Digitalis, Positive Inotropes, and Vasodilators

21
Digitalis, Positive Inotropes, and Vasodilators

Clarke E. Atkins and Marisa K. Ames

An understanding of the pharmacokinetic and pharmacodynamic characteristics of cardiac drugs is essential for veterinarians who treat cardiovascular disease. Cardiac disease is often severe and life-threatening events must be managed with these drugs. Also, states of cardiac dysfunction that are amenable to drug therapy are common in dogs and cats. This chapter considers some of the more important drugs used in therapeutic management of cardiac disorders, with focus on those that affect basic aspects of cardiovascular function, including positive inotropes, inodilators, and vasodilators. Antiarrhythmic drugs are covered in Chapter 22. Other classes of drugs that elicit prominent cardiac responses (e.g., adrenergic and cholinergic agents) are discussed in Chapter 8, while off-loading therapies, other than vasodilators and inodilators (i.e., diuretics) are discussed in Chapter 24.

Basic Aspects of Cardiac Function

The primary pathways by which the cardiovascular system can increase or decrease cardiac output, based on need, include changes in heart rate, adjustments in myocardial contractility, an intrinsic response of the cardiac muscle to changes in muscle length, and optimization of vascular size (vasodilation and vasoconstriction). This physiological (neurohormonal) control is via pressure sensors, the central nervous system, sympathetic and parasympathetic nervous systems (SNS, PSNS), and the renin–angiotensin–aldosterone system (RAAS). The control systems involved are of considerable importance to pharmacology because the net response of the heart and vascular system is to these regulatory systems and the drugs administered often provide their effect via stimulating or blunting these systems.

Intrinsic Regulation

Contractile response of cardiac muscle to a change in its own length is the primary mechanism whereby the heart adjusts its pumping activity under normal physiological conditions (Fozzard, 1976). When venous return increases, the contractile function in the healthy heart increases, thereby pumping an increased volume of blood into the arterial system. This fundamental capability of the heart to autoregulate its pumping capacity in response to end-diastolic filling is referred to as the Frank–Starling law of the heart (Frank, 1895; Starling, 1918). This force–length relationship is primarily a result of an increase in calcium sensitivity as the initial sarcomere length increases. The relationship between preload (end-diastolic filling) and cardiac output under basal conditions and under dominance by the sympathetic and parasympathetic nervous systems is shown in Figure 21.1.

Graph shows left ventricular end-diastolic pressure versus cardiac output with plots for intense sympathetic stimulation, sympathetic stimulation, normal, and parasympathetic stimulation. — **Figure 21.1** Frank–Starling law of the heart. As end-diastolic ventricular volume (preload) increases, the myofiber is stretched, enhancing the contractile state of the muscle; cardiac output is thus increased. The cardiac output curve can be influenced by different degrees of sympathetic and parasympathetic stimulation.

Regulation by the Nervous System

The autonomic nervous system regulates the cardiovascular system mainly by adjusting heart rate, vascular volume, and myocardial contractility. Details concerning cardiac effects and mechanisms of action of the sympathetic neurotransmitter norepinephrine (NE) and the parasympathetic neurotransmitter acetylcholine (ACh) are found in Chapters 6–8.

The intrinsic heart rate is determined via blockade of both arms of the autonomic nervous system. When an animal is at rest, the PSNS is likely dominant, as the resting heart rate is lower than the intrinsic heart rate. Patients with heart failure often have higher resting heart rates and less heart rate variability, suggesting that the SNS is likely dominant over the PSNS at rest. Sympathetic stimulation of cardiac muscle (via endogenous NE and certain pharmacological agents) can markedly increase the force of contraction, irrespective of end-diastolic muscle length. A change in contractile strength that is independent of muscle length is referred to as a change in contractility or inotropy. In the presence of inotropic stimulation by the sympathetic system, cardiac output at each level of ventricular filling is enhanced over the basal state (Figure 21.1). Conversely, parasympathetic nerves exert their primary influences on cardiac output, not by changing the inotropic state, but by slowing heart rate and, with that, increasing ventricular filling time. Vagal discharge, however, when it produces bradycardia, decreases cardiac output at all levels of venous return and stretch on myocardial fibers (Figure 21.1). In contrast, sympathetic stimulation produces an increase in heart rate. Within physiological limits, cardiac output increases proportionately to the change in heart rate. Importantly, myocardial blood flow is decreased in rapid tachycardia, while myocardial oxygen needs are increased.

Myocardial oxygen demand (MVO₂) varies directly with three main factors: heart rate, myocardial wall tension, and inotropic state. Myocardial wall tension is directly related to ventricular radius (cardiac size) and intraventricular pressure and indirectly related to wall thickness (i.e., the law of Laplace). Primary determinants of ventricular wall tension are preload (i.e., end-diastolic volume and stretch) and afterload (determined by cardiac luminal size, wall thickness, and systemic blood pressure). By reducing pre- or afterload, certain drugs can elicit marked reduction in cardiac work (and MVO₂) without direct inotropic action on the heart muscle cell.

Cellular Concepts

The basic contractile unit of a heart muscle cell is the sarcomere, composed of actin (thin filament) and myosin (thick filament) proteins. A protein assembly unit, associated with the actin molecule, composed of tropomyosin and troponin, regulates activation of the filaments. Availability of ionized calcium (Ca⁺⁺) in the vicinity of troponin is the obligate modulator of the diastole–systole contraction cycle. Binding of Ca⁺⁺ to a high-affinity subunit of the troponin molecule evokes the movement of tropomyosin from its diastolic blocking position on actin. Cross-linkages or “cross-bridges” are formed between projections of the myosin molecules and exposed sites on actin. As cross-bridges are formed, the thick and thin filaments slide over each other, and contraction occurs. Calcium delivery to the myofibrils is initiated by bioelectric events at the cell membrane, represented by the cardiac action potential.

Excitation–Contraction Coupling

L-type Ca⁺⁺ channels are opened as the wave of depolarization travels down the T tubules, leading to the release of a small amount of Ca⁺⁺. This Ca⁺⁺ triggers the activation of Ca⁺⁺ release channels on the sarcoplasmic reticulum (SR) and causes the release of relatively large amounts of Ca⁺⁺ into the cytosol (Opie, 2001; Fabiato and Fabiato, 1979).

