488
U N I T 5
Circulatory Function
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.
Myosin
Sarcoplasmic
reticulum
cAMP
Actin
Troponin C
Tropomyosin
Catecholamines
Myocardial
cell membrane
β
-adrenergic
receptor
ATP
ATP
L-type
calcium
channels
T
tubule
Ca
++
Ca
++
Ca
++
Ca
++
Ca
++
Na
+
K
+
Cardiac
glycosides
Na
+
–
5
7
6
4
3
2
1
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.)
