Cardiac Surgical Physiology

	INTRODUCTION

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	CELLULAR COMPONENTS AND CELLULAR ACTIVATION

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The heart beats continuously based on the unique features of its component cells. A cardiac cycle begins when spontaneous depolarization of a pacemaker cell initiates an action potential; this electrical activity is transmitted to atrial muscle cells, which contract, and to the conduction system, which transmits the electrical activity to the ventricle. Activation depends on components of the cell membrane and cell that induce and maintain the ion currents that maintain and promote electrical activation.

Similar to most excitable cells in the body, the activity of cells in the heart is triggered by an action potential. An action potential is a cyclic activation of a cell consisting of a rapid change in the membrane potential (the electrical gradient across the cell membrane) and subsequent return to a resting membrane potential. This process depends on a selectively permeable cell membrane and proteins that actively and passively direct ion passage across the cell membrane. The specific components of the myocyte action potential are detailed in Fig. 3-3. The myocyte action potential is characterized by a rapid initial depolarization mediated by fast channels (sodium channels) and then a plateau phase mediated by slow channels (calcium channels). Further details of this process are introduced as their components are described.

View larger version (16K): [in this window] [in a new window]   Figure 3-3 A typical ventricular myocyte action potential and the ion currents contributing to it are represented schematically. Inward (depolarizing) currents are depicted as positive, and outward (repolarizing) currents are depicted as negative. The horizontal filled bars show the state of the gate of the ion channel (white = open; black = closed; shaded = partially open). In the case of the sodium channel, both the activation and inactivation gates are shown (i, current; Na, sodium; Ca, calcium; K, potassium).

The cardiac cell is surrounded by a membrane (plasmalemma, or more specific to a muscle cell, sarcolemma). The structural components of the sarcolemma allow for the origination and then conduction of an electrical signal through the heart with subsequent initiation of the excitation-contraction coupling process. This leads to depolarization of atrial myocytes and, with an appropriate delay, depolarization of ventricular myocytes. The sarcolemma also participates in the regulation of excitation, contraction, and intracellular metabolism in response to neuronal and chemical stimulation. Each of these functions will be considered, with emphasis on the features of the cardiac sarcolemma that differ from the plasmalemma of other cells.

The Phospholipid Bilayer

A phospholipid bilayer provides a barrier between the extracellular compartment and the intracellular compartment, or cytosol. It is only two molecules thick, consists of phospholipids and cholesterol aligned so that the lipid, or hydrophobic, portion of the molecule is on the inside of the membrane, and the hydrophilic portion of the molecule is on the outside (Fig. 3-1). The sarcolemma which is a phospholipid bilayer, provides a fluid barrier that is particularly impermeable to diffusion of ions. Small lipid-soluble molecules such as oxygen and carbon dioxide diffuse easily through the membrane. The water molecule, although insoluble in the membrane, is small enough that it diffuses easily through the membrane (or through pores in the membrane). Other, slightly larger molecules (e.g., sodium, chloride, potassium, and calcium) cannot diffuse easily through the lipid bilayer and require specialized channels for transport.^1–3

View larger version (60K): [in this window] [in a new window]   Figure 3-1 The sarcolemma is a bilayer in which phospholipid and cholesterol molecules are arranged with hydrophobic domains within the membrane and hydrophilic domains facing outward. The membrane-spanning protein shown here is similar to many ion channels, with six hydrophobic alpha-helices spanning the membrane and surrounding a central channel.

Other proteins located in the sarcolemma serve as receptors for neuronal or chemical control of cellular processes (e.g., beta-adrenergic receptors and muscarinic acetylcholine receptors).

Sarcolemmal channels
Most of the voltage-gated channels consist of tetramers of four subunits that surround the water-filled pore through which ions cross the membrane. A schematic diagram of an ion channel is shown in Fig. 3-2. Each channel contains a selectivity filter that selectively allows the passage of particular ions based on pore size and electric charge and an activation gate that is regulated by conformational changes induced by either a voltage-sensitive or a ligand-binding region of the protein. Many channels also have an inactivation gate that is also controlled either by voltage or by ligands.^1,2,4

View larger version (33K): [in this window] [in a new window]   Figure 3-2 A voltage-gated sodium channel is depicted schematically. The shaded region is the selectivity filter. A represents the activation gate, and I represents the inactivation gate. At rest, the inactivation gate is open, and the activation gate is closed. As the transmembrane potential rises from –80 to –60 mV, the activation gate opens, and sodium ions pass through the channel. Within a few milliseconds, the inactivation gate closes. Once the cell repolarizes, the resting ion channel returns to the resting state.

Voltage-gated calcium channels
There are two important populations of calcium channels. The type T (transient) calcium channels open as the membrane potential rises to –60 to –50 mV and then close quickly by action of an inactivation gate. These type T calcium channels are important in early depolarization, especially in atrial pacemaker cells, but they contribute little to the sustained depolarization of the plateau of the action potential and have much less activity in the ventricles.

The second major calcium channel, the type L (long-lasting) channel, a slow channel, leads to an inward (depolarizing) current that is slowly inactivated and therefore prolonged. These channels open at a less negative potential (–30 to –20 mV). Once open, the slow inactivation allows an inward calcium current (Fig. 3-3) that sustains the action potential. In addition, this increase in cytosolic calcium begins the excitation-contraction sequence. Activity of this channel is altered by catecholamine stimulation. Beta-receptor stimulation induces conformational changes resulting in an increased influx of calcium ions and an associated increase in the strength of sarcomere contraction. This effect is attenuated by stimulation of acetylcholine and adenosine receptors.^8,9

Potassium channels

A number of potassium channels, both voltage- and ligand-gated, are present in cardiac cells. Three voltage-gated potassium channels moderate the delayed rectifier current that repolarizes the cell membrane^10,11 (Fig. 3-3).

Several ligand-gated potassium channels have been identified. Acetylcholine- and adenosine-activated potassium channels are time-independent and lead to hyperpolarization in pacemaker and nodal cells, thereby delaying spontaneous depolarization. A calcium-activated potassium channel opens in the presence of high levels of cytosolic calcium and probably enhances the delayed rectifier current, leading to early termination of the action potential. An ATP-sensitive potassium channel is closed in the metabolically normal myocyte but is opened in the metabolically starved myocyte in which ATP stores have been depleted, leading to hyperpolarization of the cell and thereby retarding depolarization and contraction.

Energy-Dependent Ion Pumps and Ion Exchangers

Sodium-potassium-ATP-dependent pump

The sodium-potassium pump uses the energy obtained from the hydrolysis of ATP to move three Na⁺ ions out of the cell and two K⁺ ions into the cell, each against its respective concentration gradient. Since there is a net outward current (three Na⁺ ions for two K⁺ ions), the pump contributes about 10 mV to the resting membrane potential. The activity of the pump is strongly stimulated by attachment of sodium to the sodium-binding site on the inside of the membrane. The Na,K-ATPase pump has a very high affinity for ATP, so the pump continues to function even if ATP levels are moderately reduced.

ATP-dependent calcium pump

The ATP-dependent calcium pump transports calcium out of the cell against a strong concentration gradient. This action represents a net outward current, but the magnitude of this current is quite small because the bulk of calcium transferred out of the cell occurs with sodium-calcium exchange (described below). The cytosolic protein calmodulin can complex with calcium and facilitate action of the pump; thus increased intracellular calcium levels stimulate the pump.^2,12–14

Ion exchangers

Multiple proteins that traverse the membrane allow ion exchanges using the potential energy of the electrochemical gradient—the gradient favoring the influx of sodium. The sodium-calcium exchange pump exchanges three extracellular sodium ions for one intracellular calcium ion, leading to a net single positive charge transported into the cell with each exchange. The exchange system is sensitive to the concentration of sodium and calcium on both sides of the membrane and to the membrane potential. If external sodium concentrations decrease, the driving force for removal of calcium from the cell is decreased, leading to an increase in cytosolic calcium (and a consequent increase in contractility). This explains an observation made some years ago that hyponatremia can lead to an increase in cardiac contractility. If the intracellular sodium concentration increases, as occurs with ischemia, the gradient for sodium influx is reduced, and the pump slows down or actually reverses, extruding sodium in exchange for an influx (and accumulation) of calcium. This mechanism has been suggested to be central to the accumulation of calcium during ischemia. The sodium-calcium exchange mechanism has a maximum exchange rate that is some 30 times higher than the sarcolemmal ATP-dependent calcium pump described earlier and is likely the primary mechanism for removal of excess cytosolic calcium.⁹

The sodium-hydrogen exchange pump extrudes one intracellular hydrogen ion in exchange for one extracellular sodium ion and therefore is electrically neutral. This pump prevents intracellular acidification. Acidification (e.g., during ischemia) increases the affinity of the pump for H⁺, promoting the removal of H⁺ and preserving intracellular pH at the expense of sodium accumulation. The accumulation of sodium ions then may trigger reversal of the sodium-calcium exchange pump to favor the accumulation of calcium within the cell. This is a purported mechanism underlying injury or cell death during ischemia-reperfusion.

Intracellular Communication Pathways

To allow concurrent activation of all the myofibrils in the muscle cell, the electrical activation signal must be spread rapidly and evenly through all portions of the cell. This is accomplished through the transverse tubules (t-tubules) and the subsarcolemmal cistern and sarcotubular network of the sarcoplasmic reticulum.

