Cardiac Physiology

Chapter 20 Cardiac Physiology

LENA S. SUN • JOHANNA SCHWARZENBERGER • RADHIKA DINAVAHI

K e y P o i n t s

• The cardiac cycle is the sequence of electrical and mechanical events during the course of a single heartbeat. • Cardiac output is determined by the heart rate, myocardial contractility, and preload and afterload. • The majority of cardiomyocytes consist of myofibrils, which are rodlike bundles that form the contractile elements within the cardiomyocyte. • The basic working unit of contraction is the sarcomere. • Gap junctions are responsible for the electrical coupling of small molecules between cells. • Action potentials have four phases in the heart. • The key player in cardiac excitation-contraction coupling is the ubiquitous second messenger calcium. • Calcium-induced sparks are spatially and temporally patterned activations of localized calcium release that are important for excitation-contraction coupling and regulation of automaticity and contractility. • β-Adrenoreceptors stimulate chronotropy, inotropy, lusitropy, and dromotropy. • Hormones with cardiac action can be synthesized and secreted by cardiomyocytes or produced by other tissues and delivered to the heart. • Cardiac reflexes are fast-acting reflex loops between the heart and central nervous system that contribute to the regulation of cardiac function and the maintenance of physiologic homeostasis.

In 1628, English physician, William Harvey, first advanced oxygen (O2) and nutrients and to remove carbon dioxide the modern concept of circulation with the heart as the (CO2) and metabolites from various tissue beds. generator for the circulation. Modern cardiac physiology includes not only physiology of the heart as a pump but also concepts of cellular and molecular biology of the car- PHYSIOLOGY OF THE INTACT HEART diomyocyte and regulation of cardiac function by neural and humoral factors. Cardiac physiology is a component Understanding of mechanical performance of the intact of the interrelated and integrated cardiovascular and heart begins with the knowledge of the phases of the car- circulatory physiology. This chapter discusses only the diac cycle and the determinants of ventricular function. physiology of the heart. It begins with the physiology of the intact heart. The second part of the chapter focuses CARDIAC CYCLE on cellular cardiac physiology. Finally, the various factors that regulate cardiac function are briefly discussed. The cardiac cycle is the sequence of electrical and The basic anatomy of the heart consists of two atria mechanical events during the course of a single heart- and two ventricles that provide two separate circulations beat. Figure 20-1 illustrates (1) the electrical events of a in series. The pulmonary circulation, a low-resistance and single cardiac cycle represented by the electrocardiogram high-capacitance vascular bed, receives output from the (ECG) and (2) the mechanical events of a single cardiac right side of the heart, and its chief function is bidirec- cycle represented by left atrial and left ventricular pres- tional gas exchange. The left side of the heart provides sure pulses correlated in time with aortic flow and ven- output for the systemic circulation. It functions to deliver tricular volume.1 473 Downloaded for Ivan Groisman ([email protected]) at Federacion Argentina De Asociaciones De Anestesia Analgesia Y Reanimacion from ClinicalKey.com by Elsevier on October 06, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 474 PART II: Anesthetic Physiology

The cardiac cycle begins with the initiation of the heartbeat. Intrinsic to the specialized cardiac pacemaker tissues is automaticity and rhythmicity. The sinoatrial (SA) node is usually the pacemaker; it can generate impulses at the greatest frequency and is the natural pacemaker.

Atrial systole Isovol. contract. Rapid ejection Reduced ejection Isovol. relax. Rapid ventricular filling Reduced ventricular filling—diastalsis Electrical Events and the Electrocardiogram 120 Electrical events of the pacemaker and the specialized Aortic Aortic valve closes valve conduction system are represented by the ECG at the 100 opens Aortic body surface (also see Chapters 45 and 47). The ECG is pressure the result of differences in electrical potential generated by the heart at sites of the surface recording. The action 80 potential initiated at the SA node is propagated to both Mitral Left atria by specialized conduction tissue that leads to atrial 60 valve ventricular systole (contraction) and the P wave of the ECG. At the pressure closes junction of the interatrial and interventricular septa, spe-

Pressure (mm Hg) 40 cialized atrial conduction tissue converges at the atrio- Left atrial ventricular (AV) node, which is distally connected to 20 pressure the His bundle. The AV node is an area of relatively slow Mitral valve opens conduction, and a delay between atrial and ventricular 0 contraction normally occurs at this locus. The PR interval represents the delay between atrial and ventricular con- 5 traction at the level of the AV node. From the distal His 4 bundle, an electrical impulse is propagated through large 3 left and right bundle branches and finally to the Purkinje 2 system fibers, which are the smallest branches of the (L/min) 1 specialized conduction system. Finally, electrical signals

Aortic blood flow are transmitted from the Purkinje system to individual 0 ventricular cardiomyocytes. The spread of depolarization to the ventricular myocardium is exhibited as the QRS 38 complex on the ECG. Depolarization is followed by ventricular repolarization and the appearance of the T wave 32 on the ECG.2

(mL) 26 Mechanical Events The mechanical events of a cardiac cycle begin with the

Ventricular volume 20 return of blood to the right and left atria from the sys- 1 temic and pulmonary circulation, respectively. As blood 2 4 3 accumulates in the atria, atrial pressure increases until it exceeds the pressure within the ventricle, and the AV Heart sounds a valve opens. Blood passively flows first into the ventricu- c v lar chambers, and such flow accounts for approximately 75% of the total ventricular filling.3 The remainder of pulse