Two separate pathways of movement of superficial Ca⁺⁺ are believed to be involved (Langer, 1976, 1980; Parker and Adams, 1977). The primary electrogenic route is associated with the previously discussed triggered Ca⁺⁺ release from the SR. An additional influx of Ca⁺⁺ is linked with a Ca⁺⁺–Na⁺ exchange across the sarcolemma. A schematic representation of excitation–contraction coupling in mammalian heart muscle is shown in Figure 21.2.

Diagram shows movement of cellular ions having T-tubule, trigger, sarcoplasmic reticulum, mitochondrion which are contracting and relaxing. — **Figure 21.2** Schematic representation of cellular ion movements controlling excitation–contraction coupling in heart muscle. An action potential (AP) instigates the inward movement of Ca⁺⁺ through slow Ca⁺⁺ channels of the sarcolemma (1). Inward-moving calcium fills sarcoplasmic reticulum stores of the cation and also serves as a trigger to release additional Ca⁺⁺ from storage sites of the sarcoplasmic reticulum (3). These Ca⁺⁺ sources and that resulting from Na⁺–Ca⁺⁺ exchanges across the sarcolemma (2) activate the contractile proteins (4). Relaxation occurs as calcium is sequestered at storage sites of sarcoplasmic reticulum (3). Mitochondrion (5). Ca⁺⁺ is pumped out of the cell (6). Altered sodium pump activity (7) may also affect sodium concentrations available from Na⁺–Ca⁺⁺ exchange. Source: Parker and Adams, 1977.

Relaxation

During repolarization, Ca⁺⁺ is actively sequestered by the SR, which avidly binds and stores myoplasmic Ca⁺⁺ with affinity greater than troponin. Relaxation occurs as Ca⁺⁺ moves to the SR from troponin binding sites on the myofibrils, and the cytoplasmic Ca⁺⁺ concentration decreases below the threshold required to trigger actin–myosin cross-bridge formation (Figure 21.2). Since this is an energy-requiring process, relaxation is somewhat a misnomer for the changes that occur during diastole.

Maintenance of Electrolyte Gradients

There is a net influx of Na⁺ and Ca⁺⁺ and efflux of K⁺ with each action potential. Membrane-bound enzymes act as pumps to relocate ions and prevent their improper accumulation (Gadsby, 1984). Sodium–potassium–activated adenosine triphosphatase (Na⁺,K⁺-ATPase), localized in the cell membrane, propels Na⁺ out of and K⁺ into the cell, against their respective concentration gradients. Excess intracellular Ca⁺⁺ is pumped out of the cell by systems localized in regions of the SR in close approximation to the sarcolemma (Figure 21.2). A sarcolemmal Ca⁺⁺-ATPase also contributes to extrusion of Ca⁺⁺.

Positive Inotropes and Inodilators

Digitalis and Related Cardiac Glycosides

Digitalis and several closely allied chemicals are derived from the purple foxglove plant (Digitalis purpurea), other related species of the figwort family, and some plant species unrelated to digitalis.

Chemistry and Sources

Chemical and structure–activity relationships of the digitalis glycosides are quite complex, but several basic similarities are retained in the different compounds. The nomenclature is based on botanical origins rather than chemical structure. Digitalis is the dried leaf of the purple foxglove plant. Digitoxin, digoxin, and gitoxin also can be extracted from the leaf of a related plant, D. lanata, the woolly foxglove. Strophanthidin and ouabain are glycosides contained in the seeds of Strophanthus sp. Digitoxin and ouabain have been removed from the commercial market and only digoxin will be discussed here. Because of considerable pharmacological similarities between the different glycosides, the collective term digitalis has been used to designate the entire group of drugs, including digoxin. Often, digitalis and digoxin are used interchangeably by cardiologists. The term glycoside in general refers to a compound linked by an oxygen atom to a sugar molecule(s). The basic steroid-type nucleus is a cyclopentanoperhydrophenanthrene, to which is attached an unsaturated lactone ring at carbon atom 17 (C-17). The sugar molecules usually are attached at C-3; they influence water solubility, cell penetrability, duration of action, and other pharmacokinetic characteristics. The cardioactivity of the molecule resides principally in the aglycone moiety, but the positive myocardial actions of these entities are somewhat less potent and of lesser duration than the parent glycoside.

Cardiovascular Effects

Improved myocardial contractility was once considered to be the most important trait of the glycosides and, indeed, is the primary action on which the hemodynamic benefits depend. Today however, neuroendocrine (neurohormonal) effects, including reduced SNS activity and heart rate control, are believed to be of most important in treating heart failure.

Myocardial Contractility

The ability of cardiac glycosides to increase contractility has been demonstrated in a multitude of experimental preparations with results that validate a direct effect on contractile strength, independent of changes in resting fiber length, heart rate, or afterload. The positive inotropic action of cardiac glycosides is most pronounced in the hypodynamic or failing heart, though it is less than with other inotropic agents, such as dobutamine. Digitalis was shown in one study to provide a 24% increase in cardiac index versus 34% with dobutamine CRI (continuous rate infusion; ∼3 μg/kg/min), meaning that the latter has a 42% greater inotropic effect than digoxin (Vatner et al., 1974).

Cellular Mechanisms of Inotropic Action

One of digitalis’ proposed actions in congestive failure is a positive cardiac inotropic effect, but significance of this effect has diminished after examining results of several investigations. The second restorative action is neurohormonal normalization, thought by many to be the more important of known and postulated mechanisms of digitalis’ clinical benefits (see Section Neuroendocrine Effects) (Ferguson, 1989).

Inhibition of Na⁺,K⁺-ATPase:

The Mg⁺⁺-dependent Na⁺,K⁺-ATPase of the cell membrane supplies energy for the active pumping of Na⁺ outward and K⁺ inward against their large concentration gradients (Figure 21.2). The Na⁺,K⁺-ATPase is believed to be the cellular receptor for digitalis glycosides (Schwartz, 1977; Akera and Ng, 1991; Schatzmann, 1953). Inhibition of Na⁺,K⁺-ATPase by digitalis results in progressive reduction of (K⁺)_i as the ability of the pump to transport K⁺ inward and Na⁺ outward progressively fails (Fozzard and Sheets, 1985; Katz et al., 1985). A decrease in (K⁺)_i and/or an increase in (K⁺)_o reduces resting membrane potential to a less negative value, which can lead to increased automaticity and eventually impaired conduction and excitability. Inhibition of ATPase and resulting depletion of (K⁺)_i are responsible for the arrhythmogenic properties of digitalis.