T-tubules

The basic contractile unit in a muscle cell is the sarcomere. Sarcomeres are joined together in the myofibril at the z-lines. A system of transverse tubules (t-tubules) extends the sarcolemma into the interior of the cardiac cell (Fig. 3-4). These tubules generally are perpendicular to the sarcomere near the z-lines, thus extending the extracellular space into the cell close to the contractile proteins. The t-tubules contain the calcium channels described earlier, which are in close relationship to the foot proteins of the subsarcolemmal cisternae.

View larger version (126K): [in this window] [in a new window]   Figure 3-4 Myocyte anatomy. (From Levy MN: The cardiac pump, in Berne RM, Levy MN, Koeppen BM, Stanton BA, eds: Physiology. St Louis, Mosby, 2004; p 307.)

The sarcoplasmic reticulum is a membrane network within the cytoplasm of the cell surrounding the myofibrils. The primary function of the sarcoplasmic reticulum is excitation-contraction coupling by sudden release of calcium to stimulate the contraction proteins and then rapid removal of this calcium to allow relaxation of the contractile elements. The subsarcolemmal cisternae and the sarcotubular network are the two portions of the sarcoplasmic reticulum that mediate this process.

The subsarcolemmal cisternae are beneath the sarcolemma and surround the t-tubules. Specialized bulky proteins are found in the membrane of the sarcoplasmic reticulum with a large protein component extending into the gap between the subsarcolemmal cisternae and the sarcolemma of the t-tubule. These foot proteins respond to the release of calcium by the sarcolemma (or t-tubule) by rapid opening of a calcium channel (actually a part of the foot protein), which allows release of a much larger quantity of calcium from the subsarcolemmal cisternae. This is calcium-triggered calcium release, with calcium transported across the sarcolemma leading to calcium release from the subsarcolemmal cisternae. The magnitude of calcium release from the subsarcolemmal cisternae appears to be related to the magnitude of the trigger. The calcium channels then close, and the calcium is returned to the sarcoplasmic reticulum by an ATP-dependent calcium pump located primarily in the sarcotubular network.^1,2,14 The sarcotubular network is the portion of the sarcoplasmic reticulum that surrounds the contractile elements of the sarcomere.

Regulation of calcium transport by the cardiac sarcoplasmic reticulum occurs primarily at the site of the calcium pump. Phospholamban, a cytosolic protein, inhibits the basal rate of calcium transport by this calcium pump. This inhibition can be reversed when phospholamban is phosphorylated by a cyclic AMP–dependent or a calcium-calmodulin-dependent protein kinase. This effect appears to be a very important mechanism by which beta-adrenergic stimulation regulates the heart; increased levels of cytosolic cyclic AMP are a consequence of activation of the beta-catecholamine receptor. As phospholamban is phosphorylated, there is accelerated calcium turnover and increased sensitivity of the calcium pump, which facilitates uptake of calcium from the cytosol and relaxation of the heart when the heart comes under the influence of beta-adrenergic agonists. Phosphorylation of phospholamban does not affect the sarcolemmal calcium pump, thereby tending to favor retention of calcium within the cell (increasing the calcium content of the sarcoplasmic reticulum at the expense of calcium removed from the cell through the sarcolemma). This might lead to an increased pulse of calcium within the cell, thereby favoring increased contractility.^9,14

In this ionic milieu, the importance of maintenance of intracellular pH should be stressed. Regulation of intracellular pH is complex and beyond the scope of this text, but a few simple principles are important to review. Reduced intracellular pH diminishes the amount of calcium released from the sarcoplasmic reticulum and reduces the responsiveness of myofilaments to calcium. Elevation of the pH will have the opposite effect. The clinical relevance of this observation cannot be overstressed.

	ELECTRICAL ACTIVATION OF THE HEART

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Normal Cardiac Rhythm

The resting membrane potential

The resting state of the cardiac cell is determined by a balance of forces: electrical (based on polarity differences) and chemical (based on gradients across the sarcolemma). At rest (during diastole), the cardiac cell is polarized. An electrical transmembrane potential across the sarcolemma exists determined primarily by the concentration gradient of potassium across the membrane. This gradient is established by the sodium-potassium pump. However, once this pump shuts off, the steady state is determined by the balance of electrical and chemical forces. As described earlier, the sarcolemma is impermeable to some ions, permeable to others, and selectively permeable to others. Steady-state properties of a mixture of ions of variable permeablities across a membrane are described by the Gibbs-Donnan equilibrium.¹⁵ The sarcolemma prevents the diffusion of large anions (e.g., proteins and organic phosphates). At rest, the sarcolemma is relatively permeable to potassium ions owing to the open state of most potassium channels but less permeable to sodium. The concentration gradient established by the sodium-potassium pump promotes the efflux of potassium ions across the sarcolemma. The outward flow of positive ions is counterbalanced by the increasing electronegativity of the interior of the cell owing to the impermeant anions. A Gibbs-Donnan equilibrium is established such that the electronegativity of the cell interior retards potassium ion efflux to the same degree that the concentration gradient favors K⁺ efflux. At equilibrium, the forces balance with an intracellular potassium concentration of 135 mM and an extracellular concentration of 4 mM and a predicted resting membrane potential of –94 mV. The actual resting membrane potential is measured at about –90 mV owing to smaller contributions from the current of other less permeable ions (e.g., sodium and calcium). However, the potassium current is the main determinant of the resting membrane potential.¹⁶

The action potential

The action potential represents the triggered response to a stimulus derived either internally (slow depolarizing ionic currents) or externally (depolarization of adjacent cells). A typical fast-response action potential that occurs in atrial and ventricular myocytes and special conduction fibers is depicted in Fig. 3-3. As the transmembrane potential decreases to approximately –65 mV, the "fast" sodium channels open. These channels remain open for a few milliseconds until the inactivation gate of the fast sodium channel closes. The large gradient of sodium ions (extracellular 145 mM, intracellular 10 mM) promotes rapid influx, depolarizing the cell to a slightly positive transmembrane potential. This is phase 0 of the action potential. A transient potassium current (i_to) causes a very early repolarization (phase 1) of the action potential, but this fast channel closes quickly. The plateau of the action potential (phase 2) is sustained at a neutral or slightly positive level by an inward-flowing calcium current, first from the transient calcium channel and second through the long-lasting calcium channel. The plateau also is sustained by a decrease in the outward potassium current (i_k1). With time, the long-lasting calcium channel begins to close, and the repolarizing potassium current (i_k, the delayed rectifier current) leads to the initiation of phase 3 of the action potential. As repolarization progresses, the stronger first potassium current (i_k1) dominates, leading to full repolarization of the membrane to the resting negative potential. During the bulk of the depolarized interval (phase 4), the first potassium current predominates in myocytes. Because the sodium channels cannot respond to a second wave of depolarization until the inactivation gates are reopened (by repolarization during phase 3), the membrane is refractory to the propagation of a second impulse during this time interval, referred to as the absolute refractory period. As the membrane is repolarized during early phase 3 of the action potential, and some of the sodium channels have been reactivated, a short interval exists during which only very strong impulses can activate the cell, which is termed the relative refractory period. A drug that acts to speed up the kinetics of the inactivation gate will shorten both the absolute and the relative refractory periods.^1,2,17–19

Spontaneous depolarization

The action potential of the slow-response cells of the nodal tissue [sinoatrial node (SA node) and atrioventricular node (AV node)] differs from that in the fast-response cells, as shown in Fig. 3-5. The rapid upstroke of phase 0 is less prominent owing to the absence of fast Na⁺ channels. Phase 1 is absent because there is no rapid inward potassium current. In addition, the plateau phase (phase 2) is abbreviated because of the lack of a sustained active Na⁺ inward current and the lack of a sustained calcium current. The repolarization phase (phase 3) leads to a resting phase (phase 4) that begins to depolarize again, as opposed to the relatively stable resting membrane potential of myocytes. The slowly depolarizing phase 4 resting potential is called the diastolic depolarization current or the pacemaker potential. Continued depolarization of the membrane potential ultimately reduces it to the threshold potential that stimulates another action potential. This diastolic depolarization potential is the mechanism of automaticity in cardiac pacemaker cells. Diastolic depolarization is due to the concerted and net actions of (1) a decrease in the outward K⁺ current during early diastole (phase 4), (2) persistence of the slow inward Ca²⁺ current, and (3) an increasing inward Na⁺ current during diastole. The inward Na⁺ current most likely predominates in nodal and conduction tissue. The slope of the diastolic depolarization determines the rate of action potential generation in the pacemaker cells and is the primary mechanism determining heart rate. Of all the cardiac cells, the slope of the diastolic potential is greatest (faster rate of depolarization) in the SA node, and action potentials are generated at a rate of 70 to 80 per minute. The AV node has a slower rate of depolarization, with a frequency of action potential generation of 40 to 60 times per minute. The ventricular myocytes have the slowest rate of depolarization, with a frequency of 30 to 40 times per minute. Once a depolarization is initiated in a pacemaker cell and propagated, it will depolarize the remainder of the heart in a synchronized and sequential manner. If a pacemaker site drops out owing to pathology or drug-induced slowing of the diastolic potential, the next pacemaker site in line will take over, with a heart rate typical for that site. The heart rate can be altered by changing slope of the diastolic depolarization (e.g., acetylcholine decreases the slope and heart rate; beta-adrenergic agonists increase the slope and heart rate). If the slope is unchanged, hyperpolarization (more negative resting potential) or raising the threshold potential will increase the time to reach threshold, resulting in a decrease in heart rate.

View larger version (21K): [in this window] [in a new window]   Figure 3-5 The membrane potential of a spontaneously depolarizing cell of the sinoatrial node and the ion currents contributing to it. Inward (depolarizing) currents are depicted as positive, and outward (repolarizing) currents are depicted as negative (i, current; Na, sodium; Ca, calcium; K, potassium).