Venous the blood flow is mediated by active atrial contraction R or systole, known as the atrial kick. The onset of atrial systole is coincident with depolarization of the sinus node and the P wave. While the ventricles fill, the AV PT P valves are displaced upward and ventricular contraction Q (systole) begins with closure of the tricuspid and mitral S Ventricular valves, which corresponds to the end of the R wave on systole Echocardiogram the ECG. The first part of ventricular systole is known as isovolumic or isometric contraction. The electrical impulse 0.80.70.60.50.40.30.20.10 traverses the AV region and passes through the right Time (sec) and left bundle branches into the Purkinje fibers, which Figure 20-1. Electrical and mechanical events during a single cardiac leads to contraction of the ventricular myocardium and cycle. The pressure curves of aortic blood flow, ventricular volume, a progressive increase in intraventricular pressure. When venous pulse, and electrocardiogram are shown. (From Berne RM, Levy intraventricular pressure exceeds pulmonary artery and MN: The cardiac pump. In Cardiovascular physiology, ed 8. St. Louis, aortic pressure, the pulmonic and aortic valves open and 2001, Mosby, pp 55-82.) ventricular ejection occurs, which is the second part of ventricular systole. Ventricular ejection is divided into the rapid ejection phase and the reduced ejection phase. During the rapid

ejection phase, forward flow is maximal, and pulmonary diastole. The left ventricular free wall and the septum artery and aortic pressure is maximally developed. In have similar muscle bundle architecture. As a result, the the reduced ejection phase, flow and great artery pres- septum moves inward during systole in a normal heart. sure taper with progression of systole. Pressure in both Regional wall thickness is a commonly used index of ventricular chambers decreases as blood is ejected from myocardial performance that can be clinically assessed, the heart, and ventricular diastole begins with closure such as by perioperative echocardiography or magnetic of the pulmonic and aortic valves. The initial period of resonance imaging. ventricular diastole consists of the isovolumic (isometric) Unlike the LV, which needs to pump against the relaxation phase. This phase is concomitant with repolar- higher-pressure systemic circulation, the right ventricle ization of the ventricular myocardium and corresponds (RV) pumps against a much lower pressure circuit in the to the end of the T wave on the ECG. The final portion of pulmonary circulation. Consequently, wall thickness is ventricular diastole involves a rapid decrease in intraven- considerably less in the RV. In contrast to the ellipsoidal tricular pressure until it decreases to less than that of the form of the LV, the RV is crescent shaped; as a result, the right and left atria, at which point the AV valve reopens, mechanics of right ventricular contraction are more com- ventricular filling occurs, and the cycle repeats itself. plex. Inflow and outflow contraction is not simultaneous, and much of the contractile force seems to be recruited from interventricular forces of the LV-based septum. VENTRICULAR STRUCTURE AND FUNCTION An intricate matrix of collagen fibers forms a scaffold of support for the heart and adjacent vessels. This matrix Ventricular Structure provides enough strength to resist tensile stretch. The The specific architectural order of the cardiac muscles collagen fibers are made up of mostly the thick collagen provides the basis for the heart to function as a pump. type I fiber, which cross-links with the thin collagen type The ellipsoid shape of the left ventricle (LV) is a result III fiber, the other major type of collagen.5 Elastic fibers of the laminar layering of spiraling bundles of cardiac that contain elastin are in close proximity to the collagen muscles (Fig. 20-2). The orientation of the muscle bundle fibers. They account for the elasticity of the myocardium.6 is longitudinal in the subepicardial myocardium and circumferential in the middle segment and again becomes Ventricular Function longitudinal in the subendocardial myocardium. Because Systolic Function. The heart provides the driving force of the ellipsoid shape of the LV, regional differences in for delivering blood throughout the cardiovascular sys- wall thickness result in corresponding variations in the tem to supply nutrients and to remove metabolic waste. cross-sectional radius of the left ventricular chamber. Because of the anatomic complexity of the RV, the tradi- These regional differences may serve to accommodate the tional description of systolic function is usually limited to variable loading conditions of the LV.4 In addition, such the LV. Systolic performance of the heart is dependent on anatomy allows the LV to eject blood in a corkscrew-type loading conditions and contractility. Preload and after- motion beginning from the base and ending at the apex. load are two interdependent factors extrinsic to the heart The architecturally complex structure of the LV thus that govern cardiac performance. allows maximal shortening of myocytes, which results in increased wall thickness and the generation of force Diastolic Function. Diastole is ventricular relaxation, during systole. Moreover, release of the twisted LV may and it occurs in four distinct phases: (1) isovolumic relax- provide a suction mechanism for filling of the LV during ation; (2) the rapid filling phase (i.e., the LV chamber filling at variable left ventricular pressure); (3) slow filling, or diastasis; and (4) final filling during atrial systole. The isovolumic relaxation phase is energy dependent. During the auxotonic relaxation (phases 2 through 4), ventricular filling occurs against pressure. It encompasses a period during which the myocardium is unable to generate force, and filling of the ventricular chambers takes place. The isovolumic relaxation phase does not contribute to ventricular filling. The greatest amount of ventricular fill- Cardiac ing occurs in the second phase, whereas the third phase muscle adds only approximately 5% of total diastolic volume and the final phase provides 15% of ventricular volume from atrial systole. To assess diastolic function, several indices have been developed. The most widely used index for examining the isovolumic relaxation phase of diastole is to calculate the peak instantaneous rate of decline in left ventricular pressure (−dP/dt) or the time constant of isovolumic decline in left ventricular pressure (τ). The aortic closing–mitral opening interval and the isovolumic relaxation time and Figure 20-2. Muscle bundles. (From Marieb EN: Human anatomy & peak rate of left ventricular wall thinning, as determined physiology, ed 5. San Francisco, 2001, Pearson Benjamin Cummings, p 684.) by echocardiography, have both been used to estimate