The inotropic effect involves activation of a Na⁺–Ca⁺⁺ exchange mechanism through accumulation of (Na⁺)_i. Baker et al. (1969) demonstrated with the giant squid axon that an increase in (Na⁺)_i enhanced the uptake of Ca⁺⁺ by a Na⁺–Ca⁺⁺ exchange process. This mechanism seems to be operative in other excitable tissues and has been evoked as the link between inhibition of Na⁺,K⁺-ATPase and digitalis inotropy in the heart (Langer, 1977). The sequence of events can be visualized to include the following progression: digitalis interacts with and inhibits cell membrane Na⁺,K⁺-ATPase, outward pumping of Na⁺ is slowed, (Na⁺)_i accumulates, increased (Na⁺)_i augments transmembrane exchange of intracellular Na⁺ for extracellular Ca⁺⁺, (Ca⁺⁺)_i is increased, and Ca⁺⁺ delivery to the contractile proteins is increased; thus the positive inotropic effect is gained. Dominance of Na⁺–K⁺ exchange and augmentation of Na⁺–Ca⁺⁺ exchange, with digitalis’ inhibition of ATPase is demonstrated in Figure 21.3.

Diagrams show mechanism of inotropic action at normal and after digitalis having extracellular with ca++, Na+, K+, ATPase, et cetera. — **Figure 21.3** Schematic representation of a proposed mechanism for the positive inotropic action of cardiac glycosides. Inhibition of Na⁺,K⁺–ATPase (sodium pump) by digitalis results in increased intracellular concentrations of sodium available for exchange with calcium. Heavy arrows designate the dominant pathway of ion exchange during normal conditions (A) and after inhibition by digitalis of Na⁺,K⁺–ATPase (B). Adapted from Langer, 1976; Source: Parker and Adams, 1977.

Cardiac output

Digitalis glycosides increase contractility in both the normal and failing myocardium. However, the change in cardiac output is influenced by the functional status of the cardiovascular system.

Normal heart:

Output of the normal heart increases minimally and may even decrease slightly after treatment with digitalis (Braunwald, 1985). Total peripheral resistance is increased by digitalis in the normal subject as a result of a centrally mediated increase in sympathetic vasomotor tone and direct vasoconstrictor effect. Impedance of the arterial circuit to ventricular ejection (afterload) is thereby increased, which attenuates the expected increase in cardiac output produced by the positive inotropic effect.

Failing heart:

The work capacity of the failing ventricle at any given end-diastolic volume or pressure is inadequate to generate a normal stroke volume (Figure 21.4). The ejection fraction is diminished accordingly, which increases residual blood in the ventricle after systole (Moalic et al., 1993). If diastolic filling continues at a near normal rate, the ventricle will dilate to accommodate increased end-diastolic volume. With the administration of digitalis, the above processes are reversed. Digitalis-increased myocardial contractility augments work capacity of the ventricle, at any given end-diastolic filling pressure, as illustrated in Figure 21.4, where ventricular function curves derived in the prefailure state (normal) are compared with curves derived from congestive failure patients prior to and after digitalis therapy. Digitalis shifts the complete ventricular function curve upward in the direction of improved contractility (Mason, 1973; Braunwald, 1985). Systolic emptying is now more complete (increased ejection fraction) and, therefore, residual ventricular volume is diminished. Cardiac output increases and the size of the heart is reduced.

Digitalis’ augmentation of myocardial contractility and normalization of baroreceptor function favorably affect vasomotor tone, evoking peripheral vasodilation with diminished outflow impedance (afterload). Additionally, improved cardiac performance increases venous return to the heart, thereby increasing preload and further enhancing cardiac performance by the Frank–Starling mechanism. This sequence of events continues to dominate as peripheral perfusion and tissue oxygenation improve, and it compensates for the direct vasoconstrictor effect of digitalis. The increase in cardiac output persists as long as the state of myocardial compensation prevails.

Cardiac Energy Metabolism

Digitalis increases oxygen consumption proportionately with increased contractile force in nonfailing cardiac muscle (Lee and Klaus, 1971); but patients with heart failure do not show an increase in the myocardial oxygen consumption because of the slowing of heart rate and the reversal of SNS-derived vasoconstriction.

These seemingly contradictory data can be reconciled by comparing the cardiodynamics of digitalis in normal and failing hearts. The heart with a normal ventricular volume responds to digitalis with increase in oxygen consumption commensurate with increase in contractility. Increased oxygen consumption is the direct result of increased contractility, in accordance with the concept that MVO₂ is influenced directly by the inotropic state, heart rate, and wall tension. Ventricular wall tension is directly proportional to ventricular pressure and radius (tension = (pressure × radius)/wall thickness; the Laplace relation). Tension will decrease if either pressure or radius is reduced. In the failing and dilated heart, reduction in cardiac size secondary to the inotropic action of digitalis therapy leads to a significant reduction in wall tension, which in turn leads to decreased MVO₂. The ultimate determinant of cardiac output is then a balance of the positive effect of increased preload on force of contraction and its negative effect on afterload, by reduction in cardiac chamber size (Laplace relation). Blood pressure normalization after cardiac glycoside therapy is secondary to cardiodynamic improvement in the congestive failure patient (Figure 21.4).

Neuroendocrine Effects

In heart failure patients, a lowering of heart rate accompanies the positive inotropic effect. This is apparently the result of a neuroendocrine effect and has been recognized as perhaps more important than the positive inotropic effects at therapeutic dosages. It also appears that the neuroendocrine effects are independent from the positive inotropic action and occur at lower serum digoxin levels (<1 ng/ml) (Ferguson, 1989). Neuroendocrine effects are achieved through digitalis’ increase (normalization) in the baroreceptor reflex sensitivity that has been lost, presumably because of high levels of circulating aldosterone, during heart failure (Weber, 2001). Digitalis restores baroreceptor sensitivity and thereby decreases sympathetic tone in patients with heart failure (Quest and Gillis, 1971; McRitchie and Vatner, 1976; Zucker et al., 1980; Ferrari et al., 1981). The neuroendocrine effects also are attributed to direct pharmacological vagal stimulation (parasympathomimetic effect) (Thames et al., 1982). The neuroendocrine effects are responsible for a decrease in sinus rate, afterload, and speed of atrioventricular (AV) impulse conduction, thereby reducing cardiac work and MVO₂. Ahmed and Pitt have shown that the positive effects of digoxin are maintained and survival benefits enhanced at serum digoxin concentrations of 0.7–0.9 ng/ml, but not higher (Ahmed et al., 2006a,b; Ahmed et al., 2008), for both systolic and diastolic failure.

