Chapter 3. Cardiac Surgical Physiology

A cardiac surgical procedure is the most acute application of basic dynamic physiology that exists in medical care. Basic physiologic concepts of electromechanical activation and association, loading conditions, inotropy, etc all affect a successful outcome. Working knowledge of these fundamental concepts is imperative to maintain and return a patient to normal function. The purpose of this chapter is to present a manageable outline of cardiac physiology that can be used in daily practice, as a framework against which pathologic processes can be measured, assessed, and treated.

The heart beats are 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 and the conduction system, which transmits the electrical activity to the ventricle. Activation is dependent on components of the cell membrane and cell, which induce and maintain the ion currents that promote and spread electrical activation.

The activity of cells in the heart is triggered by an action potential. An action potential is a cyclical activation of the cell comprised 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 is dependent 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), then a plateau phase mediated by slow channels (calcium channels). Further details of this process are introduced as their components are described.

The Sarcolemma

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 the conduction of an electrical signal through the heart with subsequent initiation of the excitation-contraction coupling process. The sarcolemma also participates in the regulation of excitation, contraction, and intracellular metabolism in response to neuronal and chemical stimulation.

The Phospholipid Bilayer

The sarcolemma is a phospholipid bilayer that provides a barrier between the extracellular compartment and the intracellular compartment or cytosol. The sarcolemma, which 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 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 (sodium, chloride, potassium, calcium) cannot easily diffuse through the lipid bilayer and require specialized channels for transport.1,2

The specialized ion transport systems within the sarcolemma consist of membrane-spanning proteins that float in and penetrate through the lipid bilayer. These proteins are associated with three different types of ion transport: (1) diffusion through transmembrane channels that can be opened or closed (gated) in response to electrical (voltage-gated) or chemical (ligand-gated) stimuli; (2) exchange of one ion for another by attachment to binding sites for transmission in response to an electrochemical gradient; and (3) active (energy-dependent) transport of ions against an electrochemical gradient.

Other proteins located in the sarcolemma serve as receptors for neuronal or chemical control of cellular processes.

Ion Channels

Most of the voltage-gated channels consist 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 allows the passage of particular ions based upon pore size and electrical charge, and an activation gate 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.1,3

Voltage-Gated Sodium Channels

The voltage-gated sodium channel is prominent in most electrically excitable muscle and nerve cells. Energy-dependent pumps and other ions create a large concentration gradient of positive sodium ions (142 mEq/L outside, 10 mEq/L inside) and a large electrical gradient (−70 to −90 mV outside to inside) across the cell membrane. Both gradients favor the influx of sodium. This passive influx is termed an inward current. The inward current of sodium ions begins to depolarize (reduce the electrical gradient) across the sarcolemma. When the membrane potential is raised to between −70 and −50 mV, the activation gate of the sodium channel opens. Sodium ions rapidly rush into the cell, depolarizing the sarcolemmal membrane. The inactivation gate of the sodium channel begins to close at the same voltage, with a built-in time delay, so the sodium channel is open for only a few milliseconds. Because these channels open and close so quickly, they are called fast channels. The inactivation gate of the sodium channel remains closed until the cell is repolarized to the resting negative membrane potential.4,5

Voltage-Gated Calcium Channels

There are two important calcium channels. The type T (transient)-calcium channels open as the membrane potential rises to −60 to −50 mV, and then close quickly. These T-calcium channels are important in early depolarization, especially in atrial pacemaker cells.

The second major calcium channel, 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 prolonged inward calcium current (Fig. 3-3) sustains the action potential. This increase in cytosolic calcium begins the excitation-contraction sequence. Beta-receptor stimulation induces conformational changes in the channel 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.6,7

Potassium Channels

A variety of potassium channels both voltage- and ligand-gated are present in cardiac cells. Three voltage-gated potassium channels moderate the delayed rectifier current, which repolarizes the cell membrane (see Fig. 3-3).8

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, thereby retarding depolarization and contraction.

Energy-Dependent Ion Pumps

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. Because 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 its binding site. The Na-K ATPase has a very high affinity for ATP, so that the pump continues to function even if ATP levels are 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 in the following). The cytosolic protein, calmodulin, can complex with calcium and facilitate the action of the pump; thus, increased intracellular calcium levels stimulate the pump.9,10

Ion Exchangers

Sodium-Calcium Exchanger

Multiple proteins that traverse the membrane allow ion exchanges using the potential energy of the electrochemical gradient, which favors the influx of sodium. The sodium-calcium exchanger 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 contraction). Thus hyponatremia can increase 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 of calcium. This mechanism may 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 and is the primary mechanism for removal of excess cytosolic calcium.7

Sodium-Hydrogen Exchanger

The sodium-hydrogen exchanger extrudes one intracellular hydrogen ion in exchange for one extracellular sodium ion, and is electrically neutral. This pump prevents intracellular acidification. Acidification (eg, during ischemia) increases the affinity of the pump for H+ promoting the removal of H+ preserving intracellular pH at the expense of sodium accumulation. The accumulation of sodium ions may then trigger reversal of the sodium-calcium exchange pump to favor the accumulation of calcium within the cell. This is a possible 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 rapidly and evenly spread through all portions of the cell. This is accomplished through the t-tubules, and the subsarcolemmal cistern and sarcotubular network of the sarcoplasmic reticulum.

