Cardiac Inotropy (Contractility)
Changes in stroke volume can be
accomplished by changes in ventricular inotropy (contractility). Changes in inotropy are
a prominent feature of cardiac muscle. It is important for the heart because, unlike skeletal muscle, it can not modulate its force generation by changes in motor nerve activity and motor unit recruitment. Changes in inotropy result in changes in force generation, which are
independent of preload (i.e., sarcomere length).
This is clearly demonstrated by use of length-tension diagrams
in which an increase in inotropy results in an increase in active tension at a given preload.
Furthermore, inotropy is displayed in the force-velocity relationship
as a change in Vmax; that is, a change in the maximal velocity of fiber
shortening at zero afterload. The increased velocity of fiber shortening that occurs with
increased inotropy increases the rate of ventricular pressure development.
During the phase of isovolumetric contraction, an increase
in inotropy is manifested as an increase in maximal dP/dt (i.e., rate of pressure change).
Changes in inotropy alter the rate of force and pressure
development by the ventricle, and therefore change the rate of ejection (i.e.,
ejection velocity). For example, an increase in inotropy shifts the Frank-Starling
up and to the left (point A to C in Figure 1). This causes a reduction in end-systolic
and an increase in stroke volume
as shown in
the pressure-volume loops
depicted in Figure 2. The
increased stroke volume also causes a secondary reduction in ventricular end-diastolic volume and pressure because there is less end-systolic volume to be added to the incoming venous
return. It should be noted that the active pressure curve that defines the limits of the
end-systolic pressure-volume relationship
(ESPVR) is shifted to the left and becomes
steeper when inotropy is increased. The ESPVR is sometimes used as an index of
state. It is analogous to the shift that occurs in the active tension
curve in the length-tension relationship
whenever there is
a change in inotropy.
Changes in inotropy produce significant changes in ejection fraction
calculated as stroke volume divided by end-diastolic volume). Increasing inotropy leads to an
increase in EF, while decreasing inotropy decreases EF. Therefore, EF is often used as a
clinical index for evaluating the inotropic state of the heart. In heart
, for example, there often is a decrease in inotropy that leads to a fall in
stroke volume as well as an increase in preload, thereby decreasing EF. The increased
preload, if it results in a left ventricular end-diastolic pressure greater than 20 mmHg,
can lead to pulmonary congestion and edema
. Treating a
patient in heart failure with an inotropic drug (e.g., beta-adrenoceptor agonist or
digoxin) will shift the depressed Frank-Starling curve up and to the left, thereby
increasing stroke volume, decreasing preload, and increasing EF.
Changes in inotropic state are particularly important during
exercise. Increases in inotropic state help to maintain stroke volume at high heart
rates. Increased heart rate alone decreases stroke volume because of reduced time for
diastolic filling, which decreases end-diastolic volume. When the inotropic state increases at the
same time, end-systolic volume decreases so that stroke volume can be maintained.
Factors Regulating Inotropy
The most important mechanism
regulating inotropy is the autonomic nerves
play a prominent role in ventricular and atrial inotropic regulation, while parasympathetic nerves
efferents) have a significant
negative inotropic effect in the atria but only a small effect in the ventricles. Under
certain conditions, high levels of circulating epinephrine
augment sympathetic adrenergic effects. In the human heart, an abrupt increase in afterload
can cause a small increase in inotropy (Anrep
) by a mechanism that is not fully understood. An increase in heart rate
also stimulates inotropy (Bowditch effect; treppe; frequency-dependent inotropy).
This latter phenomenon is probably due to an inability of the
to keep up with the sodium influx at higher heart rates, which leads to an accumulation of
intracellular calcium via the sodium-calcium exchanger
. Systolic failure
that results from cardiomyopathy,
ischemia, valve disease, arrhythmias, and other conditions is characterized by a
loss of intrinsic inotropy.
In addition to these physiological mechanisms, a variety of
inotropic drugs are used clinically to stimulate the heart, particularly in acute and
chronic heart failure. These drugs include
digoxin (inhibits sarcolemmal Na+/K+-ATPase),
beta-adrenoceptor agonists (e.g., dopamine, dobutamine, epinephrine, isoproterenol), and
phosphodiesterase inhibitors (e.g., milrinone).
Mechanisms of Inotropy
Most of the signal transduction
pathways that stimulate inotropy ultimately involve Ca++, either by
increasing Ca++ influx (via Ca++ channels) during the action potential (primarily during phase 2), by increasing the release of Ca++ by the sacroplasmic reticulum, or
by sensitizing troponin-C (TN-C) to Ca++.