Starling s Law Regulation of Myocardial Performance Intrinsic Regulation of Myocardial Performance

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1 Regulation of Myocardial Performance Intrinsic Regulation of Myocardial Performance Just as the heart can initiate its own beat in the absence of any nervous or hormonal control, so also can the myocardium adapt to changing hemodynamic conditions by means of mechanisms that are intrinsic to cardiac muscle itself. Experiments on denervated hearts reveal that this organ adjusts remarkably well to stress. For example, racing greyhounds with denervated hearts perform almost as well as those with intact innervation. Their maximal running speed was found to decrease only 5% after complete cardiac denervation. In these dogs, the threefold to fourfold increase in cardiac output during a race was achieved principally by an increase in stroke volume. In normal dogs, the increase of cardiac output with exercise is accompanied by a proportionate increase of heart rate; stroke volume does not change much. It is unlikely that the cardiac adaptation in the denervated animals is achieved entirely by intrinsic mechanisms; circulating catecholamines undoubtedly contribute. If /3- adrenergic receptor antagonists are given to greyhounds with denervated hearts, their racing performance is severely impaired. The heart is partially or completely denervated in various clinical situations: (1) the surgically transplanted heart is totally decentralized, although the intrinsic, postganglionic parasympathetic fibers persist; (2) atropine blocks vagal effects on the heart, and propranolol blocks sympathetic β-adrenergic influences; (3) certain drugs, such as reserpine, deplete cardiac norepinephrine stores and thereby restrict or abolish sympathic control; and (4) in chronic Two principal intrinsic mechanisms, namely the Frank-Starling mechanism and rateinduced regulation, enable the myocardium to adapt to changes in hemodynamic conditions. The Frank-Starling mechanism (also referred to as Starling s law of the heart), is invoked in response to changes in the resting length of the myocardial fibers. Rate-induced regulation is invoked in response to changes in the frequency of the heartbeat. How these two mechanisms allow the heart to adapt to alterations in hemodynamic conditions is explained below. Frank-Starling mechanism. About one century ago, the German physiologist Otto Frank and the English physiologist Ernest Starling independently studied the responses of isolated hearts to changes in preload and afterload. When the ventricular filling pressure (the preload) was increased (e.g., by raising a blood reservoir connected to the right atrium), the ventricular volume initially increased progressively. After several beats, however, the ventricles attained a constant, larger volume. At equilibrium, the volume of blood ejected by the ventricles (the stroke volume) with each heartbeat had increased to equal the greater quantity of venous return to the right atrium with each heartbeat. The increased ventricular volume had somehow facilitated ventricular contraction and had enabled the ventricles to pump a greater stroke volume, resulting in an exact match between the cardiac output and the increased venous return at equilibrium. Other researchers noted subsequently that the increased ventricular volume was associated with an increase in the length of the individual myocardial fibers that make up the ventricular chambers. On the basis of this observation, they concluded that the increase in fiber length altered cardiac performance mainly by altering the number of myofilament cross-bridges that could interact. However, more recent evidence indicates that the principal mechanism involves a stretch-

2 induced change in the sensitivity of the cardiac myofilaments to calcium. An optimal fiber length exists, however. Excessively high filling pressures that over-stretch the myocardial fibers may depress rather than enhance the pumping capacity of the ventricles. Starling also showed that isolated heart preparations were able to adapt to changes in the counterforce to the ventricular ejection of blood during systole. As the left ventricle contracts, it does not eject blood into the aorta until the ventricle has developed a pressure that just exceeds the prevailing aortic pressure. The aortic pressure during ventricular ejection essentially constitutes the left ventricular afterload. In Starling s experiments, the arterial pressure was controlled by a hydraulic device in the tubing that led from the ascending aorta to the right atrial blood reservoir, and venous return to the right atrium was held constant by maintaining the hydrostatic level of the blood reservoir. As Starling raised the arterial pressure to a new, constant level, the left ventricle responded at first to the increased afterload by pumping a diminished stroke volume. Because venous return was held constant, the diminution of stroke volume was attended by a rise in ventricular diastolic volume as well as an increase in the length of the myocardial fibers. This change in end-diastolic fiber length finally enabled the ventricle to pump a normal stroke volume against the greater peripheral resistance. Although again a change in the number of cross-bridges between the thick and thin filaments probably contributes to this adaptation, the major factor appears to be a stretch-induced change in the sensitivity of the contractile proteins to calcium. Changes in ventricular volume are also involved in the cardiac adaptation to alterations in heart rate. During bradycardia, for example, the increased duration of diastole permits greater ventricular filling. The consequent increase in myocardial fiber length increases stroke volume. Therefore, the reduction in heart rate may be fully compensated by the increase in stroke volume, and the cardiac output therefore remains constant (see Fig ).

