Advanced Search

Vinten-Johansen J, Zhao Z-Q, Guyton RA. Cardiac Surgical Physiology.
In: Cohn LH, Edmunds LH Jr, eds. Cardiac Surgery in the Adult. New York: McGraw-Hill, 2003:5384.

This Article
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Similar articles in this book
Right arrow Author home page(s):
Jakob Vinten-Johansen
Robert A. Guyton
Google Scholar
Right arrow Articles by Vinten-Johansen, J.
Right arrow Articles by Guyton, R. A.
Right arrow Articles citing this Article
Right arrow Search for Related Content
Right arrow Articles by Vinten-Johansen, J.
Right arrow Articles by Guyton, R. A.
Related Collections
Right arrow Cardiac - physiology

Chapter 3

Cardiac Surgical Physiology

Jakob Vinten-Johansen/ Zhi-Qing Zhao/ Robert A. Guyton

????The Cell Membrane or Sarcolemma
????T-tubules and the Sarcoplasmic Reticulum
????Electrical Activation of the Heart
????Regulation of Cellular Function by Sarcolemmal Receptors
????The Contractile Element (Sarcomere)
????Regulation of the Strength of Contraction by Initial Sarcomere Length
????Normal Coronary Blood Flow
????Control of Coronary Blood Flow
????Coronary Artery Stenosis
????Endothelial Dysfunction
????The Sequelae of Myocardial Hypoperfusion: Infarction, Myocardial Stunning, and Myocardial Hibernation
????Forms of Heart Failure: Systolic and Diastolic Heart Failure
????Early Cardiac and Systemic Sequelae of Heart Failure
????Cardiac and Systemic Maladaptive Consequences of Chronic Heart Failure
????Therapeutic Strategies for Managing Heart Failure

The cardiac surgeon is a practitioner of the art of medicine, a healer who attempts to understand disease processes with the goal of reversing or assuaging these disease states. Basic to the understanding of cardiac disease is a working knowledge of the normal functioning of the heart and of the specialized cells that comprise the cardiovascular system, for without this understanding of normal function, abnormal physiology escapes recognition. Hence, the cardiac surgeon must also be a practicing physiologist, continuously applying his or her understanding of cardiovascular physiology to the patient with cardiac disease. In addition, the cardiac surgeon must design and implement strategies of myocardial protection that preserve the normal physiology of the heart and constituent cells under conditions of cardiopulmonary bypass and off-pump surgery. The purpose of this chapter is to present a manageable, working outline of cardiac physiology that can be used in daily practice by the practitioner as a framework against which pathologic processes can be measured, assessed, and attacked.

The challenge of writing such a chapter of basic cardiovascular physiology is to present complex data, synthesized from numerous sources, that encapsulates our understanding at the systems level, at the cellular and subcellular levels, and finally at the molecular level. The latter is important because all the aforementioned levels are a convergence of complex and myriad molecular interactions. The challenge is to maintain simplicity without sacrificing completeness or accuracy, so that the surgeon may apply the fund of knowledge to daily practice and the broad spectrum of patients encountered. Basic, reasonably well established concepts will be presented, with the full understanding that many of these concepts are currently being challenged by our penetration to the molecular level of investigation.13

The Cell Membrane or Sarcolemma

The cardiac cell is surrounded by a membrane (plasmalemma or sarcolemma) with unique properties. These properties allow the origination and then the conduction of an electrical signal through the heart, leading to near-synchronous depolarization of atrial myocytes and, with an appropriate delay, synchronous depolarization of ventricular myocytes that optimizes ventricular loading conditions. The sarcolemma further possesses properties that lead to the initiation of the excitation-contraction coupling process. Finally, the sarcolemma allows regulation of excitation, contraction, and intracellular metabolism in response to neuronal and chemical stimulation. Each of these functions will be considered, with emphasis upon those features of the cardiac sarcolemma that differ from the plasmalemma of other cells.


A phospholipid bilayer 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, like a film of oil on the surface of water, 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 mechanisms (channels) for transport.14

View larger version (59K):
[in this window]
[in a new window]
FIGURE 3-1 The sarcolemma is a phospholipid bilayer in which molecules of phospholipids and cholesterol are aligned with both hydrophobic domains of molecules on the interior of the membrane and hydrophilic portions of molecules on the outside. Membrane-spanning proteins are located in this bilayer. The protein shown here is similar to many ion channels, with six hydrophobic alpha-helices spanning the membrane and surrounding a central channel.

The specialized ion transport systems within the sarcolemma consist of membrane-spanning proteins that float in and penetrate through the lipid bilayer, with a helical hydrophobic segment spanning the membrane and hydrophilic segments on the outside and inside of the membrane. These proteins, many of which have now been isolated and sequenced, 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 or chemical (ligand) stimuli; (2) exchange (antiport) of one ion for another with binding of these ions to portions of the transmembrane protein for exchange in response to an electrochemical gradient; and (3) active (energy-dependent) transport of ions against an electrochemical gradient.

In addition to the proteins that facilitate ion movement, other proteins are located in the sarcolemma that serve as receptors for neuronal or chemical control of cellular processes. Familiar examples of this type of protein are beta-adrenergic receptors and muscarinic acetylcholine receptors.


The protein components of many different ion channels have remarkably similar amino acid sequences, indicating a common evolutionary heritage. Most of the voltage-gated channels consist of tetrameters of four subunits that surround the water-filled pore through which ions cross the membrane. Each subunit has six membrane-spanning alpha helices. A schematic diagram of an ion channel is shown in Figure 3-2. Each channel contains a selectivity filter that selectively allows the passage of particular ions based upon pore size and electrical charge, and an activation gate that is regulated by conformational changes induced by either a voltage-sensitive or a ligand-binding region of the protein. Many channels also have an inactivation gate that is again either voltage or ligand controlled. The function of this gate will be considered in the following discussion of sodium channels.2,3,5

View larger version (32K):
[in this window]
[in a new window]
FIGURE 3-2 A sodium ion channel is schematically depicted in this figure. The shaded region within the narrow portion of the pore is the selectivity filter. A represents the activation gate, and I represents the inactivation gate. In the resting state, the inactivation gate is open and the activation gate is closed. As the transmembrane potential rises from 80 to 60 mV, the activation gate opens, leading to the open state that allows the passage of sodium ions through the channel. Within a few milliseconds, the inactivation gate closes, leading to the inactivated state.

Voltage-gated sodium channels The voltage-gated sodium channel is prominent in most electrically excitable muscle and nerve cells. As will be discussed below, the energy-dependent sodium-potassium pump generates a large concentration gradient of sodium from 142 mEq/L outside the cell to 10 mEq/L inside the cell. In addition, the resting electrical membrane potential of -70 to -90 millivolts (mv) acts as a significant magnet drawing the positively charged sodium ion inward. There is, therefore, both a powerful concentration gradient and a strong electrical force favoring the influx of Na+ from the outside of the cell to the inside; by convention, the flow of a positive ion from outside to inside is termed an inward current. As electrical depolarization begins, the activation gate of the sodium channel opens as the resting potential rises to between -70 and -50 mv. As the activation gate opens, Na+ ions rapidly rush inward, thereby depolarizing the sarcolemmal membrane. The inactivation gate of the sodium channel begins to close at about the same voltage, but with a built-in time delay such that the sodium channel is open for only a few milliseconds. Because these channels open and close so quickly, they have been called fast channels. The sodium channel remains closed by the inactivation gate until the resting negative membrane potential of -70 to -90 mv is restored. In cardiac cells, the repolarization phase is delayed by the plateau of the action potential.68

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

A second major calcium channel, the slow channel, is especially important in cardiac muscle, since it leads to an inward (depolarizing) current that is slowly inactivated and therefore prolonged. After the initial depolarization phase of the membrane during the action potential, these slow, L (long-lasting) channels open at a less negative potential (-30 to -20 mv), and are inactivated slowly, thereby contributing an inward calcium current (Fig. 3-3) that sustains the action potential and provides a pulse of cytosolic calcium that also acts as a trigger of the excitation-contraction sequence. The activity of this channel is altered by catecholamine stimulation. Beta-receptor stimulation activates a G-protein that, in turn, stimulates a cyclic AMPdependent protein kinase to phosphorylate a portion of this L-calcium channel.

View larger version (17K):
[in this window]
[in a new window]
FIGURE 3-3 A typical ventricular myocyte action potential and the ion currents contributing to it are schematically represented. Inward (depolarizing) currents are depicted as positive, and outward (repolarizing) currents are depicted as negative. The horizontal filled bars show the state of the gate of the ion channel (white = open; black = closed; shaded = partially open). In the case of the sodium channel, both the activation and inactivation gates are shown (i = current; Na = sodium; Ca = calcium; K = potassium).

Conformational changes occur that cause an increased influx of calcium ions, an increased calcium accumulation, and an associated increase in the strength of sarcomere contraction.

These effects can be attenuated by inhibitory G-proteins, which are activated by stimulation of acetylcholine and adenosine receptors. The sarcolemmal L-calcium channels are voltage-gated, but, by the receptor system, they are prominently regulated by the neurohumoral control system.9,10

Potassium channels Cardiac cells contain a variety of potassium channels, both voltage-regulated and ligand-gated. Three of these voltage-regulated potassium channels are important in the repolarization of the cell membrane.11,12

The potassium channel primarily responsible for the bulk of the potassium permeability of the sarcolemma is that channel associated with the first potassium current, or iK1. This channel is open at negative membrane potentials and tends to close at positive membrane potentials; in fact, this channel tends to favor inward K+ flow. With time, the channel reopens, strongly favoring repolarization at the end of the plateau (phase 2) of the action potential.

A second potassium channel is closed by negative membrane potentials. As the sarcolemma depolarizes, this channel opens in a delayed manner, leading to an outward current at the end of the plateau of the action (phase 2) potential, which helps to repolarize the membrane. This current is called iK or the delayed rectifier current. This channel is highly regulated, and signal transduction molecules such as cyclic AMP, protein kinase C, and protein kinase A increase this current.13

A third voltage-regulated potassium channel opens briefly with depolarization, allowing a transient outward current, ito, which contributes to very early repolarization of the action potential, thereby helping to create the hyperpolarized spike of the Purkinje fiber action potential.

Several ligand-gated potassium channels have been identified. Acetylcholine-activated 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 (KATP 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.


Sodium-potassium ATP-dependent pump The sodium-potassium pump utilizes the energy obtained from the hydrolysis of ATP to move three Na+ ions out of the cell and two K+ ions into the cell. This process is fueled by the energy provided by the hydrolysis of ATP to ADP and inorganic phosphate. The energy is expended in moving both Na+ and K+ against a concentration gradient. Because there is a net outward current (three Na+ ions for two K+ ions), the pump is electrogenic, and contributes about 10 mV to the resting membrane potential. The activity of the pump is strongly stimulated by attachment of Na+ to the Na+ binding site on the inside of the membrane; activity of the pump increases proportionately to the third power of the cytosolic sodium concentration).1 The Na-K ATPase pump has a very high affinity for ATP, so that the pump continues to function even if ATP levels are moderately reduced. There is, however, a second regulatory ATP binding site on the sodium pump with a lower affinity for ATP, which accelerates the turnover of ions when ATP is bound. This regulatory site on the Na+ -K+ ATPase pump will decrease the activity of the pump during modest reductions in intracellular ATP levels.3,14

ATP-dependent calcium pump A second energy-dependent pump is important in regulating the calcium level of the cytosol. This pump functions by binding ATP and calcium, hydrolyzing the ATP, and utilizing the consequent energy to transport 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 since the bulk of calcium transferred out of the cell occurs with sodium-calcium exchange (described below). The c-terminal portion of the protein that makes up the sarcolemmal calcium pump inhibits the pump by interacting with the ATP- and calcium-binding sites of the protein. A cytosolic protein, calmodulin, can complex with calcium and bind to this c-terminal domain, facilitating the action of the pump. The pump is therefore stimulated by increased calcium levels within the cytosol, which teleologically contributes to calcium homeostasis.3,15,16

Sodium-calcium exchange Yet another complex protein bridges the sarcolemma and facilitates an exchange of sodium ions for calcium ions. The energy used for this exchange comes from the electrochemical gradient favoring the influx of sodium ions into the cell. In the "forward direction," three extracellular sodium ions are exchanged for one intracellular calcium ion, leading to a net single positive charge transported into the cell with each exchange. The exchange is therefore electrogenic and may contribute a few millivolts to the resting membrane potential. The exchange system is sensitive to the concentration of sodium and calcium on both sides of the membrane, and to the membrane potential. Indeed, when the membrane is depolarized the pump may be temporarily reversed, pumping small amounts of calcium into the cell. 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). This explains an observation made some years ago that hyponatremia can lead to an increase in cardiac contractility. As another example, if the intracellular sodium concentration increases, as occurs with ischemia, the gradient for sodium influx is reduced, and the pump slows down or actually reverses, extruding sodium in exchange for an influx (and accumulation) of calcium. This mechanism has been suggested to be central to the accumulation of calcium during ischemia. The sodium-calcium exchange mechanism has a maximum exchange rate that is some 30 times higher than the sarcolemmal ATP-dependent calcium pump described above and is likely the primary mechanism for removal of excess cytosolic calcium.10

Sodium-hydrogen exchange The sodium-hydrogen exchange pump located in the sarcolemma normally (in the forward direction) extrudes one intracellular hydrogen ion in exchange for one extracellular sodium ion, and is therefore electroneutral. The energy to drive this exchange comes from the electrochemical gradient favoring sodium influx. This mechanism has been implicated in the maintenance of neutral intracellular pH. During ischemia, the intracellular accumulation of hydrogen ions essentially reverses the direction of the pump, thereby buffering the degree of intracellular acidosis, but at the expense of accumulating high concentrations of sodium ions. The accumulation of sodium ions may then trigger reversal of the sodium-calcium exchange pump to favor the accumulation of calcium intracellularly. This is a purported mechanism underlying injury or cell death during ischemia-reperfusion.

T-tubules and the Sarcoplasmic Reticulum


A system of transverse tubules (t-tubules) extends the sarcolemma into the interior of the cardiac cell. These tubules are generally perpendicular to the sarcomere at the level of the z-lines. The t-tubules may also run longitudinally along the sarcomere. By extending the extracellular space into the cell, the electrical excitation of the sarcolemma can be brought very close to the contractile proteins, enabling more rapid contraction and relaxation of these contractile elements than would be the case if diffusion of a transmitting chemical were the method for delivery of the contraction signal into the center of the cell. The transverse tubules contain the calcium channels described above, which are in close relationship to the foot proteins of the subsarcolemmal cisternae.


