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PART II ADULT CARDIAC SURGERY MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 336 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 337 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP

CHAPTER CARDIOVASCULAR 19 FUNCTION AND PHYSIOLOGY Jeffrey M. Dodd-O

BASIC MYOCYTE PHYSIOLOGY extracellular fluids differ because the cell’s surface mem- brane serves to maintain some compounds intracellularly Myocyte depolarization and exclude other compounds extracellularly. This segre- gating function is possible because water-insoluble com- Cardiac myocytes possess the capacity to contract because ponents of the membrane prevent free passage of water- they contain a series of protein filaments (myofibrils) ori- soluble components through the membrane. The initial ented along the longitudinal axis of the cell (see below). creation of a concentration gradient between extra- and For myocytes to shorten, these myofibrils must be stimu- intracellular ions is achieved by energy-dependent ion lated to slide. The impetus for the stimulation originates pumps located within the membrane. These pumps can on the myocyte’s surface membrane (sarcolemma) and is move ions across the membrane against a concentration transmitted to the intracellular myofibrils. Aspects of the gradient. Because of the uneven concentrations of charged composition of the sarcolemma allow it to assume this ions in the intra- and extracellular fluids separated by the function. The intra- and extracellular fluid is predomi- cell membrane, there is an electrical gradient across the nantly water. The ionic components within the intra- and membrane (i.e., a transmembrane potential).

KEY CONCEPTS ● Membrane potentials are created by energy-dependent ● A ventricle exposed chronically to high afterload will ion pumps which segregate charged ions on either adapt by concentric hypertrophy because this reduces side of hydrophobic cell membrane. wall stress according to the law of Laplace. ● Cell depolarization possible because channels open ● Myocardium receiving insufficient energy supply will within the hydrophobic membrane to allow charged either die (infarction), become dysfunctional (ischemia), ions, driven by concentration gradients, to cross the or reduce its energy needs (hibernate). Reperfused tis- membrane. sue is termed “stunned” if it does not contract up to its ● Trigger for the opening of transmembrane ion channel potential in spite of adequate energy supply. is typically a change in the membrane potential. ● Diastole is more energy-demanding than systole, and Different channels are triggered to open at different diastolic dysfunction can be more difficult to treat membrane potentials. than systolic dysfunction ● The sarcomere is the contractile element of the ● Dysfunctional endothelium leads to vascular occlu- myocyte. Each sarcomere is composed of a series of sion by: (1) exposing underlying tissue factor to circu- parallel myofilaments. Coaxial movement of these lating factor VII, initiating thrombosis; (2) does not myofilaments, some of which are tethered to the ends allow for the interaction of thrombin with thrombo- of the sarcomere, result in sarcomere shortening. modulin and the subsequent activation of protein C to ● The strength of contraction is influenced by resting its anticoagulant form; (3) does not produce nitric length of the myocyte, sudden stretch of the myocyte, oxide, important to help decrease platelet activation, or rapidly repeated contraction of the myocyte. Speed decrease vasospasm, and decrease vascular of shortening is influenced by afterload. inflammation

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338 PART II ● ADULT CARDIAC SURGERY

Physiology of the myocyte cell membrane transmembrane potentials, become exposed to the new transmembrane potential of the adjacent sarcolemma. The human body is composed predominantly of salts Exposure to this new transmembrane potential increases and water. This pool of salts and water is segregated into the open probability of these nearby channels. The pas- functional units (cells and their intracellular compo- sage of ions through these newly open channels changes nents) that locally alter the concentration of the salts the membrane potential surrounding the channel, they contain. Hydrophobic phospholipid membranes exposing an additional section of the cell membrane to a surrounding the cells (and intracellular compartments) different transmembrane potential. In this way, the new prevent the exit/entrance of water-soluble salts and allow transmembrane potential propagates along the surface of the cells to maintain this individualized environment.1 the myocytes. Invaginations in the cell membrane, called T Units within these phospholipid membranes allow contin- tubules, penetrate into the cell into close proximity to the ued adjustment of the ion content within the cell (or intra- myocyte contractile proteins. These T tubules act as exten- cellular compartment). For example, an energy-dependent sions off of the surface membrane and allow changes in the Na,K pump extrudes Na ions from the cell and takes cell surface to effect changes deep within the myocyte. K ions into the cell at an exchange of three Na ions extruded per two K ions taken in. This allows cells to raise intracellular potassium concentrations and lower Physiology of the conduction system intracellular sodium. Another pump extrudes calcium in Relative to the extracellular fluid, the intracellular fluid in exchange for sodium, increasing intracellular calcium the resting state has higher concentrations of sodium, concentrations in relation to the extracellular fluid, lower concentrations of K and of Ca2 , and a relatively although it allows Na (extruded by the Na,K pump) to negative charge. When ion channels in the cell mem- reenter the cell. This pump is driven by the Na gradient brane are opened under these conditions, Na and Ca2 created by the energy-dependent Na,K pump. Similarly, tend to enter the cell rapidly.2 They are driven both by intracellular compartments called the sarcoplasmic reticu- ion concentrations and electrical potential. By contrast, lum (SR) contain energy-dependent ion pumps in their K tends to leave the cell owing to its concentration gra- surrounding membranes that allow them to collect the dient, although the electrical potential gradient reduces majority of the intracellular calcium. Other channels its speed of exit. When the cell is depolarized so that the within the membrane act as passages that intermittently transmembrane gradient is less negative intracellularly, open to allow transit of a specific ion through the cell the rate of K exit is higher. membrane. Regulation of pump activation and channel When the transmembrane electrical potential, usually opening is vital for the proper functioning of the cell. 90 mV at rest, becomes less negative, sodium channels Moving ions against their concentration gradient to on the cell membrane are triggered to open (Fig. 19-1). create a relative intracellular deficit or abundance requires Also triggered in these channels by cell membrane depo- energy. In the cell, this energy is supplied in the form of larization is the closing of the channel, although this ATP. This segregation of ions, along with the imbalance of process is (of course) delayed until after the channel has ionic charge that is associated, creates a potential (energy) been opened. Other channels, like L-type calcium chan- gradient across the membrane, which drives the rapid flux of ions that occurs if and when a transmembrane ion chan- + 30 ms nel is opened. In the cell, the trigger to opening the ion +20 K + CI− K channels is often the potential or ionic concentration gra- C dient of the surrounding milieu. Thus, transmembrane 0 B channels are frequently described as being either voltage- gated (opening probability is increased if the transmem- K+ brane potential of the surrounding membrane is within Na+ mV certain parameters) or ion-gated (opening probability is A D increased if there is a sudden change in the concentration Na:K of an ion in the surrounding fluid). pump activated −90 T Tubules and sarcoplasmic reticulum Figure 19-1 Correlation between the changes in ion The cell-surface change initiating myofibril movement is conductance and the resultant changes in transmembrane a flux of charged ions across some point of the sar- potential during the various phases of the cardiac myocyte colemma.1 This ion flux disrupts the balance of charged action potential. A. depolarization; B. rapid repolarization; particles present in the baseline (resting) state, and a new C. plateau phase; D. late repolarization. (Modified from transmembrane electrical gradient develops at that point Rubart M, Zipes DP. Mechanisms of sudden cardiac death. on the sarcolemma. Ion channels traversing the adjacent J Clin Invest 2005;115(9):2305–2315. With permission.) sarcolemma, closed to the passage of ions under resting MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 339 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP

Chapter 19 ● Cardiovascular Function and Physiology 339

nels, also open when the cell membrane has begun to Closed depolarize. The initiation of ion passage through calcium Resting channels is delayed until after the Na channels have begun to close. The opening of these Na and Ca2 chan- nels results in the entrance of cations into the cell, decreas- (Recovery) (Activation) ing the magnitude of the membrane potential. As the membrane potential reaches a nadir, K channels are trig- gered to open. Their opening increases the rate of exit of Closed Open K from the intracellular space into which it had been Inactive (Inactivation) concentrated. The loss of cations from the intracellular space helps return the transmembrane potential back to Figure 19-2 The three states of a voltage-gated ion channel. the resting state. This K channel is inwardly rectified (i.e., Two closed and one open state are shown, along with the turned off when cell is depolarized) and is the channel transitions between these states that open the channel (activa- responsible for maintaining the resting membrane poten- tion), close the channel (inactivation), and end its refractori- tial. This basic sequence is somewhat modified by chan- ness (recovery). [From Katz AM. Cardiac ion channels. N Engl nels for Cl and transiently open channels for K (activated J Med 328(17):1244-1251,1993. With permission.] after depolarization to allow Cl entrance into cell and K efflux from cell, beginning to reverse to return the trans- membrane potential toward 90 mV). capable of being opened), the open state, or the inactive Compared with the membrane on the surface of the state (closed and incapable of being opened until modi- cell, the membrane of T tubules has a relatively high con- fied by an intermediary stimulus (Fig. 19-2). centration of L-type calcium channels. As stated earlier, Furthermore, as ions pass rapidly through a channel, these T tubules extend to close approximation with the the electrical and ion gradient in the fluid surrounding myofibrils—the contractile apparatus of the myocyte. Also the channel is rapidly changing. Some channels, described located intracellularly near the junction of the myofibrils as rectified channels, alter the resistance imposed by the and the T tubules are compartments known as SR. The channel to ion flow through the channel as the surround- membrane of the SR contains ion pumps that concentrate ing electrical or ion potential is changing. In speaking calcium within the SR. The membrane of the SR also con- of K channels, an ion whose exit from the depolarized tains channels that, when open, allow the sequestered cal- cell tends to restore the resting membrane potential (by cium to exit the SR. The stimulus for opening of the increasing the relative concentration of negatively charged calcium channels on the SR is a rise in calcium in the cyto- ions intracellularly), outward rectified channels increase plasm surrounding the SR. Thus, as membrane depo- the resistance to K passage as the membrane potential larization propagates from the cell surface down the returns to resting state. This type of channel tends to pro- invaginations known as the T tubules, it stimulates L-type mote restoration of the repolarized state. By contrast, calcium channels in the T tubules to open. This allows cal- inward rectifiying K channels are relatively more resis- cium to enter the cell at a site near the SR, raising cytoso- tant to ion passage as the membrane is depolarized. This lic calcium concentrations near the SR. These high calcium type of channel tends to promote the maintenance of the concentrations near the SR stimulate calcium release from depolarized state. the SR, a phenomenon known as calcium-induced cal- The ion channel predominating in different cell sites of cium release. The rise in calcium concentrations near the the heart (atria/ventricles vs. sinus node/AV node) dif- myofibrils results in reorientation of the troponin in the fer.3 This difference in predominating ion channel helps thin filaments, moving the tropomyosin (attached to the explain the special features of different sites of the heart. troponin) and making it sterically possible for the actin of Fast-conducting sodium channels predominate in the the thin filament to bind to myosin. Contraction is termi- atria and ventricles, allowing for rapid depolarization and nated (and relaxation initiated) by the closing of calcium expediting conduction. These channels are less promi- channels in the SR and the reuptake of calcium by the SR nent in the SA node and AV node, reducing rate of con- as a result of pumps activated on the SR. The drop in cal- duction through these sites. cium concentrations surrounding the thin/ thick filaments Additional features of the SA and AV node are responsi- results in the return of tropomyosin filaments to a position ble for the automaticity (i.e., spontaneous depolarization) preventing the interaction of actin and myosin filaments. that is characteristic of these cells. The resting membrane Ion channel activity is somewhat complex. The impe- potential of contracting atria and ventricular myocytes is tus to open a channel may also initiate the process to maintained by an inward rectifying (i.e., shuts off when cell close the channel after a set period of time. Furthermore, is depolarized) potassium channel that maintains resting a channel which has opened and closed may need an membrane potential of around –90 mV. In the nodal tis- additional stimulus to transform it back to a state where sues, additional channels (voltage-dependent slow Na it can again be stimulated to be opened. Thus, channels channel that allows Na to slowly enter cell as depolariza- can be described as being in the resting state (closed and tion reaches –70 to –90 mV and, possibly an outward MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 340 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP

340 PART II ● ADULT CARDIAC SURGERY

rectifying K channel that reduces K flow as repolarization depolarization (cellular excitation), and the cascade of progresses) result in an unstable “resting” membrane events leading to cellular concentration changes locally potential. Thus, the resting membrane potential of nodal within the cell. cells will spontaneously diminish from about 70 mV to Phase 1 depolarization, mediated by opening of volt- about 50 mV, at which time voltage-dependent Ca2 age-gated fast Na channels, depolarizes the membrane to channels will open and allow complete depolarization. a point at which L-type Ca2 channels can open (Fig. Finally, nodal tissue (predominantly AV node) con- 19-4). The influx of calcium through these (dihydropyri- tains a K channel that is central to pharmacologic inter- dine-sensitive) voltage-gated channels, especially ventions commonly used to treat dysrhythmias. This through those located along the T tubules, increases channel, activated by adenosine and by acetylcholine intracellular calcium concentration in the vicinity of the (IKach,Ado), allows K to exit the cell upon stimulation by SR. (The calcium channels on the SR are termed ryan- either adenosine or acetylcholine. The exit of K makes odine-sensitive calcium channels because the compound the membrane potential more negative, hyperpolarizing ryanodine induces their opening). This triggers the the cell and making depolarization more difficult. Thus, opening of calcium channels in the SR membrane, acetylcholine reduces sinus node spontaneous depolar- releasing calcium stored in the SR. The result of calcium ization and adenosine blocks transmission through the entrance into the cell via L-type calcium channel opening AV node (Fig. 19-3). combined with release of calcium from SR stores is a dra- As suggested earlier, intracellular calcium concentrations matic increase in calcium concentration of the cytoplasm regulate myocyte contraction by controlling the steric rela- surrounding the contractile myofilaments. High concen- tionship between myosin and actin myofilaments through trations of calcium allows binding of calcium to troponin the interaction of calcium with troponin. Cell membrane C of the thin filament, modulating the troponin such depolarization stimulates the cascade responsible for that tropomyosin (attached to troponin) gets moved changing intracellular calcium concentrations around from its position of preventing interaction between actin the contractile myofibrils. Excitation-contraction cou- (of the thin filament) and myosin. The strength of bond pling refers to the interdependence of cell-membrane between actin and myosin is decreased by acidosis, high

Atrial and ventricular cells Sinoatrial node cells INa O or small I − ICA-L CA L ICA−T ICA-T I[NS] INaCa INaCa

II

INa-B IK1 O IK IK I 1 to 2 ? IK[ACh] IK[ACh] ICI ? Ipump Ipump I[KATP] ?

Figure 19-3 A comparison of the stylized action potential of atrial and ventricular cells (left) vs sinoa- trial node cells (right) as well as the ionic currents whose contribution to each action potential is con- firmed. Other ion channels may exist. Ion current bar deflections depict only the approximate time course (not the magnitude) of the current. Brackets around channel names indicate the current is active only under pathologic conditions. Question mark indicates the uncertain presence of this chan- nel in the sinoatrial node. INS Calcium gated channel, sodium inward current; INaCa electrogenic Na -Ca2 exchange current; Ik(ACh) acetylcholine dependent potassium current INS ICl Chloride current; Ipump electrogenic pump; If sodium dependent inward current; INa-B inward background sodium current. (From Sicilian Gambit: a report of the Task Force of The Working Group on Arrythmia of the European Society of Cardiology. Circulation. 84:1831–1851, 1991 P1835, Figure 2) MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 341 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP

Chapter 19 ● Cardiovascular Function and Physiology 341

Figure 19-4 Calcium transport in ventricular myocyte. PLB phospholambam, RyR Ryanodine Receptor, X Exchanger.

concentrations of Mg2, or high concentrations of cium concentrations by facilitating calcium entrance into phosphate. This bond is enhanced by caffeine and by the cell (via L-type calcium channels) as well as calcium beta-adrenergic stimulation. Beta-adrenergic stimulation release from compartments within the cell (i.e., the SR). increases actin-myosin bonding through a cascade that Beta-agonist stimulation also expedites relaxation. results in the activation of myosin binding protein C. Relaxation results from a drop in cytosolic calcium con- centrations, decreasing calcium binding to troponin C and allowing tropomyosin to return to a position that inhibits interaction between actin and myosin. Although Regulation of myocyte function by the some cytosolic calcium leaves the myocyte through the myocyte cell-surface receptor sodium-calcium exchanger on the cell surface, the pre- dominant method of lowering cytosolic calcium levels is Beta receptors reuptake by the SR. The pump mediating calcium reup- How can beta stimulation result in so many divergent take by the SR is dependent upon ATP and regulated by effects (e.g., increased inotropy, increased lusitropy)? The the phosphorlylation of phospholamban. Beta stimula- beta receptor is a protein which is incorporated within the tion facilitates relaxation by two mechanisms. First, it cell membrane, spans the entire depth of the membrane, results in phophorylation of troponin I by PKA, expedit- and has components which extend into the cytoplasm as ing dissociation of calcium from troponin C. Beta stimu- well as components exposed on the surface of the cell.4,5 lation also results in phosphorylation of phospholamban, When an extracellular agonist stimulates the portion of which speeds up calcium reuptake into the SR. the receptor exposed on the cell surface, a conformational change in the beta receptor allows the portion of the Muscarinic receptors receptor protruding into the cytoplasm to bind to a G Muscarinic receptors sensitive to acetylcholine are also protein (i.e., it is a G protein–coupled receptor). G pro- present on the myocardium. In particular, the heart con- teins have multiple components and stimulation of the G tains the m2 subtype of muscarinic receptor.6,7 Like beta protein causes dissociation of the subunits so that each receptors, muscarinic receptors appear to be incorporated subunit is free to regulate its particular effector. One such within the cell membrane, span the entire depth of the effector is adenylate cyclase, which is activated to increase membrane, contain components exposed to the extracel- intracellular concentrations of cAMP and thereby activate lular fluid and components exposed to the intracellular protein kinase A (PKA). Activated PKA is then capable of fluid, and coupled to a G protein. The G protein to which phosphorylating multiple intermediaries of excitation- the m2 receptor is coupled has inhibitory effects upon contraction. For example, it increases intracellular cal- adenylate cyclase and is sensitive to pertussis toxin. In fact, MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 342 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP

342 PART II ● ADULT CARDIAC SURGERY

the negative inotropic effects of m2 receptor stimulation within myocytes parallel bands that appeared to move appear to be indirect; i.e., they can be demonstrated only toward each other as the myocyte shortened. These in the setting of baseline stimulation adenylate cyclase. It bands were defined as the ends of the contractile unit of therefore appears that their negative inotropy results the myocyte and given the name “sarcomeres.” The inte- entirely from this inhibitory effect on adenylate cyclase. grated shortening of a series of sarcomeres results in In the atria and nodal myocytes, m2 receptors appear myocyte contraction. to have a direct effect (i.e., not dependent on baseline The sarcomere contains two types of coaxially aligned stimulation) on the inward rectifying potassium channel filaments that differ in their component protein (myosin that maintains phase 4 (resting) membrane potential. By vs. actin/tropomyosin/troponin) as well as in thickness opening this channel though a direct action of the G (myosin myofibrils are thicker, actin/tropomyosin/tro- protein upon the channel, m2 receptor stimulation ponin myofilaments are thinner). The myosin filaments hyperpolarizes the resting membrane to slow the auto- composing the thick myofilament is a mixture of “heavy” maticity rate of the cells. and “light” chains. Specifically, each thick filament con- tains two heavy myosin chains and each heavy myosin Adenosine receptors chain is associated with two light myosin chains. Each thick Another G-protein receptor found to by physiologically filament is itself composed of an actin polymer as well as important in the heart is the adenosine receptor. There are tropomyosin and troponin proteins bound to each other. three basic subtypes of adenosine receptors (A , A , A ), 1 2 3 Thin and thick filaments are aligned as follows. Each with A and A subtypes inhibiting adenylate cyclase– 1 1 thin filament is aligned end-to-end with another thin fil- inhibitory G proteins while A receptors increase adenylate 2 ament. Each pair of thin myofibrils is straddled by a sin- cyclase via stimulatory G proteins.8 These receptors also gle thick filament lying parallel to it. Within the myocyte, regulate other pathways via G proteins. Thus, A and A 1 1 the contractile unit containing a pair of thin myofila- subtypes mediate the catabolism of phospholipids while A 2 ments and their associated thick myofilament is bound receptors regulate phosphoinositide metabolism. on the ends by a Z band. The Z band (for Zuckung, the Two clinical effects of exogenous adenosine can be German word for “contraction”) is a dark band visible by traced back to distribution and effects of various adeno- electron microscopy and corresponding to the site to sine receptors. A receptors are located with high concen- 1 which the ends of a series of parallel units of myosin with tration in the nodal tissues. Stimulation of these receptors their paired actin thin filaments are anchored. This is opens the inward rectifying potassium channel that main- considered to define the ends of a sarcomere, the con- tains phase 4 (resting) membrane potential. Like the tractile unit of the myocyte. Under appropriate stimula- effects of m2 receptor stimulation, opening this channel tion, the myofibrils of a thin-filament pair will move through a direct action of the G protein on the channel, closer to each other through an interaction with the stimulation of the m2 receptor hyperpolarizes the resting adjacent thick filament. Because each member of a thin- membrane to slow the automaticity rate of the cells. In the filament pair is anchored to Z bands, this coaxial move- coronary vasculature, A receptors predominate. Their 2 ment draws the Z bands within the cell closer to one stimulation results in vasodilation, likely through G pro- another and the cell shortens. tein–mediated activation of intracellular adenylate cyclase. The thick myosin filament is attached to the Z band by Alpha-adrenergic receptors a protein called titin or connectin. This protein contains a There is growing evidence that alpha, adrenergic stimu- nonmalleable portion that anchors the filament to the lation of myocytes results in a positive inotropic effect.9 Z band as well as a distensible portion that enfolds on The mechanism and clinical importance of this is unclear. itself if the sarcomere is not stretched. On stretching, the It may also be coupled to myocardial hypertrophy. Z bands are pulled farther apart from one another and the enfolded portion of the titin protein is extended. When stretching is relieved, the elastic recoil of the titin molecule helps to actively restore the sarcomere to its MYOCARDIAL CONTRACTILE FUNCTION resting length (Fig. 19-5). The movement of thin filaments is an energy-requiring The sarcomere as a contractile element process regulated by local calcium concentrations within Contractile apparatus the cell. Two thin filaments move toward each other in Like all muscle cells, cardiac myocytes have the capacity the longitudinal plane by each “pulling” itself along a to contract and relax. This capacity is conveyed by a shared myosin filament. Under “resting” conditions, series of protein filaments (myofibrils) oriented along physical contact between actin and myosin filaments is the longitudinal axis of the cell. The alignment of prohibited by the tropomyosin component of the thin myofibrils is consistent and repetitive, resulting in a filament. Tropomyosin is a protein strand that can inter- characteristic pattern visible by electron microscopy.1,10 digitate between actin and myosin, preventing their phys- Using electron microscopy, early investigators identified ical contact. Tropomysin can be moved out of place by MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 343 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP

Chapter 19 ● Cardiovascular Function and Physiology 343

TITIN's I-band segment anchoring segment elastic segment THIN FILAMENT slack THICK FILAMENT sarcomere A

shortening stretch 625

STRAIGHTENING OF ELASTIC SEGMENT 500

g) 375 μ ( Ti-102 9D10 T12 T12 9D10 Tr-102 passive force BC 250 125

0 1.8 1.9 2.0 2.1 2.2 2.3 2.4 40 stretch sarcomere length (μm) 20

g) 0 ELONGATION OF ELASTIC SEGMENT μ ( restoring force (UNFOLDING OF lg AND PEVK DOMAINS) −20

−40 1.7 1.8 1.9 2.0 sarcomere length (μm) D

Figure 19-5 Working hypothesis force generation (passive and active) by titin. The black beads nonelastic component of titin’s I band; white beads elastic (force-generating) component of titin. A, Slack sarcomere: the elastic component is highly folded. B, Shortened sarcomere: elastic component straightened to develop restoring forces. C, Stretched sarcomere: elastic component straightened to develop passive force. D, Further sarcomere stretch unfolds the molecular subdomains of titin’s elastic component, generating high levels of passive force.

the actions of the third protein of the thin filament, the 1.7 to 2.4 m).11,12 Mechanistically, this increased con- troponin protein. The presence of calcium sterically alters tractility can be divided into two parts: (1) an immediate the troponin, causing it to reorient itself within the thin increase in force that is unaccompanied by a change in filament and thereby moving the tropomyosin strand to intracellular calcium concentration and (2) an additional which it is attached. The movement of the tropomyosin increase in force of delayed (minutes) onset which is strand removes the physical barrier preventing actin- associated with an increase in intracellular calcium. The myosin interaction and allows the thin filaments to move increase in intracellular calcium causing the second closer to each other along a shared myosin chain. phase is probably mediated by changes in the cell mem- brane. The first phase, which apparently involves a change in myofilament sensitivity to calcium, is the Myocardial contractile physiology Frank-Starling phenomenon (named for Otto Frank and Contractility is the ability of a myocyte to shorten, mea- Ernest Starling, who initiated the concept based upon sured at a given preload and a given afterload. Changing experimental findings they made at the beginning of the the preload will alter contractility due to the length-tension twentieth century). Although it was initially hypothe- relationship. Changing the afterload will alter contractil- sized that sarcomere stretching improved myosin-actin, ity because it mandates generation of a different wall the increase in force of contraction is observed even stress to achieve shortening. when the sarcomere is stretched to distances that would begin to reduce the potential for actin and myosin cross- Length-tension (Frank-Starling) relationships bridge formation. An alternative explanation is that The force of contraction of a cardiac myocyte increases stretching the myocyte narrows the sarcomere, reducing when the sarcomere is stretched (within the lengths of the spacing between myosin and actin filaments. This MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 344 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP

344 PART II ● ADULT CARDIAC SURGERY

facilitates myosin-actin interaction. Studies in which the “Anrep effect” interfilament distance is reduced by cellular dehydration As stated above, there is a two-phase response of myocytes result in an increased calcium sensitivity of contractile to an abrupt stretch.15 The first phase is an increase in strength, as is seen by myocyte stretch.12 A stretch- contractility, which occurs without a change in cytosolic induced change in myofilament sensitivity to calcium by calcium. This is known as the Frank-Starling effect. There a yet unexplained mechanism remains a third possible is a delayed second phase, which is associated with an explanation. increase in cytosolic calcium. The change in intracellular calcium seems to be independent of the SR, although the Force-velocity relationships exact mechanism behind the rise remains obscure. To measure contractile force free of compounding influ- ences from preload, afterload, or heart rate, the concept “Treppe effect” of measuring the velocity of shortening in a myocyte Increasing heart rate increases the strength of contrac- with no afterload has been developed.13,14 In such a sce- tion. This phenomenon, termed the Treppe effect

nario, the maximal velocity of shortening (Vmax) would (Treppe, German for “step”) is associated with an increase be a measure of the inotropy of a myocyte. Practically in intracellular calcium concentrations.16 This is sug- speaking, it is difficult to completely remove external gested to be due to an inability of the SR and myocyte resistance from a contracting myocyte. The value of calcium extruding pumps to completely return cytosolic

