Porth's Essentials of Pathophysiology, 4e

488

Circulatory Function

U N I T 5

7

6

K +

Na +

Catecholamines

Myocardial cell membrane

Cardiac glycosides

β -adrenergic receptor

ATP

ATP

T tubule

Ca ++

Ca ++

Na +

5

1

Troponin C

– 2

Ca ++

cAMP

Tropomyosin

Ca ++

3

Actin

Ca ++

4

Sarcoplasmic reticulum

L-type calcium channels

Myosin

FIGURE 20-1. Schematic representation of the role of calcium ions (Ca ++ ) in cardiac excitation– contraction coupling.The influx (site 1) of extracellular Ca ++ through the L-type Ca ++ channels in the T tubules during excitation triggers (site 2) release of Ca ++ by the sarcoplasmic reticulum.This Ca ++ binds to troponin C (site 3).The Ca ++ –troponin complex interacts with tropomyosin to unblock active sites on the actin and myosin filaments, allowing cross-bridge attachment and contraction of the myofibrils (systole). Relaxation (diastole) occurs as a result of calcium reuptake by the sarcoplasmic reticulum (site 4) and extrusion of intracellular Ca ++ by the Na + /Ca ++ exchange transporter or, to a lesser extent, by the Ca ++ adenosine triphosphatase (ATPase) pump (site 5). Mechanisms that raise systolic Ca ++ increase the level of developed force (inotropy). Binding of catecholamines to β -adrenergic receptors (site 6) increases Ca ++ entry by phosphorylation of the Ca ++ channels through a cyclic adenosine monophosphate (cAMP)–dependent second messenger mechanism.The cardiac glycosides (site 7) increase intracellular Ca ++ by inhibiting the Na + /K + -ATPase pump.The elevated intracellular Na + reverses the Na + /Ca ++ exchange transporter (site 5), so less Ca ++ is removed from the cell. (Modified from Klabunde RE. Cardiovascular Physiology Concepts . Philadelphia, PA: Lippincott Williams &Wilkins; 2005:46.)

cardiac glycosides are inotropic agents that exert their effects by inhibiting the Na + /potassium ion (K + )-ATPase pump in the myocardial cell membrane, thereby leading to an increase in intracellular calcium handling through the Na + /Ca ++ exchange pump. 8 Compensatory Mechanisms In heart failure, the cardiac reserve is largely maintained through compensatory mechanisms such as the Frank- Starling mechanism, activation of neurohumoral influ- ences such as the sympathetic nervous system reflexes, the renin-angiotensin-aldosterone mechanism, natriuretic peptides, locally produced vasoactive substances, and myocardial hypertrophy and remodeling 5,10 (Fig. 20-2). The first two of these adaptations occur rapidly over minutes to hours of myocardial dysfunction and may be adequate to maintain the overall pumping performance of the heart at relatively normal levels. Myocardial hypertrophy and remodeling occur slowly over weeks to months and play an important role in the long-term

adaptation to hemodynamic overload. In the failing heart, early decreases in cardiac function may go unno- ticed because these compensatory mechanisms maintain the cardiac output. However, these mechanisms contrib- ute not only to the adaptation of the failing heart but also to the pathophysiology of heart failure. 11 Length-Tension/Frank-Starling Mechanism The Frank-Starling mechanism describes the process whereby the heart increases its stroke volume through an increase in end-diastolic volume or preload (Fig. 20-3). With increased diastolic filling, there is increased stretch- ing of the myocardial fibers, more optimal approximation of the actin and myosin filaments, and a resultant increase in the force of the next contraction (see Chapter 17). As illustrated in Figure 20-3, there is no single Frank- Starling curve. 6 An increase in contractility will increase cardiac output at any end-diastolic volume, causing the curve to move up and to the left, whereas a decrease in contractility will cause the curve to move down and to the right.