The bulk of the sarcoplasmic reticulum (SR) in the cardiac cell contains only small amounts of RNA and is not concerned with protein synthesis. Its primary function 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 concerned with this process. The subsarcolemmal cisternae are beneath the sarcolemma and surround the t-tubules. Specialized bulky proteins are found in the membrane of the sarcoplasmic reticulum with a large protein component extending into the gap between the subsarcolemmal cisternae and the sarcolemma or the t-tubule. These foot proteins respond to the release of calcium by the sarcolemma (or t-tubule) by rapid opening of a calcium channel (actually a part of the foot protein), which allows release of a much larger quantity of calcium from the subsarcolemmal cisternae. This is "calcium-triggered" calcium release with calcium transported across the sarcolemma leading to calcium release from the subsarcolemmal cisternae. The magnitude of calcium release from the subsarcolemmal cisternae appears to be related to the magnitude of the trigger. The calcium channels appear then to close (perhaps in response to the high concentrations of cytosolic calcium), and calcium uptake can occur by the energy-dependent calcium pump of the sarcoplasmic reticulum, which is located primarily in the sarcotubular network.2,3,16


The portion of the smooth sarcoplasmic reticulum that is responsible for the uptake of calcium from the cytosol is called the sarcotubular network. This network of tubules surrounds the contractile elements of the sarcomere, while the t-tubules and the sarcolemma cisternae are at the level of the z-line. Calcium uptake is accomplished by a high density of ATP-dependent calcium pumps. A large number of these pumps are necessary because calcium ion movement through the pumps is much slower than it is through calcium channels. Calcium concentration in the extracellular fluid or in the sarcoplasmic reticulum is in the millimolar level, whereas cytosolic calcium concentration is about 0.2 micromolar. This huge downhill gradient has been estimated to lead to a calcium channel flow of 3 million ions per second through a single channel. The calcium pump, on the other hand, has been estimated to pump 30 ions per second. It has been estimated that each cardiac cell contains approximately 3000 sarcolemmal calcium channels, 12,000 sarcoplasmic reticulum calcium-release channels, and 150 million sarcoplasmic reticulum calcium pump sites. The pumps appear to work throughout the cardiac cycle but their ability to remove calcium is obviously overwhelmed during the short period of time that the calcium channels are opened by depolarization.3

Regulation of calcium transport by the cardiac sarcoplasmic reticulum occurs primarily at the site of the calcium pump. The sarcolemmal calcium pump has a c-terminal portion that inhibits the ATPase- and calcium-binding sites of that protein, as described earlier. This c-terminal portion is not present on the sarcoplasmic reticulum calcium pump; instead, a protein called phospholamban in the cytosol has an amino acid sequence very similar to the c-terminal portion of the sarcolemmal calcium pump. Phospholamban inhibits the basal rate of calcium transport by the cardiac sarcoplasmic reticulum calcium pump. This inhibition can be reversed when phospholamban is phosphorylated by a cyclic AMPdependent or a calcium-calmodulindependent protein kinase. This effect appears to be a very important mechanism by which beta-adrenergic stimulation regulates the heart; increased levels of cytosolic cyclic AMP are a consequence of activation of the beta catecholamine receptor. As phospholamban is phosphorylated, there is accelerated calcium turnover and increased sensitivity of the calcium pump, which facilitates uptake of calcium from the cytosol and relaxation of the heart when the heart comes under the influence of beta-adrenergic agonists. It should be noted that 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.10,16

Electrical Activation of the Heart


The cardiac cell, in its polarized (diastolic) state, has a resting electrical transmembrane potential across the sarcolemma that is determined primarily by the concentration gradient of potassium across the membrane (developed by the sodium-potassium pump described earlier). Since the sarcolemma prevents the diffusion of large anions (e.g., proteins and organic phosphates) and is relatively permeable at rest to potassium ions because of the open state of most potassium channels but less permeable to sodium, potassium ions flow across the membrane in response to the concentration gradient. This leads to an outward flow of positive ions until a 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. For potassium ions, this electronegativity is quantified by the Nernst equation: Em = 61.5 log (Ko/Ki). With approximate K+ concentrations inside and outside the cell of 100 mM and 4 mM, respectively, the resting transmembrane potential of cardiac cells is predicted to be -86 mV, which is very close to measured values, suggesting that the transmembrane gradient at rest is largely a potassium current.1,2


A typical ventricular action potential is depicted in Figure 3-3. An electric current traveling longitudinally along the membrane from another cell, such as an upstream pacemaker cell, depolarizes the membrane. As the transmembrane potential decreases to approximately -60 millivolts, the "fast" sodium channel opens. This channel remains open for only a few milliseconds before the inactivation gate of the sodium channel closes. This inward movement of sodium ions causes the rapid spike of the action potential (phase 0); the rapid depolarization completely depolarizes the cell and, in fact, the transmembrane potential becomes slightly positive due to the positively charged amino acids on proteins. 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 current begins to close also, and the repolarizing potassium current (ik, the delayed rectifier current) leads to the initiation of phase 4 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 myocardial tissue (i.e., myocytes). Because the sodium channels cannot respond to a second wave of depolarization until the inactivation gates are reopened, 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 be propagated, which is termed the relative refractory period. A drug that acts to speed up the kinetics of the inactivation gate will shorten both the absolute and the relative refractory periods.13,1719


The action potential of the slow fibers of the nodal tissue (sinoatrial node, or SA node, and atrioventricular node, or AV node) differs from that in the fast fibers of the ventricular myocytes, as shown in Figure 3-4. The rapid upstroke and overshoot of phase 0 are less prominent or even absent due to a lack of fast Na+ channels. In addition, the plateau phase is abbreviated because of the lack of a sustained active Na+ inward current, and the lack of a sustained calcium current. Third, the repolarization phase leads to a resting phase that begins to depolarize again, as opposed to the relatively stable resting membrane potential of ventricular 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 underlying the property of automaticity in cardiac pacemaker cells. Diastolic depolarization is due to the concerted and net actions of (1) a decrease in the outward K+ current during early diastole (phase 4), (2) persistence of the slow inward Ca2 + current, and (3) an increasing inward Na+ current over time during diastole. The third 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 hence is a primary mechanism determining heart rate. The slope of the diastolic potential is greatest (faster rate of depolarization) in the SA node, and hence action potentials are generated at a faster rate of 70 to 80 per minute, followed by the AV node with a slightly slower rate of depolarization, and a frequency of action potential generation of 40 to 60 times per minute. The ventricular myocytes have the slowest rate of diastolic depolarization, with a frequency of 30 to 40 times per minute. Once a depolarization is initiated in a pacemaker cell and propagated, it will depolarize the remainder of the heart in a synchronized and well-choreographed manner. Hence, there is a hierarchy of pacemaker activity: the primary site in the SA node generates a heart rate of 70 to 80 beats per minute; the secondary pacemaker is a slower pacemaker site (40 to 60 per minute); and the ventricular myocytes generate 30 to 40 heart beats per minute. If a pacemaker site drops out due to pathology or drug-induced slowing of the diastolic potential, the next pacemaker site in line will take over, with a heart rate typical for that site. The slope of the diastolic depolarization, and hence heart rate, is decreased by acetylcholine (parasympathetic action); hyperpolarization (more negative resting potential) or raising the threshold potential will also increase the time to reach threshold and initiate another pacemaker signal, resulting in a decrease in heart rate. Beta-adrenergic agonists such as epinephrine and norepinephrine will accelerate the rate of depolarization, which will then increase heart rate.

View larger version (20K):
[in this window]
[in a new window]
FIGURE 3-4 The membrane potential of a spontaneously depolarizing cell of the SA node, and the ion currents contributing to it. Inward (depolarizing) currents are depicted as positive, and outward (repolarizing) currents are depicted as negative (i = current; Na = sodium; Ca = calcium; K = potassium).


Each myocyte is electrically connected to the next myocyte by an intercalated disc at the end of the cell. These discs contain gap junctions that allow free permeability of charged molecules from one cell to the next. These pores in the intercalated discs are composed of a protein, connexin. Permeability through the cardiac gap junction is increased by both ATP- and cyclic AMPdependent 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 AV node, the action potential is conducted throughout the heart. Special electrical pathways facilitate this conduction. These cells are, in general, large cells that lead to rapid conduction of the action potential. Three internodal paths exist through the atrium between the sinoatrial node and the atrioventricular 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 of 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 (i.e., sequential atrioventricular contraction). Slow conduction in the AV node is related to a relatively higher internal resistance because of a small number of gap junctions between cells, and to slowly rising action potentials. In parts of the AV node, functional fast sodium channels are absent and depolarization is dependent upon the "slow" calcium channels.2,3 The nodal delay allows the atrium to pump an aliquot of blood (up to 10% of left ventricular volume) into the ventricle just prior to ventricular contraction, thereby optimizing preload of the ventricle. The atrial contraction is shown as the "a" wave, also known as the "atrial kick," on a ventricular pressure tracing.


Aberrant pacemaker foci One innocuous type of abnormal cardiac rhythm that frequently occurs is the origin of extra-cardiac beats from abnormal aberrant pacemaker foci. Spontaneously depolarizing areas occur in the heart in the SA node, the AV node, and the His-Purkinje system. Ordinarily, 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 (e.g., acetylcholine), pacemakers in the AV node or the His-Purkinje system may take over. Occasionally, aberrant foci in the heart spontaneously depolarize, thereby leading to the insertion of aberrant beats from either the atrium or the ventricle. These beats ordinarily do not interfere with the normal depolarization of the heart and have a very little tendency to degenerate into disorganized electrical activity. Therefore, these beats are generally not clinically threatening.

Reentry arrhythmias, unidirectional block A second type of cardiac rhythm, reentry arrhythmias are perhaps the most common dangerous cardiac rhythm. This type of rhythm is caused by propagation of an action potential through the heart in a "circus" movement. In ordinary circumstances, 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. However, 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. 3-5). All of these situations occur clinically. Ischemia leads to slowing of the sodium-potassium pump by the ATP-dependent regulation system described above, which leads to a decreased resting membrane potential and slowing of the propagation of the action potential. Hyperkalemia similarly leads to an increase in the extracellular potassium level, a decrease in the resting membrane potential, and a slowing of the propagation of the action potential. Progressive atrial dilation, as occurs with mitral valve disease, leads to a long conduction pathway around the atrium that can ultimately lead to the development of a reentry or "circus" movement in the atrium. Adrenergic stimulation leads to a shortened refractory period (by mechanisms described below), which increases the likelihood of a reentry arrhythmia. It should be noted that most reentry circuits require unidirectional propagation of the action potential along the reentry pathway. The conditions for unidirectional propagation are often created by ischemia or by myocardial damage.3

View larger version (24K):
[in this window]
[in a new window]
FIGURE 3-5 Three conditions predisposing to reentry or "circus" pathways for action potential propagation are shown. Muscle that is refractory to action potential propagation is shown as black. Normally, as the action potential travels through the atrium or ventricle, all the muscle is depolarized sufficiently that the action potential encounters no more nonrefractory muscle and stops (A). If there is slowed conduction speed or a long pathway (B), the action potential may find repolarized (nonrefractory) muscle and continue in a circular path. Similarly, a shortened refractory period (C) may lead to rapid repolarization and predispose to a reentry continuation of the action potential.

A special type of reentry arrhythmia occurs in the 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, which meets the conditions described in the preceding paragraph for a reentry arrhythmia: conduction is unidirectional across the AV node because of the special properties of the AV node, and conduction is thereby delayed. The aberrant pathway allows retrograde induction from the ventricle back to the atrium, completing the circle necessary for the reentry circuit. We therefore have a circular pathway with unidirectional, delayed conduction. The accessory pathway of the Wolff-Parkinson-White syndrome is dangerous in another way. Because it 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, which is a potentially lethal situation in a patient with atrial fibrillation and an accessory pathway.

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

Antiarrhythmic agents, proarrhythmic agents Antiarrhythmic agents generally act on the two major factors causing arrhythmias, e.g., automaticity and reentry. There are four classes of antiarrhythmic agents.

Class I agents are sodium channel blockers. Class IA agents (quinidine, procainamide) inhibit "open" sodium channels, as opposed to class IB agents, which inhibit inactive or closed sodium channels, leading to a slowing of conduction in the heart. The class IA agents have additional effects, perhaps upon the inactivation gate of the sodium channel, that prolong the action potential and thereby increase the refractory period. Class IB agents such as lidocaine and diphenylhydantoin moderately inhibit sodium channels and may shorten the refractory interval. These agents are particularly effective in inhibiting the opening of sodium channels in relatively depolarized cells so that they are especially effective in decreasing spontaneous depolarization (or automaticity), and they are useful when the myocardium is ischemic with many depolarized myocytes. Class IC agents markedly inhibit sodium channel opening, decrease the velocity of the action potential upstroke, and mildly prolong the refractory period. These agents delay conduction and prevent automaticity.

Class II antiarrhythmic drugs are drugs that cause beta-adrenergic blockade. These drugs inhibit adrenergic stimulation of calcium channel opening by competitively inhibiting the effect of beta-adrenergic agonists, which are discussed below.

Class III antiarrhythmic agents prolong the cardiac action potential. This appears to be primarily an inhibitory effect upon the repolarizing potassium current leading to an increased refractory period without a reduced conduction velocity. Examples of these drugs are amiodarone, bretylium, and sotalol. These agents have a low arrhythmogenic potential.

Class IV agents are calcium channel blockers. These drugs are especially important in decreasing the rate of conduction through the AV node. Many antiarrhythmic drugs have a paradoxical proarrhythmic effect. As discussed above, many drugs, particularly the class IA and IC drugs, lead to a decrease in conduction velocity. As illustrated in Figure 3-5, a decrease in conduction velocity increases the likelihood of a reentry arrhythmia. If the refractory period is prolonged, as is the case with class IA drugs, then the tendency of the more rapid conduction may be counterbalanced by a longer refractory period, and reentry arrhythmias may not occur. If, on the other hand, as is the case with the class IC drugs, the conduction velocity is slowed and the refractory period is not sufficiently prolonged, reentry arrhythmias become more likely. Class IC drugs have been shown to have a great clinical risk in prolonged prophylactic use, presumably because of their proarrhythmic effect.20

Regulation of Cellular Function by Sarcolemmal Receptors


The parasympathetic nervous system is particularly important in control of the pacemaker cells of the SA node. Acetylcholine released by the nerve endings of the parasympathetic system stimulates muscarinic receptors in the heart. These activated receptors, in turn, produce an intracellular stimulatory G-protein that opens acetylcholine gated potassium channels. An increased outward (repolarizing) flow of potassium leads to hyperpolarization of the SA node cells. Stimulation of the muscarinic receptors also inhibits the formation of cyclic AMP; decreased cyclic AMP levels inhibit the opening of calcium channels. A decreased inward flow of calcium, combined with an increased outward flow of potassium, leads to a sometimes dramatic slowing of the spontaneous diastolic depolarization of the sinoatrial nodal cell (see Fig. 3-4). A similar effect in the AV node leads to slowing of conduction through the AV node by the hyperpolarization of cells and inhibition of the slow calcium channel.2


Among the most important sarcolemmal receptors are the beta-adrenergic receptors. 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 the lungs and the liver. In the human, approximately 15% of the beta receptors in the ventricles are beta2 receptors, but a larger portion of beta2 receptors are present in the atrium. Cardioselective beta blockers (metoprolol, atenolol, acebutolol) act predominantly on the heart because there are bound more tightly to beta1 receptors than to beta2 receptors. The number of beta receptors per unit area of the sarcolemma is not fixed, but can increase or decrease in various circumstances. These changes are called upregulation or downregulation of receptor density, respectively. Beta receptors are downregulated after cardiopulmonary bypass and ischemia. Beta receptors can be internalized during cardiopulmonary bypass, which leads to an attenuated beta-adrenergic response by decreased receptor density. In addition to changes in receptor density, the receptors can be desensitized or "internalized" by chemical changes such that, although the receptors are still present, they are not as available for signal transmission.21 Acidemia is associated with a desensitization of beta receptors.

