Chapter 20: Cardiovascular Physiology & Anesthesia

Anesthesiologists must have a thorough understanding of cardiovascular physiology. Anesthetic successes and failures are often directly related to the skill of the practitioner in manipulating cardiovascular physiology. This chapter reviews the physiology of the heart and the systemic circulation and the pathophysiology of heart failure.

The circulatory system consists of the heart, blood vessels, and blood. Its function is to provide oxygen and nutrients to the tissues and to carry away the products of metabolism. The heart propels blood through two vascular systems arranged in series. In the normally low-pressure pulmonary circulation, venous blood flows past the alveolar–capillary membrane, takes up oxygen, and releases CO₂. In the high-pressure systemic circulation, oxygenated arterial blood is pumped to tissues, and the byproducts of metabolism are taken up for elimination by the lungs, kidneys, or liver.

The heart can be functionally divided into right and left pumps, each consisting of an atrium and a ventricle. The atria serve as both conduits and priming pumps, whereas the ventricles act as the major pumping chambers. The right ventricle receives systemic venous (deoxygenated) blood and pumps it into the pulmonary circulation, whereas the left ventricle receives pulmonary venous (oxygenated) blood and pumps it into the systemic circulation. Four valves normally ensure unidirectional flow through each chamber. The normal pumping action of the heart is the result of a complex series of electrically driven and mechanical events. Electrical events precede mechanical ones.

The heart consists of specialized striated muscle in a connective tissue skeleton. Cardiac muscle can be divided into atrial, ventricular, and specialized pacemaker and conducting cells. The self-excitatory nature of cardiac muscle cells and their unique organization allow the heart to function as a highly efficient pump. Serial low-resistance connections (intercalated disks) between individual myocardial cells allow the rapid and orderly spread of depolarization in each pumping chamber. Electrical activity readily spreads from one atrium to another and from one ventricle to another via specialized conduction pathways. The normal absence of direct connections between the atria and ventricles except through the atrioventricular (AV) node delays ventricular depolarization, enabling the atria to prime the ventricles.

CARDIAC ACTION POTENTIALS

At rest, the myocardial cell membrane is nominally permeable to K⁺, but is relatively impermeable to Na⁺. A membrane-bound Na⁺–K⁺-adenosine triphosphatase (ATPase) concentrates K⁺ intracellularly and extrudes Na⁺ out of the cell. Relative to extracellular concentrations intracellular Na⁺ concentration is kept low and intracellular K⁺ concentration is kept high. The relative impermeability of the membrane to calcium also maintains a high extracellular to cytoplasmic calcium gradient. Movement of K⁺ out of the cell and down its concentration gradient results in a net loss of positive charges from inside the cell. An electrical potential is established across the cell membrane, with the inside of the cell negative with respect to the extracellular environment, because anions do not accompany K⁺. Thus, the resting membrane potential represents the balance between two opposing forces: the movement of K⁺ down its concentration gradient and the electrical attraction of the negatively charged intracellular space for the positively charged K⁺.

The normal ventricular cell resting membrane potential is –80 to –90 mV. As with other excitable tissues (nerve, skeletal muscle, and some endocrine cells), when the cell membrane potential becomes less negative and reaches a threshold value, a characteristic action potential (depolarization) develops (Figure 20–1 and Table 20–1). The action potential transiently increases the membrane potential of the myocardial cell to +20 mV. In contrast to action potentials in axons, the spike in cardiac action potentials is followed by a plateau phase that lasts 0.2 to 0.3 s. Whereas the action potential for skeletal muscle and nerves is due exclusively to the opening of voltage-gated sodium channels, in cardiac muscle the action potential is initiated by voltage-gated sodium channels (the spike) and maintained by voltage-gated calcium channels (the plateau). In pacemaker cells depolarization is initiated by voltage-gated calcium channels rather than by sodium channels. The plateau phase is maintained by calcium flow into the cell and potassium flow out of the cell. Voltage-gated sodium channels inactivate and cease to conduct within milliseconds of opening. Subsequent termination of calcium channel permeability and activation of several forms of voltage-gated potassium channels restores the membrane potential to its resting value.

Following depolarization, the cells are typically refractory to subsequent normal depolarizing stimuli until “phase 4.” The absolute refractory period is the minimum interval between two maximal stimuli that will result in an action potential. The relative refractory period is the additional time beyond the absolute refractory period in which a maximal stimulus, but not a stimulus of normal intensity, will produce a depolarization.

Table 20–2 lists some of the multiple types of ion channels in cardiac muscle membrane. Some are activated by a change in cell membrane voltage, whereas others open only when bound by ligands. T-type (transient) voltage-gated calcium channels play a role in phase 0 of depolarization. (A more modern nomenclature for voltage-gated calcium channels—Cav1, Cav2, Cav3—is creeping into the scientific literature but remains uncommon in clinical usage.) During the plateau phase (phase 2), Ca²⁺ inflow occurs through slow L-type (long-lasting), voltage-gated calcium channels. Multiple potassium channel forms contribute repolarization, and a full discussion of this topic is beyond the focus of this textbook.

INITIATION & CONDUCTION OF THE CARDIAC IMPULSE

The cardiac impulse normally originates in the sinoatrial (SA) node, a group of specialized pacemaker cells in the sulcus terminalis, located posteriorly at the junction of the right atrium and the superior vena cava. The slow influx of Na⁺ through so-called hyperpolarization-activated cyclic nucleotide–gated (HCN) channels results in a less negative resting membrane potential (–50 to –60 mV). This has three important consequences: near constant inactivation of voltage-gated sodium channels, an action potential that is primarily due to ion movement across the slow calcium channels and with a threshold of –40 mV, and regular spontaneous depolarizations. During each cycle, Na⁺ ions passing through HCN channels causes the cell membrane to become progressively less negative; when the threshold potential is reached, calcium channels open and an action potential develops. Inactivation of L-type calcium channels and activation of potassium channels returns the cells in the SA node to their normal resting membrane potential.

The impulse generated at the SA node is normally rapidly conducted across the atria and to the AV node. Specialized atrial fibers may speed up conduction to both the left atrium and the AV node. The AV node is located in the septal wall of the right atrium, just anterior to the opening of the coronary sinus and above the insertion of the septal leaflet of the tricuspid valve. The normally slower rate of spontaneous depolarization in AV junctional areas (40–60 times/min) allows the faster SA node to control heart rate. Any factor that decreases the rate of SA node depolarization or increases the automaticity of AV junctional areas allows the junctional areas to function as the pacemaker for the heart.