Each myocyte is electrically connected to the next myocyte by an intercalated disk at the end of the cell. These disks contain gap junctions that facilitate the flow of charged molecules from one cell to the next. These pores in the intercalated disks are composed of a protein, connexin. Permeability through the cardiac gap junction is increased by both ATP- and cyclic AMP–dependent kinases. This allows the gap junctions to close if ATP levels fall, thereby reducing electrical and presumably mechanical activity, which is essential in limiting cell death when one region of the heart is damaged. It also allows conduction to increase when cyclic AMP increases in response to adrenergic stimulation.

After spontaneous depolarization occurs in the pacemaker cells of the SA node, the action potential is conducted throughout the heart. Special electrical pathways facilitate this conduction. Three internodal paths exist through the atrium between the SA node and the AV node. After traversing the AV node, the action potential is propagated rapidly through the bundle of His and into the Purkinje fibers located on the endocardium of the left and right ventricles. Rapid conduction through the atrium causes contraction of most of the atrial muscle synchronously (within 60 to 90 ms). Similarly, the rapid conduction of the signal throughout the ventricle leads to synchronous contraction of the bulk of the ventricular myocardium (within 60 ms). The delay of the propagation of the action potential through the AV node by 120 to 140 ms allows the atria to complete contraction before the ventricles contract. Slow conduction in the AV node is related to a relatively higher internal resistance because of a small number of gap junctions between cells and to slowly rising action potentials. The nodal delay allows the atrium to pump an aliquot of blood (up to 10% of left ventricular volume) into the ventricle just prior to ventricular contraction, thereby optimizing preload of the ventricle.

Abnormal Cardiac Rhythm

Aberrant pacemaker foci

Many cardiac cells manifest an intrinsic rhythm from spontaneous depolarization. Normally, the SA node spontaneously depolarizes first such that the cardiac beat originates from this primary acemaker site. If the SA node is damaged or slowed by vagal timulation or drugs (e.g., acetylcholine), pacemakers in the AV node or the His-Purkinje system can take over. Occasionally, aberrant foci in the heart depolarize spontaneously, thereby leading to insertion of aberrant beats from either the atrium or the ventricle (noted as premature atrial or ventricular contractions). These beats ordinarily do not interfere with normal depolarization of the heart and have very little tendency to degenerate into disorganized electrical activity.

Reentry arrhythmias

Reentry arrhythmias are perhaps the most common dangerous cardiac rhythm. Under ordinary circumstances, the action potential depolarizes the entire atrium or the entire ventricle in a short enough time interval so that all the muscle is refractory to further stimulation at the same time. A reentry arrhythmia is caused by propagation of an action potential through the heart in a "circus" movement. For reentry to occur, there must be a unidirectional block (transient or permanent) to action potential propagation. Additionally, the effective refractory period of the reentered region must be shorter than the propagation time around the loop.¹⁶ For example, if a portion of the previously depolarized myocardium has repolarized before propagation of the action potential is completed throughout the atrium or ventricle, then that action potential can continue its propagation into this repolarized muscle. Such an event generally requires either dramatic slowing of conduction of the action potential, a long conduction pathway, or a shortened refractory period (Fig. 3-6). All these situations occur clinically. Ischemia leads to slowing of the sodium-potassium pump, which leads to a decreased resting membrane potential and slowing of propagation of the action potential. Hyperkalemia leads to an increase in the extracellular potassium level, a decrease in the resting membrane potential, and a slowing of propagation of the action potential. Progressive atrial dilation creates a long conduction pathway around the atrium that can allow a reentry arrhythmia. Adrenergic stimulation leads to a shortened refractory period, which increases the likelihood of a reentry arrhythmia.

View larger version (31K): [in this window] [in a new window]   Figure 3-6 Three conditions predisposing to reentry or "circus" pathways for action potential propagation are shown. Muscle that is refractory to action potential propagation is shown as black. Normally, as the action potential travels through the atrium or ventricle, all the muscle is depolarized sufficiently that the action potential encounters no more nonrefractory muscle and stops (A). If there is slowed conduction speed or a long pathway (B), the action potential may find repolarized (nonrefractory) muscle and continue in a circular path. Similarly, a shortened refractory period (C) may lead to rapid repolarization and predispose to a reentry and continuation of the action potential.

Afterpotentials or parasystole

Most ventricular tachyarrhythmias are reentry arrhythmias. The primary exception to this rule is parasystole or afterpotentials. Normally, ventricular action potentials have a flat phase 4 during diastole without spontaneous depolarization. If, however, they have elevated levels of cytosolic calcium, there may be a transient diastolic inward (depolarizing) current, probably related to activity of the sodium-calcium exchange pump. Afterpotentials are thought to underlie the development of ventricular automaticity during digitalis toxicity. The afterdepolarizations associated with digitalis toxicity appear to be delayed afterdepolarizations. Another type of afterdepolarization is an early afterdepolarization, which occurs before the end of complete repolarization. This early afterdepolarization appears to be the mechanism for the ventricular tachycardia called torsades de pointes, in which varying QRS complexes appear. A prolongation of the QT interval and the varying QRS complexes in torsades de pointes indicate heterogeneity of the action potential duration within the ventricle, thereby predisposing to ventricular fibrillation.¹⁸

	REGULATION OF CELLULAR FUNCTION BY SARCOLEMMAL RECEPTORS

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Parasympathetic Regulation

The parasympathetic nervous system is particularly important in control of the pacemaker cells of the SA node. Acetylcholine released by the nerve endings of the parasympathetic system stimulates muscarinic receptors in the heart. These activated receptors, in turn, produce an intracellular stimulatory G-protein that opens acetylcholine-gated potassium channels. An increased outward (repolarizing) flow of potassium leads to hyperpolarization of the SA node cells. Stimulation of the muscarinic receptors also inhibits the formation of cyclic AMP; decreased cyclic AMP levels inhibit the opening of calcium channels. A decreased inward flow of calcium, combined with an increased outward flow of potassium, leads to a sometimes dramatic slowing of spontaneous diastolic depolarization of the sinoatrial nodal cell (Fig. 3-5). A similar effect in the AV node leads to slowing of conduction through the AV node.¹

Adrenergic Stimulation and Blockade

Adrenergic receptors affect heart rate, contractility, conduction velocity, and automaticity in cardiac cells and smooth muscle contraction and relaxation in the vasculature. Alpha-adrenergic receptors cause vasoconstriction. There are two types of beta-adrenergic receptors: the beta₁-adrenergic receptors, which predominate in the heart, and the beta₂-adrenergic receptors, which are present in blood vessels and promote relaxation. The number of beta receptors per unit area (receptor density) of the sarcolemma can increase (upregulation) or decrease (downregulation) in response to various stimuli. Receptor sensitivity also can change depending on ambient conditions and variable stimuli.²⁰ Cardiopulmonary bypass and ischemia cause downregulation of cardiac beta receptors. Acidemia causes desensitization of beta receptors. This is particularly important in the perioperative period, when acidemia can reduce cardiac contractility, systemic vascular tone, and the response to inotropic agents significantly.

The beta-adrenergic receptor couples with adenyl cyclase (Fig. 3-7). When the receptor site is occupied by a catecholamine, a stimulatory G-protein is formed that combines with GTP. This activated G-protein–GTP complex then promotes the activity of adenyl cyclase, leading to the formation of cyclic AMP from ATP. The G-protein–GTP complex and the cyclic AMP actively promote calcium channel opening. The increased tendency for calcium channels to open during beta-receptor stimulation increases cytosolic calcium and leads to a number of electrophysiologic effects: (1) a positive chronotropic (heart rate) effect whereby the heart rate, conduction, and contraction velocity increase and the action potential is shortened leading to a shortening of systole, (2) a positive dromotropic (conduction velocity) effect of accelerated conduction through the AV node, (3) a positive inotropic (contractility) effect, and (4) increased activity of the sarcoplasmic reticulum calcium pump (more rapid calcium uptake) leading to more rapid relaxation, which facilitates ventricular filling, a positive lusitropic (relaxation) effect.^21,22

View larger version (28K): [in this window] [in a new window]   Figure 3-7 Adrenergic stimulation via the action of beta agonists on beta receptors leads to a cascade of events in the myocyte, some of which are shown here. Note that an increase in cAMP causes the activation of two inhibitory pathways, retarding excessively sustained adrenergic stimulation (Gs, stimulatory G-protein; GTP, guanosine triphosphate; SR, sarcoplasmic reticulum; cAMP, cyclic adenosine monophosphate).

The activity spectrum of adrenergic receptors forms the basis of many therapeutic interventions: perioperatively to support cardiac function and chronically to reduce mortality from myocardial infarction and to treat congestive heart failure. The selectivity of the agonists allows adaptation for various clinical scenarios. Beta₁-selective agonists and antagonists are considered cardioselective. Some examples are detailed in Table 3-1.