Transverse Tubules (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 are perpendicular to the sarcomere, near the z-lines, extending the extracellular space close to the contractile proteins. The transverse tubules contain the calcium channels, which are in close relationship to the foot proteins of the subsarcolemmal cisternae.

Sarcoplasmic Reticulum

The sarcoplasmic reticulum is a membrane network within 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 near the sarcolemma and the t-tubules. Foot 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. The foot proteins respond to the release of calcium by opening a calcium channel, which allows the 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 in the sarcotubular network.1,10 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. A calcium-calmodulin complex phosphorylates the pump to stimulate pump activity. Reduced ATP availability will slow pump function. Phospholamban inhibits the basal rate of calcium transport by the calcium pump. This inhibition is reversed when phospholamban is phosphorylated by a cyclic AMP- or calcium-calmodulin–dependent protein kinase. This is a very important mechanism for beta-adrenergic regulation; cyclic AMP levels increase with activation of the beta-adrenergic 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. 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.7,10 Phosphorylation of phospholamban, in the presence of intracellular calcium, stimulates calcium uptake to protect the heart from calcium overload.

In this ionic milieu, the importance of intracellular pH maintenance 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.

Normal Cardiac Rhythm

The Resting Membrane Potential

The state of the cardiac cell is determined by a balance of forces based on electrical and chemical gradients. At rest (during diastole), the cardiac cell is polarized. The electrical potential across the sarcolemma is primarily determined 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. 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 permeabilities across a membrane are described by the Gibbs-Donnan equilibrium.11 The sarcolemma prevents the diffusion of large anions (eg, proteins and organic phosphates). At rest, the sarcolemma is relatively permeable to potassium ions because of 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 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 because of smaller contributions from the current of other less permeable ions (eg, sodium and calcium). However, the potassium current is the main determinant of the resting membrane potential.12

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, which 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 when the inactivation gate of the “fast” sodium channel closes. The large gradient of sodium ions promotes rapid influx, depolarizing the cell to a slightly positive transmembrane potential: phase 0 of the action potential. A transient potassium current (ito) 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 is also sustained by a decrease in the outward potassium current (iK1). With time, the long-lasting calcium channels begin to close, and the repolarizing potassium current (iK, the delayed rectifier current) leads to the initiation of phase 3 of the action potential. As repolarization progresses, the stronger first potassium current (iK1) 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.

Refractory Period

The sodium channels cannot respond to a second wave of depolarization until the inactivation gates are reopened (by repolarization during phase 3). As a result, 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 inactivation gate will shorten both the absolute and the relative refractory periods.1,13,14

Spontaneous Depolarization

The action potential of the slow response cells of the nodal tissue (sinoatrial node, or SA node, and atrioventricular node, or 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 due to the absence of fast Na+ channels. Phase 1 is absent, as 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 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 caused by 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 fastest rate of depolarization is in the SA node, and action potentials are generated at a rate of 70 to 80 per minute. The AV node is a slower rate of depolarization, at 40 to 60 times per minute. The ventricular myocytes are the slowest, at 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. The heart rate can be altered by changing slope of the diastolic depolarization (eg, 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, thus decreasing the heart rate.

Propagation of the Action Potential

Each myocyte is mechanically anchored and electrically connected to the next myocyte by an intercalated disc at the end of the cell. These discs contain gap junctions that facilitate flow of charged molecules from one cell to the next. These pores 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 milliseconds). Similarly, the rapid conduction of the signal throughout the ventricle leads to synchronous contraction of the bulk of the ventricular myocardium (within 60 milliseconds). The delay in the propagation of the action potential through the AV node by 120 to 140 milliseconds 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 slowly rising action potentials.

Abnormal Cardiac Rhythm

Aberrant Pacemaker Foci

Normally the SA node spontaneously depolarizes first, such that the cardiac beat originates from this primary pacemaker site. If the SA node is damaged or slowed by vagal stimulation or drugs (eg, acetylcholine), pacemakers in the atrium, AV node, or the His-Purkinje system can take over. Occasionally, aberrant foci in the heart spontaneously depolarize, thereby leading to aberrant or “premature” contractions from the atrium or the ventricle. These contractions ordinarily do not interfere with the normal depolarization of the heart.

Re-Entry Arrhythmias

Re-entry arrhythmias are perhaps the most common dangerous cardiac rhythm. Ordinarily, the action potential depolarizes the entire atrium or the entire ventricle in a short enough time interval so that all of the muscle is refractory to further stimulation at the same time. A re-entry arrhythmia is caused by propagation of an action potential through the heart in a “circus” movement. For re-entry 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 that the propagation time around the loop.12 For example, if a portion of the previously depolarized myocardium has repolarized before the 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 of these situations occur clinically. Ischemia slows the sodium-potassium pump, which decreases the resting membrane potential and slows propagation of the action potential. Hyperkalemia decreases the resting membrane potential, which increases excitability and inactivates the sodium-potassium pump, slowing propagation of the action potential. Progressive atrial dilation creates a long conduction pathway around the atrium. Adrenergic stimulation shortens the refractory period.