Impulses from the SA node normally reach the AV node after about 0.04 s, but leave after another 0.11 s. This delay is the result of the slowly conducting small myocardial fibers within the AV node, which depend on L-type calcium channels for propagation of the action potential. In contrast, conduction of the impulse between adjoining cells in the atria and in the ventricles is due primarily to activation of sodium channels. The lower fibers of the AV node combine to form the common bundle of His. This specialized group of fibers passes into the interventricular septum before dividing into left and right branches to form the complex network of Purkinje fibers that depolarizes both ventricles. In sharp contrast to AV nodal tissue, His–Purkinje fibers have the fastest conduction velocities in the heart, resulting in nearly simultaneous depolarization of the entire endocardium of both ventricles (normally within 0.03 s). Synchronized depolarization of the lateral and septal walls of the left ventricle promotes effective ventricular contraction. When synchronized contraction of the septal and lateral walls is impaired (eg, in heart failure patients), ventricular function may be improved by biventricular pacing and cardiac resynchronization therapy. The spread of the impulse from the endocardium to the epicardium through ventricular muscle requires an additional 0.03 s. Thus, an impulse arising from the SA node normally requires less than 0.2 s to depolarize the entire heart.

Potent inhaled anesthetics depress SA node automaticity. These agents seem to have only modest direct effects on the AV node, prolonging conduction time and increasing refractoriness. This combination of effects likely explains the occurrence of junctional tachycardia when an anticholinergic is administered for sinus bradycardia during inhalation anesthesia; junctional pacemakers are accelerated more than those in the SA node. The electrophysiological effects of volatile agents on Purkinje fibers and ventricular muscle are complex due to autonomic interactions. Both antiarrhythmic and arrhythmogenic properties are described. The former may be due to direct depression of Ca²⁺ influxes, whereas the latter generally involves potentiation of catecholamines, especially with the now seldom-used halothane. Intravenous induction agents have limited electrophysiological effects in usual clinical doses. Opioids, particularly fentanyl and sufentanil, can depress cardiac conduction, increasing the time of AV node conduction and the refractory period and prolonging the duration of the Purkinje fiber action potential.

Local anesthetics have important electrophysiological effects on the heart at blood concentrations that are generally associated with systemic toxicity. In the case of lidocaine, electrophysiological effects at low blood concentrations can be therapeutic. At high blood concentrations, local anesthetics depress conduction; at extremely high concentrations, they also depress the SA node. The most potent local anesthetics—bupivacaine, etidocaine, and to a lesser degree, ropivacaine—seem to have the most potent effects on the heart, particularly on Purkinje fibers and ventricular muscle. Bupivacaine, like all local anesthetics, preferentially binds open or inactivated sodium channels. Bupivacaine dissociates from them more slowly than less toxic agents. It can cause profound sinus bradycardia and sinus node arrest and malignant ventricular arrhythmias; furthermore, it can depress left ventricular contractility. Twenty percent lipid emulsions have been used to treat local anesthetic cardiac toxicity. The mechanisms of action of this therapy are unclear, although most likely the lipid serves as reservoir for circulating bupivacaine, decreasing the amount of bupivacaine in the myocardium.

The clinically used calcium channel blockers are organic compounds that block Ca²⁺ influx through L-type but not T-type channels. In a manner reminiscent of local anesthetics and sodium channels, agents such as verapamil, and to a lesser extent, diltiazem, preferentially bind the calcium channel in its depolarized inactivated state (use-dependent blockade). Calcium channel blockers are employed perioperatively as antihypertensives and as antiarrhythmics.

MECHANISM OF CONTRACTION

Myocardial cells contract as a result of the interaction of two overlapping, rigid contractile proteins, actin and myosin. Dystrophin, a large intracellular protein, connects actin to the cell membrane (sarcolemma). Cell shortening occurs when the actin and myosin are allowed to fully interact and slide over one another. This interaction is normally prevented by two regulatory proteins, troponin and tropomyosin; troponin is composed of three subunits (troponin I, troponin C, and troponin T). Troponin is attached to actin at regular intervals, whereas tropomyosin lies within the center of the actin structure. An increase in intracellular Ca²⁺ concentration (from about 10^–7 to 10^–5 mol/L) promotes contraction as Ca²⁺ ions bind troponin C. The resulting conformational change in these regulatory proteins exposes the active sites on actin that allow interaction with myosin bridges (points of overlapping). The active site on myosin functions as a magnesium-dependent ATPase whose activity is enhanced by the increase in intracellular Ca²⁺ concentration. A series of attachments and disengagements occur as each myosin bridge advances over successive active sites on actin. Adenosine triphosphate (ATP) is consumed during each attachment. Relaxation occurs as Ca²⁺ is actively pumped back into the sarcoplasmic reticulum by a Ca²⁺–Mg²⁺-ATPase; the resulting drop in intracellular Ca²⁺ concentration allows the troponin–tropomyosin complex to again prevent the interaction between actin and myosin.

Excitation–Contraction Coupling

The quantity of Ca²⁺ ions required to initiate contraction exceeds that entering the cell through L-type calcium channels during phase 2. The small amount that does enter through slow calcium channels triggers the release of much larger amounts of Ca²⁺ stored intracellularly (calcium-dependent calcium release) within cisterns in the sarcoplasmic reticulum.

The action potential of muscle cells depolarizes their T systems, tubular extensions of the cell membrane that transverse the cell in close approximation to the muscle fibrils, via L-type voltage-gated calcium channels. This initial increase in intracellular Ca²⁺ triggers an even greater Ca²⁺ inflow across ryanodine receptors, a nonvoltage-dependent calcium channel found in the sarcoplasmic reticulum. The force of contraction is directly dependent on the magnitude of the initial Ca²⁺ influx.

During relaxation, when the L-type channels close, a membrane-bound Ca²⁺–Mg²⁺-ATPase actively transports Ca²⁺ back into the sarcoplasmic reticulum. Thus, relaxation of the heart also requires ATP. Ca²⁺ is also extruded extracellularly by an exchange of intracellular Ca²⁺ for extracellular sodium in a 1:3 ratio by the Na⁺–Ca²⁺ exchanger in the cell membrane (Figure 20–2).

The quantity of intracellular Ca²⁺ available, its rate of delivery, and its rate of removal determine, respectively, the maximum tension developed, the rate of contraction, and the rate of relaxation. Sympathetic stimulation increases the force of contraction by raising intracellular Ca²⁺ concentration via a β₁-adrenergic receptor-mediated increase in intracellular cyclic adenosine monophosphate (cAMP) through the action of a stimulatory G protein. The increase in cAMP recruits additional open calcium channels. Phosphodiesterase inhibitors, such as milrinone, produce similar effects by preventing the breakdown of intracellular cAMP. Milrinone has lusitropic effects, improving relaxation and diastolic function. Digitalis glycosides increase intracellular Ca²⁺ concentration through inhibition of the membrane-bound Na⁺–K⁺-ATPase; the resulting small increase in intracellular Na⁺ relatively disfavors the normal pumping of Ca²⁺ from the cytoplasm via the Na⁺–Ca²⁺ exchange mechanism, increasing the intracellular Ca²⁺ concentration. Glucagon enhances contractility by increasing intracellular cAMP levels via activation of a specific receptor. The newer agent levosimendan is a calcium sensitizer that enhances contractility by binding to troponin C. The investigational drug omecamtiv mecarbil is a myosin activator that increases the duration of cardiac muscle contractility. Istaroxime has both inotropic and lusitropic effects, improving both systolic and diastolic function (Table 20–3).