Phosphodiesterase Inhibition

As discussed previously, cyclic AMP plays a central role in regulation of the cardiac cell. Cytosolic levels of cyclic AMP are increased by activation of receptors other than beta receptors (i.e., for histamine, dopamine, and glucagon) and are decreased by inhibitory G-proteins produced by stimulation of muscarinic receptors by acetylcholine and by stimulation of adenosine receptors. Referring again to Fig. 3-7, one negative-feedback response to the increase in cyclic AMP is an increase in phosphodiesterase, which breaks down cyclic AMP. Phosphodiesterase inhibitors (e.g., amrinone and milrinone) inhibit the breakdown of cyclic AMP and thereby increase its level in the cytosol. Their effect is synergistic to that of beta agonists. Since they do not stimulate the production of G-protein–GTP complex, they have a lesser effect on calcium channel activation and therefore fewer of the troublesome positive chronotropic and dromotropic effects of beta-adrenergic stimulation.^22,23

Adenosine Receptors

There are four types of adenosine receptors. Adenosine receptors are linked to inhibitory and stimulatory G-proteins and various kinases. Activation of adenosine A₁ receptors leads to inhibition of the slow calcium channel and opening of an adenosine-activated ATP-sensitive potassium (K_ATP) channel. This leads to hyperpolarization, which delays conduction through the AV node and slows the ventricular response to atrial tachycardia.^1,24 Pretreatment with adenosine (also via A₁-receptor activation) confers a cardioprotective effect during ischemia and can inhibit the inflammatory responses initiated by ischemia and reperfusion.²⁴

	CONTRACTION OF CARDIAC MUSCLE

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Molecular Level (The Sarcomere)

The primary contractile unit of all muscle cells is the sarcomere (Fig. 3-4). Sarcomeres are connected end to end at the z-line to form myofibrils. The myocyte contains numerous myofibrils arranged in parallel. A portion of a sarcomere is depicted schematically in Fig. 3-8. Actin polymerizes to form the thin filaments that are anchored at the z-line. Myosin polymerizes to form the thick filaments of the sarcomere. Myosin consists of a tail of two "heavy" chains intertwined to form a helix, constituting the rigid backbone of the thick filament. The globular head of myosin is attached to the heavychain backbone by a mobile hinge and projects outward. The globular myosin head is an ATPase with a binding sight for actin. Actin monomers polymerize into a double-helical filament with a groove running the length of the filament. Actin binds to the myosin globular head, activating the myosin ATPase to hydrolyze ATP. This leads to a conformational change in the myosin that pulls the filament (Fig. 3-8B).

View larger version (29K): [in this window] [in a new window]   Figure 3-8 The interaction of actin and myosin filaments converts chemical energy into mechanical movement. In diastole, the active sites on the actin filament are covered by tropomyosin. When calcium combines with troponin, the tropomyosin is pulled away from the actin active sites, allowing the energized myosin heads (depicted in solid black and cocked at right angles to the filament) to engage and sweep the actin filament along. The myosin heads are deenergized in this process. Myosin ATPase recocks (reenergizes) the head by using the energy derived from the hydrolysis of ATP. In systole, a deenergizing head (C), a deenergized head (B), and a reenergizing head (A) are shown.

During diastole, Ca²⁺ is unavailable to bind troponin C, and the myosin-binding site on actin is blocked. Depolarization of the sarcolemmal membrane and t-tubules leads to an influx of calcium ions. The influx of Ca²⁺ and the subsequent "calcium-triggered, calcium release" from the sarcoplasmic reticulum increase the intracellular Ca²⁺ calcium levels by approximately two orders of magnitude (from 10^–7 M in diastole to 10^–5 M in systole). This provides sufficient calcium to bind to troponin C, which causes a conformational change in the troponin molecule, removing the inhibitory effect of troponin I and allowing actin-myosin cross-bridge formation (Fig. 3-8A). Cross-bridge formation activates the myosin ATPase and initiates the conformational change in the myosin "hinge," drawing the z-lines closer together (Fig. 3-8B). ADP and P_i are released, and the myosin head dissociates from the actin. ATP associates with the myosin head, realigning the myosin globular head, preparing it to repeat the process. This process cycles until the end of muscular contraction is signaled by the reduction in intracellular calcium levels by sequestration into the sarcoplasmic reticulum. This is accomplished by sarcoplasmic endoplasmic reticulum calcium ATPase (SERCA) and other energy-dependent pump systems.

The strength of the myocardial contraction is mediated primarily by the degree to which actin-binding sites are exposed. This depends on the affinity of troponin for calcium and the availability of calcium ions. The initial calcium ion influx is altered by cyclic AMP, stimulatory and inhibitory G-proteins, and acetylcholine. The magnitude of the calcium trigger determines the magnitude of the cytosolic calcium release from the sarcoplasmic reticulum. The rate of uptake of calcium from the cytosol is altered by cyclic AMP (Fig. 3-7). Cyclic AMP can phosphorylate a portion of the troponin molecule, facilitating the rapid release of calcium and increasing the rate of relaxation of the actinmyosin complex.^9,25

Regulation of the Strength of Contraction by Initial Sarcomere Length

In cardiac muscle, the strength of contraction is related to resting sarcomere length (see also "The Frank-Starling Relationship" below). Maximal contraction force occurs when the resting sarcomere length is between 2 and 2.4 µm.²⁶ At this length, there is optimal overlap of the actin and myosin, maximizing the number of actin-myosin cross-bridges. Force declines at a greater sarcomere length, with decreased overlap of actin and myosin. In the heart, a decrease in contractility related to decreased overlap of the filaments does not seem to occur clinically because the resting length of the cardiac sarcomere rarely exceeds 2.2 to 2.4 µm. Once this length is reached, a stiff parallel elastic element prevents further dilation. If chamber dilation does occur, it appears to be primarily through slippage of fibers or myofibers rather than stretching of sarcomeres.¹ Stretching the myocardium increases contractility by increasing the sensitivity of troponin C to calcium. This length-dependent sensitivity to calcium is an important part of the ascending limb of the Starling curve observed in the intact ventricle.

	THE PUMP

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Mechanics

Clinically observable physiologic parameters

Cardiac surgeons can assess the function of the heart in a number of ways. Most simply, systemic, pulmonary artery, pulmonary capillary wedge, and central venous pressures can be measured directly. Cardiac output can be estimated using thermodilution or based on oxygen saturation measurements. From these direct measurements, other parameters can be derived—though less accurately because of the cumulative error of the measured parameters inherent in the calculation—such as pulmonary and systemic vascular resistance, ventricular stroke work, etc. Ejection fraction—defined as stroke volume/end-diastolic volume—can be estimated by echocardiography and ventriculography but is subject to change based on loading conditions, heart rate, and degree of contractility. Although useful clinically, these parameters do not measure contractility directly.

The Frank-Starling relationship

Almost a century ago, two physiologists (Frank and Starling) simultaneously developed the concept that, within physiologic limits, the heart will function as a sump pump; the more the heart is filled during diastole, the greater the quantity of blood that will be pumped out of the heart during systole. (This relationship was introduced earlier in the section entitled, "Regulation of the Strength of Contraction by Initial Sarcomere Length.")

Under normal circumstances, the heart pumps all the blood that comes back to it without excessive elevation of venous pressures. In the normal heart, as ventricular filling is increased, the strength of ventricular contraction increases as sarcomeres are stretched. The influence of sarcomere length on the force of contraction is called the Frank-Starling relationship. This relationship for the left ventricle is depicted in Fig. 3-9. Also depicted in the figure are two other states, a condition of normal adrenergic stimulation and a condition of maximal adrenergic stimulation. Force is increased for the same diastolic left atrial pressure by adrenergic stimulation; this is a positive inotropic effect.

View larger version (25K): [in this window] [in a new window]   Figure 3-9 Starling curves for the left ventricle. The influence of four different states of neurohumoral stimulation on global ventricular performance is shown.

Preload is the load placed on a resting muscle that stretches it to its functional length. In the heart, preload references the volume of blood in the cavity immediately prior to contraction (at end diastole) because volume determines the degree of stretch imposed on the resting sarcomere. Since volume cannot be assessed easily clinically, pressure is used as a surrogate; thus the concept of preload is represented as the filling pressure of a chamber. The relationship between the end-diastolic pressure and the end-diastolic volume is complex. Several different diastolic pressure-volume relationships are shown in Fig. 3-11 (bold line). As end-diastolic volume increases and the heart stretches, the end-diastolic pressure also increases. The compliance, or distensibility, of the ventricle is defined as the change in volume divided by the change in pressure. Conversely, the stiffness of the ventricle is the reciprocal of compliance, or the change in pressure divided by the change in volume.

View larger version (29K): [in this window] [in a new window]   Figure 3-11 Left ventricular pressure-volume curves for various physiologic and pathologic conditions (detailed descriptions are in the text). The bold curved line at the bottom of each loop series represents the diastolic pressure-volume relationship. The straight line located on the upper left side of each loop series is the end-systolic pressure-volume relationship. The stroke volume for each curve has been arbitrarily set at 75 mL. Systolic aortic pressure is 115 mm Hg in all curves except B (increased afterload, systolic pressure 140 mm Hg) and H (reduced afterload, systolic pressure 90 mm Hg). LV, left ventricle; EF, ejection fraction; LVEDP, left ventricular end-diastolic pressure in mm Hg.

Afterload: vascular impedance

The afterload of an isolated muscle is the tension against which it contracts. In simplest terms, for the heart, the afterload is determined by the pressure against which the ventricle must eject. The greater the afterload, the more mechanical energy must be imparted to the blood mass (potential energy) to begin ejection. In addition to the potential energy imparted to the ejected blood by a change in pressure, the contracting left ventricle generates kinetic energy that overcomes the compliance of the distensible aorta and systemic arterial tree to move the blood into the arterial system. The energy necessary for this flow to occur is relatively small (potential energy >> kinetic energy). Resistance, which equals the change in pressure divided by cardiac output, reflects the potential energy imparted to blood. To describe the forces overcome to eject blood from the ventricle accurately, the compliance of the vascular system and kinetic energy imparted also must be considered: the impedance of the vascular system (commonly but less accurately referred to as aortic impedance). Compliance reflects the capacity of the vascular system to accept the volume of ejected blood. When the vascular system is very compliant, resistance impedance. As compliance decreases (e.g., with arteriosclerosis), resistance is less than impedance.²⁹ The interaction of resistance and compliance defines the dicrotic notch marking end systole (ES), closure of the aortic valve, on the aortic pressure tracing (Fig. 3-10).

