Cardiovascular Physiology Concepts
                                    Richard E. Klabunde, Ph.D.

Inotropy (Contractility)

Changes in stroke volume can be accomplished by changes in ventricular inotropy (contractility). Changes in inotropy are unique to cardiac muscle. Skeletal muscle, for example, cannot alter its intrinsic inotropic state. 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 V_max; 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 curve up and to the left (point A to C in Figure 1). This causes a reduction in end-systolic volume 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 ventricular inotropic 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 (EF, 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 failure, 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. Sympathetic nerves play a prominent role in ventricular and atrial inotropic regulation, while parasympathetic nerves (vagal 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 effect) 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 Na⁺/K⁺-ATPase 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⁺⁺.

RK Revised 04/03/2007

DISCLAIMER: These materials are for educational purposes only, and are not a source of medical decision-making advice.

© 1999-2007 Richard E. Klabunde, all rights reserved.