In contrast, release of acetylcholine following vagal stimulation depresses contractility through increased cyclic guanosine monophosphate (cGMP) levels and inhibition of adenylyl cyclase; these effects are mediated by an inhibitory G protein. Acidosis inhibits L-type calcium channels and therefore also depresses cardiac contractility by unfavorably altering intracellular Ca²⁺ kinetics (Figure 20–3).

Studies suggest that volatile anesthetics depress cardiac contractility by decreasing the entry of Ca²⁺ into cells during depolarization (affecting T- and L-type calcium channels), altering the kinetics of Ca²⁺ release and uptake into the sarcoplasmic reticulum, and decreasing the sensitivity of contractile proteins to Ca²⁺. Inhalational anesthetics appear to have minimal effect upon early diastolic relaxation in subjects without known diastolic dysfunction. However, they do decrease atrial function perhaps resulting in reduced late diastolic filling. Anesthetic-induced cardiac depression is potentiated by hypocalcemia, β-adrenergic blockade, and calcium channel blockers. Nitrous oxide also produces concentration-dependent decreases in contractility by reducing the availability of intracellular Ca²⁺ during contraction. The mechanisms of direct cardiac depression from intravenous anesthetics are not well established, but presumably involve similar actions. Of all the typical intravenous induction agents, ketamine seems to have the least depressant effect on contractility due to its central nervous system excitatory effects.

INNERVATION OF THE HEART

Parasympathetic fibers innervate the atria and conducting tissues. Acetylcholine acts on specific cardiac muscarinic receptors (M₂) to produce negative chronotropic, dromotropic, and inotropic effects. In contrast, sympathetic fibers are more widely distributed throughout the heart. Cardiac sympathetic fibers originate in the thoracic spinal cord (T1–T4) and travel to the heart initially through the cervical (stellate) ganglia and from the ganglia as the cardiac nerves. Norepinephrine release at the heart causes positive chronotropic, dromotropic, and inotropic effects primarily through activation of β₁-adrenergic receptors. β₂-Adrenergic receptors are normally fewer in number and are found primarily in the atria; activation increases heart rate and, to a lesser extent, contractility. The relative fraction of β₂- to β₁-adrenergic receptors increases in heart failure.

Cardiac autonomic innervation has an apparent sidedness, because the right sympathetic and right vagus nerves primarily affect the SA node, whereas the left sympathetic and vagus nerves principally affect the AV node. Vagal effects frequently have a very rapid onset and resolution, whereas sympathetic influences generally have a more gradual onset and dissipation. Sinus arrhythmia is a cyclic variation in heart rate that corresponds to respiration (increasing with inspiration and decreasing during expiration); it is due to cyclic changes in vagal tone.

THE CARDIAC CYCLE

The cardiac cycle can be defined by both electrical and mechanical events (Figure 20–4). Systole refers to contraction and diastole refers to relaxation. Most diastolic ventricular filling occurs passively before atrial contraction. Contraction of the atria normally contributes 20% to 30% of ventricular filling. Three waves can generally be identified on atrial or central venous pressure tracings (Figure 20–4). The a wave is due to atrial systole. The c wave coincides with ventricular contraction and is said to be caused by bulging of the AV valve into the atrium. The v wave is the result of pressure buildup from venous return before the AV valve opens again. The x descent is the decline in pressure between the c and v waves and is thought to be due to a pulling down of the atrium by ventricular contraction. Incompetence of the AV valve on either side of the heart abolishes the x descent on that side, resulting in a prominent cv wave. The y descent follows the v wave and represents the decline in atrial pressure as the AV valve opens. The notch in the aortic pressure tracing is referred to as the incisura and is said to represent the brief pressure change from transient backflow of blood into the left ventricle just before aortic valve closure.

DETERMINANTS OF VENTRICULAR PERFORMANCE

Discussions of ventricular function usually refer to the left ventricle, but the same concepts apply to the right ventricle. Although the ventricles are often thought of as functioning separately, their interdependence has clearly been demonstrated. Moreover, factors affecting systolic and diastolic functions can be differentiated: Systolic function involves ventricular ejection, whereas diastolic function is related to ventricular filling.

Ventricular systolic function is often (erroneously) equated with cardiac output, which can be defined as the volume of blood pumped by the heart per minute. Because the two ventricles function in series, their outputs are normally equal. Cardiac output (CO) is expressed by the following equation:

where SV is the stroke volume (the volume pumped per contraction) and HR is heart rate. To compensate for variations in body size, CO is often expressed in terms of total body surface area:

where CI is the cardiac index and BSA is body surface area. BSA is usually obtained from nomograms based on height and weight. Normal CI is 2.5 to 4.2 L/min/m². Because the normal CI has a wide range, it is a relatively insensitive measurement of ventricular performance. Abnormalities in CI therefore usually reflect gross ventricular impairment. A more accurate assessment can be obtained if the response of the cardiac output to exercise is evaluated. Under these conditions, failure of the cardiac output to increase and keep up with oxygen consumption is reflected by a decreasing mixed venous oxygen saturation. A decrease in mixed venous oxygen saturation in response to increased demand usually reflects inadequate tissue perfusion. Thus, in the absence of hypoxia or severe anemia, measurement of mixed venous oxygen tension (or saturation) provides an estimate of the adequacy of cardiac output.

1. Heart Rate

When stroke volume remains constant, cardiac output is directly proportional to heart rate. Heart rate is an intrinsic function of the SA node (spontaneous depolarization), but is modified by autonomic, humoral, and local factors. The normal intrinsic rate of the SA node in young adults is about 90 to 100 beats/min, but it decreases with age based on the following formula:

Enhanced vagal activity slows the heart rate via stimulation of M₂ cholinergic receptors, whereas enhanced sympathetic activity increases the heart rate mainly through activation of β₁-adrenergic receptors and, to lesser extent, β₂-adrenergic receptors (see above).

2. Stroke Volume

Stroke volume is normally determined by three major factors: preload, afterload, and contractility. This analysis is analogous to laboratory observations on skeletal muscle preparations. Preload is muscle length prior to contraction, whereas afterload is the tension against which the muscle must contract. Contractility is an intrinsic property of the muscle that is related to the force of contraction but is independent of both preload and afterload. Because the heart is a three-dimensional multichambered pump, both ventricular geometric form and valvular dysfunction can also affect stroke volume (Table 20–4).

Preload

Ventricular preload is end-diastolic volume, which is generally dependent on ventricular filling. The relationship between cardiac output and left ventricular end-diastolic volume was first described by Starling (Figure 20–5). Note that when the heart rate and contractility remain constant, cardiac output increases with increasing preload until excessive end-diastolic volumes are reached. At that point, cardiac output does not appreciably change—or may even decrease. Excessive distention of either ventricle can lead to dilation and incompetence of the AV valves.

A. Determinants of Ventricular Filling

Ventricular filling can be influenced by a variety of factors (Table 20–5), of which the most important is venous return. The heart cannot pump what the heart does not receive; therefore, venous return normally equals cardiac output. Because most of the other factors affecting venous return are usually fixed, vascular capacity is normally its major determinant. Increases in metabolic activity reduce vascular capacity, so that venous return to the heart and cardiac output increase as the volume of venous capacitance vessels decreases. Changes in blood volume and vascular capacity are important causes of intraoperative and postoperative changes in ventricular filling and cardiac output. Any factor that alters the normally small venous pressure gradient favoring blood return to the heart also affects cardiac filling. Such factors include changes in intrathoracic pressure (positive-pressure ventilation or thoracotomy), posture (positioning during surgery), and pericardial pressure (pericardial disease).