200

Optimal sarcomere length

Actin Actin

Normal resting length 100

Frank-Starling curve Stroke volume (mL)

Figure 20-3. Frank-Starling relationship. The Sarcomere length relationship between sarcomere length and tension developed in cardiac muscles is shown. In the heart, an increase in end-diastolic volume 0 is the equivalent of an increase in myocardial 0 150 300 stretch; therefore, according to the Frank-Starling law, increased stroke volume is generated. Ventricular end-diastolic volume (mL) (EDV)

which stretching of the myocardial sarcomere results in law is the relationship of left ventricular end-diastolic enhanced myocardial performance for subsequent con- volume (LVEDV) and stroke volume. The Frank-Starling tractions (see Fig. 20-3). In 1895, Otto Frank first noted mechanism may remain intact even in a failing heart.13 that in skeletal muscle, the change in tension was directly However, ventricular remodeling after injury or in heart related to its length, and as pressure changed in the heart, failure may modify the Frank-Starling relationship. a corresponding change in volume occurred.11 In 1914, E. H. Starling, using an isolated heart-lung preparation Contractility. Each Frank-Starling curve specifies a level as a model, observed that “the mechanical energy set of contractility, or the inotropic state of the heart, which free on passage from the resting to the contracted state is defined as the work performed by cardiac muscle at any is a function of the length of the muscle fiber.”12 If a given end-diastolic fiber. Factors that modify contractility strip of cardiac muscle is mounted in a muscle chamber will create a family of Frank-Starling curves with different under isometric conditions and stimulated at a fixed fre- contractility (Fig. 20-5).10 Factors that modify contractil- quency, then an increase in sarcomere length results in ity are exercise, adrenergic stimulation, changes in pH, an increase in twitch force. Starling concluded that the temperature, and drugs such as digitalis. The ability of the increased twitch force was the result of a greater interac- LV to develop, generate, and sustain the necessary pres- tion of muscle bundles. sure for the ejection of blood is the intrinsic inotropic Electron microscopy has demonstrated that sarcomere state of the heart. length (2 to 2.2 μm) is positively related to the amount In isolated muscle, the maximal velocity of contrac- of actin and myosin cross-bridging and that there is an tion (Vmax) is defined as the maximal velocity of ejection optimal sarcomere length at which the interaction is at zero load. Vmax is obtained by plotting the velocity of maximal. This concept is based on the assumption that muscle shortening in isolated papillary muscle at varying the increase in cross-bridging is equivalent to an increase degrees of force. Although this relationship can be repli- in muscle performance. Although this theory continues cated in isolated myocytes, Vmax cannot be measured in to hold true for skeletal muscle, the force-length relation- an intact heart because complete unloading is impossible. ship in cardiac muscle is more complex. When comparing To measure the intrinsic contractile activity of an intact force-strength relationships between skeletal and cardiac heart, several strategies have been attempted with vary- muscle, it is noteworthy that the reduction in force is only ing success. Pressure-volume loops, albeit requiring cath- 10%, even if cardiac muscle is at 80% sarcomere length.11 eterization of the left side of the heart, are currently the The cellular basis of the Frank-Starling mechanism is best way to determine contractility in an intact heart (Fig. still being investigated and is briefly discussed later in 20-6).10 The pressure-volume loop represents an indirect this chapter. A common clinical application of Starling’s measure of the Frank-Starling relationship between force (pressure) and muscle length (volume). Clinically, the most commonly used noninvasive index of ventricular contractile function is the ejection fraction, which is assessed by echocardiography, angiography, or radionu- LV pressure in aortic clide ventriculography. stenosis

Family of Frank-Starling curves Normal Normal—exercise LV pressure

Running Normal—rest

R Contractile state Wall thickness R of myocardum Walking Heart failure Ventricular performance Rest

Laplace's law Fatal myocardum Pressure radius Wall stressϭ depression 2 (Wall thickness) Figure 20-4. In response to aortic stenosis, left ventricular (LV) pressure increases. To maintain wall stress at control levels, compensatory Ventricular end-diastolic volume (Myocardial stretch) LV hypertrophy develops. According to Laplace’s law, wall stress = pressure ⋅ radius (R) ÷ (2 × wall thickness). Therefore the increase in Figure 20-5. A family of Frank-Starling curves is shown. A leftward wall thickness offsets the increased pressure, and wall stress is main- shift of the curve denotes enhancement of the inotropic state, whereas tained at control levels. (From Opie LH: Ventricular function. In The a rightward shift denotes decreased inotropy. (From Opie LH: Ventricu- heart. Physiology from cell to circulation, ed 4. Philadelphia, 2004, lar function. In The heart. Physiology from cell to circulation, ed 4. Lippincott-Raven, pp 355-401.) Philadelphia, 2004, Lippincott-Raven, pp 355-401.)

Ejection fraction = (LVEDV − LVESV) /LVEDV oriented outer layers). In heart failure, ventricular dila- tion reduces cardiac efficiency because it increases wall 11 where LVESV is left ventricular end-systolic volume. stress, which in turn increases O2 consumption.