The beta-adrenergic receptor couples with adenyl cyclase, another sarcolemmal protein. As diagrammed in Figure 3-6, when the receptor site is occupied by a catecholamine, a stimulatory G-protein is formed, which combines with GTP. This activated G-proteinGTP complex then promotes the activity of adenyl cyclase, leading to the formation of cyclic AMP from ATP. Cyclic AMP has classically been described as the "second messenger" of the beta-adrenergic receptor system, but one should probably consider the stimulatory G-protein to be the second messenger and cyclic AMP to be the third messenger. The stimulatory G-protein directly stimulates calcium channel opening. The third messenger, increased cyclic AMP, also actively promotes calcium channel opening. As described earlier in the discussion of the sarcoplasmic reticulum calcium channels, cyclic AMP and increased cytosolic calcium lead to phospholamban activation, which then leads to increased calcium uptake by the sarcoplasmic reticulum.

View larger version (28K):
[in this window]
[in a new window]
FIGURE 3-6 Adrenergic stimulation via the action of beta agonists on beta receptors leads to a cascade of events in the myocyte, some of which are shown here. Note that an increase in cyclic adenosine monophosphate (cAMP) causes the activation of two inhibitory pathways, retarding excessively sustained adrenergic stimulation (Gs = stimulatory G-protein; GTP = guanosine triphosphate; SR = sarcoplasmic reticulum).

The increased tendency for calcium channels to open during beta-receptor stimulation leads to a number of electrophysiologic effects associated with these drugs. There is accelerated discharge rate of the SA node and other spontaneously depolarizing areas of the heart. There is accelerated conduction through the AV node, an area of the heart in which depolarization is particularly dependent upon calcium channels. The increased cytosolic levels of calcium lead to a positive inotropic effect by mechanisms to be discussed later in the chapter. The increased activity of the sarcoplasmic reticulum calcium pump stimulated by phospholamban leads to a more rapid removal of calcium from the cytoplasm at the termination of systole, thereby leading to a more rapid relaxation of the cell. Therefore, beta-adrenergic receptor stimulation leads to a positive inotropic effect, a positive lusitropic (relaxation) effect, a positive chronotropic (heart rate) effect, and a positive dromotropic (conduction velocity) effect. These effects are mediated by a series of messengers, the stimulatory G-protein, cyclic AMP, phospholamban, and increased cytosolic calcium levels.22,23

Also shown in Figure 3-6 are two negative feedback systems that contribute to the diminished response (tachyphylaxis) observed when beta-agonist stimulation is repetitive or persistent. Increased cyclic AMP leads to increased phosphorylation of beta receptors which, in turn, leads to internalization of the receptor (or downregulation). Increased levels of cyclic AMP lead to increased activity of phosphodiesterase, the enzyme that degrades cyclic AMP.

A new class of inotropic drugs, phosphodiestrase inhibitors (amrinone, milrinone) inhibit the breakdown of cyclic AMP and thereby increase its level in the cytosol. Because of the site of action of the phosphodiestrase inhibitors, their effect is generally additive with that of beta agonists. Also, since they do not stimulate the production of the stimulatory G-protein (Gs) depicted in Figure 3-6, they have a lesser effect on calcium channel activation, and therefore have less of the troublesome positive chronotropic and dromotropic effect of beta-adrenergic stimulation.23,24

Cyclic AMP appears to play a central role in the regulation of the cardiac cell. Cytosolic levels of cyclic AMP are increased by activation of receptors other than beta receptors (i.e., for histamine, dopamine, glucagon), and are decreased by inhibitory G-proteins produced by stimulation of muscarinic receptors by acetylcholine and by stimulation of adenosine receptors.

Beta-blocking drugs compete with beta agonists for binding sites on the beta-adrenergic receptor, thereby preventing activation of the receptor. They cause, therefore, according to the scheme shown in Figure 3-6, a negative chronotropic effect, a negative inotropic effect, and a negative lusitropic effect. These drugs are particularly useful in pathologic conditions in which excessive adrenergic stimulation might cause ischemia by an undesirable increase in oxygen consumption. By decreasing cyclic AMP levels (and by other mechanisms) beta blockers lead to resensitization of beta receptors in the sarcolemma. If beta-receptor blockers are suddenly stopped, a resensitization occurs, which has led to an increased density of active beta receptors on the cell membrane. This may cause a temporarily enhanced (and potentially dangerous) sensitivity to adrenergic stimulation.


Adenosine is an especially useful drug in treating rapid supraventricular tachycardias. The vast majority of adenosine's physiological effects are exerted by interactions with sarcolemmal receptors. There are four types of adenosine receptors. The A1 receptors are located on cardiomyocytes, and inhibit adenyl cyclase activity via an inhibitory G-protein (Go, Gi). Activation of adenosine A1 receptors leads to inhibition of the slow calcium channel and opening of an adenosine-activated ATP-sensitive potassium (KATP) channel. This leads to hyperpolarization in pacemaker cells, slowing spontaneous depolarization and depressed depolarization in nodal cells (remember that calcium channels are generally responsible for depolarization in these cells rather than sodium channels), and leading to delayed conduction through the AV node and a slowed ventricular response to atrial tachycardia.2,25 Adenosine has also been used as an arresting agent in cardioplegia solutions, based on its hyperpolarizing effects, with varying degrees of success.26,27


Cardiac glycosides (oubain, digitoxin, digoxin) act, not through a separate receptor protein, but by binding to and inhibiting the ATP-dependent sodium-potassium pump. Inhibition of the pump leads to a slightly increased intracellular concentration of sodium. By the mechanism discussed earlier when considering the sodium-calcium exchange system, the driving force for calcium removal from the cell (the sodium gradient across the sarcolemma) is decreased, and the increased intracellular sodium concentration leads to less calcium binding to the intracellular portion of the sodium-calcium exchange protein. These two effects decrease the extrusion of calcium from the cell, which, in turn, leads to an increased strength of myocardial contraction, as will be discussed later. Because increased extracellular levels of potassium may stimulate the sodium-potassium pump, hyperkalemia tends to reverse the effects of digitalis toxicity, while hypokalemia tends to amplify these effects.2,3,22


Calcium channel blockers bind to the membrane-spanning protein of the L-type calcium channel. There are three chief categories of these drugs, represented by nifedipine, verapamil, and diltiazem. Each category appears to bind in a different site on the calcium channel protein, leading, to different effects upon these voltage-gated and time-dependent channels. Diltiazem and verapamil are particularly useful in slowing AV conduction, thereby decreasing the ventricular response to atrial tachycardias, because AV nodal depolarization is primarily dependent upon a calcium current in the general absence of functional sodium channels.2

The Contractile Element (Sarcomere)

The myocyte is made up of a number of myofibrils. Each myofibril is made up of a number of sarcomeres connected end-to-end by dense attachments between sarcomeres at the Z-band (the insertion site of the actin filament), which are in turn bundled to form myocytes. A portion of a sarcomere is schematically depicted in Figure 3-7. The sarcomere is considered to be the functional unit of the heart since the entire process of contraction and relaxation occurs within each sarcomeric unit. Each sarcomere is made up of several proteins that are important in generating cardiac contraction, or in regulating contraction. One of the major contractile proteins is myosin, found in the "thick filament" of the sarcomere, shown in Figure 3-7A. Myosin consists of a tail of two "heavy" chains intertwined to form a helix, forming in turn a rigid backbone of the thick filament to which a globular head is attached. The globular head of myosin is attached to the heavy chain backbone by a mobile hinge. Two pairs of light chains are associated with the hinged portion of the myosin molecule. In the sarcomere, the heavy myosin tails are connected to each other tail-to-tail, with the globular heads projecting outward. The globular head of myosin has two important biological functions. First, it binds and hydrolyzes the high-energy phosphate ATP by virtue of its ATPase activity. The resultant release of energy fuels contraction. Second, myosin has a binding site for actin, a process that is necessary for contraction to take place. Actin is the protein found in the "thin filament" of the sarcomere (Fig. 3-7A). It is a globular monomeric protein (G-actin) that is polymerized into filaments (F-actin); two filaments intertwine to form a double-stranded helix with a groove running the length of the filament. Actin has two important biological functions: (1) it binds to the myosin globular head to form the actomyosin complex; and (2) it activates the myosin ATPase to hydrolyze ATP to ADP and Pi.

View larger version (27K):
[in this window]
[in a new window]
FIGURE 3-7 The interaction of actin and myosin filaments converts chemical energy into mechanical movement. In diastole, the active sites on the actin filament are covered by tropomyosin. When calcium combines with troponin, the tropomyosin is pulled away from the actin active sites, allowing the energized myosin heads (depicted in solid black and cocked at right angles to the filament) to engage and sweep the actin filament along. The myosin heads are deenergized in this process. Myosin ATPase recocks (reenergizes) the head by utilizing the energy derived from the hydrolysis of ATP. In systole, a deenergizing head (C), a deenergized head (B), and a reenergizing head (A) are shown.

In addition to the major contractile proteins actin and myosin, there are two regulatory proteins that modulate the activity of actin and myosin during the molecular process of contraction. Tropomyosin is a filamentous protein composed of two tightly coiled helical peptide chains; the helical coil of tropomyosin lays in the groove formed by the two intertwined filaments of actin. Tropomyosin binds another complex of regulatory proteins, called troponin ("T" in Figure 3-7A). The troponin complex consists of three units. Troponin I is the inhibitory component that covers the binding site on actin and prevents interaction with myosin and formation of the actomyosin cross-bridge. Troponin T is primarily a structural component that anchors the 3-unit troponin complex to tropomyosin. The binding of calcium to troponin C removes the troponin Iinduced masking of the myosin binding site on actin, thereby allowing cross-bridge formation between actin and myosin.

During diastole, troponin C remains unbound to Ca2 +, and the myosin binding site on actin is inhibited from interacting with myosin. Depolarization of the sarcolemmal membrane and the t-tubule extensions of this membrane into the middle of the myocyte leads to influx of calcium ions via the sarcolemmal L-type calcium channels. This influx occurs in close proximity to the foot protein. These foot proteins are a portion of the subsarcolemmal cisternae in which a large quantity of intracellular calcium is concentrated. The increased intracellular pool of Ca2 + may also be contributed by the electrogenic sodium-calcium exchanger, which exchanges intracellular sodium for extracellular Ca2+ in a 3 Na+:1 Ca2 + stoichiometry. The T-type Ca2 + channel may make small contributions to the "triggering" Ca2 + pool. The intracellular accumulation of Ca2 + in the proximity of the sarcoplasmic reticulum stimulates a rapid and larger-scale release of calcium from the sarcoplasmic reticulum into the cytoplasm. This mechanism of Ca2+ release has a high gain, prompting a cyclic or regenerative release, associated with an abundant release of Ca2 + per stimulation. The influx of Ca2+ through the sarcolemmal L-type channels and the subsequent "calcium-induced calcium release" from the sarcoplasmic reticulum increases the intracellular Ca2+ calcium levels by approximately two orders of magnitude (from 10-7 M in diastole to 10-5 M in systole). This Ca2+ -induced Ca2+ release from the sarcoplasmic reticulum provides sufficient calcium to bind to troponin C which, in turn, triggers the contractile sequence: the binding of Ca2 + to troponin C causes a conformational change in the troponin molecule, which lifts the inhibitory effect of troponin I, thereby allowing the binding between actin and myosin to form the actomyosin cross-bridge (Fig. 3-7A). Formation of the cross-bridge activates the ATPase on myosin, which then hydrolyzes ATP to ADP and Pi. The hydrolysis products are released from the myosin binding site, prompting a move in the myosin "hinge" at the globular head. This movement of the myosin globular head ratchets the actin filament forward into a contraction, thereby moving the Z-lines closer together (Fig. 3-7B). At the end of the hinge movement, calcium is removed from troponin C, the inhibition of the myosin binding site is restored, and the actin and myosin disengage. ATP reassociates with the myosin head, which then cocks the myosin globular head at the hinge, making it ready for another contraction. This process then repeats itself until the end of muscular contraction is signaled, perhaps by the removal of intracellular calcium by active energy-requiring sequestration into the sarcoplasmic reticulum by action of SERCA2, the protein associated with the sarcoplasmic reticulum responsible for calcium uptake, and by other energy-dependent pump systems. According to this molecular scheme of muscle contraction, both the contraction (systole) phase and the relaxation (diastole) phase are ATP-requiring steps. The transduction of electrical depolarization into a mechanical contraction requires the presence of calcium, making calcium the excitation-contraction coupler.