Vmax must therefore be extrapolated from the maximal calcium to baseline levels between sequential cell depolar- velocities observed when a myocyte is made to contract izations. The result is a buildup of calcium within the cell. against a series of different afterloads. At one extreme of this series would be the minimal afterload at which the myocyte is no longer able to shorten at all (V 0). This max CARDIAC PUMP FUNCTION relationship is hyperbolic rather than linear. Although the reason for this hyperbolic relationship remains Myocyte cytoskeleton unclear, it is felt to be due in part to shortening inactiva- tion and in part to elastic forces that passively resist stretch Synchronized contraction of cardiac myocytes is neces- (at long sarcomere length) or shortening (at short sar- sary for most efficient pumping function of the heart.10 comere length). Such passive elastic forces could be con- This requires tight adhesion of cells along the axis of tributed by titin (Fig. 19-6). their shortening as well as organized propagation of the

2.5

Corrected for passive tension 2.0 Uncorrected

1.5

1.0 Velocity (ML/s) Velocity

0.5

0.0 0.0 0.2 0.4 0.6 0.8 1.0 Relative Tension (P/Po)

Figure 19-6 The influence of resting tension on the shortening velocity of isolated myocytes. The general relationship of faster shortening velocity observed when rest- ing external tension is decreased can be seen whether passive (intra-myocyte) ten- sion is present (open circles) or mathematically excluded from the calculations (closed circles). Figure 7 from Sweitzer NK and Moss RL. Determinants of loaded shortening velocity in single cardiac myocytes permeabilized with alpha-hemolysin. Circ Res. 73:1150-1162, 1993 MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 345 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP

Chapter 19 ● Cardiovascular Function and Physiology 345

contractile stimulus. To accomplish this, the basic struc- they are stretched. This has led physiologists to view the ture of the myocyte is one of contractile myofibrils heart as a series of sarcomeres demonstrating length-ten- attached, via fascia adherens, to cadherin anchors at the sion relationships—the model conceptualized by Frank ends of the myocyte. The myofibrils are held in align- and Starling. In this regard, the capacity of the heart to ment by an intracellular scaffold-like network consisting eject blood against a given resistance increases as the vol- of the protein desmin. These desmin “scaffolds,” travers- ume within the heart immediately prior to initiating systole ing the myocyte at intervals along its longitudinal axis, (i.e., the end-diastolic volume) increases. This relationship, are anchored to the lateral sarcolemmal wall by plaques and its analogy to the length-tension relationship of indi- called costameres. These plaques, rich in the protein vin- vidual sarcomeres, is demonstrated in Fig. 19-7A and B. culin, act both to maintain the spatial interval between Because the volume within equally compliant hearts is the desmin scaffolds as well as to mechanically link the directly proportional to the pressure within the heart, this cells laterally to the sarcolemmal membrane and extracel- Frank-Starling model can also be displayed as an effect of lular matrix. The desmins are anchored to the cadherins pulmonary capillary wedge pressure on the stroke volume at the longitudinal end of the myocyte by desmosomes. or ejection fraction of the ventricle. The site of end-to-end adherence between two myocytes is called the intercalated disk. This site func- Preload and diastolic compliance tions to physically anchor two myocytes as well as allow Filling of the ventricular chamber with blood distends the for intercellular continuity of action potential propaga- ventricle, stretching the individual sarcomeres of the com- tion and chemical signaling between these myocytes. ponent myocytes. The magnitude of force that must be The physical anchor is maintained by junctions between overcome to stretch a sarcomere to a given length varies cadherins of adjacent cells. The communication between with the recoiling forces of the sarcomere. Analogously, myocytes connected in the longitudinal axis is made pos- the magnitude of the three-dimensional force (i.e., pres- sible by channels composed of two connexons. Each sure) needed to distend the ventricular chamber to a channel is comprised of two connexons aligned coaxially, given volume varies with the compliance of the chamber. and each connexon is comprised of six connexin mole- Distending two ventricles with the same volume of blood cules arranged in a circle. There are different types of will result in a higher intraventricular pressure within the connexin and different densities of connexon channels less compliant ventricle. Furthermore, the compliance of among different myocytes. a chamber tends to decrease as the chamber is filled. The characteristics of these intercalated disks are quite Thus, adding 20 mL to a nearly empty ventricle increases important in determining the ease of communication the intraventricular pressure much less than does adding between myocytes in the longitudinal plane. Consistent 20 mL to the same ventricle already containing 200 mL with this, the composition and number of connexons of blood. varies with the electrophysiologic requirements of the myocytes involved. Myocytes of the atria and ventricles, Afterload Under normal circumstances, the pressure preventing a serving principally a contractile function, contain a fair ventricular chamber from contracting (i.e., afterload) is abundance of connexon channels, with connexin 43 being the pressure required to sufficiently distend an arterial the most abundant connexin present. In the sinus node bed to accept the blood ejected by the contracting ven- and atrioventricular node, there are few connexon chan- tricle. Thus, the afterload to the left ventricle (LV) is the nels joining cells longitudinally. In the sinus node, this pressure within the systemic arterial system. As with all allows the natural depolarization of the cells to occur elastic chambers, the compliance of the arterial bed without inhibition by the hyperpolarizing effects of the decreases as it fills with blood. Thus, the afterload of the surrounding contractile myocytes. In the atrioventricular LV increases as the ventricle empties and ejects blood node, the girth of connexon channels slows communi- into the aorta. At some point, the ventricle stops ejecting cation between cells, slowing transmission of the electrical because the pressures required to further distend the sys- impulse. By contrast, the cells of the Purkinje system temic arterial system exceed those that the ventricle is contain high numbers of large connexon channels com- capable of generating. This point marks the end of phys- posed of the high-conductance connexin 40. This allows iologic ventricular systole. rapid transmission of electrical impulses throughout the Purkinje system. The cardiac cycle Pressure-volume loops The above discussion empha- Cardiac mechanics sizes three points: (1) the extent to which ventricular con- Frank-Starling model tractility is facilitated by optimizing sarcomere length at The ability of the heart to contract is influenced by the any point in its pressure-generating cycle is reflected by resting volume within the heart in much the same way the intraventricular volume at any point during contrac- as the contractility of its component sarcomeres (and tion; (2) the compliance of the LV is reflected by the pres- myocytes) is influenced by the resting length to which sure generated within the LV for any increase in LV volume MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 346 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP

346 PART II ● ADULT CARDIAC SURGERY

Increased stiffness

Decreased distensibility

40 OS Normal LV pressure LV 4 ΔP4 30 ΔP2 OS2 20 ΔP3 ΔV 10 LV end diastolic PVR OS3 ΔP1 0 Δ LV pressure (mmHg) LV V OS1 −10 0 25 50 LV volume A LV volume (ml) B

Figure 19-7 A: Determining left ventricular compliance by changing left ventricular volume to define end-diastolic pressure- volume relationship. The curvilinear nature of ED-PVR suggests that normal LV becomes more resistant to filling as end dias- tolic volume increases B: Illustration of the effect of different left ventricular operant stiffness (OS) conditions on end-diastolic pressure-volume relationship increasing slope of ED-PVR suggests decreasing compliance of myocardium/intercellular compo- nents decreasing slope of ED-PVR Iusitropy parallel shift up of ED-PVR (with same slope) suggests extramyocardial forces (RV loading/interventricular forces; pericardial constraint)

during relaxation; and (3) the capacity of the LV to eject the pressure-volume loop. Finally, the mitral valve opens blood depends on its ability to generate enough pressure and blood starts filling the ventricle. Although the ventricle to overcome afterload. This illustrates the utility of evalu- has not yet begun to contract, the pressure within it slowly ating ventricular performance in terms of the relationship increases as blood enters across the mitral valve prior to ini- between the pressure and volume within the ventricle at tiation of myocyte shortening (Fig. 19-8). any point in time. As indicated above, the end-systolic pres- Active contraction of the ventricle is indicated by the Contractility sure-volume point on the pressure-volume loop indicates bottom right-hand corner of the pressure-volume square. the limit to the pressure-generating capacity of the ven- At this point, intraventricular volume stops increasing tricle at a given preload. By changing the afterload exper- (marking the end of diastole) and intraventricular pres- imentally, a series of pressure-volume loops can be gen- sure begins to rise rapidly. At the top right-hand corner of erated such that the minimal preload required to gener- this relationship, the aortic valve opens. Thus, by generat- ate any given pressure can be determined. The straight ing a constant pressure, the ventricle is able to continually line connecting the end-systolic pressure-volume points eject blood into the aorta. The volume within the ventri- of this series of loops is termed the end-systolic pres- cle thereby decreases, myocytes subsequently contract, sure-volume relationship (ESPVR). This relationship is and the sarcomere shortens from its ideal length for force an indication of the strength of contraction of the ven- generation. The myocyte shortens until sarcomere length tricle. A more vertical line or one shifted more to the left has been reduced so much that it is no longer able to indicates greater contractility. A more horizontal line or generate the force needed to further shorten. This point, one shifted more to the right indicates less contractility indicated by the top left-hand corner of the pressure-vol- (Fig. 19-9). ume loop, is termed the end-systolic pressure-volume point and represents the dependence of ventricular Compliance Similar to its usefulness in evaluating LV shortening on the volume of the LV and its capacity to contractility, the pressure-volume loop can be used to generate pressure. From this point, the ventricle ceases monitor the diastolic function of the heart. The bottom- generating force and the intraventricular pressure decreases right corner of the pressure-volume loop marks the point as is represented by the vertical line marking the left side of at which diastole ends and systole begins for the ventricle. MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 347 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP

Chapter 19 ● Cardiovascular Function and Physiology 347

120 ESV Myocardial wall stress C A circular object is envisioned as a series of 360 straight 90 B lines each offset from one another by 1 degree and each tangential to the radius of the circle. The stress on the 60 wall of a distended, elastic circle can then be viewed as the force distending each of these tangential lines. In the 30 case of the heart, the stress on the wall of the ventricle A PRESSURE (mmHg) LEFT VENTRICULAR D EDV can be thought of as the force stretching each of the 0 mocytes of the wall. The interrelationship of the factors 0 40 80 120 160 composing this force is a physical principle explained by LEFT VENTRICULAR VOLUME (ml) the law of Laplace. This law states that the tension in the wall is related to the pressure gradient across the wall (P), Figure 19-8 Schematic depiction of left ventricular pres- the radius of the ventricle (R), and the wall thickness (th) sure-volume relationship. A end diastole; upward arrow as follows: isovolumetric contraction; B Aortic valve open; leftward arrow = ventricular ejection; C aortic valve closure; down- T [(P)(R)] / [(2)(th)] ward arrow = isovolumetric relaxation; D mitral valve opening; rightward arrow diastolic ventricular filling Thus distending the ventricle (increasing the radius R) increases the stress on the ventricular myocytes. By con- trast, hypertrophy of the ventricle (increasing wall thick- This point, the end-diastolic pressure-volume point, ness th) decreases tension on the wall. This explains why indicates the pressure required to fill the noncontracting ventricular hypertrophy is a natural adaptation of the LV ventricle with a given volume of blood. A series of pres- to hypertension. sure-volume loops can experimentally be created to eval- Cardiac energetics uate the pressure generated within the noncontracting Molecules consist of positively charged protons and neg- heart as it is filled with greater or lesser volumes of atively charged electrons in close proximity. The close blood. The line connecting the end-diastolic pressure- proximity of the positively and negatively charged parti- volume points of this series of loops is termed the end cles is maintained by electromagnetic force or “bonds.” diastolic pressure-volume relationship (EDPVR). Unlike According to the first law of thermodynamics, the energy the ESPVR, the EDPVR tends to be curvilinear because of these bonds must be converted to another form if the the compliance of elastic containers tends to decrease as bond is broken. By breaking these bonds under controlled the container is filled. Nevertheless, an EDPVR line that conditions, living organisms can harness the energy of the is more vertical or raised higher along the vertical axis bonds and use if for doing work (moving objects over suggests decreased compliance of the ventricle. An distance). EDPVR line that is more horizontal or lowered along The energy form most efficiently utilized by cells of the vertical axis suggests an increased compliance of the living organisms is that contained in the bonds joining ventricle (Fig. 19-7A). phosphate residues to certain organic compounds in the form of adenosine triphosphate (ATP), adenosine diphos- A phate (ADP), or creatine phosphate (CP). The energy ingested by organisms is often in the form of fatty acids, proteins, and carbohydrates (having few ATP molecules). To convert the energy from the nonphosphate bonds ingested by organisms to a form that can be utilized by cells of living organisms (the phosphate bonds of ATP), a cascade of enzyme-mediated reactions is utilized. This cas-

Ventricular pressure cade is driven by the energy released from the transfer of electrons when reduced (containing electrons that can be donated) forms of the intermediaries nicotinamide ade- Ventricular volume nine dinucleotide (NADH) and flavin adenine dinu- Figure 19-9 The Frank-Starling law of the heart–End- cleotide (FADH) are oxidized (give up the electrons they systolic pressure is determined by end-systolic volume and can donate). The NADH and FADH donate these elec- 17,18 is independent of end-diastolic volume. The end-systolic trons to oxygen, forming water and releasing energy. pressure-volume relationship is altered by the ventricular The ingested form of energy (glucose, amino acids, contractile state. As indicated by dashed line, increased fatty acid) is converted to a form that can be utilized by inotropy increases the ejection volume and end systolic the cell (ATP) through a series of reactions involving pressure at any given end-diastolic ventricular volume. conversion of glucose, amino acids, and fatty acids to acetyl CoA (glycolysis converts glucose to acetyl CoA via MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 348 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP

348 PART II ● ADULT CARDIAC SURGERY

pyruvate as an intermediary; diverse processes convert energy demands of the myocardial tissue. The factors amino acids to acetyl CoA; beta oxidation converts fatty affecting flow during periods of increased metabolic acid to acetyl CoA). The Kreb cycle allows acetyl CoA to demand likely include neurohumoral factors as well as the donate the electron-containing hydrogen ions needed to factors responsible for autoregulation. reduce FAD to FADH2 and reduce NAD to NADH H. The subsequent enzyme-mediated transfer of elec- Autoregulatory mechanisms of coronary blood flow trons from FADH2 and NADH H to oxygen ini- tially creates initially creates a high concentration of Coronary blood flow is autoregulated.19 That is, factors electrons within the intermembrane space of the mito- intrinsic to the heart and its vasculature assure that flow chondria. This gradient then drives the formation of to the heart is kept constant in spite of changes in perfu- ATP from ADP and inorganic phosphate. sion pressure of the heart. It is felt that the majority of Under normal circumstances, 60 to 80 percent of the the vascular resistance to coronary blood flow is supplied ATP utilized by the heart is generated from fatty acids; by vessels smaller than 100 to 150 m in diameter and the remainder is generated predominantly from glucose. that these vessels represent the site of vascular autoregu- Paradoxically, the ATP production from fatty acids is less lation. Although the exact mechanisms responsible for sensitive to ischemia than is the production from glucose. this autoregulation remain a mystery, it is felt that a mix- Ischemia therefore results in a reduction of the conversion ture of metabolic products, myogenic factors, and extrin- of pyruvate to acetyl CoA, thereby increasing the conver- sic compression from surrounding tissue play a role. sion of pyruvate to lactate by an alternative pathway. The Metabolic products felt to be candidates for regulat- increased lactate production results in cellular acidosis. ing coronary control include adenosine, prostaglandin, The lack of oxygen available to accept hydrogen ions lib- oxygen carbon monoxide, carbon dioxide, and potas- erated by the Kreb cycle increases intracellular [H], fur- sium concentrations in the tissue. Adenosine is an obvi- ther exacerbating intracellular acidosis. Finally, the lack of ous candidate because insufficient oxygen delivery raises oxygen reduces the cellular capacity to bind phosphate to tissue adenosine levels as inorganic phosphate moieties ADP. Phosphate residues are sequentially removed from are sequentially removed from ATP in an attempt to ADP, degrading it first to adenosine monophosphate harvest the energy of their bonds during hypoxia. (AMP) and then to adenosine. The adenosine exits the However, removal of adenosine from interstitial spaces myocyte to stimulate adenosine receptors, causing pain does not prevent coronary autoregulation, leaving other (angina). candidates as contributors. Prostaglandins can also cause As an alternative to oxidative phosphorylation, the body dilation through stimulation of G protein–coupled can also restore ATP levels by transferring a phosphate receptors. This influence may be more pronounced in moiety from phosphocreatine (PC) to ADP. This phos- scenarios when nitric oxide is less abundant, as in severe phate transfer is utilized by the heart, skeletal muscle, and atherosclerotic disease. Partial pressure of oxygen in the brain [the three organs containing the enzyme creatinine circulating blood or surrounding tissue may play a direct phosphokinase (CPK) under conditions of inadequate per- role by stimulating the opening of vascular smooth mus- fusion]. The phosphocreatine is formed by the transfer of cle cell K channels, which are coupled to the hypoxia-