3 When cardiac compensation involves ventricular dilation, it is necessary to consider how the increased size of the ventricle affects the generation of the intraventricular pressure. If the ventricle enlarges, the force required by each myocardial fiber to generate a given intraventricular systolic pressure must be appreciably greater than that developed by the fibers in a ventricle of normal size. The Laplace relationship between wall tension and cavity pressure for the cardiac ventricles resembles that for cylindrical tubes, in that for a constant internal pressure, wall tension varies directly with the radius. As a consequence, more energy is required for the dilated heart to perform a given amount of external work than for the normalsized heart. Hence, in the computation of the afterload on the contracting myocardial fibers in the walls of the ventricles, the dimensions of the ventricles must be considered along with the intraventricular (and aortic) pressure. The relatively rigid pericardium that encloses the heart determines the pressure-volume relationship at high levels of pressure and volume. The pericardium exerts this limitation of volume even under normal conditions, when an individual is at rest and the heart rate is slow. In patients with chronic congestive heart failure, the cardiac dilation and hypertrophy may stretch the pericardium considerably. In such patients, the pericardial limitation of cardiac filling is exerted at pressures and volumes entirely different from those in normal individuals (Fig ). The major problem in assessing the role of the Frank-Starling mechanism in intact animals and humans is the difficulty of measuring end-diastolic volume or end-diastolic myocardial fiber length. In intact subjects, the Frank-Starling mechanism has been represented graphically by plotting some index of ventricular performance along the ordinate and some index of enddiastolic ventricular volume or fiber length along the abscissa. The most commonly used indices of ventricular performance have been cardiac output, stroke volume, and stroke work; stroke work is the product of stroke volume and mean arterial pressure. The indices of enddiastolic ventricular volume and fiber length have been end-diastolic ventricular pressure and mean atrial pressure. In plotting these indices, the Frank-Starling mechanism is better represented by a family of socalled ventricular function curves, rather than by a single curve. To construct a given ventricular function curve, blood volume is altered over a range of values, and stroke work and end-diastolic ventricular pressure are measured at each step. Similar observations are then made during the desired experimental intervention. For example, the ventricular function curve obtained during a norepinephrine infusion in an anesthetized dog lies above and to the left of a

4 control ventricular function curve (Fig ). It is evident that, for a given level of left ventricular end-diastolic pressure (an index of the preload), the left ventricle performs more work during a norepinephrine infusion than during control conditions. In this experiment, the change in arterial blood pressure (an index of the after-load) was relatively small. Hence, a shift of the ventricular function curve to the left usually signifies an improvement of ventricular contractility, which denotes a change in ventricular performance that is independent of a change in either preload or afterload. A shift to the left in a ventricular function curve usually signifies an enhancement of contractility, whereas a shift to the right usually indicates an impairment of contractility, and a consequent tendency toward cardiac failure. The Frank-Starling mechanism is ideally suited to matching the cardiac output to the venous return. Any sudden, excessive output by one ventricle soon causes an increase in the venous

5 return to the other ventricle. The consequent increase in diastolic fiber length augments the output of the second ventricle to correspond with that of its mate. In this way, the Frank- Starling mechanism maintains a precise balance between the outputs of the right and left ventricles. Because the two ventricles are arranged in series in a closed circuit, any small, but maintained, imbalance in the outputs of the two ventricles would otherwise be catastrophic. The curves that relate cardiac output to mean atrial pressure for the two ventricles do not coincide; the curve for the left ventricle usually lies below that for the right ventricle (Fig ). At equal right and left atrial pressures (points A and B), right ventricular output would exceed left ventricular output. Hence, venous return to the left ventricle (a function of right ventricular output) would exceed left ventricular output, and left ventricular diastolic volume and pressure would rise. By the FrankStarling mechanism, left ventricular output would therefore increase (from B toward C). Only when the outputs of both ventricles are identical (points A and C) would equilibrium be reached Under such conditions, however left atrial pressure (C) would exceed right atrial pressure (A) and this is precisely the relationship that ordinarily prevails. Rate-induced regulation. Myocardial performance is also regulated by changes in the frequency at which the myocardial fibers contract. The effects of changes in the frequency of contraction on the force developed in an isometrically contracting cat papillary muscle are shown in Fig Initially the strip of cardiac muscle was stimulated to contract only once every 20 seconds (Fig , A). When the muscle was suddenly made to contract once every 0.63 second, the developed force increased progressively over the next several beats. At the new steady state, the developed force was more than five times as great as it was at the larger contraction interval. A return to the larger interval (20 seconds) had the opposite influence on developed force. This greater left than right atrial pressure accounts for the observation that in individuals with congenital atrial septal defects, in which the two atria communicate with each other via a patent foramen ovale, the direction of the shunt flow is usually from left to right.