Excitability and Automaticity

As described earlier the increased excitability of digoxin on the heart is caused by ion fluxes and changes in K⁺ conductance. Pacemaker cells are characterized by phase 4 spontaneous depolarization (normal automaticity), which moves diastolic potential to the threshold required for activation of phase 0, causing spontaneous depolarization (see Chapter 22). Therapeutic doses of cardiac glycosides increase vagal tone and decrease sympathetic tone, decreasing the slope of spontaneous diastolic depolarization of the sinoatrial pacemaker. This reduces the firing frequency of the sinoatrial node, and hence heart rate. After pretreatment with atropine, or with relatively high doses of digitalis, the nonvagal effects dominate, and an increase in automaticity is observed; this response is prevalent in the specialized conducting systems of atria and, especially, the ventricles. A typical transmembrane potential recording of a subsidiary pacemaker cell prior to and after digitalis is shown in Figure 21.5. This increased automaticity evoked by cardiac glycosides is due to an accelerated rate of spontaneous diastolic depolarization. The normally latent pacemaker activities of cells within the ventricular conducting system are thereby magnified, leading to ectopic ventricular beats as an important early sign of digitalis toxicity. In contrast, muscle fibers in atria and ventricles can be depolarized to the point of inexcitability, without demonstrating spontaneous impulse generation. If excitability of ventricular muscle falls sufficiently, concomitant with increased frequency of ectopic impulses from specialized conduction fibers, the tendency for ventricular fibrillation is promoted.

Graph shows membrane potential with its scale ranging from minus 100 to plus 20 at interval of 40. — **Figure 21.5** Electrophysiological effects of digitalis on transmembrane potential of a subsidiary pacemaker cell. Digitalis (i) decreases (less negative) the maximal diastolic potential, (ii) decreases the maximal rate of depolarization of phase 0, V_max, and (iii) enhances automaticity by increasing the slope of phase 4 spontaneous depolarization. (i) and (ii) lead to decreased conduction velocity and, in conjunction with (iii), can lead to arrhythmias of both impulse formation and impulse conduction. Source: Adapted from Mason et al., 1971.

The clinical significance of the “delayed afterdepolarizations” sometimes seen with digitalis toxicity is not completely resolved. These oscillations of the transmembrane potential initially are subthreshold and appear spontaneously during diastole after a usual action potential. These afterdepolarizations can, however, reach threshold as toxicity worsens, with the resulting extrasystoles contributing to ectopic arrhythmias associated with digitalis intoxication.

Impulse Conduction and Refractory Periods

The dominant effect of digitalis on impulse conduction is to slow conduction velocity by both vagal and nonvagal mechanisms. This response is particularly prevalent in the AV node and contributes importantly to the beneficial effects of digitalis in controlling ventricular rate during atrial fibrillation and flutter. Antiarrhythmic agents are discussed further in Chapter 22 of this book.

Digitalis Effects During Atrial Fibrillation and Flutter

During atrial fibrillation, the ventricular rate is rapid and dysrhythmic, as a result of rapid transmission of impulses through the AV node. This contributes further to cardiac dysfunction by promoting incomplete ventricular filling and ejection. Because digitalis prolongs the refractory period and delays impulse conduction through the AV node, fewer impulses will effectively reach the ventricle. Thus ventricular response rate is reduced to a slower, more physiological level (Ferguson et al., 1989).

Similar benefits are gained during atrial flutter. Digitalis can slow this rhythm or convert it to atrial fibrillation. Ventricular rate is still decreased, however, through prolonged AV refractoriness and slowed impulse conduction. Conversion of atrial flutter to fibrillation by digitalis is viewed optimistically because ventricular rate is controlled more easily during fibrillation than during flutter. It has been shown that the combination of digoxin and the Ca⁺⁺ channel blocker, diltiazem (which also slows conduction through the AV node), is more effective at slowing the ventricular response to atrial fibrillation than is either drug alone (Gelzer et al., 2009).

Effects on the Electrocardiogram

The multiplicity of electrophysiological effects of cardiac glycosides on myocardial tissues can be expressed as equally complex changes in the electrocardiogram (ECG). Most conduction disturbances and dysrhythmias can be produced in normal individuals by administration of cardiac glycosides.

Congestive failure patients with sinus tachycardia or other supraventricular tachyarrhythmias usually demonstrate return toward more normal ECG patterns after digitalization. Rapid ventricular rates associated with atrial fibrillation or flutter are typically, but often inadequately, reduced by digitalis. Prolonged PR intervals, reflecting delayed AV conduction, are relatively common ECG features of digitalized dogs. Conversely, a lengthened PR interval is not necessarily a prerequisite for the therapeutic response.

Kidneys and Diuresis

After digitalization, reflex vasoconstriction decreases as cardiac output and hemodynamics are improved. Renal blood flow and glomerular filtration rate increase and stimuli for increased release of aldosterone are diminished. A fall in aldosterone secretion can be measured after digitalization in the dog with congestive failure (Figure 21.5). Diuresis results as salt and water retention by the kidneys is decreased. Diuresis, with lowering of capillary hydrostatic pressure, moves interstitial fluid back into the vascular space, providing relief from edema. Diuresis is not a prominent feature of digitalis therapy if edema does not accompany the congestive failure syndrome. Similarly, digitalis does not evoke diuresis if edema is not cardiogenic. Thus the diuretic response to digitalis is secondary to circulatory improvement and is not from a direct effect on the kidney, and is virtually never adequate without concurrent loop diuretic therapy (Robinson, 1972).

Pharmacokinetics

Dog:

The absorption of digoxin after oral administration of an elixir usually is uniform, up to 75–90%, with peak serum concentrations attained in 45–60 minutes (Krasula et al., 1976). With tablets, the peak serum concentration is less, and occurs somewhat later (90 minutes). After IV administration, the maximal positive inotropic responses to digoxin were obtained within 60 minutes after injection (Hamlin et al., 1971). Breznock (1973, 1975) reported that the plasma half-life value for digoxin was 38.9 and 55.9 hours in different studies. Others report approximate digoxin half-lives varying from 24 to 31 hours, with a median of 30 hours for six studies (Barr et al., 1972; Doherty, 1973; Breznock, 1973, 1975; Hahn, 1977; DeRick et al., 1978). The importance of interpatient variability is exemplified in a study that found the half-life for digoxin in dogs at steady state varied from 14.4 to 46.5 hours (DeRick et al., 1978). These variables strengthen the need for adoption of individual dosage regimens, depending on the patient’s response and, especially, evaluation of the serum digoxin concentration (SDC).