The strength of the myocardial contraction appears to be mediated primarily by the degree of uncovering of the actin active sites as tropomyosin is pulled away from the active sites after calcium has bound to troponin. The magnitude of this effect is dependent upon the affinity of troponin for calcium and the availability of calcium ions, that is, the magnitude of the calcium influx and accumulation during systole. The magnitude of the initial calcium ion influx through the sarcolemmal calcium channels is altered by cyclic AMP levels, by stimulatory G-proteins from beta-adrenergic receptors, and by inhibitory G-proteins from adenosine and acetylcholine receptors. This change in the magnitude of the calcium trigger leads to a change of 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, as depicted in Figure 3-6. In addition to this mechanism, cyclic AMP can phosphorylate a portion of the troponin molecule, thereby facilitating the rapid release of calcium from troponin, and increasing the rate of relaxation of the actin-myosin complex.10,28

In addition to regulation of the strength of contraction by the primary mechanism of cytosolic calcium levels, the rate at which binding of ATP reenergizes the myosin heads can alter the speed and strength of the contraction. The rate of this reaction can be altered by phosphorylation of the myosin molecule during beta-adrenergic stimulation, leading to an increased rate of the myosin ATPase activity. Changes in the rate of cross-bridge cycling may also be caused by alterations in the myosin heavy chains, which is a consequence of the synthesis of various isoforms of myosin under regulation by gene expression.3,18

Regulation of the Strength of Contraction by Initial Sarcomere Length

In the heart, as in skeletal muscle, a relationship exists between resting sarcomere length and the strength of contraction. In skeletal muscle this relationship is bell-shaped, with maximum contraction occurring at a sarcomere length of approximately 2.2 micrometers. It has been proposed that force declines at a greater sarcomere length, because there is a decreased overlap of actin and myosin and thereby a decreased availability of actin-myosin cross-bridges. 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 micrometers. As the heart attempts to dilate beyond this state, a stiff parallel elastic element prevents further dilation. Even if chamber dilation does occur, there appears to be primarily slippage of fibers or myofibers rather than stretching of sarcomeres.2 The increase in contractility that is associated with stretching of the myocardium appears rather to be related to an increased sensitivity of the contractile elements to cytosolic calcium. A calcium influx during excitation-contraction coupling that will cause approximately 50% maximal tension if the initial sarcomere length is 1.95 micrometers will lead to more than 75% maximal tension if the initial sarcomere is 2.4 micrometers.2 This poorly understood but dramatically increased length-dependent sensitivity to calcium is an important part of the ascending limb of the Starling curve observed in the intact ventricle.


The heart is a pump whose primary purpose is the conversion of chemical to mechanical energy to the end that blood flow can distribute oxygen and nutrients according to metabolic needs, and wash out carbon dioxide and waste products. In the preceding sections, an understanding of the conversion of ATP to mechanical energy in the form of sarcomere contraction has been developed. The electrical mechanism by which the mechanical activity of the heart is synchronized has also been considered. In this section, we will attempt to describe the function of the heart as an organ, a syncytium of myocytes made up of sarcomeres that contract in near synchrony to deliver external work by ejecting a volume of blood from the right or left ventricular cavity against an aortic or pulmonary artery pressure. The following discussion will center upon the left ventricle.


Almost a century ago, two renowned physiologists (Frank and Starling) simultaneously developed the concept that, within physiologic limits, the heart will function as a sump pump. That is, the greater 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. This relationship for the left ventricle is depicted in Figure 3-8. In the normal heart, as ventricular filling is increased, the strength of ventricular contraction increases as sarcomeres are stretched. This axiom is related by unknown mechanisms to increased sensitivity to cytosolic calcium as described earlier. This sarcomere lengthdependent force of contraction is know as the Frank-Starling relationship. Also depicted in Figure 3-8 are two other states, a condition of normal adrenergic stimulation and a condition of maximal adrenergic stimulation. With sympathetic stimulation, the heart contracts more forcefully with every beat, termed a positive inotropic effect. Equally important, however, are the other stimulatory effects on chronotropic, dromotropic, and lusitropic states. The heart rate increases dramatically, conduction velocity increases, the action potential is shortened, and the velocity of contraction is increased, leading to a shortening of systole with sympathetic stimulation. An increased rate of relaxation (lusitropy) facilitates a greater rate of ventricular filling. This is particularly important with tachycardia. During pacing, the duration of systole remains relatively constant, while it is the duration of diastole that is abbreviated. If the length of systole remains at 300 milliseconds as the heart rate is increased, as it tends to do if the heart rate is increased by pacing, then when the heart rate reaches 120 with a cardiac cycle duration of 500 milli-seconds, the time available for the heart to relax and fill is shortened to only 200 milliseconds. This reduction in filling time will lead to a dynamic diastolic failure of the heart with backing up of blood in the systemic and pulmonary veins. With electrical pacing, a heart rate of between 100 and 150 beats per minute will achieve a maximal cardiac output. With sympathetic stimulation, however, the accompanying positive dromotropic and inotropic effects lead to a dramatic shortening of systole relative to diastole. Because of these effects, the optimal heart rate for maximal cardiac output during sympathetic stimulation is approximately 200 beats per minute (with a cardiac cycle length of only 300 milliseconds).1

View larger version (28K):
[in this window]
[in a new window]
FIGURE 3-8 Starling curves for the left ventricle. The influence of four different states of neurohumoral stimulation on global ventricular performance is shown.


The preload of the left ventricle describes the intracavitary pressure and volume immediately prior to contraction. From the clinician's point of view, preload has traditionally been considered to be the filling pressure. Since physiologists are more concerned with the degree of stretch of the sarcomere, preload to them generally means the initial volume of the ventricle. The relationship between the end-diastolic pressure and the end-diastolic volume is complex. Several different diastolic pressure-volume relationships are shown in Figure 3-9. As end-diastolic volume increases, and the heart stretches, the end-diastolic pressure also increases. The compliance, or distensibility of the ventricle, is defined as the change in volume divided by the change in pressure. Conversely, the stiffness of the ventricle is the reciprocal of compliance, or the change in pressure divided by the change in volume.

View larger version (29K):
[in this window]
[in a new window]
FIGURE 3-9 Left ventricular pressure-volume curves for various physiologic and pathologic conditions. The bold curved line at the bottom of each loop series represents the diastolic pressure-volume relationship. The straight line located on the upper left side of each loop series is the end-systolic pressure-volume relationship. The stroke volume for each curve has been arbitrarily set at 75 mL. Systolic aortic pressure is 115 mm Hg in all curves except B (increased afterload, systolic pressure 140 mm Hg) and H (reduced afterload, systolic pressure 90 mm Hg); LV = left ventricle; EF = ejection fraction; LVEDP = left ventricular end-diastolic pressure, in mm Hg.

A number of factors affect the diastolic pressure-volume relationship. A fibrotic heart, a hypertrophied heart, or an aging heart becomes increasingly stiff (Figs. 3-9C and 3-9E). 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, as described earlier, is an active, energy-requiring process. This process is accelerated by catecholamine stimulation, but is impaired by ischemia, by hypothyroidism, and by chronic congestive heart failure. Examination of the diastolic pressure-volume curves in Figure 3-9 allows one to appreciate the potential importance of these changes in static (end-diastolic) and dynamic (from mitral valve opening to beginning of systole) diastolic distensibility in pathologic cardiac conditions.29,30


The afterload of an isolated muscle is the tension against which it contracts. When considering the heart as an organ, the afterload of the left ventricle is generally considered to be the pressure developed during ventricular systole, which in turn is determined by the aortic pressure against which the ventricle must eject. The greater the afterload, the more mechanical energy that must be imparted to the ejected blood to bring it from atrial pressure to aortic pressure. In addition to the potential energy imparted to the ejected blood by a change in pressure, the contracting left ventricle generates an additional kinetic energy. This additional kinetic energy is utilized to overcome the compliance of the distensible aorta and systemic arterial tree in order to cause the actual flow of blood into the arterial system. The energy necessary for this flow to occur is ordinarily small unless there is some obstruction to flow, such as aortic stenosis. If one considers only the energy used to change the pressure of blood, one relates afterload to resistance, which equals the change in pressure divided by cardiac output. If one wishes to more accurately describe the forces resisting ejection of blood from the ventricle, then one must consider compliance, kinetic energy, and potential energy, and one must speak therefore of aortic impedance rather than resistance. This distinction becomes important if there is an impediment to aortic flow or if disease processes alter the compliance of the aortic/arterial system.


The function of the heart is to generate a cardiac output and pressure that are sufficient to adequately perfuse all tissues of the body under a very wide range of conditions ranging from total rest (sleep) to strenuous exercise. Accordingly, the function of the heart can be described and quantified in terms of the pressure and volumes generated, i.e., the pressure-volume relationship. As discussed below, the position of the loops on the volume axis, the stroke volume (together reflecting the ejection fraction), and the trajectory (slope and x-axis intercept) of the end-systolic pressure-volume point as preload or afterload are varied are used to describe the inotropic state and overall performance of the heart, independent of preload or afterload. The basic ventricular pressure-volume "loop" formed by the simultaneous development of pressure and volume in the left ventricle is shown in Figure 3-9A. The basis for the ventricular pressure-volume relationship is the force-length relationship between sarcomere length and peak developed force in cardiac muscle. The Frank-Starling mechanism regulating force and extent of contraction (stroke volume) as a function of end-diastolic length (volume) is consistent with the pressure-volume relationships of the heart. However, the latter perspective of cardiac function has distinct advantages over the Frank-Starling relationship, as will be discussed.

Referring to Figure 3-9A, the end-diastolic point is a conventional starting point to describe the trajectory of the pressure-volume loop. Blood pressure increases after electrical activation of the left ventricle, thereby closing the mitral valve, and intraventricular pressure is generated isovolumically without ejection of blood volume (isovolumic contraction in Fig. 3-9A). When left ventricular pressure exceeds that in the aorta, the aortic valve opens, and ejection of blood into the aorta is accompanied by a corresponding decrease in ventricular volume (ejection phase). At the end of systolic ejection, left ventricular pressure decreases rapidly, and pressure differential between ventricle and aorta closes the aortic valve, forming the dichrotic notch, or incisura, in the aortic pressure wave, which is used clinically to mark the end of systole. Relaxation proceeds first isovolumically, since the mitral and aortic valves are both closed, followed by rapid and then slower filling phases of the ventricular chamber after the mitral valve opens (diastolic filling phase). The most important points of the pressure-volume loop from which descriptive data are derived are the end-systolic pressure-volume (ESPV) point located in the upper left corner of the loop, and end-diastolic pressure-volume (EDPV) point located in the lower right corner of the loop. The area within the pressure-volume loop represents the internal work of the chamber, as opposed to the external work determined by the product of stroke volume and aortic pressure measured external to the heart. Pressure-volume loops may be visualized clinically with ventriculography during left heart catheterization, and with echocardiography. However, accurate representation, particularly of left ventricular pressure, requires that high-fidelity measurements be made to avoid artifacts found in simple fluid-filled systems.

The inotropic state (contractility) of the left ventricular chamber relates to the strength of contraction, expressed physiologically in terms of force, velocity, and extent of muscle shortening, and expressed clinically in terms of stroke volume, cardiac output, and end-diastolic pressure and volume. Unfortunately, contractility is influenced by so many different factors, including preload, afterload, and heart rate, that it is difficult to quantify in clinically useful terms. One might compare the attempt to quantify the contractility of the heart to quantifying the vitality of a society. One can easily say that contractility and vitality have improved or diminished, but quantification and describing how and why contractility and vitality have changed are elusive. However, the instantaneous pressure-volume relationship can be used to quantify contractility, or the inotropic state, of the left (and right) ventricle. Contractility can be described physiologically using the end-systolic pressure-volume relationship (ESPVR) by the slope (Ees) and volume axis intercept (V0) of the ESPVR (Fig. 3-10). A series of pressure-volume loops are inscribed during transient preload reduction induced by temporary caval occlusion, during which the loops move from right to left, or conversely during increased preload, during which the loops move from left to right. The end-systolic points in the series of declining loops conform to a linear relationship, forming the linearized end-systolic pressure-volume relationship, or ESPVR. The line connecting end-systolic pressure and volume of all the loops is actually somewhat curvilinear over a wide range of ventricular pressures (from 150 to 30 mm Hg ventricular pressure); it asymptotes horizontally at higher pressures and vertically at lower pressures. However, 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 slope and sometimes a decrease in V0. Conversely, a decrease in inotropic state is expressed as a decrease in slope (sometimes together with an increase in V0; Fig. 3-10). The advantage of using the ESPVR to describe and quantify contractility is that hemodynamic conditions (i.e., preload, afterload) do not affect the slope or intercept descriptors used to quantify inotropic state to the same extent as they do when using the Starling curve concept of describing inotropic state.

View larger version (36K):
[in this window]
[in a new window]
FIGURE 3-10 Two series of declining left ventricular pressure loops generated during transient bicaval occlusion. Loops were generated in normal left ventricles (Normal) and after 30 minutes of global normothermic ischemia and subsequent reperfusion (dashed lines). The end-systolic pressure-volume points from each series are connected the a line generated by linear regression. The end-diastolic pressure-volume relationship indicating chamber stiffness (inverse of compliance) is generated by fitting the end-diastolic point from each loop to an exponential curve. The volume axis intercept (V0) is shown in the inset. A negative inotropic effect (i.e., ischemia/reperfusion) is characterized by a decrease in the ESPVR slope, while a positive inotropic state is characterized by an increase in ESPVR slope. Notice that the V0 for these conditions are in close proximity (inset). In some cases, a negative inotropic state is associated with a decrease in slope and an increase in V0.

Besides quantifying global contractility of the left ventricle, pressure-volume loops can be used to analyze various physiologic and pathophysiologic situations. Figure 3-9B demonstrates the effect of an increase in afterload. Increased afterload moves the end-systolic pressure-volume point slightly upward and to the right, thereby also increasing end-diastolic volume. In the normal heart, stroke volume can be maintained during increased afterload by increasing end-diastolic volume with a minimal rise in end-diastolic pressure, and no change in contractility is required. Note, however, that because the pressure-volume loop is shifted to the right secondary to increased end-diastolic volume, the ejection fraction is slightly decreased if stroke volume remains constant. Figure 3-9C shows the effect of a decrease in ventricular compliance (bold curve) such as may result from hypertrophy, fibrosis, or cardiac tamponade. If systolic function is maintained (same slope and volume axis intercept of the end-systolic pressure-volume line), stroke volume can be maintained without ventricular distention, but at the price of an increased end-diastolic pressure. Note that ejection fraction in this circumstance has not changed, indicating that ejection fraction generally reflects contractility or systolic function rather than diastolic function. Figure 3-9D demonstrates the effect of adrenergic stimulation under the conditions that stroke volume is held constant. A positive inotropic effect combines with the positive lusitropic effect of adrenergic stimulation leading to a decrease in end-diastolic pressure, a shift of the pressure-volume loop to the left, and an increase in the ejection fraction. Figure 3-9E represents the hypertrophied heart with adrenergically mediated compensation. In this situation, as opposed to that in Fig. 3-9C, diastolic compliance is decreased and systolic contractility is increased. A constant stroke volume leads to an increase in end-diastolic filling pressure with a shift of the pressure-volume loop to the left with decreased intropy, and a consequent decrease in ejection fraction. Note that the ability of the hypertrophied heart to increase stroke volume is severely limited because of decreased diastolic compliance. This example illustrates the advantage of the pressure-volume loop approach of analyzing function, in that the separate contributions of inotropic state change and preload changes can be dissected out, in contrast to the Starling curve approach. Figure 3-9F represents an ischemic heart with decreased diastolic compliance and decreased contractility. Ischemia, and subsequent reperfusion, leads to an acute shift in the pressure-volume loop to the right (reflecting loss of contractility) and up (representing a decrease in compliance) if stroke volume is to be maintained. These changes in the position of the loops in the pressure-volume plane are consistent with clinical observations of an acute decrease in ejection fraction and increase in left ventricular filling pressure. Figure 3-9G shows the right shift of failing hearts that have undergone significant dilatation. Notice that it can be determined that filling pressures are not increased due to compliance changes per se, but rather because the left ventricle has moved upward on the compliance curve reflecting the mechanical properties of the dilated myocardium as opposed to a fibrotic process. Figure 3-9H shows the benefits of afterload reduction in the failing heart. Notice compared to Figure 3-9G that afterload reduction has moved the curve back to the left, thereby decreasing both the degree of chamber dilatation and ejection fraction. However, little benefit is gained in stroke volume unless positive inotropic agents are used, which 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.