The most important determinant of right ventricular preload is venous return. In the absence of significant pulmonary or right ventricular dysfunction, venous return is also the major determinant of left ventricular preload.

Both heart rate and rhythm can affect ventricular preload. Increases in heart rate are associated with proportionately greater reductions in diastole than systole. Ventricular filling therefore progressively becomes impaired at increased heart rates (>120 beats/min in adults). Absent (atrial fibrillation), ineffective (atrial flutter), or altered timing of atrial contraction (low atrial or junctional rhythms) can also reduce ventricular filling by 20% to 30%. Patients with reduced ventricular compliance are more affected by the loss of a normally timed atrial systole than are those with normal ventricular compliance.

B. Diastolic Function and Ventricular Compliance

Left ventricular end-diastolic pressure (LVEDP) can be used as a measure of preload only if the relationship between ventricular volume and pressure (ventricular compliance) is constant. However, ventricular compliance is normally nonlinear (Figure 20–6). Impaired diastolic function reduces ventricular compliance. Therefore, the same LVEDP that corresponds to a normal preload in a normal patient may correspond to a decreased preload in a patient with impaired diastolic function. Many factors are known to influence ventricular diastolic function and compliance. Nonetheless, measurement of LVEDP or other pressures approximating LVEDP (such as pulmonary artery occlusion pressure) are potential means of estimating left ventricular preload. Changes in central venous pressure can be used as a rough index for changes in right and left ventricular preload in most normal individuals.

Factors affecting ventricular compliance can be separated into those related to the rate of relaxation (early diastolic compliance) and passive stiffness of the ventricles (late diastolic compliance). Hypertrophy (from hypertension or aortic valve stenosis), ischemia, and asynchrony reduce early compliance; hypertrophy and fibrosis reduce late compliance. Extrinsic factors (such as pericardial disease, excessive distention of the contralateral ventricle, increased airway or pleural pressure, tumors, and surgical compression) can also reduce ventricular compliance. Because of its normally thinner wall, the right ventricle is more compliant than the left.

Afterload

Afterload for the intact heart is commonly equated with either ventricular wall tension during systole or arterial impedance to ejection. Wall tension may be thought of as the pressure the ventricle must overcome to reduce its cavity volume. If the ventricle is assumed to be spherical, ventricular wall tension can be expressed by Laplace’s law:

where P is intraventricular pressure, R is the ventricular radius, and H is wall thickness. Although the normal ventricle is usually ellipsoidal, this relationship is still useful. The larger the ventricular radius, the greater the wall tension required to develop the same ventricular pressure. Conversely, an increase in wall thickness reduces ventricular wall tension.

Systolic intraventricular pressure is dependent on the force of ventricular contraction; the viscoelastic properties of the aorta, its proximal branches, and blood (viscosity and density); and systemic vascular resistance (SVR). Arteriolar tone is the primary determinant of SVR. Because viscoelastic properties are generally fixed in any given patient, left ventricular afterload is usually equated clinically with SVR, which is calculated by the following equation:

where MAP is mean arterial pressure in millimeters of mercury, CVP is central venous pressure in millimeters of mercury, and CO is cardiac output in liters per minute. Normal SVR is 900–1500 dyn · s cm^–5. Systolic blood pressure may also be used as an approximation of left ventricular afterload in the absence of chronic changes in the size, shape, or thickness of the ventricular wall or acute changes in systemic vascular resistance. Some clinicians prefer to use CI instead of CO in calculating a systemic vascular resistance index (SVRI), so that SVRI = SVR × BSA (body surface area).

Right ventricular afterload is mainly dependent on pulmonary vascular resistance (PVR) and is expressed by the following equation:

where PAP is mean pulmonary artery pressure and LAP is left atrial pressure. In practice, pulmonary capillary wedge pressure (PCWP) can be substituted as an approximation for LAP. Normal PVR is 50 to 150 dyn · s cm^–5.

Cardiac output is inversely related to large changes in afterload on the left ventricle; however, small increases or decreases in afterload may have no effect on cardiac output. Because of its thinner wall, the right ventricle is more sensitive to changes in afterload than is the left ventricle. Cardiac output in patients with marked right or left ventricular impairment is very sensitive to acute increases in afterload. The latter is particularly true in the presence of drug- or ischemia-induced myocardial depression or chronic heart failure.

Contractility

Cardiac contractility (inotropy) is the intrinsic ability of the myocardium to pump in the absence of changes in preload or afterload. Contractility is related to the rate of myocardial muscle shortening, which is, in turn, dependent on the intracellular Ca²⁺ concentration during systole. Increases in heart rate can also enhance contractility under some conditions, perhaps because of the increased availability of intracellular Ca²⁺.

Contractility can be altered by neural, humoral, or pharmacological influences. Sympathetic nervous system activity normally has the most important effect on contractility. Sympathetic fibers innervate atrial and ventricular muscle, as well as nodal tissues. In addition to its positive chronotropic effect, norepinephrine release also enhances contractility primarily via β₁-receptor activation. α-Adrenergic receptors are also present in the myocardium, but seem to have only minor positive inotropic and chronotropic effects that are overwhelmed by the vascular actions of α-adrenergic agonists when these drugs are administered systemically. Sympathomimetic drugs and secretion of epinephrine from the adrenal glands similarly increase contractility via β₁-receptor activation.

Myocardial contractility is depressed by hypoxia, acidosis, depletion of catecholamine stores within the heart, and loss of functioning muscle mass as a result of ischemia or infarction. At large enough doses, most anesthetics and antiarrhythmic agents are negative inotropes (ie, they decrease contractility).

Wall Motion Abnormalities

Regional wall motion abnormalities cause a breakdown of the analogy between the intact heart and skeletal muscle preparations. Such abnormalities may be due to ischemia, scarring, hypertrophy, or altered conduction. When the ventricular cavity does not collapse symmetrically or fully, emptying becomes impaired. Hypokinesis (decreased contraction), akinesis (failure to contract), and dyskinesis (paradoxic bulging) during systole reflect increasing degrees of contraction abnormalities. Although contractility may be normal or even enhanced in some areas, abnormalities in other areas of the ventricle can impair emptying and reduce stroke volume. The severity of the impairment depends on the size and number of abnormally contracting areas.

Valvular Dysfunction

Valvular dysfunction can involve any one of the four valves in the heart and can include stenosis, regurgitation (incompetence), or both. Stenosis of an AV valve (tricuspid or mitral) reduces stroke volume primarily by decreasing ventricular preload, whereas stenosis of a semilunar valve (pulmonary or aortic) reduces stroke volume primarily by increasing ventricular afterload. In contrast, valvular regurgitation can reduce stroke volume without changes in preload, afterload, or contractility and without wall motion abnormalities. The effective stroke volume is reduced by the regurgitant volume with every contraction. When an AV valve is incompetent, a significant part of the ventricular end-diastolic volume can flow backward into the atrium during systole; the stroke volume is reduced by the regurgitant volume. Similarly, when a semilunar valve is incompetent, a fraction of end-diastolic volume arises from backward flow into the ventricle during diastole.