Cardiac Work. The work of the heart can be divided into Heart Rate and Force-Frequency Relationship. In isolated external and internal work. External work is expended cardiac muscle, an increase in the frequency of stimulation to eject blood under pressure, whereas internal work is induces an increase in the force of contraction. This relation- expended within the ventricle to change the shape of the ship is termed the treppe, which means staircase in German, heart and to prepare it for ejection. Internal work con- and is the phenomenon or the force-frequency relation- tributes to inefficiency in the performance of the heart. ship.8,15 At between 150 and 180 stimuli per minute, maxi- Wall stress is directly proportional to the internal work mal contractile force is reached in an isolated heart muscle of the heart.14 at a fixed muscle length. Thus an increased frequency incre- External work, or stroke work, is a product of the stroke mentally increases inotropy, whereas stimulation at a lower volume (SV) and pressure (P) developed during ejection frequency decreases contractile force. However, when the of the SV. stimulation becomes extremely rapid, the force of contraction decreases. In the clinical context, pacing-induced posi- Stroke work = SV × P or (LVEDV − LVESV) × P tive inotropic effects may be effective only up to a certain The external work and internal work of the ventricle heart rate, based on the force-frequency relationship. In a both consume O2. The clinical significance of internal failing heart, the force-frequency relationship may be less work is illustrated in the case of a poorly drained LV dur- effective in producing a positive inotropic effect.8 ing cardiopulmonary bypass. Although external work is provided by the roller pump during bypass, myocardial CARDIAC OUTPUT ischemia can still occur because poor drainage of the LV creates tension on the left ventricular wall and increases Cardiac output is the amount of blood pumped by the internal work. heart per unit of time (Q˙ ) and is determined by four fac- The efficiency of cardiac contraction is estimated by tors: two factors that are intrinsic to the heart—heart rate the following formula8: and myocardial contractility—and two factors that are extrinsic to the heart but functionally couple the heart Cardiac efﬁciency = External work/Energy equivalent and the vasculature—preload and afterload. of O2 consumption Heart rate is defined as the number of beats per min- The corkscrew motion of the heart for the ejection of ute and is mainly influenced by the autonomic nervous blood is the most favorable in terms of work efficiency, system. Increases in heart rate escalate cardiac output as based on the architecture in a normal LV (with the car- long as ventricular filling is adequate during diastole. diac muscle bundles arranged so that a circumferentially Contractility can be defined as the intrinsic level of con- oriented middle layer is sandwiched by longitudinally tractile performance that is independent of loading conditions. Contractility is difficult to define in an intact heart because it cannot be separated from loading con- 8,15 Internal work ditions. For example, the Frank-Starling relationship External work is defined as the change in intrinsic contractile performance, based on changes in preload. Cardiac output in a living organism can be measured with the Fick principle End-systolic (ES) PV relationship (a schematic depiction is illustrated in Fig. 20-7).1 The Fick principle is based on the concept of conserva- End-systolic tion of mass such that the O2 delivered from pulmonary Aortic valve c Ejection open venous blood (q3) is equal to the total O2 delivered to b pulmonary capillaries through the pulmonary artery (q1) Contraction and the alveoli (q2). Relaxation The amount of O2 delivered to the pulmonary capil- End-diastolic laries by way of the pulmonary arteries (q1) equals total a ˙ pulmonary arterial blood flow Q( ) times the O2 concen- Mitral d Filling e opening tration in pulmonary arterial blood (CpaO2): ˙ q1 = Q × CpaO2

Ventricular volume The amount of O2 carried away from pulmonary venous blood (q3) is equal to total pulmonary venous Figure 20-6. Pressure-volume (PV) loop. Point a depicts the start of blood flow Q( ˙ ) times the O concentration in pulmonary isovolumetric contraction. The aortic valve opens at point b, and ejec- 2 venous blood (Cpvo ): tion of blood follows (points b c). The mitral valve opens at point d, 2 → ˙ and ventricular filling ensues. External work is defined by pointsa, b, c, q3 = Q × CpvO2 and d, and internal work is defined by points e, d, and c. The PV area is the sum of external and internal work. (From Opie LH: Ventricular The pulmonary arterial O2 concentration is the mixed function. In The heart. Physiology from cell to circulation, ed 4. Phila- systemic venous O2, and the pulmonary venous O2 con- delphia, 2004, Lippincott-Raven, pp 355-401.) centration is the peripheral arterial O2. O2 consumption

is the amount of O2 delivered to the pulmonary capillar- and (3) extracellular connective tissue. A group of cardio- ies from the alveoli (q2). Because q1 + q2 = q3, myocytes with its connective tissue support network or ˙ ˙ extracellular matrix make up a myofiber Fig.( 20-9). Adja- Q CpaO2 + q2 = Q CpvO2 cent myofibers are connected by strands of collagen. The ( ˙ ) ˙ ( ) extracellular matrix is the synthetic product of fibroblasts q2 = Q CpvO2 − Q CpaO2 and is made up of collagen, which is the main determinant (˙ ) ( ) of myocardial stiffness, and other major matrix proteins. q2 = Q Cpvo2 − CpaO2 One of the matrix proteins, elastin, is the chief constitu- ˙ ( ) ent of elastic fibers. The elastic fibers account for, in part, Q = q2/ CpvO2 − CpaO2 the elastic properties of the myocardium.6 Other matrix ( ) proteins include the glycoproteins or proteoglycans and Thus if the CpaO2, CpvO2, and O2 consumption (q2) matrix metalloproteinases. Proteoglycans are proteins are known, then the cardiac output can be determined. with short sugar chains, and they include heparan sul- The indicator dilution technique is another method fate, chondroitin, fibronectin, and laminin. Matrix metal- for determining cardiac output also based on the law loproteins are enzymes that degrade collagen and other of conservation of mass. The two most commonly used extracellular proteins. The balance between the accumu- indicator dilution techniques are the dye dilution and the lation of extracellular matrix proteins by synthesis and thermodilution methods. Figure 20-8 illustrates the prin- 1 ciples of the dye dilution method. Mixer

