the heart beat to the increased HR and thus maintaining an adequate duration for ventricular filling during diastole. Figure 1 also illustrates that the volume changes are associated with shortening of the cells making up the left ventricular chamber and that the changes in cell length reflect changes in sarcomere length. We next consider the cellular and molecular mechanisms responsible for the changes in cardiac function demonstrated in Figures 2 and 3.

Figure 4

Changes in dynamics of the cardiac cycle as illustrated by the time dependence of left ventricular volume before and during exercise. The panel on the left demonstrates the relation between myocyte and sarcomere length at end diastole and end systole. (more...)