ASSESSMENT OF VENTRICULAR FUNCTION

1. Ventricular Function Curves

Plotting cardiac output or stroke volume against preload can be useful in evaluating pathological states and understanding drug therapy. Normal right and left ventricular function curves are shown in Figure 20–7.

Ventricular pressure–volume diagrams dissociate contractility from both preload and afterload. Two points are identified on such diagrams: the end-systolic point (ESP) and the end-diastolic point (EDP) (Figure 20–8). ESP is reflective of systolic function, whereas EDP is more reflective of diastolic function. For any given contractile state, all ESPs are on the same line (ie, the relationship between end-systolic volume and end-systolic pressure is fixed). Figure 20–9 describes the events occurring in the left ventricle during each cardiac cycle.

2. Assessment of Systolic Function

The change in ventricular pressure over time during systole (dP/dt) is defined by the first derivative of the ventricular pressure curve and can be used as a measure of contractility. Contractility is directly proportional to dP/dt, but accurate measurement of this value requires a high-fidelity (“Millar”) ventricular catheter. Ventricular systolic function is routinely estimated using echocardiography.

Ejection Fraction

The ventricular ejection fraction (EF), the fraction of the end-diastolic ventricular volume ejected, is the most commonly used clinical measurement of systolic function. EF can be calculated by the following equation:

where EDV is left ventricular diastolic volume and ESV is end-systolic volume. Normal EF is approximately 0.67 ± 0.08. Measurements can be made preoperatively from cardiac catheterization, radionucleotide studies, or transthoracic (TTE) or transesophageal echocardiography (TEE). Pulmonary artery catheters with fast-response thermistors allow measurement of the right ventricular EF. Unfortunately, when pulmonary vascular resistance increases, decreases in right ventricular EF may reflect afterload rather than contractility. Left ventricular EF is not an accurate measure of ventricular contractility in the presence of mitral insufficiency.

Myocardial deformation analysis provides another measure to quantify ventricular function by assessing the movement of speckles from echocardiographic images. Deformation of the heart occurs along three dimensions: circumferential, radial, and longitudinal (Figure 20–10). Strain is a measure of the change of length between two points. Using strain analysis, echocardiography can determine the percent change in length at different points of the myocardium (Figure 20–11). Longitudinal strain is measured at various segments during systole and diastole; the global strain is −21%, reflecting the average deformation for all segments. Normal estimates for strain under anesthesia are not established; however, −19% to −22% longitudinal strain is a normal range established for healthy patients undergoing transthoracic echocardiography. Longitudinal strain is a negative change because during systole the ventricle shortens, resulting in L being less than L₀. The degree to which estimates of myocardial deformation will be incorporated into perioperative management remains to be determined.

3. Assessment of Diastolic Function

Left ventricular diastolic function can be assessed clinically by Doppler echocardiography on a transthoracic or transesophageal examination. Flow velocities are measured across the mitral valve during diastole, or by interrogation of the motion of the mitral valve annulus (“tissue Doppler”). Three patterns of diastolic dysfunction are generally recognized based on isovolumetric relaxation time, the ratio of peak early diastolic flow (E) to peak atrial systolic flow (A), and the deceleration time (DT) of E (DT_E) (Figure 20–12). Tissue Doppler is frequently used to distinguish “pseudonormal” from normal diastolic function. Tissue Doppler discerns the velocity of movement of the myocardial tissue during the cardiac cycle. During systole the mitral annulus moves toward the apex of the heart, away from the echocardiography probe in the esophagus. A negative deflection s' wave is generated, reflecting systolic movement away from the probe. During diastolic filling the mitral annulus moves toward the transesophageal echocardiography probe, producing a positive e' wave. An e' wave peak velocity of less than 8 cm/s is associated with impaired diastolic function. An E/e' wave ratio that is greater than 15 is consistent with elevated left ventricular end-diastolic pressure (Figures 20–13 and 20–14).

The systemic vasculature can be divided functionally into arteries, arterioles, capillaries, and veins. Arteries are the high-pressure conduits that supply the various organs. Arterioles are the small vessels that directly feed and control blood flow through each capillary bed. Capillaries are thin-walled vessels that allow the exchange of nutrients between blood and tissues. Veins return blood from capillary beds to the heart.

The distribution of blood between the various components of the circulatory system is shown in Table 20–6. Note that most of the blood volume is in the systemic circulation—specifically, within systemic veins. Changes in systemic venous tone allow these vessels to function as a reservoir for blood. Following significant blood or fluid losses, a sympathetically mediated increase in vascular tone reduces the capacity of these vessels and shifts blood into other parts of the vascular system. Conversely, increased capacity (“venodilation”) allows these vessels to accommodate increases in blood volume. Sympathetic control of vascular tone is an important determinant of venous return to the heart. Reduced venous tone following induction of anesthesia frequently results in pooling of blood, reduced cardiac output, and hypotension.

Many factors influence blood flow in the vascular tree, including metabolic products, endothelium-derived factors, the autonomic nervous system, and circulating hormones.

AUTOREGULATION

Most tissue beds regulate their own blood flow (autoregulation). Arterioles generally dilate in response to reduced perfusion pressure or increased tissue demand. Conversely, arterioles constrict in response to increased pressure or reduced tissue demand. These phenomena are likely due to both an intrinsic response of vascular smooth muscle to stretch and the accumulation of vasodilatory metabolic byproducts. The latter may include K⁺, H⁺, CO₂, adenosine, and lactate.

ENDOTHELIUM-DERIVED FACTORS

The vascular endothelium is metabolically active in elaborating or modifying substances that directly or indirectly play a major role in controlling blood pressure and flow. These include vasodilators (eg, nitric oxide, prostacyclin [PGI₂]), vasoconstrictors (eg, endothelins, thromboxane A₂), anticoagulants (eg, thrombomodulin, protein C), fibrinolytics (eg, tissue plasminogen activator), and factors that inhibit platelet aggregation (eg, nitric oxide and PGI₂). Nitric oxide is synthesized from arginine by nitric oxide synthetase. This substance has a number of functions. It binds guanylate cyclase, increasing cGMP levels and potently produces vasodilation. Endothelially derived vasoconstrictors (endothelins) are released in response to thrombin and epinephrine.

AUTONOMIC CONTROL OF THE SYSTEMIC VASCULATURE

Although the parasympathetic system can exert important influences on the circulation, autonomic control of the vasculature is primarily sympathetic. Sympathetic outflow to the circulation passes out of the spinal cord at all thoracic segments and the first two lumbar segments. These fibers reach blood vessels via specific autonomic nerves or by traveling along spinal nerves. Sympathetic fibers innervate all parts of the vasculature except for capillaries. Their principal function is to regulate vascular tone. Variations of arterial vascular tone serve to regulate blood pressure and the distribution of blood flow to the various organs, whereas variations in venous tone alter vascular capacity, venous pooling, and venous return to the heart.