CELLULAR CARDIAC PHYSIOLOGY A B Lamp Photocell CELLULAR ANATOMY q mg dye injected At the cellular level, the heart consists of three major Densitometer components: (1) cardiac muscle tissue (contracting cardiomyocytes), (2) conduction tissue (conducting cells),

From pulmonary To pulmonary artery veins 0

Terminal Dye concentration at point B bronchiole Alveoli t1 t2 Time Figure 20-8. Illustration demonstrates the principle of determining cardiac output with the indicator dilution technique. This model assumes that there is no recirculation. A known amount of dye (q) is injected at point A into a stream flowing atQ ˙ (mL/min). A mixed sample of the fluid flowing past pointB is withdrawn at a constant rate through a densitometer. The change in dye concentration over time is depicted in a curve. Flow may be measured by dividing the amount of indicator injected upstream by the area under the downstream con- O2 Consumption 250 mL centration curve. (From Berne RM, Levy MN: The cardiac pump. In Car- diovascular physiology, ed 8. St. Louis, 2001, Mosby, pp 55-82.) O2 /min

q1 q2 q3

[O2 ] pa [O2 ] pv 0.15 mL O2 /mL blood 0.20 mL O2 /mL blood

q1ϩq2ϭq3 Figure 20-7. Illustration demonstrates the principle of determination of cardiac output according to the Fick formula. If the oxygen (O2) concentration in pulmonary arterial blood (CpaO ), the O concen- 2 2 Myofibrils tration of the pulmonary vein (CpvO2), and the O2 consumption are known, then cardiac output can be calculated. pa, Pulmonary artery; Figure 20-9. Organization of cardiomyocytes. Fifty percent of car- pv, pulmonary vein. (From Berne RM, Levy MN: The cardiac pump. In diomyocyte volume is made up of myofibrils; the remainder consists of Cardiovascular physiology, ed 8. St. Louis, 2001, Mosby, pp 55-82.) mitochondria, nucleus, sarcoplasmic reticulum, and cytosol.

Intercalated disks

Gap junction Mitochondrion Cardiac muscle cell

Nucleus

Sarcolemma Desmosome Figure 20-10. The sarcolemma that envelops cardiomyocytes becomes highly specialized to form the intercalated disks where ends of neighboring cells are in contact. The intercalated disks consist of gap junctions and spot and sheet desmosomes. their breakdown by matrix metalloproteins contributes Mitochondria are immediately found beneath the sar- to the mechanical properties and function of the heart.6 colemma, wedged between myofibrils within the cell. They contain enzymes that promote the generation of CARDIOMYOCYTE STRUCTURE AND adenosine triphosphate (ATP), and they are the energy FUNCTION powerhouse for the cardiomyocyte. In addition, mitochondria can also accumulate Ca2+ and thereby contrib- Individual contracting cardiomyocytes are large cells ute to the regulation of the cytosolic Ca2+ concentration. between 20 μm (atrial cardiomyocytes) and 140 μm Nearly all of the genetic information is found within the (ventricular cardiomyocytes) in length. Approximately centrally located nucleus. The cytosol is the fluid-filled 50% of the cell volume in a contracting cardiomyocyte microenvironment within the sarcolemma, exclusive of is made up of myofibrils, and the remainder consists of the organelles and the contractile apparatus and proteins. mitochondria, nucleus, sarcoplasmic reticulum (SR), and Cardiac muscle cells contain three different types cytosol. The myofibril is the rodlike bundle that forms the of intercellular junctions: gap junctions, spot desmo- contractile elements within cardiomyocytes. Within each somes, and sheet desmosomes (or fasciae adherens) (Fig. contractile element are contractile proteins, regulatory 20-10).18,21 Gap junctions are responsible for electrical proteins, and structural proteins. Contractile proteins coupling and the transfer of small molecules between cells, make up approximately 80% of the myofibrillar protein, whereas desmosome-like junctions provide mechanical with the remainder being regulatory and structural pro- linkage. The adhesion sites formed by spot desmosomes teins.16,17 The basic unit of contraction is the sarcomere anchor the intermediate filament cytoskeleton of the cell; (see discussion under “Contractile Elements” later in this those formed by the fasciae adherens anchor the contrac- chapter). tile apparatus. Gap junctions consist of clusters of plasma The sarcolemma, or the outer plasma membrane, membrane channels directly linking the cytoplasmic separates the intracellular and extracellular space. It sur- compartments of neighboring cells. Gap junction chan- rounds the cardiomyocyte and invaginates into the myo- nels are constructed from connexins, a multigene family fibrils through an extensive tubular network known as of conserved proteins. The principal connexin isoform of transverse tubules or T tubules, and it also forms specialized the mammalian heart is connexin 43; other connexins, intercellular junctions between cells.18,19 notably connexins 40, 45, and 37, are also expressed but Transverse or T tubules are in close proximity to an in smaller quantities.20,21 intramembranous system and the SR, which plays an The conducting cardiomyocytes, or Purkinje cells, are important role in the calcium (Ca2+) metabolism that is cells specialized for conducting propagated action poten- critical in the excitation-contraction coupling (ECC) of tials. These cells have a low content of myofibrils and a the cardiomyocyte. The SR can be further divided into prominent nucleus, and they contain an abundance of the longitudinal (or network) SR and the junctional SR. gap junctions. Cardiomyocytes can be functionally sepa- The longitudinal SR is involved in the uptake of Ca2+ for rated into (1) the excitation system, (2) the ECC system, the initiation of relaxation. The junctional SR contains and (3) the contractile system. large Ca2+-release channels (ryanodine receptors [RyRs]) that release SR Ca2+ stores in response to depolarization- Excitation System stimulated Ca2+ influx through the sarcolemmal Ca2+ The cellular action potential originating in the specialized channels. The RyRs are not only Ca2+-release channels, conduction tissue is propagated to individual cells where but they also form the scaffolding proteins that anchor it initiates the intracellular event that leads to the contrac- many of the key regulatory proteins.20 tion of the cell through the sarcolemmal excitation system.