Digoxin is 25% protein bound (Breznock, 1973) and urinary excretion seems to be the most important route of elimination. Digitalis glycosides and their biotransformation products can follow an enterohepatic cycle, in which compounds are excreted by the liver into bile and some parent glycoside and metabolites are subsequently reabsorbed. See Section Digitalis in Cats.

Horse:

The pharmacokinetics in horses have been studied because digoxin is occasionally considered for congestive heart failure and supraventricular arrhythmias in these animals (Sweeney et al., 1993). After oral administration of 44 μg/kg, the oral absorption was approximately 23%, with a peak concentration of 2.2 ng/ml (Brumbaugh et al., 1983). The half-life was approximately 17 hours based on mean serum concentrations. The authors presented oral doses needed to attain predicted steady-state serum concentrations that ranged from 28 μg/kg to 64 μg/kg loading dose, followed by 11–25 μg/kg maintenance dose every 12 hours. The specific dose depends on the therapeutic target concentrations cited in their paper (Brumbaugh et al., 1983).

Digitalis Toxicity

Plasma concentrations:

In humans and dogs, therapeutic and toxic serum drug concentrations (SDCs) are in the range of 0.8–1.6 ng/ml and greater than 2.4 ng/ml, respectively (Moe and Farah, 1975). In dogs, concentrations from 0.8 to 2.4 ng/ml have been considered to be therapeutic, whereas SDC greater than 2.5–3 ng/ml are associated with increased probability of toxicosis. Nontoxic digoxin plasma concentrations have been determined for horses (0.5–2 ng/ml; Button et al., 1980); for cats (≤2.3 ng/ml; Erichsen et al., 1980); and for dogs (≤2.5 ng/ml; DeRick et al., 1978). Toxicity signs are generally mild or absent when serum digoxin concentrations are less than 2.5 ng/ml; moderate with SDC of 2.5–6 ng/ml; and severe, even fatal, when SDC exceeds 6 ng/ml (Fillmore and Detweiler, 1973; Teske et al., 1976).

Today, with the knowledge that neurohormonal and clinical benefits occur at much lower serum concentrations than needed for inotropic benefit (Ahmed et al., 2006a, 2006b; Ahmed et al., 2008) digoxin toxicity is much less a problem. In nonemergent situations, the authors advocate an initial low dosage, relying upon other drugs discussed in this chapter to control immediate signs. This is followed by uptitration of digoxin dosage over 2–3 weeks, using serum concentrations taken 8 hours posttreatment with a target SDC of 0.8–1.2 ng/ml. If kidney function declines, dose adjustments may be necessary to prevent accumulation of high concentrations of digoxin.

Clinical signs:

Digitalis intoxication is characterized by clinical signs varying from mild gastrointestinal upset to neurological signs and death (Detweiler, 1977; Tilley, 1979). Relative inappetance, depression, and loose stools are common side effects, which are often self-limiting. Vomiting, however, is viewed more seriously, especially if protracted diarrhea is an accompaniment and these individuals should be examined for additional evidence of toxicity. Lethal outcomes are most often due to cardiac arrhythmias. The authors emphasize that the presence of any sign that can be seen with toxicosis should be considered to indicate toxicosis and action taken. This ideally triggers an office visit, SDC measurement, and serum biochemistry to evaluate kidney values. An ECG should be examined in dogs suspected of digoxin toxicity. The effects of digoxin on the ECG were described in Section Effects on the Electrocardiogram. Occurrence of ECG abnormalities necessitates: complete withdrawal of digitalis therapy; measurement of SDC; possibly other medical intervention; and reduction in dosage when reinstituted.

Electrolyte Involvement:

Low K⁺ concentration potentiates digitalis arrhythmogenicity and lessens efficacy of its treatment, whereas excess K⁺ antagonizes arrhythmogenic activity. The antiarrhythmic activity of K⁺ in digitalis intoxication is probably related to inhibition by the cation of glycoside binding to the Na⁺,K⁺-ATPase.

Treatment:

Discontinuing digoxin administration is the first step to treat toxicity. Serum drug concentrations and ECG should be evaluated. Other drugs can be considered to replace digoxin in treatment (other drugs discussed in this chapter).

Digoxin immune FAB (Digibind^®):

This is an ovine source of antidigoxin antibodies. This treatment has been used in animals but is expensive. One vial contains 38 mg digoxin immune FAB and will neutralize 500 μg of digoxin. Animals will improve quickly after administration. After therapy with Digibind, free digoxin levels decreased whereas bound digoxin (to FAB) levels will rise.

Antiarrhythmic therapy:

Antiarrhythmic therapy for digitalis intoxication is not specific and treatment of specific arrhythmias is handled elsewhere (see Chapter 22). Atropine may be helpful in cases with severe sinus bradycardia or AV block. In the presence of AV block, therapy with beta-blockers and calcium channel blockers should be avoided. Quinidine should be avoided as it may actually cause an increase in plasma concentrations of digoxin, probably by blocking the efflux transporter, p-glycoprotein (Discussed in Chapter 22).

Therapeutic Indications for Digitalis

Congestive heart failure:

Controversy exists relative to the actual survival benefits of digitalis glycosides in the long-term therapeutic management of cardiac disease in animal and human patients (Hamlin et al., 1973; Patterson et al., 1973; Braunwald, 1985; Kittleson et al., 1985a). In man, no study has ever shown overall improvement in survival with digitalis therapy. However, improvement in quality of life and reduction in hospitalization have been demonstrated (Packer et al., 1993;Digitalis Investigation Group, 1997;Whitbeck et al., 2013). With low serum digoxin levels (0.5–0.9 ng/ml) there was a benefit, which was lost at higher serum levels (Ahmed et al., 2006a,b; Ahmed et al., 2008).

Cardiac glycosides are theoretically indicated in systolic heart failure of any etiology. New inodilator drugs (pimobendan discussed in Section Inodilators: Pimobendan) have largely taken the place of digitalis in managing heart failure in animals.

Atrial arrhythmias:

Many specialists use digoxin (often with diltiazem) to control the heart rate in atrial fibrillation, when there is a rapid ventricular response (Gelzeret al., 2009).This therapeutic choice is made easier if heart failure is also present, especially with evidence of poor systolic function (e.g., dilated cardiomyopathy). However, digoxin does not produce conversion to a sinus rhythm, but reduces ventricular rate by slowing AV conduction (Meijler, 1985).

Precautions:

The authors do not initiate digoxin treatment unless rate control is needed and/or if inotropic support is needed and finances precluded the use of other positive inotropic agents. Digitalis therapy is not used in the presence of heart block or ventricular tachycardia.