The vasculature has sympathetic vasoconstrictor and vasodilator fibers, but the former are more important physiologically in most tissue beds. Sympathetic-induced vasoconstriction (via α₁-adrenergic receptors) can be potent in skeletal muscle, kidneys, gut, and skin; it is least active in the brain and heart. The most important vasodilatory fibers are those feeding skeletal muscle, mediating increased blood flow (via β₂-adrenergic receptors) in response to exercise. Vasodepressor (vasovagal) syncope, which can occur following intense emotional strain associated with high sympathetic tone, results from reflex activation of both vagal and sympathetic vasodilator fibers.

Vascular tone and autonomic influences on the heart are controlled by vasomotor centers in the reticular formation of the medulla and lower pons. Distinct vasoconstrictor and vasodilator areas have been identified. Vasoconstriction is mediated by the anterolateral areas of the lower pons and upper medulla. They are also responsible for adrenal secretion of catecholamines, as well as the enhancement of cardiac automaticity and contractility. Vasodilatory areas, which are located in the lower medulla, are also adrenergic. They function by projecting inhibitory fibers upward to the vasoconstrictor areas. Vasomotor output is modified by inputs from throughout the central nervous system, including the hypothalamus, cerebral cortex, and the other areas in the brainstem. Areas in the posterolateral medulla receive input from both the vagal and the glossopharyngeal nerves and play an important role in mediating a variety of circulatory reflexes. The sympathetic system normally maintains some tonic vasoconstriction on the vascular tree. Loss of this tone following induction of anesthesia or sympathectomy frequently contributes to perioperative hypotension.

ARTERIAL BLOOD PRESSURE

Systemic blood flow is pulsatile in large arteries because of the heart’s cyclic activity; when the blood reaches the systemic capillaries, flow is continuous (laminar). The mean pressure falls to less than 20 mm Hg in the large systemic veins that return blood to the heart. The largest pressure drop, nearly 50%, is across the arterioles, and the arterioles account for the majority of SVR.

MAP is proportionate to the product of SVR × CO. This relationship is based on an analogy to Ohm’s law, as applied to the circulation:

Because CVP is normally very small compared with MAP, the former can usually be ignored. From this relationship, it is readily apparent that hypotension is the result of a decrease in SVR, CO, or both: To maintain arterial blood pressure, a decrease in either SVR or CO must be compensated by an increase in the other. MAP may be estimated by the following formula:

where pulse pressure is the difference between systolic and diastolic blood pressure. Arterial pulse pressure is directly related to stroke volume, but is inversely related to the compliance of the arterial tree. Thus, decreases in pulse pressure may be due to a decrease in stroke volume, an increase in SVR, or both. Increased pulse pressure increases shear stress on vessel walls, potentially leading to atherosclerotic plaque rupture and thrombosis or rupture of aneurysms. Increased pulse pressure in patients undergoing cardiac surgery has been associated with adverse renal and neurological outcomes.

Transmission of the arterial pressure wave from large arteries to smaller vessels in the periphery is faster than the actual movement of blood; the pressure wave velocity is 15 times the velocity of blood in the aorta. Moreover, reflections of the propagating waves off arterial walls widen pulse pressure before the pulse wave is completely dampened in very small arteries. Thus, the pulse pressure is generally greater when measured in the femoral or dorsalis pedis arteries than in the aorta.

Control of Arterial Blood Pressure

Arterial blood pressure is regulated by a series of immediate, intermediate, and long-term adjustments that involve complex neural, humoral, and renal mechanisms.

A. Immediate Control

Minute-to-minute control of blood pressure is primarily the function of autonomic nervous system reflexes. Changes in blood pressure are sensed both centrally (in hypothalamic and brainstem areas) and peripherally by specialized sensors (baroreceptors). Decreases in arterial blood pressure result in increased sympathetic tone, increased adrenal secretion of epinephrine, and reduced vagal activity. The resulting systemic vasoconstriction, increased heart rate, and enhanced cardiac contractility serve to increase blood pressure.

Peripheral baroreceptors are located at the bifurcation of the common carotid arteries and the aortic arch. Elevations in blood pressure increase baroreceptor discharge, inhibiting systemic vasoconstriction and enhancing vagal tone (baroreceptor reflex). Reductions in blood pressure decrease baroreceptor discharge, allowing vasoconstriction and reduction of vagal tone. Carotid baroreceptors send afferent signals to circulatory brainstem centers via Hering’s nerve (a branch of the glossopharyngeal nerve), whereas aortic baroreceptor afferent signals travel along the vagus nerve. Of the two peripheral sensors, the carotid baroreceptor is physiologically more important and serves to minimize changes in blood pressure caused by acute events, such as a change in posture. Carotid baroreceptors sense MAP most effectively between pressures of 80 and 160 mm Hg. Adaptation to acute changes in blood pressure occurs over the course of 1 to 2 days, rendering this reflex ineffective for longer term blood pressure control. All volatile anesthetics depress the normal baroreceptor response, but isoflurane and desflurane seem to have less effect. Cardiopulmonary stretch receptors located in the atria, left ventricle, and pulmonary circulation can cause a similar effect.

B. Intermediate Control

In the course of a few minutes, sustained decreases in arterial pressure, together with enhanced sympathetic outflow, activate the renin–angiotensin–aldosterone system, increase secretion of arginine vasopressin (AVP), and alter normal capillary fluid exchange. Both angiotensin II and AVP are potent arteriolar vasoconstrictors. Their immediate action is to increase SVR. In contrast to formation of angiotensin II, which responds to relatively smaller changes, sufficient AVP secretion to produce vasoconstriction will only occur in response to more marked degrees of hypotension. Angiotensin constricts arterioles via AT₁ receptors. AVP mediates vasoconstriction via V₁ receptors and exerts its antidiuretic effect via V₂ receptors.

Sustained changes in arterial blood pressure can also alter fluid exchange in tissues by their secondary effects on capillary pressures. Hypertension increases interstitial movement of intravascular fluid, whereas hypotension increases reabsorption of interstitial fluid. Such compensatory changes in intravascular volume can reduce fluctuations in blood pressure, particularly in the absence of adequate renal function (see below).

C. Long-Term Control

The effects of slower renal mechanisms become apparent within hours of sustained changes in arterial pressure. As a result, the kidneys alter total body sodium and water balance to restore blood pressure to normal. Hypotension results in sodium (and water) retention, whereas hypertension generally increases sodium excretion in normal individuals.

ANATOMY & PHYSIOLOGY OF THE CORONARY CIRCULATION

1. Anatomy

Myocardial blood supply is derived entirely from the right and left coronary arteries (Figure 20–15). Blood flows from epicardial to endocardial vessels. After perfusing the myocardium, blood returns to the right atrium via the coronary sinus and the anterior cardiac veins. A small amount of blood returns directly into the chambers of the heart by way of the thebesian veins.