+25 L-type Ca2+ channels and the efflux of K+ through several + 1 K channels—the inwardly rectifying ik, the delayed recti- 2 fier ik1, and ito. Repolarization (phase 3) is brought about 0 when an efflux of +K from the three outward K+ currents exceeds the influx of Ca2+, thus returning the membrane to the resting potential. Very little ionic flux occurs dur- –25 ing diastole (phase 4) in a fast-response action potential. In contrast, during diastole (phase 4), pacemaker cells –50 3 that show slow-response action potentials have the capa- bility of spontaneous diastolic depolarization and generate the automatic cardiac rhythm. Pacemaker currents during phase 4 are the result of an increase in the three Transmembrane potential, mV –75 4 inward currents and a decrease in the two outward currents. The three inward currents that contribute to spon- –100 taneous pacemaker activity include two carried by Ca2+, 22 iCaL and iCaT, and one that is a mixed cation current, If. The two outward currents are the delayed rectifier K+ cur- Na+ Ca+ K+ Na+ K+ rent, i , and the inward rectifying K+ current, i . When influx influx efflux efflux influx k k1 compared with the fast-response action potential, phase 0 Figure 20-11. Phases of cellular action potentials and major associ- is much less steep, phase 1 is absent, and phase 2 is indis- ated currents in ventricular myocytes. The initial phase (0) spike and tinct from phase 3 in the slow-response action potential.23 + overshoot (1) are caused by a rapid inward sodium (Na ) current, the In SA node cells, the pacemaker I current is the principal plateau phase (2) by a slow calcium (Ca2+) current through L-type f Ca channels, and repolarization (phase 3) by outward potassium (K+) determinant of duration diastolic depolarization, and it currents. Phase 4, the resting potential (Na+ efflux, K+ influx), is main- is encoded by four members of the hyperpolarization- 24 tained by Na+-K+-adenosine triphosphatase (ATPase). The Na+-Ca2+ activated cyclic nucleotide-gated gene (HCN1-4) family. exchanger is mainly responsible for extrusion of Ca2+. In specialized During the cardiac action potential, movement of Ca2+ conduction system tissue, spontaneous depolarization takes place dur- into the cell and Na+ out of the cell creates an ionic imbal- ing phase 4 until the voltage resulting in opening of the Na channel is ance. The Na+-Ca2+ exchanger restores cellular ionic bal- reached. (From LeWinter MM, Osol G: Normal physiology of the cardio- ance by actively transporting Ca2+ out of the cell against vascular system. In Fuster V, Alexander RW, O’Rourke RA, editors: Hurst’s a concentration gradient while moving Na+ into the cell the heart, ed 10. New York, 2001, McGraw-Hill, pp 63-94.) in an energy-dependent manner. Excitation-Contraction Coupling Action Potential. Ion fluxes across plasma membranes Structures that participate in cardiac ECC include the sar- result in depolarization (attaining a less negative mem- colemma, transverse tubules, SR, and myofilaments (Fig. brane potential) and repolarization (attaining a more 20-12, A).25 The process of ECC begins with depolariza- negative membrane potential). They are mediated by tion of the plasma membrane and spread of electrical membrane proteins with ion-selective pores. Because excitation along the sarcolemma of cardiomyocytes. these ion channel proteins open and close the pores in The ubiquitous second messenger Ca2+ is the key response to changes in membrane potential, the channels player in cardiac ECC (see Fig. 20-12, B).23 Cycling of Ca2+ are voltage gated. In the heart, sodium (Na+), potassium within the structures that participate in ECC initiates and (K+), Ca2+, and chloride (Cl−) channels contribute to the terminates contraction. Activation of the contractile sys- action potential. tem depends on an increase in free cytosolic Ca2+ and its The types of action potential in the heart can be subsequent binding to contractile proteins. separated into two categories: (1) fast-response action Ca2+ enters through plasma membrane channels con- potentials, which are found in the His-Purkinje system centrated at the T tubules, and such entry through L-type and atrial or ventricular cardiomyocytes; and (2) slow- Ca2+ channels (dihydropyridine receptors) triggers the response action potentials, which are found in the pace- release of Ca2+ from the SR.26 This evokes a Ca2+ spark. maker cells in the SA and AV nodes. A typical tracing of an Ca2+ sparks are considered to be the elementary Ca2+ sig- action potential in the His-Purkinje system is depicted in naling event of ECC in heart muscle. A Ca2+ spark occurs Figure 20-11.8 The electrochemical gradient for K+ across with the opening of a cluster of SR RyRs to release Ca2+ the plasma membrane is the determinant for the resting in a locally regenerative manner. It, in turn, activates the membrane potential. Mostly as a result of the influx of Ca2+-release channels and induces further release of Ca2+ Na+, the membrane potential becomes depolarized, which from subsarcolemmal cisternae in the SR and thus leads to leads to an extremely rapid upstroke (phase 0). As the a large increase in intracellular Ca2+ (iCa2+). These spatially membrane potential reaches a critical level (or threshold) and temporally patterned activations of localized Ca2+ during depolarization, the action potential is propagated. release, in turn, stimulate myofibrillar contraction. The The rapid upstroke is followed by a transient repolariza- increase in iCa2+, however, is transient inasmuch as Ca2+ tion (phase 1). Phase 1 is a period of brief and limited is removed by (1) active uptake by the SR Ca2+ pump ade- repolarization that is largely attributable to the activa- nosine triphosphatase (ATPase), (2) extrusion of Ca2+ from + + 2+ tion of a transient outward K current, ito. The plateau the cytosol by the Na -Ca exchanger, and (3) binding of phase (phase 2) occurs with a net influx of Ca2+ through Ca2+ to proteins.27 Ca2+ sparks have also been implicated