View larger version (19K): [in this window] [in a new window]   Figure 3-10 Temporal correlation of left atrial and ventricular, aortic, and systemic venous pressures, aortic flow, left ventricular volume, and surface electrocardiogram.

Multiple parameters of the cardiac cycle are represented in Fig. 3-10. By convention, the cardiac cycle begins at end diastole (ED), just prior to electrical activation of the ventricle. As the heart contracts, intracavitary pressure closes the mitral valve and then increases rapidly until the systemic diastolic pressure is reached (isovolumic contraction) and the aortic valve opens. Ejection begins and the intracavitary pressure continues to rise and then fall as the ventricular volume decreases (ejection). When ejection ceases and the aortic valve closes, intracavitary pressure decreases rapidly until the mitral valve opens (isovolumic relaxation). Once the mitral valve opens, the ventricle fills rapidly and then more slowly as the intracavitary pressure slightly increases from distension prior to atrial systole (diastolic filling phase). The completion of atrial systole is the end of ventricular diastole.

A conceptual understanding of the venous pressure changes is important in diagnosing certain pathologic processes. The right atrial pressure is measured easily, and pulmonary capillary wedge pressure is reflective of left atrial pressure. The a wave corresponds to atrial systole as pressure increases at ED to complete ventricular filling. The c wave reflects pressure pushing the atrioventricular (AV) valve back into the atrium as the ventricular pressure rises and then falls during systole. The x descent results from atrial relaxation and downward displacement of the AV valve with ventricular emptying. The v wave reflects the increasing atrial pressure from filling before the AV valve opens. The y descent is due to rapid emptying of the atrium after the AV valve opens. Characteristic changes in these waveforms are used to diagnose and differentiate constrictive and restrictive processes, as discussed elsewhere in this text. A prominent left atrial v wave suggests mitral regurgitation.

Ventricular pressure-volume relationships

The function of the heart can be described and quantified based on the relative intraventricular pressure and volume during the cardiac cycle (Fig. 3-11). Based on this relationship, various measures can be derived to assess cardiac performance (discussed below). The ventricular pressure-volume relationship derives from the Frank-Starling relationship of sarcomere length and peak developed force: The force and extent of contraction (stroke volume) is a function of end-diastolic length (volume).

ED is represented at the lower right corner of the loop in Fig. 3-11A. The pressure-volume loop then successively tracks changes through isovolumic contraction (up to the upper right corner), ejection [left to the upper left corner—which represents ES], isovolumic relaxation (down to the bottom left corner), and then filling (right to the lower right corner). Descriptive data to assess ventricular function are derived from the end-systolic pressure-volume point located in the upper left corner of the loop and the end-diastolic pressure-volume point located in the lower right corner of the loop. The area within the pressure-volume loop represents the internal work of the chamber.

Contractility

The term contractility (inotropic state) refers to the intrinsic performance of the ventricle for a given preload, afterload, and heart rate. Although the inotropic state affects cardiac output, it is difficult to quantify in clinically useful terms. For research purposes, the pressure-volume relationship can be used to quantify contractility by deriving the end-systolic pressure-volume relationship (ESPVR): Contractility is reflected in the slope (E_ES) and volume axis intercept (V₀) of the ESPVR (Fig. 3-12). Holding afterload and heart rate constant, a series of pressure-volume loops is inscribed during transient preload reduction induced by temporary vena caval occlusion; the area of the loops decreases, and the loops are shifted to the left. The progressive pressure-volume points at ES then are linearized to derive the ESPVR. Within a clinical range of systolic pressures (80 to 120 mm Hg), the end-systolic pressure-volume line is largely linear. An increase in inotropic state of the left ventricle is expressed as an increase in E_ES and sometimes a decrease in V₀. Conversely, a decrease in inotropic state is expressed as a decrease in E_ES and sometimes an increase in V₀ (Fig. 3-12). As the ESPVR describes systolic function, the end-diastolic pressure volume relationship (EDPVR; Fig. 3-12) describes ventricular diastolic compliance (specifically, the inverse of the slope of the EDPVR is compliance).

View larger version (39K): [in this window] [in a new window]   Figure 3-12 Two series of declining left ventricular pressure-volume loops generated during transient bicaval occlusion. Loops were generated in normal left ventricles (Normal) and after 30 minutes of global normothermic ischemia and subsequent reperfusion (dashed lines). The end-systolic pressure-volume points from each series are connected by a line generated by linear regression. The end-diastolic pressure-volume relationship indicating chamber stiffness (inverse of compliance) is generated by fitting the end-diastolic point from each loop to an exponential curve. The volume axis intercept (V0) is shown in the inset. A negative inotropic effect (i.e., ischemia-reperfusion) is characterized by a decrease in the ESPVR slope, whereas a positive inotropic state is characterized by an increase in ESPVR slope. Notice that the V0 for these conditions are in close proximity (inset). In some cases, a negative inotropic state is associated with a decrease in slope and an increase in V0.

Another index of contractility, perhaps less influenced by other parameters, is the preload recruitable stroke work (PRSW) relationship. Stroke work is the area of the pressure-volume loop. For each pressure-volume loop derived by vena caval occlusion, the stroke work is plotted relative to its end-diastolic volume³⁰ (Fig. 3-13). The slope of the derived linear relationship is a measure of contractility independent (within physiologic ranges) of preload and afterload. The PRSW relationship reflects overall performance of the left ventricle, combining systolic and diastolic components.³¹

View larger version (21K): [in this window] [in a new window]   Figure 3-13 Plot of hypothetical measurement of preload recruitable stroke work.

Clearly, from the preceding discussion, the degree of contractility can be assessed, but unlike blood pressure, an ideal number or range to describe it cannot be derived. Since ESPVR and PRSW are unique for each ventricle, these parameters more accurately measure changes in contractility. The greatest impediment to the clinical application of the ESPVR and PRSW is the difficulty in measuring ventricular volume and inducing preload reduction to derive the pressure-volume loops. More easily measurable indices of contractility have been actively sought.

Ejection fraction is used by many clinicians as a measure of contractility. However, as noted in the discussion of Fig. 3-11, ejection fraction is influenced by preload and afterload alterations without any change in contractility. Depending on loading conditions, hearts with a lower ejection fraction can produce a greater cardiac output. Although roughly indicative of cardiac reserve, ejection fraction is an inconsistent marker for overall cardiac function perioperatively.

Myocardial wall stress

The left ventricle is a pressurized, irregularly shaped chamber. During systole, wall stress develops to overcome afterload and eject the blood. The pressure within the chamber and the geometry of the ventricle determine the tension in the wall. A model of the ventricle as a cylinder can be used to examine the effects of chamber size and wall thickness on wall stress. In this model, circumferential stress is based on the law of LaPlace, that is,

where is wall stress, P is transmural pressure, r is radius, and w is wall thickness. This relationship has several important clinical implications. Wall tension must be balanced by the energy available. The only nutrient nearly completely extracted from the blood by the heart is oxygen, and wall tension is the primary determinant of oxygen consumption.

In one scenario, the heart can compensate for changes in wall stress. If systolic pressure within the ventricle is increased chronically (e.g., aortic stenosis or systemic hypertension), then compensatory hypertrophy or thickening of the ventricular wall can return systolic wall stress close to normal. However, as detailed in Fig. 3-11E, the price paid is that end-diastolic pressures must be higher.

In another scenario, the function of a heart that has dilated for other reasons is further compromised by the relationship between wall stress and oxygen consumption. As a result of or to compensate for systolic failure, the ventricle will dilate. The increased diastolic diameter proportionally increases wall stress and oxygen consumption. The ability of the heart to increase cardiac output in response to exercise will be limited, leading to symptoms.

Energetics

Chemical fuels

Nearly all chemical energy used by the heart is generated by oxidative phosphorylation. Anaerobic metabolism is very limited because anaerobic enzymes are not present in sufficient concentrations. The major fuels for the myocardium are carbohydrates (i.e., glucose and lactate) and free fatty acids. When sufficient oxygen is present, these fuels are used to generate ATP. Most of the ATP used by the heart (60 to 70%) is expended in the cyclic contraction of the muscle; 10 to 15% is required for maintaining the concentration gradients across the cell membrane; the rest is used in the constant uptake and release of calcium by mitochondria, the breakdown and regeneration of glycogen, and the synthesis of triglycerides.

The heart is quite flexible in the aerobic state in its use of fuels. In the fasting state, lipids may account for 70% of the fuel used by the heart. After a high-carbohydrate meal, blood glucose and insulin levels are high and free fatty acids are low, and glucose accounts for close to 100% of the metabolism. During exercise, elevated lactate levels inhibit the uptake of free fatty acids, and carbohydrates, mostly lactate, can account for up to 70% of the metabolism.³²

Whatever the fuel source, oxygen is necessary for its efficient utilization. In the absence of oxygen, there are two mechanisms to provide ATP, glycolysis and conversion of phosphate stored in creatine phosphate, because free fatty acids and the by-products of glycolysis cannot be metabolized. Glycolysis is very inefficient—for 1 mol of glucose, 2 mol of ATP is produced by anaerobic glycolysis, compared with 38 mol of ATP with aerobic metabolism. One by-product of glycolysis is lactic acid, which lowers intracellular pH, impairing muscular function. Phosphate stored in creatine phosphate can convert ADP to ATP, but this is not stored in significant amounts.