Digoxin should not be used to reduce heart rate when sinus tachycardia is present without evidence of heart failure. Tachycardia, associated with other conditions, such as fever, thyrotoxicosis, pain, anxiety, or even cardiac conditions, such as pericardial effusion with tamponade or with hypertrophic cardiomyopathy (HCM), is not amenable to digitalis therapy.

Clinical Practice

Generally, digoxin is initiated at the low end of the dose range listed below, then increased gradually if necessary to achieve the desired therapeutic outcome. If toxicity is observed, monitoring and assessment – as described in this chapter – should be used to adjust the dosage or make a determination about discontinuing digoxin administration. A listing of average digitalis glycoside dosages is provided in formularies for dogs and cats (Tables 21.1 and 21.2). The dosage regimens published for dogs have used both a mg/kg and mg/m² dosing schedule, the latter based on body surface area. There is some evidence that dosing on a body surface area basis may be safer than mg/kg dosing (Kittleson, 1983).

Table 21.1 Medical management of factors contributing to signs of systolic heart failure in dogs. Source: Adapted from Atkins CE. Atrioventricular valvular insufficiency. In Allen DG (ed): Small Animal Medicine, Lippincott, 1992.

Factor	Strategy	Agent and dosage
Fluid retention/ excessive preload	Salt restriction Diuresis	Senior diet, renal diet or, late in course, heart (heavily salt-restricted) diet Furosemide 1–4 mg/kg SID–TID, IV, IM, SC, or PO or CRI at 0.66 mg/kg/min Torsemide 0.2 mg/kg PO SID–TID Hydrochlorothiazide or aldactazide 2–4 mg/kg QID–BID PO Chlorthiazide 20–40 mg/kg BID PO Spironolactone 2.0 mg/kg SID PO
	Venodilation	Triamterene 2–4 mg/kg/day PO Nitroglycerin 2% ointment 0.5 cm per 5kg TID topically for 1st 24 hours Captopril 0.5–2 mg/kg TID PO Enalapril 0.5 mg/kg SID–BID PO Benazepril 0.25–0.5 mg/kg SID PO Prazosin 1 mg TID if <15 kg; 2 mg TID if >15 kg Sodium nitroprusside 1–5 μg/kg/min IV
Neurohormonal aberration	Blunt RAAS	Captopril 0.5–2 mg/kg TID PO Enalapril 0.5–1 mg/kg SID–BID PO Benazepril 0.25–0.5 mg/kg SID PO Spironolactone 2.0 mg/kg/day PO Angiotensin II receptor blocker (e.g., losartan) dosage TBD
	Blunt SNS	Digoxin 0.005–0.01 mg/kg or 0.22 mg/m² body surface BID PO for maintenance Propranolol 5–40 mg TID PO Atenolol 0.25–1 mg/kg PO^b Carvedilol 0.1–0.2 mg/kg SID PO, increasing to 0.5–1mg/kg BID over 6 weeks
Increased afterload	Arterial vasodilation	Hydralazine 1–3 mg/kg BID PO Captopril 0.5–2 mg/kg TID PO Enalapril 0.5 mg/kg SID–BID PO Benazepril 0.25–0.5 mg/kg SID PO Prazosin 1 mg TID PO if <15 kg; 2 mg TID if >15 kg PO Sodium nitroprusside 1–5 μg/kg/min IV Diltiazem 0.1–0.2 mg/kg IV slowly; 0.5–1.5 mg/kg TID PO Amlodipine 0.1–0.2 mg/kg SID–BID PO Sildenafil 0.5–1 mg/kg SID–BID PO
Diminished contractility^a	Positive inotropic support	Digoxin 0.005–0.01 mg/kg or 0.22 mg/m² body surface BID PO for maintenance Rapid oral: 0.01 mg/kg BID to 0.02 mg/kg TID for 1 day, then to maintenance Rapid IV: 001–0.02 mg/kg given one half IV immediately and one-fourth IV at 30 to 60-min intervals PRN Dobutamine 1.5–20 μg/kg/min IV for <72 hours Dopamine 2–10 μg/kg/min IV for <72 hours Amrinone 1–3 mg/kg IV followed by 10–100 μg/kg/min Pimobendan 0.25 mg/kg BID PO

^aIn most instances of mitral insufficiency, positive inotropic support is unnecessary.

^bCalcium channel (verapamil and diltiazem) and beta-blockers (propranolol, esmolol, atenolol) should be used with caution in patients in heart failure.

SID, once daily; BID, twice daily; TID, three times daily; QID, four times daily; IM, intramuscularly; IV, intravenously; SC, subcutaneously; PO, per os; PRN, as needed; RAAS, renin–angiotensin–aldosterone system; SNS, sympathetic nervous systems.

Table 21.2 Feline formulary

Drug	Trade Name^a	Formulation(s)^b	Dosage	Use
Amlodipine	Norvasc	1.25 mg tablets	0.625 mg PO QD–BID	Antihypertensive
Diltiazem	Cardizem	30 mg tablets	7.5 mg PO TID	Lusitrope, Vasodilator, Negative chronotrope
Diltiazem – LA
	Dilacor XR	180, 240 mg capsule	30 mg PO BID	same
	Cardizem CD	180, 240 mg capsule	45 mg PO QD	same
Enalapril	Enacard (Vasotec)	1, 2.5, 5 mg tablet	0.5 mg/kg PO QD	ACEI (CHF, Hypertension)
Benazepril	Lotensin (Foretkor)	5, 10 mg tablet	0.25–0.5 mg/kg PO QD–BID	same
Atenolol	Tenormin	25 mg tablet	6.25–12.5 mg PO QD	Negative chronotrope, Antiarrhythmic, Lusitrope, Antihypertensive
Esmolol	Brevibloc	10, 250 mg/ml injectable	50–500 (100 usually) μg/kg IV	same
Sotalol	Betapace	80 mg tablet	2 mg/kg PO BID	Antiarrhythmic
Procainamide	Pronestyl, Procan SR	250 mg tablet 100 mg/ml injectable	2–5 mg/kg PO BID–TID	Antiarrhythmic
Furosemide	Lasix	12.5 mg tablet 50 mg/ml injectable	1–4 mg/kg PO BID–q 48 h; 0.5–2 mg/kg SQ, IM, IV PRN	Diuretic
Nitroglycerin	Nitrol, Nitro-Bid	2% ointment	2–5 cm topically TID for 24 h	Venodilator (CHF)
Warfarin	Coumadin	1, 2, 2.5, 4 mg tablet	0.1–0.2 mg QD	Anticoagulant
Heparin		Multiple	250–300 U/kg SQ TID	Anticoagulant
LMW Heparin	Fragmin	2500 U/0.2 ml	100 U/kg SQ QD	Anticoagulant
Aspirin	Plavix	81 mg	40–80 mg q 72 h	Anticoagulant
Clopidogrel		75 mg	17.5 mg daily	Anticoagulant
Digoxin	Lanoxin	0.05 mg/ml elixir 0.125 mg tablet	0.007 mg/kg POq 48 h (check serum [digoxin])	Positive inotrope, Negative chronotrope (CHF, SVT)
Taurine		250 mg tablet	250 mg PO QD	Taurine deficiency
Cyproheptadine	Periactin	4 mg tablet	2 mg BID	Prevent SAE vasoconstriction (?)