Extracellular space

Plasma Ca2+-ATPase Na+-Ca+ exchanger Sodium pump Na Na membrane

B1 B2

Cytosol

Calcium release L-type calcium channel Sarcotubular channel network T tubule Subsarcolemmal cisterna

Calsequestrin Sarcolplasmic reticulum A G Phospholamban SERCA 2A

A1 D

Extracellular space Thick Thin filament filament Mitochondria E F H

Actin Myosin Troponin Z line cross-bridge ABContractile proteins Figure 20-12. A, Diagram depicts the components of cardiac excitation-contraction coupling. Calcium pools are noted in bold letters. B, Extra- cellular (arrows A, B1, B2) and intracellular calcium flux (arrows C, D, E, F, and G) are shown. The thickness of the arrows indicates the magnitude of the calcium flux, and the vertical orientations describe their energetics:downward-pointing arrows represent passive calcium flux, whereas upward-pointing arrows represent energy-dependent calcium transport. Calcium entering the cell from extracellular fluid through L-type calcium channels triggers the release of calcium from the sarcoplasmic reticulum. Only a small portion directly activates the contractile proteins (arrow A1). Arrow B1 depicts active transport of calcium into extracellular fluid by means of the plasma membrane calcium adenosine triphosphatase (Ca2+-ATPase) pump and the sodium-calcium (Na+-Ca2+) exchanger. Sodium that enters the cell in exchange for calcium (dashed line) is pumped out of the cytosol by the sodium pump. SR regulates calcium efflux from the subsarcolemmal cisternae (arrow C) and calcium uptake into the sarcotubular network (arrow D). Arrow G represents calcium that diffuses within the SR. Calcium binding to (arrow E) and dissociation from (arrow F) high-affinity calcium-binding sites of troponin C activate and inhibit interactions of the contractile proteins.Arrow H depicts movement of calcium into and out of mitochondria to buffer the cytosolic calcium concentration. SERCA 2A, Sarcoplasmic/endoplasmic reticulum Ca2+-ATPase. (From Katz AM: Calcium fluxes. In Physiology of the heart, ed 3. Philadelphia, 2001, Lippincott-Raven, pp 232-233.)

in pathophysiologic diseases such as hypertension, cardiac rest. Phospholamban is an SR membrane protein that is arrhythmias, heart failure, and muscular dystrophy.28-30 active in the dephosphorylated form. Phosphorylation by The SR provides the anatomic framework and is the a variety of kinases as a result of β-adrenergic stimulation major organelle for the cycling of Ca2+. It is the depot or other stimuli inactivates phospholamban and releases for iCa2+ stores. The cyclic release plus reuptake of Ca2+ its inhibitory action on SERCA. Positive feedback ensues by the SR regulates the cytosolic Ca2+ concentration and and leads to further phospholamban phosphorylation couples excitation to contraction. The physical proximity and greater SERCA activity. Active reuptake of Ca2+ by between L-type Ca2+ channels and RyRs at the SR mem- SERCA then promotes relaxation.17,27,31 brane makes Ca2+-induced Ca2+ release to occur easily. Once taken up into the SR, Ca2+ is stored until it is The foot region of the RyR is the part that extends from released during the next cycle. Calsequestrin and calre- the SR membrane to the T tubules, where the L-type Ca2+ ticulin are two storage proteins in the SR. Calsequestrin is channels are located.17,27,31 a highly charged protein located in the cisternal compo- The SR is also concerned with the reuptake of Ca2+ that nent of the SR near the T tubules. Because it lies close to initiates relaxation or terminates contraction. The sarco- the Ca2+-release channels, the stored Ca2+ can be quickly plasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) discharged for release once the Ca2+-release channels are pump is the ATP-dependent pump that actively pumps stimulated. Cytosolic Ca2+ can also be removed by extru- the majority of the Ca2+ back into the SR after its release. sion through the sarcolemmal Ca2+ pump and the activ- SERCA makes up close to 90% of all of the SR proteins and ity of the Na+-Ca2+ exchanger. The protein, calmodulin, is is inhibited by the phosphoprotein, phospholamban, at an important sensor and regulator of iCa2+.19