A special type of reentry arrhythmia occurs in Wolff-Parkinson-White syndrome in which an accessory pathway electrically connects the atrium and the ventricle. This accessory pathway can complete a circular electrical pathway between the atrium and the ventricle. Conduction is unidirectional across the AV node and the accessory pathway creates a loop that has a propagation time that is greater than the AV node refractory period, resulting in supraventricular tachycardia. In an alternative situation, because the accessory pathway does not have the inherent delay and refractory period of the AV node, rapid atrial tachycardias can be conducted in a 1:1 manner across the accessory pathway, leading to ventricular rates as fast as 300 beats per minute.

Types of Receptors and Second Messengers

Numerous types of receptors are involved in regulating cardiovascular function. They include G-protein (GTP-binding proteins)–coupled receptors, enzyme-linked receptors, ion channel-linked receptors, and nuclear receptors. Other ligands, such as nitric oxide, bind directly to their intracellular target.15 G-protein–coupled receptors are the most important. Ligand binding activates the synthesis of intracellular second messengers, protein kinases, and voltage-gated potassium channels.16 The most important second messenger is cyclic AMP, which transmits the response to sympathetic stimulation. Cyclic AMP is produced from ATP by adenylyl cyclase and broken down to AMP by phosphodiesterases. Cyclic AMP production is promoted by sympathetic and inhibited by parasympathetic stimulation. Another second messenger, cyclic GMP is similarly produced, in response to nitric oxide and naturetic peptides, by guanylyl cyclase and broken down by phosphodiesterases and opposes the actions of cyclic AMP.17 These and other second messengers activate signaling enzymes within the cell such as protein kinases.

Innervation of the Heart

Sympathetic fibers originate from the fourth and fifth thoracic spinal cord regions. Parasympathetic innervation derives through the vagus nerve connecting to the SA and AV nodes, atria, and blood vessels. Stretch receptors located in the atria and ventricles provide feedback to the central nervous system. Atrial natriuretic peptide (similar to B-type natriuretic peptide, which is clinically measured) is secreted by atrial myocytes in response to stretch and promotes natriuresis, diuresis, and smooth muscle relaxation. Stretch receptors on the posterior and inferior ventricular wall can trigger parasympathetic stimulation and inhibit sympathetic activity, leading to bradycardia and conduction block (von Bezold-Jarisch reflex).18

Parasympathetic Regulation

The parasympathetic nervous system is particularly important in control of the SA node. Acetylcholine released by the nerve endings of the parasympathetic system stimulates muscarinic receptors in the heart. The activated receptors 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, inhibiting the opening of calcium channels. A decreased inward flow of calcium, combined with an increased outward flow of potassium, leads to slowing of the spontaneous diastolic depolarization of the SA node class (see Fig. 3-5). A similar effect in the AV node leads to slowing of conduction through the AV node.1

Sympathetic Stimulation and Blockade

Sympathetic or adrenergic receptors in the heart affect heart rate, contractility, conduction velocity, and automaticity; and in the peripheral vasculature they affect smooth muscle contraction and relaxation. 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 be upregulated or downregulated in response to various stimuli. Receptor sensitivity can also change depending on ambient conditions and variable stimuli.19 Cardiopulmonary bypass and ischemia cause downregulation of cardiac beta receptors. Acidemia causes desensitization of beta receptors. This is important in the perioperative period when acidemia can reduce cardiac contractility, systemic vascular tone, and the response to inotropic agents.

The beta1-adrenergic receptor couples with adenylyl cyclase (Fig. 3-7). When the receptor site is occupied by an adrenergic agonist, a stimulatory G-protein is formed, which combines with GTP. This activated G-protein–GTP complex then promotes the activity of adenylyl 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 beta1-receptor stimulation increases cytosolic calcium and leads to a number of physiologic 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; and (3) a positive inotropic (contractility) effect. Increased activity of the sarcoplasmic reticulum calcium pump (more rapid calcium uptake) leads to more rapid relaxation, which facilitates ventricular filling; (4) a positive lusitropic (relaxation) effect.20

Two negative feedback systems diminish the response to beta agonists when stimulation is repetitive or persistent (tachyphylaxis). Increased cyclic AMP leads to: (1) increased phosphorylation of beta receptors leading to downregulation; and (2) increased activity of phosphodiesterase, the enzyme that degrades cyclic AMP. Acidosis will inhibit many steps in the sympathetic activation cascade, impairing contractility.

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 treat congestive heart failure. The selectivity of the agonists and antagonists allows adaptation for various clinical scenarios. Some examples are detailed in Table 3-1.

Reduction in inotropy, lusitropy, chronotropy, and dromotropy by beta blockade will reduce myocardial oxygen consumption contributing to many of its beneficial effects. As beta blockade will lead to upregulation of sarcolemmal receptors, sudden cessation of beta blockade may cause a temporarily enhanced (and potentially dangerous) sensitivity to adrenergic stimulation.