With ischemia and hypoxia, ATP breaks down to ADP and subsequently to AMP, adenosine, and inosine. The nucleoside building blocks of ATP—adenosine, inosine, and hypoxanthine—are lost from the ischemic myocardium. If oxygen is restored, ATP levels can be restored rapidly in part by salvage pathways with inosine, hypoxanthine, or inosine monophosphate. However, de novo synthesis of ATP is also required and can take hours or even days to restore significant ATP levels.

Determinants of oxygen consumption

Since nearly all the energy used by the heart is generated by oxidative metabolism, the rate of oxygen consumption (MVO₂) is indicative of the metabolic rate of the heart:

where MVO₂ is myocardial oxygen consumption, CaO₂ is arterial oxygen content in milliliters of O₂ per 100 mL of blood, CVO₂ is coronary venous oxygen content in milliliters of O₂ per 100 mL of blood, and CBF is coronary blood flow in milliliters per minute. Since the bulk of the energy is expended on contraction, changes in the rate of oxygen consumption of the heart are directly related to changes in the contraction cycle and workload. Energy utilization can be increased by an increase in cardiac workload or by a decrease in the efficiency of conversion of chemical to mechanical energy.

Minute work of the heart is the product of heart rate, stroke volume, and developed pressure. A change in each of these factors alters oxygen demand; however, minute work is not the direct determinant of oxygen consumption. As noted earlier, the primary determinant of oxygen demand is the wall tension or stress developed in each cardiac cycle. Indeed, during the period of isovolumic contraction, energy is expended by the heart without the delivery of any kinetic energy to the blood.³³ The energetic cost of ejecting blood from the ventricular chamber is approximately 20 to 30% of that required for isovolumic contraction. To restate this simply, the principal determinant of the cardiac energy requirement is the pressure against which blood is ejected and the volume ejected at that pressure.

Cardiac efficiency relates oxygen consumption to cardiac work. Hence cardiac efficiency = work /MVO₂. The overall efficiency of the heart ranges from 5 to 40% depending on the type of work (pressure versus volume versus velocity) performed.^34–37 The low efficiency of the heart is due to the expenditure of a predominant portion of the oxygen consumed in generating pressure and stretching internal elastic components of the myocardium during isovolumic systole (a form of internal work). The velocity of shortening, affected in part by the inotropic state of the myocardium, also is not factored into the work equation but contributes significantly to oxygen consumption.

Following cardiac surgery, cardiac efficiency generally decreases owing to the increase in MVO₂ relative to the cardiac work performed. The additional oxygen consumed may be due to an increase in basal metabolism and/or an increase in the cost of the excitation-contraction process or inefficiencies of ATP production at the mitochondrial level.

A clear understanding of the role of wall tension and its relation to oxygen demand is essential in cardiac surgery. Excessive systemic pressure may place inordinate energy demands on a compromised ventricle. An intra-aortic balloon pump may shift the energy balance by reducing afterload and improving coronary blood flow. Ventricular distension from an incompetent aortic valve in the absence of left ventricular venting, during the weaning process after removal of the aortic cross-clamp, or with heart failure may create wall stress that outstrips the capacity to deliver oxygen to the myocardium. In the failing heart, where stroke volume is reduced, cardiac output is maintained by increasing heart rate, which increases the percentage of time that the myocardial wall stress is elevated, reduces the time when diastolic blow flow occurs, and creates an imbalance between oxygen demand and delivery.

	CORONARY BLOOD FLOW

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Normal Coronary Blood Flow

Resting coronary blood flow is slightly less than 1 mL/g of heart muscle per minute. This blood flow is delivered to the heart through large epicardial conductance vessels and then into the myocardium by penetrating arteries leading to a plexus of capillaries. The bulk of the resistance to coronary flow is in the penetrating arterioles (20 to 120 µm in size). Because the heart is metabolically very active, there is a high density of capillaries such that there is approximately one capillary for every myocyte, with an intercapillary distance at rest of approximately 17 µm. Capillary density is greater in subendocardial myocardium than in subepicardial tissue. When there is an increased myocardial oxygen demand (e.g., with exercise), myocardial blood flow can increase to three or four times normal (coronary flow reserve). This increased blood flow is accomplished by vasodilation of the resistance vessels and by recruitment of additional capillaries (many of which are closed in the resting state). This capillary recruitment is important in decreasing the intercapillary distance and thereby decreasing the distance that oxygen and nutrients must diffuse through the myocardium. The blood flow pattern from a coronary artery perfusing the left ventricle, measured by flow probe, is phasic in nature, with greater blood flow occurring in diastole than in systole.³⁸ The cyclic contraction and relaxation of the left ventricle produce this phasic blood flow pattern by extravascular compression of the arteries and intramyocardial microvessels during systole. There is a gradient in these systolic extravascular compressive forces, being greater or equal to intracavitary pressure in the subendocardial tissue and decreasing toward the subepicardial tissue. Measurement of transmural blood flow distribution during systole shows that subepicardial vessels are perfused preferentially, whereas subendocardial vessels are hypoperfused significantly. Toward the end of systole, blood flow actually reverses in the epicardial surface vessels.³⁹ Hence the subendocardial myocardium is perfused primarily during diastole, whereas the subepicardial myocardium is perfused during both systole and diastole. A greater capillary density per square millimeter in the subendocardium than in the subepicardial tissue facilitates the distribution of blood flow to the inner layer of myocardium, and myocardial blood flow normally is greater in the subendocardial tissue than in the subepicardial tissue.⁴⁰ This places the subendocardium at greater risk of dysfunction, tissue injury, and necrosis during any reduction in perfusion. This is related to (1) the greater systolic compressive forces, (2) the smaller flow reserve owing to a greater degree of vasodilation, and (3) the greater regional oxygen demands owing to wall tension and segmental shortening. If end-diastolic pressure is elevated to 25, 30, or 35 mm Hg, then there is diastolic as well as systolic compression of the subendocardial vasculature. Flow to the subepicardium is effectively autoregulated as long as the pressure in the distal coronary artery is above approximately 40 mm Hg. Flow to the subendocardium, however, is effectively autoregulated only down to a mean distal coronary artery pressure of approximately 60 to 70 mm Hg. Below this level, local coronary flow reserve in the subendocardium is exhausted, and local blood flow decreases linearly with decreases in distal coronary artery pressure. Subendocardial perfusion is further compromised by pathologic processes that increase wall thickness and systolic and diastolic wall tension. Aortic regurgitation in particular threatens the subendocardium because systemic diastolic arterial pressure is reduced and intraventricular systolic and diastolic pressures are elevated.^38,41

In contrast to the phasic nature of blood flow in the left coronary artery, blood flow in the right coronary artery is relatively constant during the cardiac cycle. The constancy of blood flow is related to the lower intramural pressures and near absence of extravascular compressive forces in the right ventricle compared with the left ventricle.

Control of Coronary Blood Flow

Coronary blood flow is tightly coupled to the metabolic needs of the heart. Under normal conditions, 70% of the oxygen available in coronary arterial blood is extracted, near the physiologic maximum. Any increase in oxygen delivery comes mostly from an increase in blood flow. To maximize efficiency, local coronary blood flow is precisely controlled by a balance of vasodilator and vasoconstrictor mechanisms, including (1) a metabolic vasodilator system, (2) a neurogenic control system, and (3) the vascular endothelium.⁴² Blood flow is controlled by moment-to-moment adjustment of coronary tone of the resistance vessels, i.e., arterioles and precapillary sphincters.

The metabolic vasodilator mechanism responds rapidly when local blood flow is insufficient to meet metabolic demand. The primary mediator is adenosine generated within the myocyte and released into the interstitial compartment. Adenosine relaxes arteriolar smooth muscle cells by activation of A₂ receptors. Adenosine is formed when the oxygen supply cannot sustain the rapid rephosphorylation of ADP to ATP. Once sufficient oxygen is supplied to the myocardium, less adenosine is formed. Adenosine is therefore the coupling agent between oxygen demand and supply. Other local vasodilators that influence coronary blood flow are carbon dioxide, lactic acid, and histamine.

The sympathetic nervous system acts through alpha receptors (which cause vasoconstriction) and beta receptors (which cause vasodilation). There is direct innervation of the large conductance vessels and lesser direct innervation of the smaller resistance vessels. Sympathetic receptors on the smooth muscle cells of the resistance vessels respond to humoral catecholamines. Alpha receptors predominate over beta receptors such that when norepinephrine is released from the sympathetic nerve endings, vasoconstriction ordinarily occurs.

Endothelium-dependent regulation of coronary artery blood flow is a dynamic balance between vasodilating and vasoconstricting factors. Vasodilators include nitric oxide (NO^•) synthesized from L-arginine by endothelial nitric oxide synthase and endothelially released adenosine. The principal vasoconstrictor is the endothelially derived constricting peptide endothelin-1. Other vasoconstrictors include angiotensin II and superoxide free radical.⁴³ NO^• is dominant in local regulation of coronary arterial tone by overwhelming the action of endothelium-derived vasoconstrictor substances, which are tonically released by the coronary artery endothelium. NO^• is released by the coronary vascular endothelium by both soluble factors (e.g., acetylcholine, adenosine, and ATP) and mechanical signals (e.g., shear stress and pulsatile stress secondary to increased intraluminal blood flow). If the endothelium is intact, acetylcholine from the sympathetic nerves causes vasodilation through generation of NO^•. If the endothelium is not functionally intact, acetylcholine causes vasoconstriction by direct stimulation of the vascular smooth muscle. NO^• is a potent inhibitor of platelet aggregation and neutrophil function (i.e., superoxide generation, adherence, and migration), which has implications in the anti-inflammatory response to ischemia-reperfusion and cardiopulmonary bypass.