For decades clinicians have attempted to assess contractility with an index that was independent of heart rate, preload, and afterload. Contractility, however, is clearly not independent of heart rate, afterload, or preload, and this attempt is futile. However, a number of indices have been described that allow the clinician to determine, in general, whether contractility has increased or decreased in clinical situations. One measure of contractility is represented by the family of Frank-Starling curves depicted in Figure 3-8. If one can determine, for example, that at a constant heart rate, aortic pressure, and cardiac output, the left ventricular preload is higher at time B than it is at time A, then one might conclude that contractility is diminished at time B relative to time A. This conclusion makes, however, the somewhat tenuous assumption that the diastolic pressure-volume relationship of the heart has not changed between time A and time B.

Ejection fraction is a second clinical index of contractility that is commonly utilized. Again ejection fraction gives one a general idea of contractility but, as can be seen by examination of the pressure-volume loops in Figure 3-9, ejection fraction is easily changed by preload and afterload alterations without requiring any change in contractility.

The use of the end-systolic pressure-volume relationship to quantify inotropic state of the left ventricle has been discussed above. The advantages of using this index, rather than the more commonly used ejection fraction and filling pressures, is that the contribution of changes in inotropic state (contributed by pathology such as ischemia, or therapy such as inotropic agents) can be separated from hemodynamic conditions or chronotropic changes. In addition, as has been discussed above, changes in inotropy can be separated from changes in filling dynamics. The disadvantage in using the pressure-volume concept clinically is that volume, or its surrogate measure diameter, is difficult to obtain.

A final index of contractility, which is perhaps a better index with regards to independence from other parameters, is the preload recruitable stroke work (PRSW) relationship. If one plots end-diastolic volume on the abscissa and stroke work on the ordinate from a family of pressure-volume loops obtained by inferior vena cava occlusion, one obtains a quite linear relationship, the slope of which appears to be related to contractility in a manner that is independent (within physiologic ranges) of preload and afterload. Internal stroke work can be determined by integration of the area of the pressure-volume loops as described above.31 The preload recruitable stroke work can be viewed as complementary to the ESPVR. The advantage of the PRSW relationship is that it gives overall performance of the left ventricle, combining systolic and diastolic components, while the ESPVR allows one to separate these two components of performance. The PRSW shares the same difficulty in obtaining the measurement in the clinical setting.


As changes in left ventricular geometry are considered, one must remember that the left ventricle is a pressurized, irregularly shaped chamber. The pressure within the chamber and the geometry of the ventricle determine the circumferential stress or tension in the wall of this chamber. The model of the ventricle as a cylinder can be used to approximate the effects of ventricular dilation on wall tension. In this circumstance, wall tension is proportional to the pressure times the radius of the cylinder, a relationship known as the law of LaPlace. Because the cylinder is thick walled, increasing wall thickness leads to decreased tension as a greater number of muscle fibers reduces the tension on each fiber. Tension, therefore, is proportional to pressure times radius divided by wall thickness. This concept has several important implications. If systolic pressure within the ventricle is chronically increased (as it is in aortic stenosis), then compensatory hypertrophy or thickening of the ventricular wall can bring systolic wall tension back close to normal. The price that is paid for this return of systolic wall tension to normal is that end-diastolic pressures must be higher (with increased wall thickness and constant chamber radius) in order to achieve the same diastolic wall tension, and thereby end-diastolic sarcomere length. This is the geometric explanation for the shift in the diastolic pressure-volume curve observed in Figure 3-9E in the hypertrophied heart.

In the heart that has systolic failure, compensation can occur with progressive ventricular dilation. This allows wall tension and diastolic sarcomere stretching to be increased at nearly normal end-diastolic pressures due to the increased diastolic diameter of the heart. Once again, there is a price to be paid. As the heart contracts, it remains dilated throughout the cardiac cycle (Fig. 3-9G). This dilation means that wall tension at end systole is also increased, thereby requiring excessive energy utilization from this dilated, failing heart as will be discussed in the following section.



The major fuels that serve as an energy supply for the myocardium are carbohydrates (glucose and lactate) and nonesterified free fatty acids. Under ordinary conditions, when sufficient oxygen is present, these fuels are broken down to acetyl coenzyme A, which enters the tricarboxylic acid cycle (Krebs cycle) in the mitochondria to form ATP. The heart is quite flexible in the aerobic state in its use of fuels. In the fasting state when free fatty acid levels are high, lipids may account for 70% of the fuel utilized by the heart. On the other hand, after a high carbohydrate meal or glucose feeding, blood glucose and insulin levels are high and free fatty acids are low. Glucose will then become the major fuel of the heart, accounting for close to 100% of metabolism. During acute exercise, lactate levels rise. These elevated lactate levels inhibit the uptake of free fatty acids. Carbohydrates, mostly lactate, can then account for up to 70% of the cardiac fuel use.32

In hypoxic or relatively anaerobic conditions, glycolysis is stimulated, with concomitant increase in glucose uptake from the blood and breakdown of glycogen in the myocyte to glucose. This anaerobic glycolysis can produce two moles of ATP from every mole of glucose metabolized. By-products of this anaerobic system of ATP production are lactate or hydrogen ions, which, when combined with decreased cytosolic ATP levels, lead to a rapid diminution in contractility and a decreased rate of relaxation of the affected sarcomeres. There is a dramatic difference in the quantity of ATP produced by oxidative metabolism; i.e., for 1 mole of glucose, 2 moles of ATP are produced by anaerobic glycolysis, compared to 38 moles of ATP with aerobic metabolism. Most of the ATP utilized by the heart (60%70%) is expended in the cyclic contraction of the muscle. An additional 10% to 15% of the ATP is required for maintaining the concentration gradients across the cell membrane (primarily through the sodium-potassium pump). A small portion is wasted in so-called futile cycles, such as the constant uptake and release of calcium by mitochondria, the breakdown and regeneration of glycogen, and the synthesis of triglycerides. In all of these situations a great portion of the actual energy liberated by ATP hydrolysis is converted into heat. Only about 20% to 25% of the total chemical energy of ATP is actually converted into mechanical work.

ATP is compartmentalized in the cell in the mitochondrial and cytosolic compartments. ATP molecules generated within the mitochondria cannot cross the mitochondrial membrane into the cytosol. A mitochondrial creatine kinase isoenzyme is situated within the mitochondrial membrane such that intramitochondrial ATP can lead to generation of creatine phosphate, which freely traverses the outer myocardial membrane into the cytosol. In the cytosol, the shuttled creatine phosphate reacts with ADP to form ATP. The rapid formation of ATP from creatine phosphate explains the observation that, when the cell becomes acutely hypoxic, creatine phosphate levels fall rapidly to near zero, while ATP levels fall much more slowly. A specific cardiac isoenzyme of creatine kinase (CK-MB) is released into the circulating blood with myocyte necrosis, and is used as a marker for myocardial cell death.32

With ischemia and hypoxia, ATP breaks down to ADP and subsequently to AMP, adenosine, and inosine. Adenosine is particularly important because diffusion of this nucleoside to local coronary vessels can lead to coronary vasodilatation, which may increase local coronary flow and reverse the ischemic/hypoxic state (metabolic control mechanism of blood flow, discussed later). Adenosine, inosine, and hypoxanthine are lost from the ischemic myocardium by washout. If an aerobic state is restored, ATP levels can be partially restored by salvage pathways leading to regeneration of adenosine nucleotides from inosine, hypoxanthine, or inosine monophosphate. These salvage pathways operate fairly quickly. The de novo synthesis of ATP also operates in the postischemic recovery period. However, this de novo synthesis takes hours or even days to restore significant ATP levels. Considerable controversy has existed concerning the ATP levels found in damaged cells, and the prediction of recovery, viability, or function. Because very low ATP values have been found in cells that subsequently recovered, it is now thought that very low ATP levels are not necessarily a cause of cellular necrosis, but cells dying of ischemia always contain very low levels of ATP. It may be that the ATP turnover rate, of which the oxygen consumption rate is a surrogate measure, is more indicative of cell viability and function.


In the normal myocardium with adequate oxygen delivery, nearly all chemical energy used by the heart is generated by oxidative phosphorylation, regardless of the substrate used. The anaerobic metabolism is very limited in the heart since anaerobic enzymes are not present in sufficient concentrations. Therefore, the rate of oxygen consumption (MVO2) is largely indicative of the metabolic rate of the heart assuming that oxygen supply is adequate to meet or exceed demands. Therefore, measurement of MVO2 has been used to estimate the energy expenditure of the heart. Oxygen consumption is calculated as the product of the arterial-venous oxygen content difference and coronary blood flow, optionally indexed to heart weight in one fashion or another. Therefore, MVO2 = ((CaO2 CvO2/CBF)/heart weight, where MVO2 is myocardial oxygen consumption, CaO2 is arterial oxygen content in mL O2/100 mL blood, CvO2 is coronary venous (i.e., coronary sinus) oxygen content in mL O2/100 mL blood, and CBF is coronary blood flow in mL/min.

As discussed above, the bulk of the energy utilized by the contracting heart is expended in the contractile cycle. The remainder of the energy is expended in cellular homeostasis (maintaining ionic balance, cell viability) and electrical activation. Changes in the rate of oxygen consumption of the heart are directly related to changes in the contraction cycle and workload. Energy utilization by the heart can be increased by an increase in the workload of the heart, that is, the energy which the heart must impart to the blood as it passes through the left ventricle, or by a decrease in the efficiency with which the heart converts chemical energy to mechanical energy. Since the minute work of the heart is the heart rate times the stroke volume times developed pressure, then the energy imparted by the heart to the blood is related to each of these three factors. An increase in heart rate, an increase in stroke volume, or an increase in left ventricular (or aortic) pressure leads to an increase in oxygen demand. There is a great difference, however, in the change in cardiac efficiency as heart rate, stroke volume, or aortic pressure is altered.

The primary determinant of oxygen demands in the heart is the development of tension or wall stress with each cardiac cycle. This tension or wall stress must first alter series elastic elements and parallel elastic elements and to rearrange the geometry of the ventricle with each cardiac cycle before ejection even occurs. Indeed, during the period of isovolumic contraction, energy is expended by the heart without the delivery of any potential energy to the blood.33 The energetic cost of actually ejecting blood out of the ventricular chamber is approximately 20% to 30% of that required to generate pressure isovolumically. This may lead to the conclusion that pressure work (generating pressure) is much more costly than is the volume work used to generate increased stroke volume. Studies more recent than those conducted by Sarnoff et al in the mid-1950s have shown that indeed volume work is only slightly less expensive compared to pressure work. Since the increase in stroke volume as a form of volume work is also accompanied by an increase in aortic pressure, some of the energy requirement comes from generating pressure. The concept unifying pressure work and volume work, as codeterminants of oxygen demands, into a single determinant is that wall stress or wall tension is the major determinant of oxygen utilization of the heart.

Cardiac efficiency relates oxygen consumption to cardiac work. Hence, cardiac efficiency = work / MVO2. The overall efficiency of the heart ranges from 5% to 40% depending on the type of work (pressure vs. volume vs. velocity) performed.3437 The low efficiency of the heart is due to the expenditure of a predominant portion of the oxygen consumed in generating pressure and stretching internal elastic components of the myocardium during isovolumic systole (a form of internal work), which does not contribute to the development of stroke volume and hence to external 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.

Following cardiac surgery, cardiac efficiency generally decreases due to the increase in MVO2 relative to the cardiac work performed. The additional oxygen consumed may be due to an increase in basal metabolism and/or an increase in the cost of the excitation-contraction process, or inefficiencies of ATP production at the mitochondrial level. These changes can only be assessed using the pressure-volume approach, which limits its clinical applicability because of the problems associated with attaining ventricular volume measurements as discussed above.

Because heart rate and aortic pressure are relatively prominent in the determination of myocardial oxygen consumption, two clinical indices based upon heart rate and aortic pressure have been developed for estimation of myocardial oxygen consumption. These are the double product (the heart rate times the blood pressure) and the tension time index (the average ejection pressure of the left ventricle multiplied by the duration of ejection). Both of these indices correlate well with cardiac oxygen consumption, but neither takes into account the effect of ventricular dilation or altered contractility.38 Dilation of the heart during cardiac surgery, i.e., during aortic regurgitation in the absence of left ventricular venting, during the weaning process after removal of the aortic cross-clamp, or with heart failure, is an energetic disaster. Because of the law of LaPlace, the wall tension is much greater in a dilated heart than in a small heart for any given value of developed pressure. Because the inefficiencies of cardiac contraction are associated with the development of tension in the myocardium, these inefficiencies are greatly exaggerated in the dilated heart. In the failing heart, an increase in work output cannot generally be achieved by increased contractility because of receptor downregulation or desensitization, and increased stroke volume can be accomplished only by an increase in end-systolic volume and an increase in heart rate. This leads to an exaggerated increase in oxygen utilization by the dilated heart secondary to both increased wall stress and heart rate. Similar considerations apply to the postsurgical heart, which demonstrates chamber dilatation and a decrease in stroke volume or cardiac index early after weaning from cardiopulmonary bypass.

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 (20120 ?m 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 ?m. There is a greater capillary density in subendocardial myocardium compared to subepicardial tissue. When there is an increased myocardial oxygen demand (e.g., with exercise), myocardial blood flow can increase to three or four times normal. This increased blood flow is accomplished by vasodilation of the resistance vessels, and by recruitment of additional capillaries (many of which are closed in the resting state). This capillary recruitment is important in decreasing the intercapillary distance and thereby decreasing the distance that oxygen and nutrients must diffuse through the myocardium.