Phosphodiesterase Inhibition

Cyclic AMP plays a central role in the regulation of the cardiac cell. Cytosolic levels of cyclic AMP are also increased by activation of receptors other than beta receptors (ie, for histamine, dopamine, glucagon), and are decreased by inhibitory G-proteins produced by stimulation of muscarinic receptors by acetylcholine and by stimulation of adenosine receptors. Referring 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 (amrinone, milrinone) inhibit the breakdown of cyclic AMP and thereby increase its level in the cytosol. Their effect is synergistic to that of beta agonists. Because they do not stimulate the production of the G-protein–GTP complex, they have a lesser effect on calcium channel activation, and therefore less of the troublesome positive chronotropic and dromotropic effects of beta-adrenergic stimulation.21

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 cyclic AMP production, inhibition of the slow calcium channel, and opening of an adenosine-activated ATP-sensitive potassium (KATP) channel. This leads to hyperpolarization, which delays conduction through the AV node and slows the ventricular response to atrial tachycardia.1,22 Pretreatment with adenosine confers a cardioprotective effect during ischemia and can inhibit the inflammatory responses initiated by ischemia and reperfusion.22

Other Regulators of Hemodynamic Function

Angiotensin II is a vasoconstrictor and reduces renal fluid excretion. It is the final effector of the renin-angiotensin-aldosterone system. Renin, secreted by the juxtaglomerular apparatus in the kidney, splits angiotensin I from angiotensinogen, produced by the liver. Angiotensin I is converted to angiotensin II by the angiotensin-converting enzyme (ACE or kininase II, the target of ACE inhibitors) mainly in the lungs. Angiotensin II acts by causing: 1) vasoconstriction to increase systemic vascular resistance; and (2) stimulation of the adrenal cortex to secrete aldosterone, which increases fluid volume and thus cardiac output. Through both actions, angiotensin II modifies blood pressure. Angiotensin II receptor blockers (ARBs) directly inhibit angiotensin II subtype IA receptors.

The endothelins (ETs) have multiple effects. When bound to ET-A receptors they cause vasoconstriction, increased contractility, and proliferation. When bound to ET-B receptors they stimulate the release of NO and prostacyclin and have a vasodilatory effect.23

Bradykinins, acting through their receptors, cause vasodilation. Arginine vasopressin promotes reabsorption of water by the kidney and has a vasoconstrictor effect. Naturetic peptides, released in response to atrial distention, promote diuresis and arteriolar dilatation. Nitric oxide at low concentrations causes vasodilation, reduces chronotropy, and has a positive inotropic effect.24

Molecular Level (the Sarcomere)

The primary contractile unit of all muscle cells is the sarcomere (see 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 schematically depicted 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, forming the rigid backbone of the thick filament. The globular head of myosin is attached to the heavy chain backbone by a mobile hinge and projects outward. The globular myosin head is an ATPase with a binding site for actin. 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).

Two proteins modulate the interaction of actin and myosin; troponin and tropomyosin. Troponin (“T” in Fig. 3-8A) is composed of three units: Tn-C, the regulatory calcium binding unit; Tn-T, which binds the troponin complex to tropomyosin; and Tn-I, which facilitates interruption of actin-myosin interaction by tropomyosin. Associated with each troponin complex is tropomyosin; a filamentous protein composed of two tightly coiled chains that lays in the groove formed by the two intertwined filaments of actin. In the absence of calcium, Tn-I is tightly bound to actin so that tropomyosin blocks the binding of myosin to actin. When calcium binds to troponin C, Tn-I becomes unbound, the tropomyosin moves to expose the myosin binding site on actin, thereby allowing cross-bridge formation between actin and myosin. Tn-C has several regulatory sites that are affected by phosphorylation in response to hormonal and other stimuli, to alter the sensitivity and degree of force generation. Acidosis will reduce contractile force through an allosteric affect because of protons binding to Tn-I, and reducing affinity of calcium binding sites.25

During diastole, Ca2+ is unavailable to bind troponin C and the myosin binding site on actin is blocked. Depolarization leads to an influx of calcium ions and the subsequent “calcium-triggered, calcium release” increases the intracellular Ca2+ 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-tropomyosin, 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 Pi are released. ATP binds to the myosin head, allowing dissociation from the actin and 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.

The strength of the myocardial contraction is primarily mediated 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 (see Fig. 3-7). Cyclic AMP can phosphorylate a portion of the troponin molecule, facilitating the rapid release of calcium, increasing the rate of relaxation of the actin-myosin complex.7,26

The Cytoskeleton

Cytoskeletal elements include microfilaments composed of actin, intermediate filaments composed of desmin, and microtubules made of tubulin.27 The cytoskeleton maintains cellular anatomy, transmits developed tension, and links adjacent myocytes. It also has a role in intracellular signaling. Cardiac myocytes are mechanically linked through the intercalated discs by the fascia adherens and desmosomes.28 Sarcomere tension is transmitted through actin microfilaments to the fascia adherens of the intercalated discs. Intermediate filaments of adjacent cells are linked through desmosomes.

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 in the following). Maximal contraction force occurs when the resting sarcomere length is between 2 and 2.4 mm. 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, as the resting length of the cardiac sarcomere rarely exceeds 2.2 to 2.4 mm. 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.

Microscopic Architecture

Each myocyte is surrounded by a connective tissue framework called the endomysium. Groups of myocytes are joined within the perimysium, and the entire muscle within the epimysium. Muscle bundles are anchored in the fibrous skeleton at the base of the heart. Muscle bundles spiral around the cavity in overlapping patterns.

Macroscopic Architecture

The geometry of each ventricle is adapted to the function required of it. The left ventricle, which must eject against high pressure, is conical in shape with inlet and outlet adjacent at the base of the cone. Cavity volume is reduced during systole by a combination of concentric contraction and wall thickening, the latter predominating. The right ventricle wraps around the left ventricle, its cavity is crescent shaped with separated points of inflow and outflow. Cavity reduction is primarily a result of concentric contraction of the right ventricular free wall against the septum.