6 The effects of a wide range of intervals between contractions on the steady-state levels of developed force are shown in Fig , B. As the interval was diminished from 300 seconds down to about 20 seconds, little change occurred in developed force. As the interval was reduced further, to a value of about 0.5 second, force increased sharply. Further reduction of the interval to 0.2 second had little additional effect on developed force. The initial progressive rise in developed force when the interval between beats was suddenly decreased (e.g., from 20 seconds to 0.63 second in Fig , B) is caused by a gradual increase in intracellular Ca ++ concentration. Two mechanisms contribute to the rise in Ca ++ concentration: (1) an increase in the number of depolarizations per minute and (2) an increase in the inward Ca ++ current per depolarization. In the first mechanism, Ca ++ enters the myocardial cell during each action potential plateau. As the interval between beats is diminished, the number of plateaus per minute increases. Although the duration of each action potential (and of each plateau) decreases as the interval between beats is reduced, the overriding effect of the increased number of plateaus per minute on the influx of Ca ++ prevails, and the intracellular concentration of Ca ++ increases. In the second mechanism, as the interval between beats is suddenly diminished, the inward Ca ++ current (i Ca ) progressively increases with each successive beat until a new steady state is attained at the new basic cycle length. Fig shows that in an isolated ventricular myocyte subjected to repetitive depolarizations, the influx of Ca ++ into the myocyte increased on successive beats. For example, the maximal i Ca was considerably greater during the seventh depolarization than it was during the first depolarization. Furthermore, the decay of that current (i.e., its rate of inactivation) was substantially slower during the seventh depolarization than during the first

7 depolarization. Both of these characteristics of the i Ca would result in a greater influx of Ca ++ into the myocyte during the seventh depolarization than during the first depolarization. The greater influx of Ca ++ would, of course, strengthen the contraction. Transient changes in the intervals between beats also profoundly affect the strength of contraction. When the left ventricle contracts prematurely (Fig , beat A), the premature contraction (extrasystole) itself is feeble, whereas beat B (postextrasystolic contraction) after the compensatory pause is very strong. In the intact circulatory system, this response depends partly on the Frank-Starling mechanism. Inadequate ventricular filling just before the premature beat accounts partly for the weak premature contraction. Subsequently, the exaggerated degree of filling associated with the compensatory pause (see p 356) explains in part the vigorous postextrasystolic contraction. Although the Frank-Starling mechanism is certainly involved in the usual ventricular adaptation to a premature beat, it is not the exclusive mechanism. Fig shows the ventricular pressure curves recorded from an isovolumic left ventricle preparation, in which neither filling nor ejection takes place during the cardiac cycle. Although the left ventricular volume remained constant throughout the entire tracing, the premature beat (A) was feeble and the postextrasystolic contraction (B) was supernormal. Such enhanced contractility in the postextrasystolic contraction is an example of postextrasystolic potentiation, and it may persist for one or more additional beats (e.g., contraction C). The weakness of the premature beat is directly related to its degree of prematurity. In other words, the earlier the premature beat occurs, the weaker is its force of contraction. Conversely, as the time (coupling interval) between the premature beat and the preceding beat increases, the strength of contraction of the premature beat moves toward normal. The curve that relates the strength of contraction of a premature beat to the coupling interval is called a mechanical restitution curve. Fig shows the restitution curve obtained by varying the coupling intervals of test beats in an isolated ventricular muscle preparation from a guinea pig. The restitution of the force of contraction probably depends on the time course of the intracellular circulation of Ca ++ in the

8 cardiac myocytes during the contraction and relaxation process. During relaxation, the Ca ++ that dissociates from the contractile proteins is taken up by the sarcoplasmic reticulum for subsequent release. However, there is a lag of about 500 to 800 msec before this Ca ++ becomes available for release from the sarcoplasmic reticulum in response to the next depolarization. If we look once again at the experiment depicted in Fig (beat A), the premature beat itself was feeble, probably because there is insufficient time during the preceding relaxation to allow much of the Ca ++ taken up by the sarcoplasmic reticulum to become available for release during the premature beat. The postextrasystolic beat (B), conversely, was considerably stronger than normal. A plausible explanation for the increase in contraction force developed in beat B is that a relatively large quantity of Ca ++ was taken up by the sarcoplasmic reticulum during the time that had elapsed from the end of the last regular beat until the beginning of the postextrasystolic beat, and this quantity of Ca ++ would have been available for release during beat B.

9 msec before this Ca ++ becomes available for release from the sarcoplasmic reticulum in response to the next depolarization. If we look once again at the experiment depicted in Fig (beat A), the premature beat itself was feeble, probably because there is insufficient time during the preceding relaxation to allow much of the Ca ++ taken up by the sarcoplasmic reticulum to become available for release during the premature beat. The postextrasystolic beat (B), conversely, was considerably stronger than normal. A plausible explanation for the increase in contraction force developed in beat B is that a relatively large quantity of Ca ++ was taken up by the sarcoplasmic reticulum during the time that had elapsed from the end of the last regular beat until the beginning of the postextrasystolic beat, and this quantity of Ca ++ would have been available for release during beat B.