phosphate from ATP to creatine, a transfer occurring most sensitive cytochrome b558. Similarly, dropping levels of readily under conditions of adequate tissue perfusion. ATP can stimulate the opening of ATP-sensitive K chan- nels in smooth muscle cells, causing vascular dilation. Nitric oxide is known to dilate coronary vasculature through a mechanism involving the activation of soluble CORONARY BLOOD FLOW guanylate cyclase. The release of nitric oxide is stimu- lated by hypoxia. Carbon monoxide can also activate sol- Normal coronary blood flow uble guanylate cyclase, making carbon monoxide Coronary blood flow supplies 60 to 90 mL/min of blood (produced from the breakdown of heme to biliverdin) a per 100 g of resting myocardium. The energy driving this possible mediator. Similarly, carbon dioxide has been perfusion is the pressure gradient between the proximal shown to cause coronary dilation, possibly through a aorta (the origin of the coronary arteries) and the intraven- mechanism involving nitric oxide and/or cyclic guano- tricular pressure.19 The influence of the intraventricular sine monophosphate (GMP). pressure derives from the fact that the same wall stresses Myogenic contributions to autoregulation involve the responsible for generating intraventricular pressure also act ability of smooth muscle cells to “sense” flow and alter to compress the coronary vessels traveling through the tone to maintain flow constant. Mechanisms by which myocardial wall. Because the gradient between intraaortic smooth muscle cells accomplish this are both unclear and pressure and intraventricular pressure is greatest when the difficult to evaluate in vitro. Still, it is apparent that the ventricle is not contracting, the majority of coronary blood majority of this response is contributed by vessels flow occurs during ventricular diastole. Coronary blood between 30 and 70 m in diameter. The cascade proba- flow is both autoregulated and influenced by changing bly involves the sensing of altered intraluminal pressure MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 349 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP

Chapter 19 ● Cardiovascular Function and Physiology 349

or shear stress, the activation of nonspecific ion channels as well as conduction through AV node and Purkinje in the smooth muscle cell, and the phosphorylation of cells. myosin light chains in the smooth muscle cell by myosin light chain kinase. Myocardial infarction An insufficient myocardial oxygen supply, if maintained External compression of the coronary microvascula- too long, results in the utilization of all energy reserves ture by contraction of the surrounding tissue can also act by the myocardium. This leads to irreversible myocyte as a feedback control of coronary blood flow. As coro- damage and begins to be seen after 20 min to 2 h of nary blood flow becomes inadequate, the force of ischemia. With no energy, even the basic requirements myocyte contraction decreases due to limited energy for cell survival (i.e., exclusive of contractile function) supplies. This decreases the magnitude of the external cannot be maintained. Transmembrane ion concentra- forces acting to compress small coronary microvascula- tions are lost, and osmotic forces cause cell expansion to ture, facilitating coronary blood flow. the point of membrane disruption as well as lysis of intra- cellular organelles. The tight junctions of intercalated disks between cells are disrupted, and cell-to-cell com- Physiologic consequences of coronary insufficiency munication is lost. Recovery cannot occur following such catastrophic changes. Myocardial ischemia Myocardial ischemia is the condition whereby the myocar- dial blood flow and/or oxygen supply is insufficient to sat- “Stunned” myocardium isfy the demands of the myocardial tissue. This can reflect Reperfusion of ischemic myocardium does not always 20,21 either an inappropriate limitation to blood flow (i.e., result in the return of normal myocyte function. low-flow ischemia), an inappropriate excess in myocardial There is often a persistent dysfunction of reperfused demand (i.e., high-flow ischemia), or low blood oxygen tissue in spite of blood and energy delivery capable of content such that oxygen delivery is insufficient in spite supporting much greater energy expenditure by the of appropriate blood supply and tissue demand (i.e., myocytes. The dysfunction that persists under these hypoxia). Myocytes respond by shifting their energy conditions is termed “stunning,” an important charac- metabolism from aerobic (mitochondrial) to anaerobic teristic of which is that it persists in the setting of a rela- (glycolytic) pathways. Alternative sources of stored energy tive abundance of energy delivery. Other characteristics (other than ATP) are utilized, such as creatine phosphate. include the retained capacity of stunned myocardium to These stores, however, are quite limited. As a result, increase the force of contraction on exposure to metabolites of the complete breakdown of ATP (such as inotropes as well as the lack of influence of beta ago- adenosine), metabolites of glycolysis (such as lactate), and nists or beta blockers on the rate of recovery of stunned a host of other substances (such as bradykinin and myocardium. The duration of stunning depends on fac- angiotensin) are released into the interstitial fluid. tors such as the severity and duration of ischemia as well When myocardial energy demands exceed the supply, as the adequacy and immediacy of return of normal energy reserves begin to decrease. This can result in blood flow. dysfunction of any of the energy-dependent activities The cascade responsible for stunning is incompletely commonly attributed to the myocyte. Thus diastolic understood. Still, it is felt to involve oxygen-derived free function, systolic function, automaticity, and/or inter- radicals released during the early moments of reperfusion. cellular communication can each be impaired. Diastolic Furthermore, it can be attenuated by utilizing iron chela- dysfunction impairs relaxation, making it more difficult tors such as deferoxamine. This suggests that hydroxyl to fill the ventricle with blood. Diastole, driven by ATP- radicals, generated from superoxide by an iron-catalyzed dependent calcium uptake by the SR, is more sensitive reaction, mediate at least part of the reaction. There is to limited energy supplies than is systole. Still, insuffi- speculation that nitric oxide released during reperfusion cient energy impairs force generation by the sarcom- may contribute through the formation of peroxynitrite eres, limiting ventricular contraction. The lack of after binding with the superoxide radicals. Unfortunately, ventricular filling resulting from diastolic dysfunction free-radical scavengers have thus far been only inconsis- hinders compensation by the Frank-Starling mechanism. tently beneficial in preventing myocardial stunning. In any With more dramatic imbalances between myocardial case, altered availability of calcium or sensitivity of myocyte oxygen supply and demand, all contractile capacity of myofibrils to calcium are chief suspects as to the mecha- the ventricle is lost. Whether this loss of contractile nism by which contractile function is impaired. function is temporary or permanent depends in part upon the severity of the energy supply-demand mis- “Hibernating” myocardium match as well as the duration of its existence. Finally, Myocardial hibernation is another state of reversible insufficient energy impairs maintenance of membrane myocyte dysfunction related to an insufficient blood sup- potentials by the nodal cells. This compromises the ply.22 In contrast to myocardial stunning, which occurs normal development of automaticity by SA node cells following reperfusion, myocardial hibernation occurs MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 350 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP

350 PART II ● ADULT CARDIAC SURGERY

while impaired blood delivery is ongoing. Thus, it is felt factor IXa. This three-pronged approach to the inactiva- to be a way by which the myocyte preserves itself through tion of thrombin helps ensure the inability of thrombin decreasing energy expenditures to meet the energy sup- to convert fibrinogen to a fibrin clot. The activity of ply available. The mechanism of myocardial hibernation antithrombin is increased several thousandfold by the is also unclear. Light-microscopically, there is a decrease presence of heparin, another endothelial product. This in contractile elements, an increase in glycogen accumu- suggests that most of the effects of antithrombin likely lation, and an alteration in the morphology of both the occur on vascular surfaces. The protein C–protein S- mitochondria and the T tubules. These changes are thrombomodulin system works to destroy activated reversible, and contractile function is restored with the coagulation factors Va and VIIIa. Thus thrombin binds return of a normal blood supply. to thrombomodulin, which both removes the thrombin and allows the thrombomodulin to activate protein C. The protein C destroys coagulation factors Va and VIIIa Coronary endothelial function in a reaction that is accelerated by the vitamin K–depen- dent glycoprotein protein S. Tissue plasminogen activa- Rather than serving as a passive lining between the blood tor, a serine protease released by the endothelium, is and vascular smooth muscle, coronary endothelial cells responsible for the conversion of inactive plasminogen to play an active role in preventing the development of plasmin, which mediates fibrinolysis (Fig. 19-10). myocardial ischemia.23–25 Thus the endothelium promotes The vasodilatory effects of nitric oxide result from its anticoagulation, fibrinolysis, and vasodilation. It inhibits stimulation of soluble guanylate cyclase, leading to a inflammation, platelet aggregation, leukocyte adhesion, decrease in intracellular calcium. Nitric oxide’s anti- and smooth muscle cell proliferation. It also provides inflammatory effect results principally from its ability to antioxidant effects. The healthy endothelium accomplishes inhibit nuclear factor K-B, a transcription factor impor- these roles through the release of a series of mediators. tant in the regulation of many inflammatory proteins. It These include the antithrombotics (i.e., fibrin deposition inhibits platelet aggregation by decreasing intraplatelet inhibitors); antithrombin; protein C, protein S, throm- concentrations of calcium through a cascade similar to bomodulin, and tissue factor pathway inhibitor; and that by which nitric oxide causes vasodilation. It reduces the fibrinolytic tissue plaminogen activator. In addition, leukocyte adhesion by decreasing the expression of vascu- nitric oxide produced by healthy endothelium provides a lar cell adhesion molecule via inhibition of nuclear factor wide range of anti-ischemic actions from vasodilation, to K-B. Nitric oxide’s capacity to inhibit smooth muscle cell antithrombosis, to antiproliferation. proliferation is poorly understood but may involve its Antithrombin is a serine protease inhibitor which neu- activation of PKA. The effects of nitric oxide on free radi- tralizes thrombin and inhibits activated factor Xa and cal balance is complex, although it is a potent inhibitor of