^aSelected name brands, some available as generic.

^bMost appropriate formulations for cats; other sizes available for many drugs.

BID, twice daily; TID, three times daily; IM, intramuscularly; IV, intravenously; SQ, subcutaneously; PO, per os; PRN, as needed.

Parenteral schedules:

IV administration increases the likelihood for toxicity, including life-threatening arrhythmias, and this route is rarely used for administration. Digoxin is sufficiently absorbed by the oral route that IV administration is not ordinarily necessary. Intravenous dosing regimens are provided in previous editions of this book.

Digitalis in Cats

There are less data on administration of digoxin to cats compared to dogs. There are no studies of survival or quality of life (Atkins et al., 1988, 1989, 1990); however, there are evaluated clinically relevant aspects of digitalis therapy in cats.

The effect of concurrent therapies on digoxin pharmacokinetics was measured and results presented in Table 21.3. The study showed that other drugs can affect digoxin through unidentified mechanisms. The authors also compared results between the 10 and 20-day evaluations, indicating that at steady state there is no effect of duration of therapy on pharmacokinetics in normal cats (Atkins et al., 1988). Pharmacokinetics were also examined in cats with compensated dilated cardiomyopathy (DCM) compared with six clinically normal cats (Atkins et al., 1989) at a dosage of 0.01 mg/kg, q 48 h for 10 days. There were no differences between control and heart failure cats. Other studies have shown hemodynamic improvement in cats with heart failure due to DCM (Atkins et al., 1990).

Table 21.3 Digoxin pharmacokinetic properties in cats after treatment with digoxin tablets (0.01 mg/kg of body weight, q 48 h). Source: Adapted from Atkins et al., 1988.

	Group 1 (n = 6)	Group 2 (n = 3)
Peak [DXN] (ng/ml)	2.1 ± 0.35 (0.95 to 3.69)	3.3^* ± 0.60 ( 1.31 to 5.64)	1.8 ± 0.38 (1.11 to 2.69)	1.4 ± 0.08 (1.31 to 1.63)
8-Hour [DXN] (ng/ml)	1.4 ± 0.35 (0.56 to 3.03)	2.5 ± 0.64 (0.63 to 5.01)	1.1 ± 0.33 (0.58 to 1.91)	0.8 ± 0.29 (0.58 to 1.71)
Mean [DXN] (ng/ml)	1.1 ± 0.22 (0.44 to 1.85)	2.2^* ± 0.57 (0.55 to 4.15)	0.93 ± 0.2 (0.57 to 1.41)	0.69 ± 0.1 (0.54 to 0.95)
t (hours)	40.1 ± 11.7 (13.2 to 99)	81.8^* ± 21.8 (30.1 to 173)	61.8 ± 24.0 (23 to 119.6)	47.7 ± 13.8 (24.7 to 80.7)
Oral clearance (L/h.kg)	0.15 ± 0.035 (0.05 to 0.27)	0.07^* ± 0.02 (0.01 to 0.17)	0.10 ± 0.02 (0.08 to 0.14)	0.16 ± 0.04 (0.07 to 0.24)
Hours [DXN] in toxic range	3 ± 1.7 (0 to 6)	24.7^* ± 9.8 (0 to 48)	2 ± 1.6 (0 to 6)	0 ± 0 (0)

Group 1 (n = 6)

Group 2 (n = 3)

Variable

DXN alone

DXN, FRS, ASA

DXN 10 days

DXN 20 days

Peak [DXN] (ng/ml)

2.1 ± 0.35

(0.95 to 3.69)

3.3^* ± 0.60

( 1.31 to 5.64)

1.8 ± 0.38

(1.11 to 2.69)

1.4 ± 0.08

(1.31 to 1.63)

8-Hour [DXN] (ng/ml)

1.4 ± 0.35

(0.56 to 3.03)

2.5 ± 0.64

(0.63 to 5.01)

1.1 ± 0.33

(0.58 to 1.91)

0.8 ± 0.29

(0.58 to 1.71)

Mean [DXN] (ng/ml)

1.1 ± 0.22

(0.44 to 1.85)

2.2^* ± 0.57

(0.55 to 4.15)

0.93 ± 0.2

(0.57 to 1.41)

0.69 ± 0.1

(0.54 to 0.95)

t (hours)

40.1 ± 11.7

(13.2 to 99)

81.8^* ± 21.8

(30.1 to 173)

61.8 ± 24.0

(23 to 119.6)

47.7 ± 13.8

(24.7 to 80.7)

Oral clearance (L/h.kg)

0.15 ± 0.035

(0.05 to 0.27)

0.07^* ± 0.02

(0.01 to 0.17)

0.10 ± 0.02

(0.08 to 0.14)

0.16 ± 0.04

(0.07 to 0.24)

Hours [DXN] in toxic range

3 ± 1.7

(0 to 6)

24.7^* ± 9.8

(0 to 48)

2 ± 1.6

(0 to 6)

0 ± 0

(0)

^*Significantly different from that value within the same group (P <0.05).

ASA, aspirin; DXN, digoxin; FRS, furosemide.

One can conclude from these studies, and others, that digoxin is effective in cats with DCM, when given q 48 h, that concurrent treatment alters pharmacokinetics, predisposing to toxicity, but that the heart failure state per se and prolonged therapy does not further affect these parameters. The recommended dosage for cats in heart failure is 0.007 mg/kg q 48 h and SDC should be determined at steady state, 8 hours posttreatment, with a goal of 0.8–1.2 ng/ml.