The blood flow pattern from a coronary artery perfusing the left ventricle, measured by flow probe, is phasic in nature, with greater blood flow occurring in diastole than in systole.39 The cyclical contraction and relaxation of the left ventricle produces these phases in the blood flow pattern by increasing mechanical resistance forces due to extravascular compression of the arteries and intramyocardial microvessels. 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. Hence, compression of subendocardial vessels is greater than of subepicardial vessels. Coronary blood flow is less during systole relative to that occurring during diastole. During contraction of the myocardium, the squeezing of the myocardium increases resistance of the arterial vasculature by compressing it, termed extravascular compression. The extravascular compression and resistance to blood flow are greatest in the subendocardial tissue. Measurement of transmural blood flow distribution during systole shows that subepicardial vessels are preferentially perfused, while subendocardial vessels are significantly hypoperfused. During the end of systole, blood flow actually reverses, and becomes retrograde primarily in the epicardial surface vessels due to greater pressure generation in the underlying midmyocardial layers and endocardial layer compared to the overlying epicardial tissue.40 During diastole, the mural vascular resistance due to extravascular compressive forces releases, and blood flow is distributed to both subepicardial and subendocardial tissue. Hence, the subendocardial myocardium is perfused primarily during diastole, while subepicardial myocardium is perfused during both systole and diastole. A greater capillary density per square millimeter in the subendocardium compared to the subepicardial tissue facilitates the distribution of blood flow to the inner layer of myocardium. In addition, the subendocardial tissue has a greater oxygen demand, requiring a greater oxygen supply from blood flow, since the wall tension generated and the sarcomere shortening is greater in this region. Therefore, the greater blood flow during diastole is due to (1) selective perfusion of the subendocardial myocardium, (2) the higher metabolic demands of the subendocardial myocardium, and (3) continued perfusion of the subepicardial tissue. Myocardial blood flow is normally greater in the subendocardial tissue than in the subepicardial tissue, reflecting the greater oxygen demands in this region.41 This regional distribution of blood flow during the cardiac cycle has implications regarding the susceptibility of the subendocardium to tissue injury and necrosis during severe coronary artery stenosis and total ischemia. 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 to the left ventricle. The lower extravascular compressive forces generated in the myocardial wall of the right ventricle do not impede blood flow to the same degree as in the left ventricle.

Control of Coronary Blood Flow

Nutrient coronary blood flow is ordinarily tightly coupled to the metabolic needs of the heart. Since approximately 70% of the oxygen available in coronary arterial blood is extracted under normal conditions, and blood flow can increase 3- to 5-fold, adjustments in coronary blood flow are the primary mechanism by which increased oxygen demands are met. Because of the aerobic nature of the myocardium, sufficient oxygen is required to meet the ambient demands of the heart. A delicate balance between oxygen needs and oxygen availability requires a precise system for regulating local coronary blood flow. Local coronary blood flow is controlled by a balance of vasodilatory and vasoconstrictor mechanisms. The three components of this delicate system are (1) the metabolic vasodilatory system, (2) the neurogenic control system, and (3) the vascular endothelium.42 Mechanical factors, such as extravascular compressive forces or myogenic responses, play little part in adjusting coronary blood flow to meet ambient demands under normal circumstances.

The metabolic vasodilatory mechanism causes local vasodilation of resistance vessels whenever local nutrient blood flow is insufficient to meet metabolic demand. Moment-to-moment control of coronary tone is imposed by appropriate adjustment, principally of the resistance vessels, i.e., arterioles and precapillary sphincters. The primary mediator of the metabolic control mechanism appears to be adenosine, which is generated within the myocyte, is freely diffusible across the cell membrane, and is released into the interstitial compartment. In the abluminal compartment, adenosine acts directly upon the smooth muscle cells in the arterioles to cause relaxation by activation of A2 receptors. Adenosine is the breakdown product of ATP hydrolysis to ADP and AMP. When blood flow is sufficient to meet oxygen demands, ADP is efficiently phosphorylated to ATP, and little adenosine is formed. However, when the oxygen supply falls below the demands even temporarily, the oxygen supply/demand mismatch can not sustain the rapid rephosphorylation of ADP to ATP, and ultimately more adenosine is formed and diffuses into the parenchyma and adjacent microvessels. This increased adenosine then dilates the vessels until sufficient oxygen is supplied to the myocardium to support ADP phosphorylation and less adenosine is formed. Adenosine is therefore the coupling agent between oxygen demands and oxygen supply. This metabolic control mechanism can rapidly adjust blood flow in response to even transient increases or decreases in energy need. Other mediators of local control of coronary blood flow are carbon dioxide, lactic acid, and histamine. Ions may play an important role in regulating coronary blood flow. A buildup of hydrogen ions in myocardium causes vasodilation; recent evidence suggests the role of a chloride channel in regulation of microcirculation. The sympathetic nervous system acts through alpha receptors (which cause vasoconstriction) and beta receptors (which cause vasodilation). There appears to be direct innervation of the large conductance vessels and lesser direct innervation of the smaller resistance vessels, although sympathetic receptors on the smooth muscle cells of the resistance vessels certainly can respond to humoral catecholamines. Alpha receptors predominate over beta receptors such that when norepinephrine is released from the sympathetic nerve endings, vasoconstriction ordinarily occurs. A second substance, neuropeptide-y, appears to be stored with and released with norepinephrine, and may have a role in coronary vasoconstriction.

The endothelium plays a very important role in the regulation of local coronary blood flow. Endothelium-dependent adjustment of coronary artery blood flow is accomplished by a dynamic balance between vasodilator and vasoconstrictor factors. Vasodilators include endothelial derived relaxing factor (EDRF), identified as nitric oxide (NO") synthesized from L-arginine by endothelial nitric oxide synthase, or eNOS) and endothelially released adenosine. The vasoconstrictors are principally represented by the endothelially derived constricting peptide endothelin-1. Nitric oxide generation from the endothelium is stimulated by a number of factors including adenosine, acetylcholine, and shear stress secondary to increased intraluminal blood flow. This nitric oxide leads to powerful vasodilation of the resistance vessels. If the endothelium is intact, acetylcholine from the sympathetic nerves or coronary artery shear stress causes vasodilation through generation of NO". If the endothelium is not functionally intact, acetylcholine causes vasoconstriction by direct stimulation of the vascular smooth muscle to contract. 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 (ET-1) is a 21-amino-acid peptide derived from preproendothelin-1 in the endothelium by the actions of endothelin-converting enzyme (ECE). 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), and is important in regulating basal coronary artery blood flow in health and disease. This balance between endogenous vasoconstrictors and vasodilators in control of basal coronary artery blood flow was demonstrated in experimental studies in which ETA receptor antagonists were infused into the coronary circulation, accompanied by an increase in coronary blood flow due to a block of endogenous ET-1mediated constriction, and an unmasking of endogenous vasodilation, (mediated partially by NO"). Endothelin-1 is rapidly synthesized in vascular endothelium, particularly during ischemia, hypoxia, and other stress conditions, where it acts in a paracrine fashion similar to the local effects of adenosine and NO". ET-1 has a short half-life (47 minutes), which exceeds that of adenosine (812 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 potentially important consequences in the control of coronary blood flow in humans. Changes in coronary blood flow in ischemia-reperfusion, congestive heart failure, hypertension, and atherosclerosis may be, in part, mediated or exacerbated by an overexpression of endothelin-1, which may overwhelm the vasodilatory effects of local autacoids like adenosine and NO". Increased age may exacerbate the vasoconstrictor responses to ET-1, which are further exaggerated by a concomitant decrease in tonic NO" production. In addition, the levels of ET-1 have been observed to increase with myocardial ischemia-reperfusion and after cardiac surgery.

Under ordinary circumstances the metabolic vasodilatory system is by far the most powerful 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.4345


Coronary artery blood flow is also determined by perfusion pressure. In a noncompliant and nonreactive conduit such as plastic tubing, the flow is linearly related to pressure, and inversely related to resistance. In the coronary vasculature, however, blood flow can remain constant over a range of perfusion pressures at a constant level of work. This autoregulation of blood flow adjusts vascular resistance appropriately to match blood flow needs, likely by the metabolic mechanisms described above. For example, at a given level of cardiac work, a reduction in perfusion pressure is associated with a decrease in vascular resistance, thereby maintaining blood flow. Conversely, if perfusion pressure increases, vascular resistance decreases to maintain relatively constant blood flow. This autoregulatory "plateau" occurs between approximately 60 and 120 mm Hg perfusion pressure. If distal coronary artery perfusion pressure is reduced, for example, by a greater than critical stenosis (see below) or by hypotension, vasodilator capacity will be exhausted and coronary blood flow will decrease, following a linear relationship with perfusion pressure. Because the subendocardial regional 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.

Coronary Artery Stenosis

Atherosclerotic coronary artery disease is the most common cause of death in the United States, accounting for approximately one third of all mortality. Atherosclerotic disease primarily affects the large conductance vessels of the heart. The hemodynamic effect that a coronary artery stenosis has upon blood flow may be considered in terms of Poiseuille's law, which describes the resistance of a viscous fluid to laminar flow through a cylindrical tube. Resistance is inversely proportional to the fourth power of the radius and directly proportional to the length of the narrowing. Therefore, diameter narrowing has a tremendous effect on distal vascular resistance in a diseased coronary artery. Generally, 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%, however, the small decreases in diameter have significant effects on blood flow. By Poiseuille's law a 1-cm, 80% stenosis has a resistance that is 16 times as high as the resistance of a 1-cm, 60% stenosis. Similarly, if this stenosis progresses to a 90% stenosis, the resistance is 256 times as great as the resistance of a 60% stenosis.46

These considerations are especially important when one understands that atherosclerosis may leave partially intact the ability of the conductance vessel to constrict. Indeed, the endothelium is often destroyed or damaged, so that the vasoconstrictor mechanisms are often relatively unopposed by the impaired vasodilatory mechanism, and hence constriction is exaggerated. Suppose an epicardial vessel has an atherosclerotic lesion leading to an 80% diameter reduction in the lumen of that vessel. If the individual should attempt to exercise or should become excited, sympathetic stimulation could lead to vasoconstriction of that epicardial vessel such that the residual lumen is further narrowed to a 90% obstruction. This would lead to a 16-fold increase in coronary vascular resistance.47

Another important concept is that of coronary blood flow reserve. Coronary reserve may be defined as the capacity of the coronary vasculature to increase nutrient flow. A short-term occlusion of the coronary artery, or a local infusion of a vasodilator such as adenosine, will maximally dilate the target coronary artery and unmask its coronary reserve. Ordinarily, coronary flow reserve is such that blood flow may be increased to three to four or more times resting levels. As proximal atherosclerotic disease progresses, coronary reserve remains essentially normal until the proximal stenosis exceeds 60%. As the proximal resistance with stenosis increases between 60% and 90%, coronary reserve progressively decreases as the capacity of the distal resistance vessels to dilate is exhausted. At the point where there is no coronary reserve left, but basal blood flow is not affected by the stenosis (i.e., is sufficient to meet demands), the stenosis becomes a critical lesion. As the proximal narrowing approaches 90%, the ability of the resistance vessels to dilate is essentially fully utilized, further dilation is not possible, and coronary reserve becomes zero. In this condition, a stimulus that increases myocardial oxygen demand (such a tachycardia, hypertension, or exercise) cannot be met by dilation of the distal vasculature, and myocardial ischemia results.42 During exercise, turbulence in the coronary artery or sympathetic stimulation may further decrease blood flow below that predicted from the fixed stenosis, so that the degree of stenosis is dynamic.

In the human, coronary arterial vessels are end vessels with little collateral flow between major branches except in pathologic situations. With sudden coronary occlusion in the human heart there usually is very modest collateral flow through very small vessels (20200 microns in size). Unfortunately, this flow is generally insufficient to maintain cellular viability in the collateralized region. Collateral flow gradually begins to increase over the next 8 to 24 hours, doubling by about the third day after total occlusion. Collateral blood flow development appears to be nearly complete after 1 month, restoring normal or nearly normal resting flow to the surviving myocardium in the ischemic region. Previous ischemic events or gradually developing stenoses can lead to larger preexisting collaterals in the human heart. The presence of these preexisting collaterals has been shown to be important in the prevention of ischemic damage if coronary occlusion should occur.48

The development of collateralized regions in the human heart leads to some unusual pathophysiologic possibilities. Presuming that the collateralized region is distal to a totally occluded conductance vessel, flow into the collateralized region is dependent upon a second, nearby conductance vessel. If this second conductance vessel develops a flow-limiting stenosis and there is a sudden sustained increase in myocardial oxygen demand, then the resistance vessels related to that second conductance vessel will dilate, causing an increased pressure gradient across the secondary proximal stenosis, decreased pressure in the collateral vessels, and consequent ischemia of the collateralized region similar to coronary steal. This can cause angina pectoris or even infarction at a distance (narrowing of the stenotic left anterior descending by this mechanism could cause infarction of a collateralized region on the inferior surface of the heart).

The subendocardium of the heart is particularly susceptible to reductions in perfusion caused by proximal stenosis or total occlusion. This is related to (1) the greater systolic compressive forces exerted on subendocardial vasculature during systole, (2) the smaller flow reserve in the subendocardial vascular bed due to a greater degree of vasodilation, and (3) the greater degree of wall tension and segmental shortening, and hence regional oxygen demands, compared to the subepicardial region. In addition, if the heart begins to fail acutely and end-diastolic pressure is elevated to 25, 30, or 35mm Hg, then there is diastolic as well as systolic compression of the subendocardial vasculature. Studies have shown that flow to the subepicardium of the heart 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 as alluded to above. 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. These effects generally lead to more extensive subendocardial ischemia and infarction than subepicardial ischemia in the face of severe coronary stenosis or coronary occlusion. Subendocardial perfusion problems are obviously increased by situations such as chronic hypertension and aortic stenosis, which lead to an increased wall thickness and increased systolic and diastolic wall tension. Aortic regurgitation particularly threatens the subendocardium as diastolic systemic arterial pressures are reduced at the same time that intraventricular systolic and diastolic pressures are elevated.39,49

Endothelial Dysfunction

During the last two decades, much has been learned about the active participation of the coronary vascular endothelium in regulating both coronary blood flow and interactions with inflammatory blood cells, notably polymorphonuclear leukocytes (neutrophils, PMNs). The regulation of coronary blood flow and cell-cell interactions involves vasodilator and vasoconstrictor substances released by the coronary artery vascular endothelium. One of the most well-known vasoactive substances is endothelium-derived relaxing factor (EDRF). In 1986, Furchgott first proposed that EDRF is the diffusible free radical gas nitric oxide (NO"). NO" is synthesized from L-arginine by nitric oxide synthase in the presence of molecular oxygen, and with triggering from calcium. Besides endothelium-derived NO", a number of vasoconstrictor substances are produced by the endothelium, including endothelin-1, angiotensin II, and superoxide free radical. Under normal conditions, endothelium-derived vasodilator substances are in balance with vasoconstrictor substances. This delicate balance can be tipped by numerous diseases, including ischemia-reperfusion, hypertension, diabetes, and hypercholesterolemia, that reduce the tonic generation and release of NO", and allow an overbalance of vasoconstrictor substance, both effects causing vasoconstriction. This impaired generation of NO" is a major manifestation of endothelial dysfunction caused by all the aforementioned diseases. Endothelial dysfunction contributes to the microvascular blood flow defects and increased inflammatory-like responses mediated principally by neutrophils that occur particularly with ischemia-reperfusion injury.