Contact HMWK Factor VII XII KAL XIIa XI Tissue XIa Ca++ Factor IX ++ PL, Ca IXa

++ VIIIa + Ca + PL Factor VIIa

X Xa

++ Va + Ca + PL

Prothrombin Thrombin

Fibrinogen Fibrin

PL = Phospholipid

Figure 19-10 Intrinsic (Contact HMWK)/Extrinsic (Factor VII) pathways are labo- ratory classifications within the body, clotting initiated by exposure of Tissue Factor to factor VII (Extrinsic Pathway). The subsequent cascade results in pro- duction of Thrombin and Fibrin. HMWK = high molecular weight kininogen; kal kallidrein; PL phospholipid; Ca ionic calcium. MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 351 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP

Chapter 19 ● Cardiovascular Function and Physiology 351

free fatty acid, phosphatidylcholine, and low-density neurohypophysis releases vaopressin, stimulating vaso- lipoprotein (LDL) oxidation. constriction and thus exacerbating the demands on the The production of nitric oxide can be stimulated by dysfunctional myocytes. There is decreased sensitivity to neurohumoral mediators (e.g., acetylcholine), by prod- atrial and brain natriuretic peptides, probably as a result ucts released by circulating cells (e.g., bradykinin, sero- of receptor downregulation as well as increased activity tonin), or by mechanical forces (e.g., shear stress). Nitric of cyclic guanosine monophosphodiesterase. The loss of oxide production is impaired in the presence of athero- vasodilatory effects, a result of decreased sensitivity to sclerosis through a series of mechanisms. First, athero- these peptides, compounds the vasoconstrictive influence sclerotic plaques physically exclude endothelial cells from of angiotensin II and vasopressin. the stimulants for its release (e.g., shear stress). Second, A series of randomized placebo-controlled studies there is a direct effect of cholesterol components (e.g., have documented the beneficial effects of various medica- lysophosphatidylcholine, a component of oxidized tion classes in the progression and mortality of systolic LDL) on the nitric oxide signaling pathway [i.e., pro- dysfunction. Beta blockers, likely due (at least in part) to tein kinase C, G proteins, and caveolin–endothelial nitric their inhibition of the adrenergic pathway, improve both oxide synthase (eNOS) interaction]. Finally, cholesterol clinical status and overall mortality. Angiotensin-convert- enhances the activity of the superoxide-producing ing enzyme (ACE) inhibitors, likely due to their effect NADPH (reduced nicotinamide adenine dinucleotide upon the renin-angiotensin-aldosterone system, show ben- phosphate) oxidase and xanthine oxidase enzyme sys- efits similar to those of beta blockade. The effects of ACE tems within the vascular wall. Since oxygen radicals scav- inhibitors may be additive to those of beta blockers. There enge nitric oxide, this effectively decreases the is growing evidence that angiotensin-receptor antagonists bioavailability of the decreased amounts of nitric oxide demonstrate benefits similar to those of ACE inhibitors, produced. also likely through inhibition of the renin-angiotensin- aldosterone system. The effects of this class of medications may be additive to those of both beta blockers and ACE PHYSIOLOGY OF HEART FAILURE inhibitors. Although growing evidence as well as our cur- rent understanding of the pathophysiology of systolic dys- Systolic dysfunction function suggests that the role of angiotensin II receptor Systolic dysfunction is the impaired ability of the ventri- blockers will be similar to that of ACE inhibitors in the cle to generate force and shorten.26,27 This leads to fail- therapy of systolic dysfunction, they are currently not rec- ure when the compromise results in dyspnea, fatigue, ommended as an alternative to ACE inhibitors except in and/or fluid retention. The precipitating events can be those patients who cannot tolerate the latter. Similarly, ischemic or idiopathic. Although infiltrative (e.g., amy- although hydralazine with a nitrate may help to reduce loidosis) processes may cause systolic dysfunction, these the progression of abnormal myocardial/vascular growth, usually lead primarily to diastolic dysfunction. Symptoms there is currently not enough evidence to recommend this of systolic dysfunction lead to progressive deterioration combination as an alternative to ACE inhibitors except in in health-related quality of life and increased mortality. those patients who cannot tolerate the latter. Digoxin has Prognosis is worse when the etiology is ischemic rather been shown to improve symptoms, but it does not alter than nonischemic in origin. mortality. Calcium channel blockers may actually worsen The cascade leading to systolic dysfunction and its mortality in patient with compromised LV systolic func- progression is likely multifactorial. Endothelial dysfunc- tion. tion leads to the loss of beneficial products (nitric oxide, prostacyclin) and an increase in deleterious products (endothelin, angiotensin) from the endothelial cells. Diastolic dysfunction Decreasing blood pressure, a consequence of decreasing Diastolic dysfunction is an inability of the myocardium cardiac output, stimulates the adrenergic, the renin- to stop generating force and shortening as well as to angiotensin-aldosterone, and hypothalamic-neurohypophy- completely return to its unstressed force and length in seal systems as well as the natriuretic peptide pathways. the normal time period.28,29 This can occur in combina- Increased beta stimulation increases heart rate and may tion with or in the absence of systolic dysfunction. impair the ability of the SR to efficiently gather released Unfortunately there is no consensus definition of normal calcium. Chronic beta stimulation also increases the pro- systolic function. It is also difficult to determine what the duction of tumor necrosis factor alpha, interleukin-6, normal time interval is for the myocardium to revert and other inflammatory cytokines that exacerbate inflam- from a force-generating, contracting state to a state of mation, apoptosis, and fibrosis. Norepinephrine can exacer- unstressed force and length. Thus, although it is increas- bate myocardial ischemia, promote myocyte hypertrophy, ingly appreciated that isolated diastolic dysfunction can and affect apoptosis. Stimulation of the renin-angiotensin- cause symptomatic heart failure, this diagnosis requires aldosterone system increases cellular hypertrophy, inter- verification of the presence of heart failure, the absence of stitial fibrosis, and vascular myocyte mitogenesis. The systolic dysfunction, and the exclusion of other processes MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 352 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP

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(e.g., anemia, pulmonary dysfunction, hypothyroidism) mandated to compensate for this appear to be less dra- that can masquerade as heart failure. matic. Whether this represents influence from the Frank- Isolated diastolic heart failure may account for up to Starling effect is unclear. Nevertheless, the myocyte’s one-third of the cases of congestive heart failure. It appears replication is predominantly serial, with some parallel repli- more prominent in older patient than younger ones, cation when volume overload is the predominant stimulus. hypertensive (particularly isolated systolic hypertension) The pathways leading to these changes seem to involve patients, and females rather than males. It dramatically a number of mediators. There is reexpression of fetal reduces health-related quality of life. Acute exacerba- proteins which, although they increase myocyte mass, tions can lead to hospital admission, and mortality in the contract less effectively than their adult counterparts. recently hospitalized or elderly is similar to that of systolic There is an increase in collagen and fibrous tissue deposi- heart dysfunction. The mechanism leading to its develop- tion, both interstitial and perivascular. This may decrease ment is unclear, although increasing interest is being diastolic compliance (to limit the use of Frank-Starling directed at the role of aldosterone. Aldosterone also means to compensate for myocardial dysfunction) as well acts via mineralocorticoid receptors to stimulate deposi- as to limit dilatory reserve of the coronaries. There is a tion of collagen and extracellular matrix. The RALES paucity of mitochondrial and vascular growth relative to (Randomized ALdactone Evaluation Study) trial showed myocyte replication, decreasing the vascularity and energy that the aldosterone inhibitor spironolactone, at doses available relative to the number of myocytes. Calcium devoid of blood pressure effects and having little or no handling deteriorates, due both to a relative decrease effect on LV mass, prevents cardiac collagen accumulation in the amount of SR and in the function of the calcium in renovascular hypertension with high aldosterone levels. pumps on the SR. Finally, the composition of the This cascade may be responsible for the benefits of ACE myosin light chains in the ventricular sarcomeres changes, inhibitors and angiotensin II receptor antagonists, which decreasing the effectiveness of the actin-myosin unit and also reduce extracellular matrix and collagen deposition. possibly its sensitivity to calcium. As stated earlier, the cas- Angiotensin I stimulation, reduced by ACE inhibition and cades leading to this remodeling appear to involve the by angiotensin receptor inhibition, promotes aldosterone adrenergic system, the renin-angiotensin-aldosterone sys- release. Furthermore, aldosterone can have a positive feed- tem, neurohumeral pathways, and dysfunction of the back effect to stimulate angiotensin II receptors. endothelial system. This understanding has led to our cur- There are no randomized double-blind prospective rent therapy profile to prevent the progression of remodel- studies to guide our therapy of this disease process. The ing from beneficial to maladaptive. In addition, there is potential role of the renin-angiotensin-aldosterone path- anecdotal evidence suggesting that mechanical unloading way suggests that ACE inhibitors, angiotensin II recep- of decompensated hearts may lead to a regression of the tor blockers, and a reduction in aldosterone may each be maladaptive changes by a yet unclear mechanism. helpful. The role of beta blockade has been debated. Although myocardial relaxation is more energy-depen- dent than is contraction, canine studies suggest that early diastolic relaxation is impaired by beta-adrenergic inhibi- Cardiac chamber remodeling after tion. Furthermore, a lack of reduction of episodes of pul- surgical correction monary edema following coronary revascularization in Coronary artery bypass grafting patients with isolated diastolic dysfunction suggests that Revascularization is felt to improve regional and global ischemia does not play a predominant role. Still, the gen- ventricular function in addition to reducing infarct eral long-term benefits of beta blockade combined with size.30–33 Thus, complete revascularization of patients its ability to reverse LV hypertrophy make it difficult to with recent heart failure, left ventricle ejection fraction exclude. Few data exist as to the effects of calcium chan- (LVEF) below 40 percent, and large areas of myocardium nel blockade, particularly utilizing dihydropyridine cal- at risk (as evidenced by thallium imaging or nitrate- cium channel antagonists, in this process. enhanced 99m-technetium sestamibi) increases LVEF and decreases LV end-systolic volume. This correlates with a significant trend toward improved 40-month survival. Adaptive changes in chronic congestive Although the mechanism of this salutary effect on remod- heart failure eling is unclear, it is felt that revascularization, by recaptur- Chronic heart failure results in myocardial adaptations ing maximal function in previously hibernating and teleologically consistent with optimizing distribution of stunned myocardium through reestablishment of the wall stress as explained by Laplace’s law. Thus when pres- proper relationship between myocardial oxygen supply and sure overload increases wall stress, the myocyte wall demand, will reduce wall stress on individual myocytes and thickens through parallel hypertrophy to reduce the ten- thereby help reduce/reverse the cascade leading to remod- sion sensed by each myocyte back down to normal levels. eling. Furthermore, vascular stenosis leads to thickening Although volume overload also increases the stresses and perivascular fibrosis of arteries and small vessels distal on individual myocytes, the changes in wall thickness to the stenosis. This process is felt to limit the vasodilatory MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 353 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP

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reserve of these vessels, compounding the limitations to Mitral valve replacement and repair blood flow that are associated with vascular remodeling. Mitral stenosis Mitral valve surgery for mitral stenosis involves either dilation (i.e., commissurotomy), repair (i.e., Aortic valve replacement reconstruction), or replacement. The relative benefits of Aortic stenosis Aortic valve replacement (AVR) surgery mitral commissurotomy versus mitral valve replacement is currently recommended for patients with sympto- (MVR) vary among investigators.25,43,44 Universally, how- matic aortic stenosis and hemodynamic evidence that ever, commissurotomy is associated more frequently with a their aortic stenosis is severe (i.e., with an aortic valve area higher likelihood of traumatic insufficiency as well as higher 0.9 cm2). It is recommended for otherwise asympto- reoperation rates (for insufficiency as well as for restenosis). matic patients who have a hypotensive response to exer- On the other hand, commissurotomy can often be per- cise or evidence of progressive LV dysfunction or who formed with equal success transvenously rather than sur- are undergoing another cardiovascular surgery. LV dys- gically, dramatically reducing early postprocedure morbid- function can be systolic or diastolic in nature. ity and recovery time. This makes transvenous commis- The hemodynamic response to AVR is quite dra- surotomy an attractive alternative for the older patient matic when it is performed to relieve aortic stenosis.34–39 with limited life expectancy. Complete recovery of both systolic and diastolic function is The inconsistent benefit of MVR for mitral stenosis may possible, although recovery of systolic function usually pre- reflect the fact that rheumatic mitral valvular stenosis varies cedes recovery of diastolic function and recovery is more both in its pathology and its progression. Additionally, likely if preoperative impairment is less severe. Still, the however, it is becoming appreciated that maintenance of elevated LV mass characteristic of severe aortic stenosis is an intact subvalvular apparatus (i.e., mitral ring, chordae, reduced 18 months following AVR and almost completely and papillary muscles) is both possible and important resolved by 5 years following AVR. Regression may be in MVR surgery for mitral stenosis. This apparatus can more rapid when stentless aortic valves are used. Because be responsible for 25 percent of LV contractile function. the renin-angiotensin system appears to play a prominent Although long-term follow-up is lacking, early hemody- role in the LV hypertrophy associated with aortic stenosis, namic results suggest that modification of prosthetic valves some patients may be more (e.g., deletion/deletion poly- to more closely duplicate the native valve in form and func- morphism for the angiotensin-converting enzyme gene) tion (e.g., quadricusp mitral valve) as well as facilitate or less (e.g., insertion/insertion polymorphisms for the maintenance of the subvalvular apparatus is possible. angiotensin-converting enzyme gene) predisposed to left ventricular hypertrophy (LVH) with aortic stenosis. These Mitral insufficiency Mitral valve surgery for insuffi- patients may also be more or less likely, respectively, to ciency can involve either repair (e.g., reconstructive) or experience regression of LVH following surgical alleviation replacement. Options for repair include annuloplasty of aortic stenosis. Furthermore, although operative mortal- (often including the rigid Carpentier or pliable Duran ity is higher and complete functional recovery less likely if prosthetic rings), resection of the prolapsing segment, and preoperative contractile function is severely depressed repair (i.e., shortening, elongating, reimplanting, replac- [New York Heart Association (NYHA) class III or IV], the ing) of dysfunctional chordae tendineae or papillary mus- poor prognosis of these patients with medical treatment cle. Such procedures are more likely to be successful when alone often makes AVR the most advisable option. patients are younger (more pliable valves), the procedure requires chordal/papillary muscle shortening (rather Aortic insufficiency Surgical repair of aortic valvular than lengthening), and the etiology is endocarditis or insufficiency is indicated in symptomatic patients as well ischemia. They are less likely to be successful when the as asymptomatic patients with evidence of progressive patient is older, the valves are deformed, or the disease deterioration of LV function. This can be defined as process is rheumatic heart disease. LVEF less than 50 percent or an increase in the LV The increasing interest in mitral valve repair rather end-diastolic diameter greater than 5.5 cm. Surgery in than replacement surgery stems from incomplete satis- asymptomatic patients is encouraged, because awaiting faction with the effects of replacement surgery upon LV the development of severe LV dysfunction worsens the function.45,46 It has long been recognized that LV con- prognosis following AVR. tractile function, as depicted by LVEF, is depressed fol- Like AVR for stenotic disease, AVR for insufficiency lowing MVR for mitral insufficiency. This was initially results in a regression of the adaptive changes precipi- felt to represent an unmasking, by the removal of the low tated by the insufficiency.36,38,40–42 Thus, myocardial pressure “pop-off” of regurgitant flow into the low-pres- hypertrophy is regressing toward normal at 1.6 years sure left atrium, of preexisting LV dysfunction. It is more following surgery and is often normal by 8.1 years. recently appreciated, however, that disruption of the Regression is delayed and less complete in patients subvalvular apparatus (i.e., annulus, chordae, and papil- with severe preoperative dysfunction, as evidenced by lary muscle structure) contributed to this deterioration NYHA classification III or IV or LV ejection fraction in LV function. Thus, the subvalvular apparatus is felt to below 25 percent. prepare the LV for normal contraction and to account MHBD054-CH19[335-356].qxd 09/05/2007 8:05 AM Page 354 PMAC-291 PMAC-291:Books:DAMS/ARCHIVE:MHBD054:Chapters:CH-19: TechBooks [PP

354 PART II ● ADULT CARDIAC SURGERY

for up to 25 percent of the LV systolic function. As such, improve symptomatically, their left ventricular ejection conservation of an intact subvalvular apparatus is becom- fraction often deteriorates. Preoperative predictors of ing more of a priority when mitral valve surgery is under- poor outcomes include NYHA classification III or IV, age taken. above 60 years, end-systolic left ventricular diameter Long-term results of surgical intervention for mitral greater than 5.2 cm, and LVEF less than 50 percent. For insufficiency vary significantly with the age of the patients below age 60 in NYHA classification I or II, patient, the severity of the preoperative ventricular dys- with end-systolic left ventricular diameter less than 4.5 cm function, and the capacity to preserve subvalvular struc- and LVEF greater than 60 percent, functional survival is tures intact. Thus, unlike remodeling following AVR for excellent. The likelihood of improving left ventricular aortic stenosis, the left ventricle typically does not contractile function is greater both in patients without improve its contractile function following MVR for severe preoperative dysfunction and in those capable of mitral insufficiency. Although the majority of patients having their subvalvular apparatus maintained intact.

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