Endothelin-1 (ET-1) interacts principally with specific endothelin receptors (ET_A) on vascular smooth muscle and causes smooth muscle vasoconstriction. Endothelin-1 counteracts the vasodilator effects of endogenous adenosine, NO^•, and prostacyclin (PGI₂). Endothelin-1 is synthesized rapidly in vascular endothelium, particularly during ischemia, hypoxia, and other stress conditions, where it acts in a paracrine fashion. ET-1 has a short half-life (4 to 7 minutes), which exceeds that of adenosine (8 to 12 seconds) and NO^• (microseconds). However, the avid binding of ET-1 to ET_A receptors prolongs its effects beyond the half-life. Human coronary arteries demonstrate abundant ET-1 binding sites, suggesting that ET-1 has an important role in the control of coronary blood flow in humans. Changes in coronary blood flow in ischemia-reperfusion, congestive heart failure, hypertension, and atherosclerosis may be, in part, mediated or exacerbated by an overexpression of ET-1, which may overwhelm the vasodilating effects of local autacoids such as adenosine and NO^•.⁴⁴ Increased age may exacerbate the vasoconstrictor responses to ET-1, which are further exaggerated by a concomitant decrease in tonic NO^• production. In addition, the levels of ET-1 have been observed to increase with myocardial ischemia-reperfusion and after cardiac surgery.

Under ordinary circumstances, the metabolic vasodilator system is the dominant force acting on the resistance vessels. For example, the increased metabolic activity caused by sympathetic stimulation leads to vasodilation of the coronary arterioles through the metabolic system despite a direct vasoconstriction effect of norepinephrine.^45–47

Coronary artery blood flow is also determined by perfusion pressure. However, in the coronary vasculature, blood flow can remain constant over a range of perfusion pressures. The control mechanisms described allow autoregulation of blood flow, adjusting vascular resistance to match blood flow requirements. The autoregulatory "plateau" occurs between approximately 60 and 120 mm Hg of perfusion pressure. If distal coronary artery perfusion pressure is reduced by a critical stenosis or hypotension, vasodilator capacity will be exhausted, and coronary blood flow will decrease, following a linear relationship with perfusion pressure. Since the subendocardial regional of the left ventricle has a lower coronary vascular reserve, maximal dilation is reached in this region before it occurs in the subepicardial tissue, and a preferential hypoperfusion of the subendocardial tissue results.

Hemodynamic Effect of Coronary Artery Stenosis

Surgically treatable atherosclerotic disease primarily affects the large conductance vessels of the heart. The hemodynamic effect of a stenosis is determined by Poiseuille’s law, which describes the resistance of a viscous fluid to laminar flow through a cylindrical tube; specifically,

where Q is flow, P is the pressure change, is viscosity, r is radius, and l is the length of the resistance segment. Resistance (pressure change/flow)

is inversely proportional to the fourth power of the radius and directly proportional to the length of the narrowing. Therefore, a small change in diameter has a magnified effect on vascular resistance (Table 3-2). Conductance vessels are sufficiently large that a 50% reduction in the diameter of the vessel has minimal hemodynamic effect. A 60% reduction in the diameter of the vessel has only a very small hemodynamic effect. As the stenosis progresses beyond 60%, small decreases in diameter have significant effects on blood flow. For a given segment length, an 80% stenosis has a resistance that is 16 times greater than that of a 60% stenosis. For a 90% stenosis, the resistance is 256 times greater than that of a 60% stenosis.⁴⁸ Furthermore, for successive stenoses in the same vessel, the resistance is additive. An additional factor in resistance to flow is turbulence. Stenotic lesions can cause conversion from laminar to turbulent flow.⁴⁹ With laminar flow, the pressure drop is proportional to flow rate Q; with turbulent flow, pressure drop is proportional to (Q²). For all these reasons, patients who have had a small progression in the degree of coronary stenosis may experience a rapid acceleration of symptoms.

As noted earlier, when a stenosis is less than 60%, little change is flow is noted. This is due to compensation by the coronary flow reserve of the resistance vessels distal to the stenotic conductance vessel. Since resistance to flow is additive, a decrease in distal resistance will balance an increase in proximal resistance, and flow will be unchanged. As flow reserve decreases, any stimulus that increases myocardial oxygen demand (such a tachycardia, hypertension, or exercise) cannot be met by dilation of the distal vasculature, and myocardial ischemia results.⁴²

In the human, coronary arterial vessels are end vessels with little collateral flow between major branches except in pathologic situations. With sudden coronary occlusion, though, there usually is modest collateral flow through very small vessels (20 to 200 µm in size); this flow generally is insufficient to maintain cellular viability. Collateral flow gradually begins to increase over the next 8 to 24 hours, doubling by about the third day after total occlusion. Collateral blood flow development appears to be nearly complete after 1 month, restoring normal or nearly normal resting flow to the surviving myocardium in the ischemic region. Previous ischemic events or gradually developing stenoses can lead to larger preexisting collaterals in the human heart. The presence of these preexisting collaterals has been shown to be important in the prevention of ischemic damage if coronary occlusion should occur.⁵¹

Endothelial Dysfunction

As noted previously, NO^•, adenosine, and endothelin-1 are synthesized and released by the endothelium.^52,53 Ischemiareperfusion, hypertension, diabetes, and hypercholesterolemia can impair generation of NO^•, and vasoconstriction may predominate, mediated by the relative overexpression of endothelin-1. Reperfusion after temporary myocardial ischemia is one situation in which NO^• production may be impaired, leading to a vicious cycle in which the vasodilator reserve of the resistance vessels is reduced with a consequent and progressive "low flow" or "no flow" phenomenon. The coronary vascular NO^• system also may be impaired in some cases after coronary artery bypass surgery.

The endothelium helps to prevent cell-cell interactions between blood-borne inflammatory cells (i.e., leukocytes and platelets) that initiate a local or systemic inflammatory reaction. Inflammatory cascades occur with sepsis, ischemia-reperfusion, and cardiopulmonary bypass. Under normal conditions, the vascular endothelium resists interaction with neutrophils and platelets by tonically releasing adenosine and NO^•, which have potent antineutrophil and platelet-inhibitory effects. Damage to the endothelium lowers the resistance to neutrophil adhesion. Neutrophils can damage the endothelium by adhesion to its surface and subsequent release of oxygen radicals and proteases. This amplifies the inflammatory response and decreases the tonic generation and release of adenosine and NO^•, which then permits further interaction with activated inflammatory cells. The products released by activated neutrophils have downstream physiologic consequences on other tissues, notably the heart, including increasing vascular permeability, creating blood flow defects (no-reflow phenomenon), and promoting the pathogenesis of necrosis and apoptosis.⁵⁴

The triggers of these inflammatory reactions in the heart include cytokines [i.e., interleukin 1 (IL-1), IL-6, and IL-8], complement fragments (C3a, C5a, membrane attack complex), oxygen radicals, and thrombin, which upregulate adhesion molecules expressed on both inflammatory cells (CD11a/CD18) and endothelium (e.g., P-selectin, E-selectin, and ICAM-1). The release of cytokines and complement fragments during cardiopulmonary bypass activates the vascular endothelium on a systemic basis, which contributes to the inflammatory response to cardiopulmonary bypass.⁵⁵ Both adenosine and NO^• have been used therapeutically to reduce the inflammatory responses to cardiopulmonary bypass and to reduce ischemia-reperfusion injury. This treatment has reduced endothelial damage from surgical and nonsurgical ischemia-reperfusion injury and cardiopulmonary bypass.^56–58

The Sequelae of Myocardial Hypoperfusion: Infarction, Myocardial Stunning, and Myocardial Hibernation

Normally contracting muscle in the left ventricle uses 8 mL of oxygen per 100 g of muscle every minute. Of this, 1.3 mL/100 g of muscle per minute is necessary for cell survival; the rest supports contraction. As oxygen delivery is reduced, contraction strength decreases rapidly (within 8 to 10 heartbeats). This is seen acutely in response to acute ischemia and is reversed rapidly with reperfusion. If the extent of reduction of coronary blood flow is severe, mild to moderate abnormalities in cellular homeostasis occur. Reduced cellular levels of ATP lead to a loss of adenine nucleotides from the cell. If the reduction in coronary blood flow is sustained, progressive loss of adenine nucleotides and elevation of intracellular and intramitochondrial calcium may lead to cellular death and subsequent necrosis. If the myocyte is reperfused before subcellular organelles are irreversibly damaged, the myocyte may recover slowly. A period of days is necessary for full recovery of myocyte ATP levels because adenine nucleotides must be resynthesized. During this time, contractile processes are impaired. This impairment is related to reversible damage to the contractile proteins such that their responsiveness to cytosolic levels of calcium is diminished. The magnitude of the cytosolic pulse of calcium with each heartbeat appears to be nearly normal, but the magnitude of the consequent contraction is greatly reduced. Over a period of 1 to 2 weeks, this myocardium recovers gradually. This viable but dysfunctional myocardium is called stunned myocardium.^59,60,65