The right coronary artery (RCA) normally supplies the right atrium, most of the right ventricle, and a variable portion of the left ventricle (inferior wall). In 85% of persons, the RCA gives rise to the posterior descending artery (PDA), which supplies the superior–posterior interventricular septum and inferior wall—a right dominant circulation; in the remaining 15% of persons, the PDA is a branch of the left coronary artery—a left dominant circulation.

The left coronary artery normally supplies the left atrium and most of the interventricular septum and left ventricle (septal, anterior, and lateral walls). After a short course, the left main coronary artery bifurcates into the left anterior descending artery (LAD) and the circumflex artery (CX); the LAD supplies the septum and anterior wall and the CX supplies the lateral wall. In a left dominant circulation, the CX wraps around the AV groove and continues down as the PDA to also supply most of the posterior septum and inferior wall.

The arterial supply to the SA node may be derived from either the RCA (60% of individuals) or the LAD (the remaining 40%). The AV node is usually supplied by the RCA (85–90%) or, less frequently, by the CX (10–15%); the bundle of His has a dual blood supply derived from the PDA and LAD. The anterior papillary muscle of the mitral valve also has a dual blood supply that is fed by diagonal branches of the LAD and marginal branches of the CX. In contrast, the posterior papillary of the mitral valve is usually supplied only by the PDA and is therefore much more vulnerable to ischemic dysfunction.

2. Determinants of Coronary Perfusion

Coronary perfusion is unique in that it is intermittent rather than continuous, as it is in other organs. During contraction, intramyocardial pressures in the left ventricle approach systemic arterial pressure. The force of left ventricular contraction almost completely occludes the intramyocardial part of the coronary arteries. Coronary perfusion pressure is usually determined by the difference between aortic pressure and ventricular pressure. The left ventricle is perfused almost entirely during diastole. In contrast, the right ventricle is perfused during both systole and diastole (Figure 20–16). Moreover, as a determinant of left heart myocardial blood flow, arterial diastolic pressure is more important than MAP. Therefore, left coronary artery perfusion pressure is determined by the difference between arterial diastolic pressure and left ventricular end-diastolic pressure (LVEDP).

Decreases in aortic pressure or increases in ventricular end-diastolic pressure can reduce coronary perfusion pressure. Increases in heart rate also decrease coronary perfusion because of the disproportionately greater reduction in diastolic time as heart rate increases (Figure 20–17). Because the endocardium is subjected to the greatest intramural pressures during systole, it tends to be most vulnerable to ischemia during decreases in coronary perfusion pressure.

Control of Coronary Blood Flow

Coronary blood flow normally parallels myocardial metabolic demand. In the average adult man, coronary blood flow is approximately 250 mL/min at rest. The myocardium regulates its own blood flow closely between perfusion pressures of 50 and 120 mm Hg. Beyond this range, blood flow becomes increasingly pressure dependent.

Under normal conditions, changes in blood flow are entirely due to variations in coronary arterial tone (resistance) in response to metabolic demand. Hypoxia—either directly, or indirectly through the release of adenosine—causes coronary vasodilation. Autonomic influences are generally weak. Both α₁- and β₂-adrenergic receptors are present in the coronary arteries. The α₁-receptors are primarily located on larger epicardial vessels, whereas the β₂-receptors are mainly found on the smaller intramuscular and subendocardial vessels. Sympathetic stimulation generally increases myocardial blood flow because of an increase in metabolic demand and a predominance of β₂-receptor activation. Parasympathetic effects on the coronary vasculature are generally minor and weakly vasodilatory.

3. Myocardial Oxygen Balance

Myocardial oxygen demand is usually the most important determinant of myocardial blood flow. Relative contributions to oxygen requirements include basal requirements (20%), electrical activity (1%), volume work (15%), and pressure work (64%). The myocardium usually extracts 65% of the oxygen in arterial blood, compared with 25% in most other tissues. Coronary sinus oxygen saturation is usually 30%. Therefore, the myocardium (unlike other tissues) cannot compensate for reductions in blood flow by extracting more oxygen from hemoglobin. Any increases in myocardial metabolic demand must be met by an increase in coronary blood flow. Table 20–7 lists the most important factors in myocardial oxygen demand and supply. Note that the heart rate and, to a lesser extent, ventricular end-diastolic pressure are important determinants of both supply and demand.

EFFECTS OF ANESTHETIC AGENTS

Most volatile anesthetic agents are coronary vasodilators. Their effect on coronary blood flow is variable because of their direct vasodilating properties, reduction of myocardial metabolic requirements, and effects on arterial blood pressure.

Volatile agents exert beneficial effects in experimental myocardial ischemia and infarction. They reduce myocardial oxygen requirements and protect against reperfusion injury; these effects are mediated by activation of ATP-sensitive K⁺ (K_ATP) channels. Some evidence also suggests that volatile anesthetics enhance recovery of the “stunned” myocardium (hypocontractile, but recoverable, myocardium after ischemia). Moreover, although volatile anesthetics decrease myocardial contractility, they can be potentially beneficial in patients with heart failure because most of them decrease preload and afterload.

The Pathophysiology of Heart Failure

Systolic heart failure occurs when the heart is unable to pump a sufficient amount of blood to meet the body’s metabolic requirements. Clinical manifestations usually reflect the effects of the low cardiac output on tissues (eg, fatigue, dyspnea, oxygen debt, acidosis), the damming-up of blood behind the failing ventricle (dependent edema or pulmonary venous congestion), or both. The left ventricle is most commonly the primary cause, often with secondary involvement of the right ventricle. Isolated right ventricular failure can occur in the setting of advanced disease of the lung parenchyma or pulmonary vasculature. Left ventricular failure is most commonly the result of myocardial dysfunction, usually from coronary artery disease, but may also be the result of viral disease, toxins, untreated hypertension, valvular dysfunction, arrhythmias, or pericardial disease.

Diastolic dysfunction can be present in the absence of signs or symptoms of heart failure, as for example in patients with hypertension or aortic valve stenosis. Symptoms arising from diastolic dysfunction are the result of atrial hypertension and pulmonary congestion (Figure 20–18). Failure of the heart to relax during diastole leads to elevated left ventricular end-diastolic pressure, which is transmitted to the left atrium and pulmonary vasculature. Common causes of diastolic dysfunction include hypertension, coronary artery disease, hypertrophic cardiomyopathy, valvular heart disease, and pericardial disease. Diastolic dysfunction is not the same as diastolic heart failure. In the patient with systolic heart failure the heart compensates by dilating, which leads to an increase in end-diastolic ventricular volume in an attempt to preserve the stroke volume. In patients with diastolic failure, poor ventricular relaxation leads to a higher LVEDP than would be noted in a patient without diastolic dysfunction for the same end-diastolic volume.