Preparations

Digoxin, USP – cardiotonic glycoside from D. lanata.
Digoxin Injection, USP – digoxin in 10% alcohol; injections, 0.5 mg/2 ml.
Digoxin Tablets, USP – tablets, 0.25 and 0.5 mg.
Digoxin Solution – digoxin, 0.05 mg/ml in oral solution.

Sympathomimetic Agents: Dobutamine and Dopamine

Sympathomimetic drugs, such as dobutamine and dopamine, can be used to support cardiac function and blood pressure acutely. Veterinary cardiologists have most often employed dobutamine for the emergency management of heart failure in dogs; there is less support for administration of dopamine.

Dobutamine

This agent, a synthetic sympathomimetic, produces improvement in cardiac performance by complexing primarily with myocardial β₁ receptors, which, through second messengers, increase intracellular calcium and, thereby, myocardial contractility. There is both agonist and antagonist effects on α receptors, the clinical effects of which are uncertain. Dobutamine is unique as a SNS-agonist as it has relatively little effect on heart rate, is minimally proarrhythmic, and has a very short half-life (1–2 minutes). The short half-life allows for quick adjustment of dose rates and if the infusion is discontinued the effects quickly dissipate. The short half-life also requires that it be administered as a constant rate infusion (CRI). Additionally, it results in down-regulation of β₁ receptors 48–72 hours after its institution, rendering the drug ineffective after this time. Furthermore, there is concern that the positive dromotropic effect of dobutamine in dogs with atrial fibrillation, not receiving digitalis, may increase AV nodal conduction to a degree that a life-threatening ventricular response rate may result in ventricular fibrillation. There are no clinical trials involving dobutamine in natural canine heart disease, but anecdotal evidence that it may be helpful for the acute management of heart failure in hospitalized patients.

Dobutamine is beneficial for emergency management of DCM, without atrial fibrillation or other supraventricular tachycardia. It provides inotropic support without increasing heart rate and can be life-saving when there is profound myocardial systolic dysfunction. There is no evidence of benefit for treatment of long-standing mitral valve regurgitation.

Dopamine

Dopamine, unlike dobutamine, is not a synthetic catecholamine, occurring naturally and formed endogenously from L-Dopa. It has a significant first pass effect and very short half-life, dictating that it can only be administered IV with a CRI. It has two known receptor subtypes with which it interacts (DA₁ and DA₂). DA₁ subserves vasodilation in the renal, cerebral, mesenteric, and coronary vasculature. DA₂ stimulation inhibits norepinephrine release from the postsynaptic nerves and autonomic ganglia. However, dopamine also stimulates β₁– and α_1,2-adrenoreceptors, with the expected positive inotropic, chronotropic, dromotropic, and vasoconstrictive effects.

With this wide spectrum of effects, it is not surprising that clinical effects vary with dosage. At a low dosage (0.5–1 μg/kg/min), dopamine stimulates DA₁ only, thereby lowering blood pressure, without other hemodynamic effects. At intermediate dosages, cardiac benefits are recognized, with variable effects on heart rate, a lack of reduction in pulmonary capillary wedge pressure, but positive effects on cardiac output and renal blood flow. At high doses, vasoconstriction may be observed with increased cardiac afterload. Dopamine does not dilate capacitance vascular beds, so is sometimes accompanied by venodilators (nitroglycerin or nitroprusside) or by dobutamine. Concerns at this dosage range include arrhythmias and tachycardia. High dosages (2–10 μg/kg/min in normal humans to >50 μg/kg/min in shock patients) produce, in addition to tachycardia and arrhythmia, elevation of blood pressure and systemic vascular resistance through α₁ and α₂-adrenoreceptor stimulation with resultant vasoconstriction (Horowitz et al., 1962; Sprung et al., 1984). This is desirable only in shock management and should be preceded by fluid therapy to correct deficits.

In veterinary medicine, dopamine has found its greatest utility in the management of hypotension during anesthesia and treating noncardiogenic shock. Sisson and Kittleson (1999) recommend a starting dosage of 2 μg/kg/min, with upward titration or retreat as the clinical situation dictates. The ultimate dosage typically ranges from 1 to 8 μg/kg/min, administered by CRI (in 5% D/W, using an infusion pump to avoid excessive volumes in heart failure patients). Although it has been used, at low doses, to stimulate DA receptors, dilate renal vessels, and treat acute kidney disease, it has not been shown to produce these benefits in animal studies.

Preparations:

Supplied in 5-ml vials containing 40, 80, 160 mg/ml.

Inodilators: Pimobendan

Agents that have both vasodilatory and positive inotropic properties are classified as inodilators (Opie, 2001). Historically, short-term management of acute or decompensated heart failure characterized by systolic dysfunction benefited from a combination of dobutamine (positive inotrope) and nitroprusside (vasodilator). Inodilators combine these properties and agents such as pimobendan, which is available in an oral formulation, make chronic therapy a possibility. Levosimendan, another drug from this class having been investigated in animals, is not available for clinical use at this time.

Clinical Application

Pimobendan is a novel agent with properties useful in the clinical management of canine heart failure secondary to either DCM or myxomatous mitral valvular disease (MMVD). The efficacy of pimobendan in the treatment of heart failure, arising from DCM and MMVD, has been evaluated more thoroughly in dogs than have other cardioactive medications to date.

In dogs (English Cocker spaniels and Doberman Pinschers) with DCM and heart failure pimobendan was associated with a significant improvement in heart disease class (modified New York Heart Association [NYHA] functional class; overall, median NYHA 2 to NYHA 3), regardless of breed (Figure 21.6, Table 21.4). Other agents (furosemide, enalapril, and digoxin) also were allowed. However, only in the Doberman pinschers was there a significant survival benefit (Fuentes, 2004).

A. Modified New York Heart Association (NYHA) system (American)
Class I	Includes patients with asymptomatic heart disease (typically murmur only)
Class II	Includes patients with signs of cardiac dysfunction only with strenuous exercise
Class III	Includes patients with heart disease that causes clinical signs with routine daily activities or mild exercise
Class IV	Includes patients with heart disease that causes severe clinical signs even at rest
B. International Small Cardiac Health Council (ISACHC) system
Class I	The asymptomatic patient:
	Class IA: Signs of heart disease are present, but no signs of compensation (volume or pressure load ventricular hypertrophy) are evident
	Class IB: Signs of heart disease are present and signs of compensation (volume or pressure overload ventricular hypertrophy) are detected radiographically or echocardiographically
Class II	Mild-to- moderate heart failure; clinical signs of heart failure are evident at rest or with mild exercise, and adversely affect the quality of life
Class III

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