Chronic hypoperfusion and oxygen delivery at a reduced level but above the level required for cell viability can cause a chronic hypocontractile state known as hibernation. Hibernation appears to be associated with a decrease in the magnitude of the pulse of calcium involved in the excitation-contraction process such that the calcium levels developed within the cytosol during each heartbeat are inadequate for effective contraction to occur. Histologic examination shows islets in the subendocardium where there is a loss of contractile proteins and sarcoplasmic reticulum and alterations in other subcellular structures.^61,62 With reperfusion, hibernating myocardium can resume normal and effective contraction very quickly, although complete recovery may be delayed for several months.^63–66 This is of particular importance for patients with poor ventricular function but viable heart muscle.⁶⁷

Reperfusion of acutely ischemic myocardium may cause further cellular damage and necrosis rather than immediate recovery. The etiology of reperfusion injury is multifactorial. Damage to endothelium in the reperfused region fails to prevent adhesion and activation of leukocytes and platelets. Oxygen free radicals are released. Derangement of the ATP-dependent sodium-potassium pump disrupts cell volume regulation with consequent leakage of water into the cell, explosive cell swelling, and rupture of the cell membrane. Techniques attempting to reduce reperfusion injury, minimize adverse sequelae, and preserve myocytes include leukocyte depletion or inactivation, prevention of endothelial activation, free-radical scavenging, reperfusion with solutions low in calcium, and reperfusion with hyperosmolar solutions.^68,69 Both adenosine and low-dose NO^• are potent cardioprotective agents that attenuate neutrophil-mediated damage, infarction, and apoptosis.^56,70

The metabolic changes that occur with ischemia-reperfusion represent a complex system of adaptive mechanisms that allow the myocyte to survive despite a temporary reduction in oxygen delivery. These adaptive mechanisms may be triggered by a very brief coronary occlusion (as short as 5 minutes) such that the negative sequelae of a subsequent prolonged coronary occlusion are greatly minimized. This phenomenon has been called ischemic preconditioning. A coronary occlusion that might cause as much as 40% myocyte death in a region subjected to prolonged ischemia may be reduced to only 10% myocyte death if the prolonged period of ischemia is preceded by a 5-minute interval of "preconditioning" coronary occlusion.^68,71,72

	PHYSIOLOGY OF HEART FAILURE

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Definition and Classification

Heart failure is the inability of the heart to deliver adequate blood to the tissues to meet metabolic needs at rest or during mild to moderate exercise. Components include low cardiac output, an impaired exercise capacity, neurohormonal activation, enhanced oxidative stress, and premature myocardial cell death. Processes that cause heart failure can impair systolic function (the ability to contract and empty) or diastolic function (the ability to relax and fill) or both. The acute and chronic stages of a myocardial infarction involving a large area of the left ventricle cause systolic heart failure. The acute loss of contractile function compromises the ability of the ventricle to maintain a normal stroke volume (Fig. 3-11F). As the infarction heals, the adaptive response of ventricular dilation reduces the heart’s systolic functional reserve. Cardiomyopathies affect the myocardium globally, leading to reduced systolic function. In both cases, the left ventricle dilates, which causes the pressure-volume relations of the left ventricle to shift to the right (Fig. 3-11G). In this situation, the diastolic portion of the pressure-volume curves is not greatly changed. However, the global systolic performance of the heart (i.e., the ability to pump blood) may be inadequate to meet even resting needs (particularly if there is systolic bulging of a large infarction).^73,74

Diastolic failure may occur without an impairment of systolic contractility if the myocardium becomes fibrotic or hypertrophied or if there is an external constraint on filling such as with pericardial tamponade.⁷⁵ Increased stiffness of the left ventricular myocardium is associated with an excessive upward shift in the diastolic pressure-volume curve (Fig. 3-11C and E). The most common cause of increased myocardial stiffness is chronic hypertension with consequent left ventricular hypertrophy and diastolic stiffness (related both to myocyte hypertrophy and to increased fibrosis of the ventricle).^76,77

It should be noted from these examples that although one process may predominate, most patients with heart failure manifest both systolic and diastolic dysfunction.

Early Cardiac and Systemic Sequelae of Heart Failure

The adaptive homeostatic reactions of the body leading to heart failure depend on the duration of the ongoing pathologic process. When cardiac function deteriorates acutely and cardiac output diminishes, neurohumoral reflexes attempt to restore both cardiac output and blood pressure. Activation of the sympathetic adrenergic system in the heart and in the peripheral vasculature causes systemic vasoconstriction (via an alpha-adrenergic effect) and increases heart rate and contractility (via a beta-adrenergic effect). A number of mediators formed during this adaptive stage, including norepinephrine, angiotensin II, vasopressin, brain natriuretic peptide (BNP), and endothelin, not only help in renal retention of salt and water leading to rapid volume expansion but also cause vasoconstriction. Aldosterone output is increased, again helping conserve sodium. The concerted responses of the adrenergic system and the renin-angiotensin system, therefore, recruit changes in the primary determinants of stroke volume and cardiac output—preload, afterload, and contractility. The heart responds to loss of systolic function by dilating progressively. This dilation leads to preservation of stroke volume by Frank-Starling mechanisms, but increased stroke volume is achieved at the expense of ejection fraction, as shown in Fig. 3-11G as a right shift in the pressure-volume relationship of the left ventricle with an increase in end-diastolic volume (and pressure). In addition to a global dilatation response, acute alterations in cardiac geometry may occur early after a large myocardial infarction, with thinning of the left ventricular wall in the region of the infarct as well as expansion of overall left ventricular cavity size. This is particularly true if the infarct is apical because of geometric considerations related to the thinness of the left ventricular wall in the region of the apex and to the short radius of curvature of the left ventricular apex. As volume expansion occurs, production of the cardiac atrial natriuretic peptide is increased, which tends to prevent excessive sodium retention and inhibit activation of the renin-angiotensin and aldosterone systems.^78–84

Cardiac and Systemic Maladaptive Consequences of Chronic Heart Failure

The acute-phase response just described, while acutely beneficial, becomes maladaptive and contributes significantly to long-term problems in patients with heart failure (Figure 3-14). In the latter stages of heart failure, the kidney tends to retain sodium and become hyporesponsive to atrial natriuretic peptide and BNP.⁷⁹ Desensitization of beta-adrenergic receptors is a consequence of sustained stimulation with a reduced response to elevated circulating catecholamine levels.²⁰

View larger version (31K): [in this window] [in a new window]   Figure 3-14 Pathophysiology of heart failure from stimulus (etiology) to acute adaptive and chronic maladaptive responses. (+) indicates positive stimulation; (–) indicates negative factors that tend to reduce stimulation of heart failure.

Angiotensin and aldosterone stimulate collagen formulation and proliferation of fibroblasts in the heart, leading to an increase in the ratio of interstitial tissue to myocardial tissue in the noninfarcted regions of the heart.⁸⁵ The impact of aldosterone has been documented by the effectiveness of aldosterone receptor antagonists in improving the morbidity and mortality of patients with heart failure.⁸⁶ The progressive fibrosis leads to increased diastolic stiffness, which limits diastolic filling and increases end-diastolic pressure. Fibrosis and increased ventricular size predispose to reentry ventricular arrhythmias that are a common cause of death in the late stages of heart failure. This rapidly deteriorating clinical cycle explains the result in one clinical study in which the 5-year survival rate was only 25% in men and 38% in women.^81,83,84,87 Hence heart failure progresses as a result of a vicious cycle of left ventricular dilatation and remodeling, responses that decrease cardiac performance further.

Evidence has accumulated over the past decade that suggests that endothelial dysfunction, release of cytokines, and apoptotic cell death may participate in the development of heart failure as a maladaptive reaction (Fig. 3-14). Reduced availability of nitric oxide and increased production of vasoconstrictor agents such as endothelin and angiotensin II have been reported in failing hearts.^88,89 Heart failure is often accompanied by changes in the endogenous antioxidant defense mechanisms of the heart, as well as evidence of oxidative injury to the myocardium. Cytokines, released from systemic and local inflammatory responses in the failing heart, directly activate inflammatory cells to release superoxide radicals and cause endothelial dysfunction by augmenting inflammatory cell–endothelial cell interactions. Cytokines also may induce necrotic and apoptotic myocyte cell death directly.^90,91

Cardiac secretion of B-type natriuretic peptide (BNP) has been shown to be increased with heart failure.⁹² BNP is a cardiac neurohormone released as preproBNP that is enzymatically cleaved to N-terminal proBNP and BNP on ventricular myocyte stretch.⁹³ The physiologic effects of BNP include natriuresis, vasodilation, and neurohumoral changes. Plasma measurement of BNP is emerging as a useful and cost-effective marker for heart failure. A BNP level below 100 pg/mL excludes acutely decompensated heart failure.⁹⁴ However, BNP is not specific for heart failure. Other factors rather than stretch may stimulate BNP release, including fibrosis, arrhythmias, ischemia, endothelial dysfunction, and cardiac hypertrophy. BNP levels greater than 20 pg/mL are associated with an increased risk for atrial fibrillation and heart failure. Nesiritide is a synthetic analogue of human BNP. In clinical trials, nesiritide has been shown to decrease cardiac filling pressures, increase cardiac index, and improve the clinical status of patients with acute decompensated heart failure.⁹⁵

	ACKNOWLEDGMENT

 
The authors would like to acknowledge the work of the authors of this chapter in the previous edition, Jacob Vinten-Johansen, Zhi-Qing Zhao, and Robert A. Guyton. The current revision was based on the solid foundation that they had prepared.