Diastolic dysfunction is diagnosed echocardiographically. Placing the pulse wave Doppler sample gate at the tips of the mitral valve during left ventricular filling will produce the characteristic diastolic flow pattern (Figure 20–13). In patients with normal diastolic function, the ratio between the peak velocities of the early (E) and the atrial (A) waves is from 0.8 to 2. In the early stages of diastolic dysfunction, the primary abnormality is impaired relaxation. When left ventricular relaxation is delayed, the initial pressure gradient between the left atrium and the left ventricle is reduced, resulting in a decline in early filling, and, consequently, a reduced peak E wave velocity. The A wave velocity is increased relative to the E wave, and the E/A ratio is reduced. As diastolic dysfunction advances, the left atrial pressure increases, restoring the gradient between the left atrium and left ventricle with an apparent restoration of the normal E/A ratio. This pattern is characterized as “pseudonormalized.” Using the E/A ratio alone cannot distinguish between a normal and pseudonormalized pattern of diastolic inflow. As diastolic dysfunction worsens further, a restrictive pattern is obtained. In this scenario, the left ventricle is so stiff that pressure builds in the left atrium, resulting in a dramatic peak of early filling and a prominent, tall, narrow E wave. Because the ventricle is so poorly compliant, the atrial contraction contributes little to filling, resulting in a diminished A wave and an E/A ratio greater than 2:1.

Doppler patterns of pulmonary venous flow have been used to distinguish between a pseudonormalized and normal E/A ratio. Currently, most echocardiographers use tissue Doppler to examine the movement of the lateral annulus of the mitral valve during ventricular filling (Figure 20–13). Tissue Doppler allows the echocardiographer to determine both the velocity and the direction of the movement of the heart. During systole, the heart contracts toward the apex, away from a TEE transducer in the esophagus. This motion produces the s' wave of systole. During early and late diastolic filling, the heart moves toward the transducer producing the e' and a' waves. Like the inflow patterns achieved with pulse wave Doppler, characteristic patterns of diastolic dysfunction are reflected in the tissue Doppler trace. An e' wave less than 8 cm/s is consistent with diastolic dysfunction. Of note, the tissue Doppler trace does not produce a pseudonormalized pattern, permitting the echocardiographer to readily distinguish between normal and abnormal diastolic function.

Cardiac output may be reduced at rest with heart failure, but the key point is that the heart is incapable of appropriately increasing cardiac output and oxygen delivery in response to demand. Inadequate oxygen delivery to tissues is reflected by a low mixed venous oxygen tension and an increase in the arteriovenous oxygen content difference. In compensated heart failure, the arteriovenous difference may be normal at rest, but it rapidly widens during stress or exercise.

COMPENSATORY MECHANISMS

Compensatory mechanisms generally present in patients with heart failure include activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system and increased release of AVP. One result is increased preload (fluid retention). Although these mechanisms can initially compensate for mild to moderate cardiac dysfunction, with increasing severity of dysfunction, they may actually worsen the cardiac impairment. Many of the drug treatments of chronic heart failure serve to counteract these mechanisms.

Increased Preload

An increase in ventricular size not only reflects an inability to keep up with an increased circulating blood volume, but also serves to increase stroke volume by moving the heart up the Starling curve (see Figure 20–5). Even when EF is reduced, an increase in ventricular end-diastolic volume can maintain a normal stroke volume. Worsening venous congestion caused by the pooling of blood behind the failing ventricle and excessive ventricular dilation can rapidly lead to clinical deterioration. Left ventricular failure results in pulmonary vascular congestion and progressive transudation of fluid, first into the pulmonary interstitium and then into alveoli (pulmonary edema). Right ventricular failure leads to systemic venous hypertension, which results in peripheral edema, hepatic congestion and dysfunction, and ascites. Dilation of the annulus of either the mitral or tricuspid valves from ventricular dilation leads to valvular regurgitation, further impairing ventricular output.

Increased Sympathetic Tone

Sympathetic activation increases release of norepinephrine from nerve endings in the heart and secretion of epinephrine from the adrenal glands into the circulation. Although enhanced sympathetic outflow can initially maintain cardiac output by increasing heart rate and contractility, worsening ventricular function elicits increasing degrees of vasoconstriction in an effort to maintain arterial blood pressure. The associated increase in afterload, however, reduces cardiac output and exacerbates the ventricular failure.

Chronic sympathetic activation in patients with heart failure eventually decreases the response of adrenergic receptors to catecholamines (receptor uncoupling), the number of receptors (downregulation), and cardiac catecholamine stores. Nonetheless, the failing heart becomes increasingly dependent on circulating catecholamines. Abrupt withdrawal in sympathetic outflow or decreases in circulating catecholamine levels, such as can occur following induction of anesthesia, may lead to acute cardiac decompensation. A reduced density of M₂ receptors also decreases parasympathetic influences on the heart.

Sympathetic activation tends to redistribute systemic blood flow output away from the skin, gut, kidneys, and skeletal muscle to the heart and brain. Decreased renal perfusion, together with β₁-adrenergic activity at the juxtaglomerular apparatus, activates the renin–angiotensin–aldosterone axis, which leads to sodium retention and interstitial edema. Moreover, vasoconstriction secondary to elevated angiotensin II levels increases left ventricular afterload and causes further deterioration of systolic function. The latter partially accounts for the efficacy of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers in heart failure. Symptoms may also improve in some patients with careful, low-dose β-adrenergic blockade. Outcomes in heart failure are improved by administration of ACE inhibitors (and/or angiotensin receptor blockers), certain long-acting β-blockers (carvedilol or extended-release metoprolol), and aldosterone inhibitors (spironolactone or eplerenone).

Circulating AVP levels, often markedly increased in patients with severe heart failure, will increase ventricular afterload and are responsible for a defect in free water clearance that is commonly associated with hyponatremia.

Brain natriuretic peptide (BNP) is produced in the heart in response to myocyte distention. Elevated BNP concentration (>500 pg/mL) usually indicates heart failure, and measurement of BNP concentration can be used to distinguish between heart failure and lung disease as a cause of dyspnea. Recombinant BNP was developed as a vasodilator and inhibitor of the renin–angiotensin–aldosterone system for use in patients with severe decompensated heart failure, but outcomes were not improved with its use.

Ventricular Hypertrophy

Ventricular hypertrophy can occur with or without dilation, depending on the type of stress imposed on the ventricle. When the heart is subjected to either pressure or volume overload, the initial response is to increase sarcomere length and optimally overlap actin and myosin. With time, ventricular muscle mass begins to increase in response to the abnormal stress.

In the volume-overloaded ventricle, the problem is an increase in diastolic wall stress. The increase in ventricular muscle mass is sufficient only to compensate for the increase in diameter: The ratio of the ventricular radius to wall thickness is unchanged. Sarcomeres replicate mainly in series, resulting in eccentric hypertrophy. Although ventricular EF remains depressed, the increase in end-diastolic volume can maintain normal at-rest stroke volume (and cardiac output).

The problem in a pressure-overloaded ventricle is an increase in systolic wall stress. In this case, sarcomeres mainly replicate in parallel, resulting in concentric hypertrophy: The hypertrophy is such that the ratio of myocardial wall thickness to ventricular radius increases. As can be seen from Laplace’s law, systolic wall stress can then be normalized. Ventricular hypertrophy, particularly that caused by pressure overload, usually results in progressive diastolic dysfunction. The most common reasons for isolated left ventricular hypertrophy are hypertension and aortic stenosis.