NO" normally is a major player in local regulation of coronary arterial tone by overwhelming the action of endothelium-derived vasoconstrictor substances, which are also tonically released by the coronary artery endothelium. NO" is released by the coronary vascular endothelium by both soluble factors and mechanical signals. Acetylcholine and ATP stimulate the release of NO", while shear stress and pulsatile stress also prompt elaboration of NO". Shear stress in the coronary vasculature is related to perfusion pressure and blood flow velocity. However, in some pathologic states the ability of the endothelium to generate nitric oxide is impaired, 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 vasodilatory 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. As discussed below, the involvement of endothelium-derived NO" has an impact on the pathogenesis of postoperative infarction of a revascularized area, even if that same area was not ischemic preoperatively.5052

In addition to the vasodilatory effects of autacoids such as NO", the endothelium is important in preventing cell-cell interactions between blood-borne inflammatory cells (i.e., leukocytes and platelets) that initiate a local or systemic inflammatory reaction. Inflammatory cascades occur with sepsis, ischemia-reperfusion, and cardiopulmonary bypass. Under normal conditions, the vascular endothelium repels the interaction of neutrophils and platelets with the vascular endothelium by tonically releasing adenosine and NO", both of which have potent antineutrophil and platelet inhibitory effects. However, damage to the vascular endothelium caused by adhesion of neutrophils to its surface, and subsequent release of oxygen radicals and proteases, 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 activities of activated neutrophils have downstream physiological 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.53 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.54 Both adenosine and NO" have been used therapeutically to reduce the inflammatory responses to cardiopulmonary bypass, and to reduce ischemic-reperfusion injury. This treatment has reduced endothelial damage from surgical and nonsurgical ischemia-reperfusion and cardiopulmonary bypass.5557

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

If local coronary blood flow is acutely reduced to less than 20% of resting levels, a portion of the myocardium in the affected region will die. Cardiac muscle requires approximately 1.3 mL of oxygen per 100 g of muscle per minute for cellular survival, in comparison with approximately 8 mL of oxygen per 100 g per minute in the normally contracting left ventricle. As oxygen delivery is reduced, contraction decreases dramatically (within 8 to 10 heartbeats). If the reduction in regional myocardial blood flow is moderate, regional contraction is prominently diminished, but the metabolic processes of the heart remain intact. Stated another way, the contractile activity of the heart decreases to the point that is sustainable by the oxygen availability. This condition can lead to 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. With reperfusion, hibernating myocardium can very quickly resume normal and effective contraction.5860

If the extent of reduction of coronary blood flow is more severe, mild to moderate abnormalities in cellular homeostasis occur. There is reduction in cellular levels of ATP leading to a loss of adenine nucleotides from the cell. If this 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. If the myocyte is reperfused prior to irreversible damage to subcellular organelles, 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 seems to be 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 gradually recovering myocardium is called stunned myocardium.59,61

Reperfusion of ischemic myocardium may lead to a further progression of cellular damage and necrosis rather than to immediate recovery. This reperfusion injury is multifactorial. Damaged endothelium in the reperfused region can cause adhesion and activation of leukocytes and platelets as described above. Oxygen free radicals can be released, particularly if reperfusion is accomplished with blood that is excessively oxygenated, causing further damage to subcellular organelles. Membrane leakage often leads to elevation of intracellular calcium levels with uptake of calcium into the mitochondria and subsequent formation of insoluble calcium phosphate crystals. Temporary derangement of the ATP-dependent sodium-potassium pump can lead to loss of cell volume regulation with consequent leakage of water into the cell, explosive cell swelling, and rupture of the cell membrane. Techniques have been developed for modification of reperfusion injury with the goal being to minimize the adverse sequelae of reperfusion, so that the maximum number of myocytes may be salvaged. As might be suspected from the previous discussion, these techniques have included leukocyte depletion or inactivation, prevention of endothelial activation, free radical scavenging, reperfusion with solutions low in calcium content, and reperfusion with hyperosmolar solutions.62,63 Both adenosine and low-dose NO" are among potent inflammatory agents that have shown benefit in attenuating neutrophil-mediated damage, infarction, and apoptosis.55,64

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. After more than 13 years of aggressive research, the mechanisms of this intrinsic protective system are still elusive, and are still currently a topic of intense investigation.62,65,66

Forms of Heart Failure: Systolic and Diastolic Heart Failure

Heart failure is a progressive and chronic disorder that occurs when the ability of the heart to fill and/or pump is impaired such that the heart is unable, with acceptable filling (venous) pressures, to deliver adequate blood to the tissues to meet metabolic needs at rest or during mild to moderate exercise. The syndrome of heart failure is characterized by low cardiac output, impaired exercise capacity, neurohormonal activation, and enhanced oxidative stress, as well as premature myocardial cell death. Heart failure may be primarily systolic failure such that an impairment of contractility leads to low cardiac output and excessive filling pressures (Fig. 3-9F). The early stages of acute myocardial infarction involving a large area of the left ventricle at risk are an example of systolic heart failure. With the loss of contractile function of the area of myocardium undergoing infarction, the ventricular mass is insufficient to maintain a normal stroke volume. Cardiomyopathy is a form of disease that affects the global myocardium, as opposed to a specific region as in myocardial infarction. In both cases, the left ventricle dilates, which causes the pressure-volume relations of the left ventricle to shift to the right (Fig. 3-9F). In this situation, the diastolic portion of the pressure-volume curves is not greatly changed. However, the global systolic performance of the heart (i.e., the ability to pump blood) may be inadequate to meet even resting needs (particularly if there is systolic bulging of a large infarction).67,68

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. Increased stiffness of the left ventricular myocardium is associated with an excessive upward shift in the diastolic pressure-volume curve (Fig. 3-9C and 9E). 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).69,70

The most common form of heart failure is mixed systolic and diastolic failure. This is the case in chronic cardiac decompensation in which systolic function has been impaired (often by multiple myocardial infarctions) and diastolic stiffness has increased because of proliferation of interstitial cells and collagen, leading to a fibrotic heart.

Early Cardiac and Systemic Sequelae of Heart Failure

The adaptive homeostatic reactions of the body leading to heart failure depend upon the duration of the ongoing pathologic process. When cardiac function acutely deteriorates and cardiac output diminishes, adaptive hemodynamic responses come into play as an early compensatory mechanism. Neurohumoral reflexes attempt to restore both cardiac output and blood pressure. Activation of the sympathetic adrenergic system in the heart and in the peripheral vasculature causes systemic vasoconstriction (via an alpha-adrenergic effect) and increases heart rate and contractility (via a beta-adrenergic effect), responses that are evoked to maintain blood pressure. A variety of mediators formed during this adaptive stage, including norepinephrine, angiotensin II, vasopressin (antidiuretic hormone), and endothelin, not only help in renal retention of salt and water leading to rapid volume expansion but also cause vasoconstriction. Aldosterone output is increased, again helping conserve sodium. The concerted responses of the adrenergic system and the renin-angiotensin system, therefore, recruit changes in the primary determinants of stroke volume and cardiac outputpreload, afterload, and contractility. These early compensatory responses to hypotension secondary to heart failure lead to an expansion of blood volume, thereby shifting the pressure-volume loop to the left as shown in Figure 3-9F (dashed line), which in turn restores cardiac output and blood pressure despite diminished 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 Figure 3-9G as a right shift in the pressure-volume relations of the left ventricle with an increase in end-diastolic volume (and pressure). In addition to a global dilatation response, acute alterations in cardiac geometry may occur early after a large myocardial infarction, with thinning of the left ventricular wall in the region of the infarct as well as expansion of overall left ventricular cavity size. This is particularly true if the infarct is apical, because of geometric considerations related to the thinness of the left ventricular wall in the region of the apex related to the short radius of curvature of the left ventricular apex. As volume expansion occurs, production of the cardiac atrial naturetic peptide is increased, which tends to prevent excessive sodium retention and inhibit activation of the renin-angiotensin and aldosterone systems.7177

Cardiac and Systemic Maladaptive Consequences of Chronic Heart Failure

During the acute phase of heart failure, the above-described hemodynamic responses are adaptive and help the heart to respond to exercise, blood loss, and acute myocardial ischemia. However, as the pathological process progresses, this response becomes maladaptive and contributes significantly to long-term problems in patients with heart failure (Fig. 3-11). In the late stage of heart failure, the kidney tends to continue to retain sodium and become hyporesponsive to atrial naturetic peptide. The initial response of the heart to sympathetic stimulation is diminished with desensitization of beta-adrenergic receptors as a consequence of sustained stimulation. Circulating catecholamine levels are elevated, but these increased circulating levels are of little benefit because of progressive desensitization of receptors.21,72

View larger version (32K):
[in this window]
[in a new window]
FIGURE 3-11 A flow chart shows the pathophysiology of heart failure from stimulus (etiology) to acute adaptive and chronic maladaptive responses. (+) indicates positive stimulation; (-) indicates negative factors that tend to reduce stimulation of heart failure.

Left ventricular dilation is accompanied, at least in the early phases, by hypertrophy of the myocytes as well as by lengthening of the myocytes as sarcomeres are added. In addition, there is significant slippage of myofibrils leading to dilation without an increase in the number of myocytes. Angiotensin and aldosterone both appear to 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. The progressive dilation of the heart after chronic heart failure leads to an increase in the wall tension necessary to generate systolic intracavitary pressures by the law of LaPlace. The progressive fibrosis of the heart caused by left ventricular remodeling leads to increased diastolic stiffness and an inability to increase contractility in response to increased filling pressure. Fibrosis and increased ventricular size predispose to reentry ventricular arrhythmias that are a common cause of death in the late stages of heart failure. This rapidly deteriorating clinical cycle explains the result in one clinical study in which the 5-year survival rate was only 25% in men and 38% in women.74,7680 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 (including tumor necrosis factor, interleukins, interferons, and transforming growth factor), and apoptotic cell death may participate in the development of heart failure as a maladaptive reaction (Fig. 3-10). Endothelial dysfunction is evidenced by reduced responses to the endothelium-dependent vasodilator acetylcholine, reduced production of the vasodilator autacoids adenosine and nitric oxide, and an overproduction of endothelin-1. In support of this, reduced availability of nitric oxide and increased production of vasoconstrictor agents such as endothelin and angiotensin II have been reported in failing hearts.81 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, not only directly activate inflammatory cells to release superoxide radicals and cause endothelial dysfunction by augmenting inflammatory cellendothelial cell interactions as discussed previously, but may also directly induce necrotic and apoptotic myocyte cell death.82,83 More recent data from experimental studies and clinical observations suggest that cardiomyocyte apoptosis detected in the perinecrotic zone of infarcts may account for the progression of tissue injury towards to development of negative ventricular remodeling and heart failure.84,85 Compensatory hemodynamic alterations seen at this stage, coupled with ventricular dilation, may continually induce transcription factors and maladaptive hypertrophy. Persistent growth stimulation in terminally differentiated cells may lead paradoxically to apoptotic cell death. Recently, activation of sodium-hydrogen exchange has been linked with the hypertrophic processes and induction of the remodeling at late stage of heart failure.86

Therapeutic Strategies for Managing Heart Failure

Treatment of the patient with heart failure is primarily based on diagnosis, identification of causes, and the etiology of failure.81 The interventions commonly used to treat heart failure include angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers, beta-adrenergic receptor blockers, diuretics, and aldosterone blockers. For heart failure with left ventricular systolic dysfunction induced by ischemic heart disease, for example, ACE inhibitors have shown particular clinical benefit in treating peripheral vasoconstriction by reducing afterload and diminishing the direct effect of angiotensin II in promoting fibrosis in the remodeling heart. It has not yet been established that angiotensin-receptor blockers are as effective as the ACE inhibitors, and therefore they are only good for patients who are unable to tolerate ACE inhibitors because of cough or angioedema.87 Treatment of heart failure with beta-adrenergic receptor blockers often leads to a temporary increase in symptoms followed by a sustained and long-term improvement in cardiovascular function. This appears to be related to a reversal, at least in part, of the desensitization of adrenergic receptors. Diuretics reduce extracellular fluid retention and alleviate symptoms of heart failure, but they also lower preload and consequently decrease cardiac output by Frank-Starling mechanisms. Therefore, they should be used with frequent monitoring in patients with end-stage heart failure.81 It has been proposed that aldosterone blockers may contribute the beneficial long-term effects in inhibition of growth factorstimulated response that causes left ventricular dilation, remodeling, and fibrosis.29,77,88 To date, there are several promising studies that show beneficial effects in the treatment of heart failure with antioxidant therapy, antiapoptotic agents, vasopeptide inhibitors, endothelin antagonists, tumor necrosis factor-alpha inhibitors, and sodium-hydrogen exchange inhibitors.86,87 Progress in the treatment of chronic congestive heart failure is a dramatic example of successful therapy based upon an understanding of pathophysiology, which in turn is possible by increasingly accurate concepts of normal cardiac physiology.