Mechanics

Clinically Measureable Physiologic Parameters

Cardiac surgeons can assess the function of the heart in a number of ways. Aortic, 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—although less accurate because of the cumulative error of the measured parameters inherent in the calculation—such as pulmonary and systemic vascular resistance, and ventricular stroke work. 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 clinically useful, these parameters do not directly measure contractility.

The Frank-Starling Relationship

Within physiologic limits, the heart functions 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. 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. 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 Fig. 3-9 are two other states, a condition of normal adrenergic stimulation and a condition of maximal adrenergic stimulation. Force is increased for the same resting conditions by adrenergic stimulation; this is a positive inotropic effect.

Preload: Diastolic Distensibility and Compliance

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. As volume cannot be easily assessed 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.

A number of factors affect the diastolic pressure-volume relationship. A fibrotic heart, a hypertrophied heart, or an aging heart becomes increasingly stiff (Figs. 3-11C and 3-11E). In the case of fibrosis, this increasing stiffness is related to the development of a greater collagen network. In the case of hypertrophy, this increased stiffness is related both to stiffening of the noncontractile components of the heart and also to impaired relaxation of the heart. Relaxation is an active, energy-requiring process. This process is accelerated by catecholamine stimulation, but is impaired by ischemia, hypothyroidism, and chronic congestive heart failure. Examination of the diastolic pressure-volume curves in Fig. 3-11 reveals the importance of changes in diastolic distensibility in pathologic cardiac conditions.

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 that 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 which 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 accurately describe the forces overcome to eject blood from the ventricle, the compliance of the vascular system and kinetic energy imparted must also 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 (eg, with arteriosclerosis), resistance is less than impedance.29 The interaction of resistance and compliance define the dicrotic notch, marking end-systole, closure of the aortic valve, on the aortic pressure tracing (Fig. 3-10).

The Cardiac Cycle

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, then rapidly increases until the systemic diastolic pressure is reached (isovolumic contraction) and the aortic valve opens. Ejection begins and the intracavitary pressure continues to rise 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, 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. Atrial systole serves to increase the preload of the ventricle at a given systemic venous pressure.

A conceptual understanding of the venous pressure changes is important in diagnosing certain pathologic processes. The right atrial pressure is easily measured and pulmonary capillary wedge pressure is reflective of left atrial pressure. The “a” wave corresponds to atrial systole as pressure increases at end-diastole to complete ventricular filling. The “c” wave reflects pressure pushing the atrioventricular (AV) valve back into the atrium as the ventricular pressure rises 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 caused by 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 the 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. 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).

End-diastole (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 end-systole [ES]); isovolumic relaxation (down to the bottom left corner); 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 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. Otherwise stated, all the factors that impact cardiac performance independent of the acute effects of preload, afterload, and heart rate. In the purest sense, at a level of constant contractility, increased preload will increase cardiac output and stroke volume; increased afterload will decrease cardiac output and stroke volume; and increased heart rate (assuming adequate time for complete diastolic filling) will increase cardiac output without changing stroke volume. Although the inotropic state impacts 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 (EES) and volume axis intercept (V0) of the ESPVR (Fig. 3-12). Holding afterload and heart rate constant, a series of pressure-volume loops are 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 end systole are then 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 EES and sometimes a decrease in V0. Conversely, a decrease in inotropic state is expressed as a decrease in EES and sometimes an increase in V0 (see Fig. 3-12). As the ESPVR describes systolic function, the end-diastolic pressure volume relationship (EDPVR) (see Fig. 3-12) describes ventricular diastolic compliance (more specifically, the inverse of the slope of the EDPVR is compliance) a measure of lusitropy. The EDPVR is impacted by calcium uptake, ease of dissociation of contractile proteins, the cytoskeleton, ventricular wall thickness, and the pericardium.

