The tension developed by a skeletal muscle can be increased when rapid stimulation by motor neurons causes summation or tetanic contractions (see Chapter 6); however, these mechanisms are of little physiological importance because most skeletal muscle contractions are brief tetani. Exceptions are the contractions of extraocular muscles, which are often twitches, but these brief contractile responses, which resemble the knee jerk reflex, would not be useful for most movements.

Summation plays no role in the heart because cardiac action potentials normally last almost to the end of the active state. For this reason, an activated cardiac myocyte cannot respond to additional electrical stimuli until relaxation is virtually complete, which makes it impossible for summation and tetanic contraction to be used for physiological regulation.

Skeletal muscles are composed of groups of myocytes, called motor units, each of which is innervated by a single motor neuron that operates independently of other motor units. This allows performance to be regulated by the central nervous system, which can vary the number
of active motor units. For example, when a muscle is called upon to lift a light load, only a small fraction of its motor units are activated, whereas a greater proportion of the motor units are activated via their motor neurons when the same muscle lifts a heavy load. This mechanism is the major determinant of skeletal muscle performance.

In the heart, the number of active muscle fibers cannot be varied because the interiors of adjacent cardiac myocytes are linked by the gap junctions in the intercalated discs (see Chapters 1, 13, and 16). Because these structures provide a low electrical resistance between adjacent cells, the heart operates as a functional syncytium, where depolarization of any region normally activates the entire heart.

The length-tension relationship allows preload to influence the performance of both skeletal and cardiac muscle (see Chapter 6). In most skeletal muscles, rest length is determined largely by the angles at the joints; as these angles are generally chosen to optimize leverage, rather than to set sarcomere length along the length-tension curve, variations in rest length are of little regulatory importance.

Changes in sarcomere length play a key role in matching the heart’s output during systole to the return of blood during diastole. Because cardiac muscle normally operates on the ascending limb of the length-tension curve (see Chapter 6), an increase in the return of blood during diastole increases the ability of the heart to eject during systole. These length-dependent changes allow the heart to “fine tune” its performance to match venous return and cardiac output, to vary cardiac performance in response to short-term hemodynamic changes, and to equalize the outputs of the right and left ventricles (see below).

Changes in contractility and relaxation play little role in skeletal muscle, where the high content of sarcoplasmic reticulum allows excitation-contraction coupling to deliver enough calcium to saturate virtually all of the binding sites on troponin C; as a result, even under basal conditions, skeletal muscle tension is at or near the maximum that the muscle can generate. Although trains of stimuli normally maximize tension by generating brief tetani, periods of inactivity allow time for skeletal muscles to relax completely when their tasks are completed.

The situation in the heart, however, is quite different. Because excitation-contraction coupling does not provide enough activator calcium to saturate all of the troponin C in myocardial cells operating under basal conditions, myocardial contractility and relaxation can be regulated by modification of the calcium cycles described in Chapter 7. These functional responses allow the heart to meet a variety of sustained physiological stresses, such as the hemodynamic defense reactions described in Chapter 8. Furthermore, long-term changes in the demands on the heart evoke proliferative responses that change the architecture and composition of the myocardium (see Chapters 9 and 18).

Starling’s law of the heart can be viewed as a mechanism that maintains hemodynamic equilibria by allowing changes in preload and afterload to modify cardiac performance.

Although Starling’s law plays a central role in beat-to-beat and short-term regulation of cardiac performance, length-dependent changes are of limited importance when circulatory changes are sustained. Evidence that factors other than end-diastolic volume regulate cardiac performance is found in Starling’s original papers, which document a positive inotropic effect, sometimes called “homeometric autoregulation” or the “Anrep effect,” which develops after a sudden increase in left ventricular systolic pressure. Once thought to be caused by an undiscovered mechanism within cardiac myocytes, this increase in contractility is now recognized to occur when delayed dilatation of the coronary microcirculation overcomes the negative inotropic effect of the state of energy starvation that occurs when the increased systolic wall stress reduces blood flow to the left ventricle. A more important exception to Starling’s law, described more than 75 years ago, is that the heart can become smaller during upright exercise in humans, even though cardiac output increases several fold (Nylin, 1934). By the mid-1950s, a substantial body of evidence indicated that regulatory mechanisms other than end-diastolic fiber length regulate cardiac performance (Katz et al., 1955), but it was not until Sarnoff described the “family of Starling curves” (1955) that the role of changes in myocardial contractility became clear. Contractility is often referred to as inotropy; a positive inotropic intervention increases contractility while a negative inotropic intervention reduces contractility.

The clinical importance of lusitropic abnormalities was not generally appreciated until the 1970s, almost 20 years after the role of changing contractility had been recognized. This is largely because the initial clinical applications of hemodynamic physiology focused on pressures, which were readily measured by the equipment that was then available. These led to the early use of pressure-based indices, such as the rate of pressure rise during isovolumic contraction (+dP/dt), to quantify myocardial contractility (see Chapter 12). Initial efforts to quantify lusitropic state were also based on pressure measurements; in this case the rate of pressure fall during isovolumic relaxation (-dP/dt). However, the latter is highly dependent on ventricular systolic pressure, so that use of pressure measurements to define lusitropic properties requires corrections that are both difficult and imprecise. It was not until echocardiography and nuclear techniques made it possible to measure changes in the rate and extent of ventricular filling that diastolic function could be characterized in patients (see Chapter 12).

The finding that changing coronary perfusion pressure can modify the ability of the heart to develop tension, even after the ventricles are drained of blood and cavity pressure is zero (Salisbury et al., 1960), revealed the existence of an unexpected regulatory mechanism. Evidence that increasing coronary arterial pressure has an “erectile” effect that increases cardiac oxygen consumption (Vogel et al., 1982) demonstrated that the heart’s performance is regulated by distension within its walls, much as occluding the outlet of a garden hose increases its internal diameter. This mechanism, often called the garden hose effect, was initially explained by postulating that higher intramyocardial pressures increase cardiac performance by increasing sarcomere length (Starling’s law of the heart). However, evidence that this phenomenon cannot be explained simply on the basis of changes in sarcomere length (Kitakaze and Marban, 1989; Koretsune et al., 1991; May-Newman et al., 1994; Matsushita et al., 1995) suggests that the garden hose effect occurs when cytoskeletal deformation modifies the intensity of excitation-contraction coupling.