  1. Guyton AC: Muscle blood flow and cardiac output during exercise; the coronary circulation; and ischemic heart disease, in Guyton AC (ed): Textbook of Medical Physiology, Philadelphia, WB Saunders, 1991; p 234.
  2. Opie LH: Fuels: carbohydrates and lipids, in Swynghedauw B, Taegtmeyer H, Ruegg JC, Carmeliet E(eds): The Heart: Physiology and Metabolism. New York, Raven Press, 1991; p 208.
  3. Katz AM: The cardiac action potential, in Katz AM (ed): Physiology of the Heart. New York, Raven Press, 1992; p 438.
  4. Katz AM: Regulation of cardiac contraction and relaxation, in Willerson JT, Cohn JN (eds): Cardiovascular Medicine. New York, Churchill Livingstone, 1995; p 790.
  5. Andersen OS, Koeppe RE: Molecular determinants of channel function. Physiol Rev 1992; 72:S89.[Abstract/Free?Full?Text]
  6. Catterall WA: Cellular and molecular biology of voltage-gated sodium channels. Physiol Rev 1992; 72:S15.[Free?Full?Text]
  7. Armstrong CM: Voltage-development ion channels and their gating. Physiol Rev 1992; 72:S5.[Free?Full?Text]
  8. Levitan IB: Modulation of ion channels by protein phosphorylation and dephosphorylation. Annu Rev Physiol 1994; 56:193.[Medline]
  9. McDonald TF, Pelzer S, Trautwein, et al: Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol Rev 1994; 74:365.[Free?Full?Text]
  10. Barry WH, Bridge JHB: Intracellular calcium homeostasis. Circulation 1993; 87:1806.[Medline]
  11. Pongs O: Molecular biology of voltage-dependent potassium channels. Physiol Rev 1992; 72:S69.[Free?Full?Text]
  12. Pallotta BS, Wagoner PK: Voltage-dependent potassium channels since Hodgkin and Huxley. Physiol Rev 1992; 72:S49.[Free?Full?Text]
  13. Agus ZS, Morad M: Modulation of cardiac ion channels by magnesium. Annu Rev Physiol 1991; 53:299.[Medline]
  14. Horisberger JD, Lemas V, Kraehenbuhl JP: Structure-function relationship of Na, K-ATPase. Annu Rev Physiol 1991; 53:565.[Medline]
  15. Carafoli E: Calcium pump of the plasma membrane. Physiol Rev 1991; 71:129.[Free?Full?Text]
  16. Pozzan T, Rizzuto R, Volpe P, et al: Molecular and cellular physiology of intracellular calcium stores. Physiol Rev 1994; 74:595.[Free?Full?Text]
  17. Coraboeuf E, Nargeot J: Electrophysiology of human cardiac cells. Cardiovasc Res 1993; 27:1713.[Medline]
  18. Swynghedauw B: Cardiac hypertrophy and failure, in Willerson JT, Cohn JN(eds): Cardiovascular Medicine. New York, Churchill Livingstone, 1995; p 771.
  19. Naccarelli GV: Recognition and physiologic treatment of cardiac arrhythmias and conduction disturbances, in Willerson JT, Cohn JN (eds): Cardiovascular Medicine. New York, Churchill Livingstone, 1995; p 1282.
  20. Naccarelli GV: Anti-arrhythmic drugs, in Willerson JT, Cohn JN (eds): Cardiovascular Medicine. New York, Churchill Livingstone, 1995; p 1421.
  21. Homcy CJ, Vatner ST, Vatner DE: Beta-adrenergic receptor regulation in the heart in pathophysiologic states: abnormal adrenergic responsiveness in cardiac disease. Ann Rev Physiol 1991; 53:137.[Medline]
  22. Feldman AM: Classification of positive inotropic agents. J Am Coll Cardiol 1993; 22:1223.[Abstract]
  23. Leier CV: Current status of non-digitalis positive inotropic drugs. Am J Cardiol 1992; 69:120G.[Medline]
  24. Honerjager P: Pharmacology of bipyridine phosphodiesterase III inhibitors. Am Heart J 1991; 1939.
  25. Olah ME, Stiles GL: Adenosine receptors. Annu Rev Physiol 1992; 54:211.[Medline]
  26. de Jong JW, van der Meer P, Owen P, et al: Prevention and treatment of ischemic injury with nucleosides. Bratislavske Lekarske Listy 1991; 92:165.[Medline]
  27. Boehm DH, Human PA, Reichenspurner H, et al: Adenosine and its role in cardioplegia: effects on postischemic recovery in the baboon. Transplant Proc 1990; 22:545.[Medline]
  28. Ebashi S: Excitation-contraction coupling and the mechanism of muscle contraction. Annu Rev Physiol 1991; 53:1.[Medline]
  29. Klug D, Robert V, Swynghedauw B: Role of mechanical and hormonal factors in cardiac remodeling and the biologic limits of myocardial adaptation. Am J Cardiol 1993; 71:46A.[Medline]
  30. Folkow B, Svanborg B: Physiology of cardiovascular aging. Physiol Rev 1993; 73:725.[Free?Full?Text]
  31. Glower DD, Spratt JA, Snow ND, et al: Linearity of the Frank-Starling relationship in the intact heart: the concept of preload recruitable stroke work. Circulation 1985; 71:994.[Medline]
  32. Taegtmeyer H: Myocardial metabolism, in Willerson JT, Cohn JN(eds): Cardiovascular Medicine. New York, Churchill Livingstone, 1995; p 752.
  33. Indolfi C, Ross J: The role of heart rate in myocardial ischemia and infarction: implications of myocardial perfusion-contraction matching. Prog Cardiovasc Dis 1993; 36:61.[Medline]
  34. Carden DL, Young JA, Granger DN: Pulmonary microvascular injury after intestinal ischemia-reperfusion: role of P-selectin. J Appl Physiol 1993; 75:2529.[Abstract/Free?Full?Text]
  35. Luscinskas FW, Brock AF, Arnaout MA, et al: Endothelial-leukocyte adhesion molecule-1-dependent and leukocyte (CD11/CD18)-dependent mechanisms contribute to polymorphonuclear leukocyte adhesion to cytokine-activated human vascular endothelium. J Immunol 1989; 142:2257.[Abstract]
  36. Li J, Bukoski RD: Endothelium-dependent relaxation of hypertensive resistance arteries is not impaired under all conditions. Circ Res 1993; 72:290.[Abstract]
  37. Johnston WE, Robertie PG, Dudas LM, et al: Heart rate-right ventricular stroke volume relation with myocardial revascularization. Ann Thorac Surg 1991; 52:797.[Abstract]
  38. Vinten-Johansen J, Duncan HW, Finkenberg JG, et al: Prediction of myocardial O2 requirements by indirect indices. Am J Physiol 1982; 243:H862.
  39. Beyar R: Myocardial mechanics and coronary flow dynamics, in Sideman S, Beyar R(eds): Interactive Phenomena in the Cardiac System. New York, Plenum Press, 1993; p 125.
  40. Yamada H, Yoneyama F, Satoh K, et al: Comparison of the effects of the novel vasodilator FK409 with those of nitroglycerin in isolated coronary artery of the dog. Br J Pharmacol 1991; 103:1713.[Medline]
  41. Vinten-Johansen J, Weiss HR: Regional O2 consumption in canine left ventricular myocardium in experimental acute aortic valvular insufficiency. Cardiovasc Res 1981; 15:305.[Medline]
  42. Bradley AJ, Alpert JS: Coronary flow reserve. Am Heart J 1991; 1116.
  43. Umans JG, Levi R: Nitric oxide in the regulation of blood flow and arterial pressure. Annu Rev Physiol 1995; 57:771.[Medline]
  44. Gross SS, Wolin MS: Nitric oxide: pathophysiological mechanisms [review]. Annu Rev Physiol 1995; 57:737.[Medline]
  45. Highsmith RF, Blackburn K, Schmidt DJ: Endothelin and calcium dynamics in vascular smooth muscle. Ann Rev Physiol 1992; 54:257.[Medline]
  46. Katritsis D, Choi MJ, Webb-Peploe MM: Assessment of the hemodynamic significance of coronary artery stenosis: theoretical considerations and clinical measurements. Prog Cardiovasc Dis 1991; 34:69.[Medline]
  47. Cohn PF: Mechanisms of myocardial ischemia. Am J Cardiol 1992; 70:14G.[Medline]
  48. Charney R, Cohen M: The role of the coronary collateral circulation in limiting myocardial ischemia and infarct size. Am Heart J 1993; 126:937.[Medline]
  49. Guyton RA, McClenathan JH, Newman GE, et al: Significance of subendocardial ST segment depression, local ischemia and subsequent necrosis. Am J Cardiol 1997; 40:373.
  50. Treasure CB, Alexander RW: The dysfunctional endothelium in heart failure. J Am Coll Cardiol 1993; 22:129A.
  51. Meredith IT, Anderson TJ, Uehata A, et al: Role of endothelium in ischemic coronary syndromes. Am J Cardiol 1993; 72:27C32C.[Medline]
  52. Harrison DG: Endothelial dysfunction in the coronary microcirculation: a new clinical entity or an experimental finding? [editorial; comment]. J Clin Invest 1993; 91:1.
  53. Jordan JE, Zhao Z-Q, Vinten-Johansen J: The role of neutrophils in myocardial ischemia-reperfusion injury. Cardiovasc Res 1999; 43:860.[Medline]
  54. Boyle EM, Pohlman TH, Johnson MC, et al: Endothelial cell injury in cardiovascular surgery: the systemic inflammatory response. Ann Thorac Surg 1997; 63:277.[Abstract/Free?Full?Text]
  55. Vinten-Johansen J: Cardioprotection from ischemic-reperfusion injury by adenosine, in Abd-Elfattah AS, Wechsler AS(eds): Purines and Myocardial Protection. Boston, Kluwer Academic Publishers, 1995; p 315.
  56. Vinten-Johansen J, Thourani VH, Ronson RS, et al: Broad spectrum cardioprotection with adenosine. Ann Thorac Surg 1999; 68:1942.[Abstract/Free?Full?Text]
  57. Vinten-Johansen J, Sato H, Zhao Z-Q: The role of nitric oxide and NO-donor agents in myocardial protection from surgical ischemic-reperfusion injury. Int J Cardiol 1995; 50:273.[Medline]
  58. Ross J: Myocardial perfusion-contraction matching implications for coronary heart disease and hibernation. Circulation 1991; 83:1076.[Medline]
  59. Marban E: Myocardial stunning and hibernation: the physiology behind the colloquialisms [review]. Circulation 1991; 83:681.[Medline]
  60. Guth BD, Schulz R, Heusch G: Time course and mechanisms of contractile dysfunction during acute myocardial ischemia. Circulation 1993; 87(suppl IV):IV-35.
  61. Kusuoka H, Marban E: Cellular mechanisms of myocardial stunning [review]. Ann Rev Physiol 1992; 54:243.[Medline]
  62. Granger DN, Korthuis RJ: Physiologic mechanisms of postischemic tissue injury. Annu Rev Physiol 1995; 57:311.[Medline]
  63. Vinten-Johansen J, Thourani VH: Myocardial protection: an overview. J Extracorp Tech 2000; 32:38.[Medline]
  64. Vinten-Johansen J, Zhao Z-Q, Sato H: Reduction in surgical ischemic-reperfusion injury with adenosine and nitric oxide therapy. Ann Thorac Surg 1995; 60:852.[Abstract/Free?Full?Text]
  65. Klonger RA, Yellon D: Does ischemic preconditioning occur in patients? J Am Coll Cardiol 1994; 24:1133.[Abstract]
  66. Carroll R, Yallon DM: Myocardial adaptation to ischemiathe preconditioning phenomenon. Int J Cardiol 1999; 68(suppl I): S93.
  67. Gaasch WH: Diagnosis and treatment of heart failure based on left ventricular systolic or diastolic dysfunction. JAMA 1994; 271:1276.[Abstract]
  68. Goldsmith SR, Dick C: Differentiating systolic from diastolic heart failure: pathophysiologic and therapeutic considerations. Am J Med 1993; 95:645.[Medline]
  69. Litwin SE, Grossman W: Diastolic dysfunctions a cause of heart failure. J Am Coll Cardiol 1993; 22(suppl A):49A.
  70. Bonow RO, Udelson JE: Left ventricular diastolic dysfunction as a cause of congestive heart failure. Ann Intern Med 1992; 117:502.
  71. Brandt RR, Wright RS, Redfield, et al: Atrial natriuretic in heart failure. J Am Coll Cardiol 1993; 22(suppl A):86A.
  72. Floras JS: Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure. J Am Coll Cardiol 1993; 22(suppl A):72A.
  73. Swan HJC: Left ventricular systolic and diastolic dysfunction in the acute phases of myocardial ischemia and infarction, and in the later phases of recovery: function follows morphology. Eur Heart J 1993; 14(suppl A):48.
  74. Pfeffer MA: Left ventricular remodeling after acute myocardial infarction. Annu Rev Med 1995; 46:455466.[Medline]
  75. Cohn JN: Heart failure, in Willerson JT, Cohn JN (eds): Cardiovascular Medicine. New York, Churchill Livingstone, 1995; p 947.
  76. Komuro I, Yazaki I: Control of cardiac gene expression by mechanical stress. Annu Rev Physiol 1993; 55:55.[Medline]
  77. Schwartz K, Chassagne C, Boheler K: The molecular biology of heart failure. J Am Coll Cardiol 1993; 22(suppl A):30A.
  78. Weber KT, Brilla CG: Pathological hypertrophy and cardiac interstitium. Circulation 1991; 83:1849.[Medline]
  79. Ross J: Left ventricular function after coronary artery reperfusion. Am J Cardiol 1993; 72:91G.[Medline]
  80. Pfeffer JM, Fischer TA, Pfeffer MA: Angiotensin-converting enzyme inhibition and ventricular remodeling after myocardial infarction. Annu Rev Physiol 1995; 57:805826.[Medline]
  81. Katz AM (eds): Heart Failure: Pathophysiology, Molecular Biology, and Clinical Management. Philadelphia, Lippincott Williams & Wilkins, 2000.
  82. Mak S, Newton GE: The oxidative stress hypothesis of congestive heart failure: radical thoughts [reviews]. Chest 2001; 120:2035.[Abstract/Free?Full?Text]
  83. Zhao Z-Q, Velez DA, Wang N-P, et al: Progressively developed myocardial apoptotic cell death during late phase of reperfusion. Apoptosis 2001; 6:279.[Medline]
  84. Leri A, Liu Y, Malhotra A, et al: Pacing-induced heart failure in dogs enhances the expression of p53 and -53-dependent genes in ventricular myocytes. Circulation 1998; 97:194.[Medline]
  85. Els?sser A, Suzuki K, Schaper J: Unresolved issues regarding the role of apoptosis in the pathogenesis of ischemic injury and heart failure. J Mol Cell Cardiol 2000; 32:711.[Medline]
  86. Karmazyn M: Role of sodium-hydrogen exchange in cardiac hypertrophy and heart failure: a novel and promising therapeutic target. Basic Res Cardiol 2001; 96:325.[Medline]
  87. Kostuk WJ: Congestive heart failure: what can we offer our patients? CMAJ 2001; 165:1053.[Free?Full?Text]
  88. Bristow MR: Changes in myocardial and vascular receptors in heart failure. J Am Coll Cardiol 1993; 22(suppl A):61A.

This Article
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Similar articles in this book
Right arrow Author home page(s):
Jakob Vinten-Johansen
Robert A. Guyton
Google Scholar
Right arrow Articles by Vinten-Johansen, J.
Right arrow Articles by Guyton, R. A.
Right arrow Articles citing this Article
Right arrow Search for Related Content
Right arrow Articles by Vinten-Johansen, J.
Right arrow Articles by Guyton, R. A.
Related Collections
Right arrow Cardiac - physiology