Pressure-volume loops can be used to analyze various physiologic situations. Increased afterload (see Fig. 3-11B) moves the end-systolic pressure-volume point slightly upward and to the right. If stroke volume is maintained, end-diastolic volume must increase. Thus, though contractility is unchanged, ejection fraction is slightly decreased. Figure 3-11C shows the effect of a decrease in ventricular compliance (increased EDPVR) such as may result from hypertrophy, fibrosis, or cardiac tamponade. Systolic function is maintained (EES and V0 are unchanged), and stroke volume and ejection fraction can be maintained but require an increased end-diastolic pressure. The positive inotropic (increased EES) and lusitropic (decreased EDPVR) effects of adrenergic stimulation (see Fig. 3-11D), at constant stroke volume, shift the pressure-volume loop to the left, and increase the ejection fraction. In the hypertrophied heart (see Fig. 3-11E), in contrast to Fig. 3-11C, diastolic compliance is decreased and systolic contractility is increased. A constant stroke volume leads to an increase in end-diastolic filling pressure and decreased end-diastolic volume. The pressure-volume loop shifts to the left with an increase in ejection fraction. The ability of the hypertrophied heart to increase stroke volume is limited. Acute ischemia (see Fig. 3-11F) decreases diastolic compliance (increases EDPVR) and contractility. The pressure-volume loop shifts to the right and up to maintain stroke volume, consistent with the clinical observation of an acute decrease in ejection fraction and increase in left ventricular filling pressure. In the dilated heart of chronic congestive heart failure (see Fig. 3-11G) the pressure-volume loop is shifted to the right. Note that the slope of the diastolic pressure-volume curve (EDPVR) changes little, rather the curve shifts to the right. The end-diastolic pressure is not increased because of a change in compliance; instead, to maintain stroke volume, the pressure-volume loop has moved upward on the compliance curve. Contrast this with the fibrotic process discussed in the preceding. The effect of afterload reduction on the chronically failing heart from Fig. 3-11G is demonstrated in Fig. 3-11H. Note that the ESPVR, EDPVR, and stroke volume are unchanged. The pressure volume loop has moved back to the left, decreasing both the degree of chamber dilatation, end-diastolic pressure, and ejection fraction. A positive inotropic agent would shift the ESPVR line to the left (toward the dashed line), and the degree of dilatation would be reduced and both stroke volume and ejection fraction would be increased. It is important to remember that these relationships are idealized and may not completely reflect true clinical responses. For example, reduced diastolic dilatation from afterload reduction could return the ventricle to a state of improved intrinsic contractility. Despite these interactions, the pure concepts discussed here are very helpful in understanding the response of the heart to clinical interventions.

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 volume (Fig. 3-13).30 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

Clinical Indices of Contractility

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. Because 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 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 but is a useful, gross measure of cardiac reserve.

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

where σ is wall stress (≈ tension), 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 chronically increased (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.

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 (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. Ten to fifteen percent 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. When present in adequate amounts, fatty acids will inhibit use of glucose by the heart.32 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.33

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, since free fatty acids and the by-products of glycolysis cannot be metabolized. Glycolysis is very inefficient—for 1 mole of glucose, 2 moles of ATP are produced by anaerobic glycolysis, compared with 38 moles of ATP with aerobic metabolism. Phosphate stored in creatine phosphate can convert ADP to ATP, but this is not stored in significant amounts.

The availability of ADP is the primary determinant of the rate of oxidative phosphorylation. 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 partially restored rapidly 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. Glycolysis becomes the primary, albeit inefficient source of ATP with ischemia; this leads to an increase in lactate. The increase in lactate and inorganic phosphate causes acidosis. Acidosis slows glycolysis by reducing the activity of 6-phosphofructo-1-kinase, the rate-limiting enzyme in the glycolytic pathway.34 The excess protons compete with calcium-binding sites, interfering with contraction and relaxation. Nevertheless, ATP generated by glycolysis maintains cell viability. Glucose, insulin, and potassium support glycolysis and may be the source of the benefit of administering this combination after an ischemic insult.35

Determinants of Oxygen Consumption

Because nearly all the energy used by the heart is generated by oxidative metabolism, the rate of oxygen consumption (MV̇O2) is indicative of the metabolic rate of the heart:

where MV̇O2 is myocardial oxygen consumption, CaO2 is arterial oxygen content in mL O2/100 mL blood, CvO2 is coronary venous oxygen content in mL O2/100 mL blood, CBF is coronary blood flow in mL/min. Because 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 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. 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.36 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. An increase in afterload requires greater energy than an increase in volume ejected. Oxygen consumption is also increased as the heart dilates and begins ejection from a greater diastolic volume.

Cardiac efficiency relates oxygen consumption to cardiac work. Hence, cardiac efficiency = work/MV̇O2. The overall efficiency of the heart ranges from 5 to 40% depending on the type of work (pressure versus volume versus velocity) performed.37–40 The low efficiency of the heart is caused by 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 inotropic state of the myocardium, also is not factored into the work equation, but contributes significantly to oxygen consumption. Dilation of the ventricle reduces efficiency because as cavity size increases the reduction in wall stress with ejection is decreased.

Following cardiac surgery, cardiac efficiency generally decreases because of the increase in MV̇O2 relative to the cardiac work performed. The additional oxygen consumed may result from 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 distention 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 blood flow occurs, and creates an imbalance between oxygen demand and delivery.

See reference 41.

There are three distinct responses to altered metabolic demands. Two are responses to acute short-term alterations; the third is a response to chronic alterations in metabolic demands.

Acute Physiologic Responses

These responses consist of intrinsic physiologic adaptations to acute changes in hemodynamics and metabolic demands. Generally, these responses are regulated by changes in end-diastolic volume mediated by changes in preload and afterload. Beat-to-beat responses to changes in end-diastolic volume are important to equalizing the output of the ventricles.

Alterations of Biochemical Functions

Contractility (inotropy) and relaxation (lusitropy) change in response to altered metabolic demands. These are principally mediated by alterations in calcium fluxes in the myocyte.42 The principal determinant of calcium concentration is the flux across the sarcoplasmic reticulum membrane. The fluxes are determined by the amount of calcium in the sarcoplasmic reticulum and the amount of calcium crossing the plasma membrane to stimulate calcium release. Reduced ATP levels inhibit calcium release and uptake. Enzymatic phosphorylation of myosin can increase the rate of cross-bridge cycling, and phosphorylation of troponin I facilitates relaxation.43 Acidosis reduces contraction and relaxation by inhibiting many calcium pumps, channels, and exchangers.44

Altered Gene Expression

Chronic changes in metabolic demands will provoke proliferative responses leading to altered gene expression. These include changes in the types of myosin and actin and changes in the number of membrane channels and pumps.

Normal Coronary Blood Flow

Resting coronary blood flow is slightly less than 1 mL per gram 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 compared with subepicardial tissue. When there is an increased myocardial oxygen demand, myocardial blood flow can increase to three or four times normal (coronary flow reserve). This is accomplished by vasodilation of the resistance vessels and recruitment of additional capillaries (many of which are closed in the resting state). Capillary recruitment is important in decreasing the intercapillary distance and 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.45 The cyclic contraction and relaxation of the left ventricle produces 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 preferentially perfused, whereas subendocardial vessels are significantly hypoperfused. Toward the end of systole, blood flow actually reverses in the epicardial surface vessels.46 Hence, the subendocardial myocardium is perfused primarily during diastole, whereas subepicardial myocardium is perfused during both systole and diastole. A greater capillary density per square millimeter in the subendocardium compared with the subepicardial tissue facilitates the distribution of blood flow to the inner layer of myocardium.47 The subendocardium is 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 resulting from 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 that 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 particularly threatens the subendocardium, because systemic diastolic arterial pressure is reduced and intraventricular systolic and diastolic pressures are elevated.45,48

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.49 Blood flow is controlled by moment-to-moment adjustment of coronary tone of the resistance vessels, that is, 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 re-phosphorylation 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 (vasoconstriction) and beta receptors (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.50 NO• is dominant in local regulation of coronary arterial tone. NO• is released by the coronary vascular endothelium by both soluble factors (acetylcholine, adenosine, and ATP) and mechanical signals (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 (superoxide generation, adherence, and migration), which has implications in the anti-inflammatory response to ischemia-reperfusion and cardiopulmonary bypass.

Endothelin-1 interacts principally with specific endothelin receptors, ETA, 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 rapidly synthesized 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 ETA receptors prolongs its effects beyond the half-life. Human coronary arteries demonstrate abundant endothelin-1 binding sites, suggesting that ET-1 has an important role in the control of coronary blood flow in humans.51 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.52–54

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 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. Because the subendocardial region of the left ventricle has a lower coronary vascular reserve, maximal dilation is reached in this region before 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, ΔP is the pressure change, ν is viscosity, r is radius, and l is 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 a 60% stenosis. For a 90% stenosis, the resistance is 256 times greater than a 60% stenosis.55 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.56 With laminar flow the pressure drop is proportional to flow rate Q; with turbulent flow pressure drop is proportional to (Q2). For all of these reasons patients who have had a small progression in the degree of coronary stenosis may experience a rapid acceleration of symptoms.

Atherosclerosis also alters normal vascular regulatory mechanisms. The endothelium is often destroyed or damaged, so vasoconstrictor mechanisms are relatively unopposed by the impaired vasodilator mechanism; constriction is exaggerated and responses to stimuli that require dilatation are blunted.57

As noted, when a stenosis is less than 60%, little change is flow is noted. This is caused by compensation by the coronary flow reserve of the resistance vessels distal to the stenotic conductance vessel. As 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 as tachycardia, hypertension, or exercise) cannot be met by dilation of the distal vasculature, and myocardial ischemia results.49

In the human, coronary arterial vessels are end vessels with little collateral flow between major branches except in pathologic situations. With sudden coronary occlusion, although there is usually modest collateral flow through very small vessels (20 to 200 μm in size), this flow is generally 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 pre-existing collaterals in the human heart. The presence of these pre-existing collaterals has been shown to be important in the prevention of ischemic damage if coronary occlusion should occur.58

Endothelial Dysfunction

As previously noted, nitric oxide, adenosine, and endothelin-1 are synthesized and released by the endothelium.59,60 Ischemia-reperfusion, 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 may also be impaired in some cases after coronary artery bypass surgery.

The endothelium helps prevent cell-cell interactions between blood-borne inflammatory cells (ie, 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.61

The triggers of these inflammatory reactions in the heart include cytokines (IL-1, IL-6, 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 (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.62 Both adenosine and NO• have been used therapeutically to reduce the inflammatory responses to cardiopulmonary bypass, and to reduce ischemic-reperfusion injury and endothelial damage.63,64

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

As oxygen delivery is reduced, contraction strength decreases rapidly (within 8 to 10 heartbeats). This is seen acutely in response to ischemia and is rapidly reversed 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 flow is sustained, progressive loss of adenine nucleotides and the elevation of intracellular and intramitochondrial calcium may lead to cellular death and subsequent necrosis. Increased intramitochondrial calcium uncouples oxidative phosphorylation, creating a vicious cycle.65 If the myocyte is reperfused before subcellular organelles are irreversibly damaged, the myocyte may slowly recover. A period of days is necessary for full recovery of myocyte ATP levels as 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 gradually recovers. This viable but dysfunctional myocardium is called stunned myocardium.66–68

With chronic hypoperfusion, oxygen delivery is at a reduced level but above the level required for cell viability. This 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, sarcoplasmic reticulum, and alterations of other subcellular structures.69,70 With reperfusion, hibernating myocardium can very quickly resume normal and effective contraction, though complete recovery may be delayed for several months.66,71–73 This is of particular importance for patients with poor ventricular function but viable heart muscle.74

Reperfusion of acutely ischemic myocardium may cause further cellular damage and necrosis rather than lead to immediate recovery. The etiology of reperfusion injury is multifactorial. Damaged 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 applied 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 content, and reperfusion with hyperosmolar solutions.75,76 Both adenosine and low-dose NO• are potent cardioprotective agents that attenuate neutrophil-mediated damage, infarction, and apoptosis.77

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.75,78,79

Definition and Classification

Heart failure is the inability of the heart to deliver adequate blood to the tissues to meet end-organ metabolic needs at rest or during mild to moderate exercise. 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. Long-standing valvular insufficiency alters ventricular geometry and muscular function leading to ventricular failure. In all these examples, the left ventricle dilates, which causes the pressure-volume relationship of the left ventricle to shift to the right (Fig. 3-11G). In these situations, the diastolic portion of the pressure-volume curves is not greatly changed. However, the global systolic performance of the heart (ie, the ability to pump blood) may be inadequate to meet even resting needs.80,81

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.82 Increased stiffness of the left ventricular myocardium is associated with an excessive upward shift in the diastolic pressure-volume curve (Figs. 3-11C and 3-11E). 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 increased fibrosis of the ventricle).83,84

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 acutely deteriorates 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 and increases heart rate and contractility. A variety of mediators formed during this adaptive stage, including norepinephrine, angiotensin II, vasopressin, B-type natriuretic peptic, and endothelin, not only promote renal retention of salt and water leading to volume expansion but also cause vasoconstriction. Aldosterone output is increased, conserving sodium. The concerted responses of the adrenergic system and the renin-angiotensin system alter the primary determinants of stroke volume and cardiac output—preload, afterload, and contractility. The heart responds to loss of systolic function by progressively dilating. 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 dilation 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. 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.85–89

Cardiac and Systemic Maladaptive Consequences of Chronic Heart Failure

The acute phase response is initially beneficial but becomes maladaptive and contributes to long-term problems in patients with heart failure (Fig. 3-14). In the latter stages of heart failure, the kidneys tend to retain sodium and become hyporesponsive to atrial natriuretic peptide and B-type natriuretic peptide.86 Desensitization of beta-adrenergic receptors is a consequence of sustained stimulation with a reduced response to elevated circulating catecholamine levels.19

Left ventricular dilation is caused by hypertrophy of the myocytes as well as lengthening of the myocytes as sarcomeres are added. However, there is significant slippage of myofibrils leading to dilation without an increase in the number of myocytes. Progressive dilation of the heart leads to an increase in oxygen consumption during systole. Ventricular remodeling leads to progressive fibrosis.

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.90 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.91 The progressive fibrosis leads to increased diastolic stiffness which limits diastolic filling and increases end-diastolic pressure. Fibrosis and increased ventricular size predispose to re-entry ventricular arrhythmias that are a common cause of death in the late stages of heart failure.92 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 endothelial dysfunction, release of cytokines, and apoptotic cell death may participate in the development of heart failure as a maladaptive reaction (see Fig. 3-14). Reduced availability of nitric oxide and increased production of vasoconstrictor agents such as endothelin and angiotensin II has been reported in failing hearts.93 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 may also directly induce necrotic and apoptotic myocyte cell death.94

Cardiac secretion of B-type natriuretic peptide (BNP) has been shown to be increased with heart failure. BNP is a cardiac neurohormone released as preproBNP that is enzymatically cleaved to N-terminal-proBNP and BNP upon ventricular myocyte stretch. The physiologic effects of BNP include natriuresis, vasodilation and neurohumoral changes. Measurement of plasma BNP is a useful and cost-effective marker for heart failure.95 Other factors rather than stretch may stimulate BNP release including fibrosis, arrhythmias, ischemia, endothelial dysfunction, and cardiac hypertrophy.

The authors would like to acknowledge the work of the authors of this chapter in the 2nd edition, Jakob Vinten-Johansen, Zhi-Qing Zhao, and Robert A. Guyton. The current revision was based on the solid foundation they had prepared.

• The myocardial cell is electrically active in a state of balance maintained by the flux of ions across a semipermeable membrane, tightly regulated by variable responses to external stimuli. The metabolic balance is maintained by voltage gated channels, energy-dependent pumps, and ion exchangers. Electrical stimulation is communicated efficiently through the cell and between cells to allow the release of calcium and coordinate contraction.
• The cardiac pump is designed to respond acutely to changes in preload and afterload and the response can be impacted by changes in intrinsic inotropy and lusitropy. This response is impacted by innervation, and paracrine and endocrine effects.
• The heart can use a number of different fuels, lipid or carbohydrates, but the rate-limiting step in cardiac energetics is the delivery of oxygen. Because of its high metabolic requirements, cardiac function quickly falters if oxidative phosphorylation is not possible.
• In the setting of reduced oxygen delivery the heart implements a number of acute and chronic adaptations that initially ensure continued function but eventually are maladaptive.
• Contractility is the intrinsic functional state of the heart at a constant preload, afterload, and heart rate. Indices of contractility are useful to understand and explain pathologic responses but difficult to measure in the clinical setting.
• Endothelial cell function is important for autoregulation of coronary blood flow and can be disrupted during cardiac surgical procedures.