A Z I bilobar myosin head. The myosin head is made up of one H heavy chain and two light chains. The heavy head chain has two domains: the larger one interacts with actin at Relaxed sarcomere the actin cleft and has an ATP-binding pocket where myosin ATPase is located, and the other smaller one is Actin flexible and attached to the two light chains. The regula- Myosin Titin tory troponin heterotrimer complex is found at regular intervals along tropomyosin. The heterotrimer troponins are made up of troponin C (TnC), the Ca2+ receptor; TnI, an inhibitor of actin-myosin interaction; and TnT, which Contracted sarcomere links the troponin complex to tropomyosin. Tropomodu- lin is another regulatory protein. It is located at the end of the thin-filament actin and caps the end to prevent any Figure 20-13. The basic unit of contraction is the sarcomere. A con- 32,33 tracted and relaxed sarcomere is depicted. Z lines are located at the excessive elongation of the thin filament. ends of the sarcomere. The A band is the site of overlap between myosin and actin filaments. The I band is located on either side of the A Myocyte Contraction and Relaxation. At rest, cross- band and contains only actin filament. The H zone is located in the bridge cycling and generation of force do not occur center of the A band, and only myosin is present. because either the myosin heads are blocked from physi- cally reacting with the thin filament or they are only weakly bound to actin (Fig. 20-14).16 Cross-bridge cycling Contractile System is initiated on binding of Ca2+ to TnC, which increases Contractile Elements. The basic working unit of contrac- TnC-TnI interaction and decreases the inhibitory TnI- tion is the sarcomere. A sarcomere is defined as the distance actin interaction. These events, which ensue from the between Z lines (Z is an abbreviation for the German word, binding of Ca2+ to TnC, lead to conformational changes in Zuckung, meaning contraction), which join the sarcomeres tropomyosin and permit attachment of the myosin head in series. Each sarcomere consists of a central A band that to actin. Cross-bridging involves the detachment of the is separated by one half of an I band from the Z lines on myosin head from actin and a reattachment of myosin each side because the Z line bisects the I band. A schematic to another actin on hydrolysis of ATP by myosin ATPase. representation is depicted in Figure 20-13.8 Within each Binding of ATP to the nucleotide pocket of the myosin sarcomere are two principal contractile proteins (see the head leads to the activation of myosin ATPase,31-33 ATP next section, “Contractile Proteins”) and one noncontrac- hydrolysis, and changes in the configuration of the myo- tile protein, titin.27 The two contractile proteins are actin, sin head, all of which facilitate binding of the myosin the thin filament, and myosin, the thick filament. Actin head to actin and the generation of the power stroke of filaments and titin are both tethered to the Z line, but the the myosin head. Based on this model, the rate of cross- thick myosin filaments do not actually reach the Z lines. bridge cycling is dependent on the activity of myosin Titin, the third filament protein, tethers the thick-filament ATPase.36 Turnoff of cross-bridge cycling is largely initi- myosin to the Z line. The Z lines at the two ends of the ated by the decrease in cytosolic Ca2+. sarcomere are brought closer together during contraction Myocyte relaxation is an energy-dependent process as the thick-filament myosin heads interact with the thin because restoration of cytosolic Ca2+ to resting levels actin filaments and slide over each other.32,33 requires the expenditure of ATP. The decrease in cyto- Familial hypertrophic cardiomyopathy is an inherited solic Ca2+ occurs through active reuptake of Ca2+ into autosomal dominant sarcomeric disease34 that is the most the SR by SERCA and extrusion of Ca2+ by the Na+-Ca2+ common cause of sudden death in otherwise healthy indi- exchanger. This activity results in the release of Ca2+ bind- viduals. Its clinical features are left ventricular hypertro- ing to TnC and the separation of the myosin-actin cross- phy and myocyte and myofibrillar disarray. Mutations in bridge. Myocyte relaxation is dependent on the kinetics at least eight different genes encoding sarcomere proteins of cross-bridge cycling, the affinity of Ca2+ for TnC, and have been identified to be the molecular basis for the the activity of the Ca2+-reuptake mechanisms. Relaxation disorder. These genes are β-cardiac myosin heavy chain, is enhanced by the increased kinetics of cross-bridge cardiac troponin T (TnT), α-tropomyosin, cardiac myosin- cycling, decreased Ca2+ affinity for TnC, and increased binding protein C, essential or regulatory myosin light activity of Ca2+-reuptake mechanisms.27 chain, cardiac troponin I (TnI), α-cardiac actin, and titin.34 Titin is a giant stringlike protein that acts as the third filament within the sarcomere. A single titin molecule Contractile Proteins. The contractile apparatus within spans one half of the sarcomere. Structurally, titin consists the cardiomyocyte consists of contractile and regulatory of an inextensible anchoring segment and an extensible proteins.19,35,36 The thin-filament actin and the thick- elastic segment. Its two main functions involve muscle filament myosin are the two principal contractile pro- assembly and elasticity. Titin is the principal determinant teins. Actin contains two helical chains. Tropomyosin, of the passive properties of the myocardium at small ven- a double-stranded α-helical regulatory protein, winds tricular volumes.37 around the actin array and forms the backbone for the The Frank-Starling relationship states that an increase thin-filament actin. The thick-filament myosin is made in end-diastolic volume results in enhanced systolic func- up of 300 myosin molecules. Each myosin molecule has tion.38,39 At the cellular level, the key component for the two functional domains: the body or filament and the Frank-Starling relationship is a length-dependent shift

A Actin and myosin B Myosin head and neck Actin cleft and binding

Myosin

Head ATP pocket and ATPase activity Fulcrum

Neck Essential Actin or light chain arm

Regulatory Actin Tropomyosin light chain

TnC

TnI Diastole

TnI

TnC TnT Inhibition TnT TnI

TnC Ca2+

TnI

Figure 20-14. Molecules of the con- TnT Systole C Thin filament tractile system, troponins C, I, and T (TnC, TnI, and TnT). ATP, Adenosine triphosphate; ATPase, adenosine triphosphatase. (From Opie LH: Ventricular Deinhibition function. In The heart. Physiology from Tropomyosin cell to circulation, ed 4. Philadelphia, 2004, Lippincott-Raven, pp 209-231.) D Troponin I and T

(FDCM) is a disease of cytoskeleton proteins. The genetic a tonic level of parasympathetic cardiac nerve firing and basis of FDCM includes two genes for X-linked FDCM (dys- little, if any, sympathetic activity. Therefore, the major trophin, G4.5) and four genes for the autosomal dominant influence on the heart at rest is parasympathetic. During form (actin, desmin, lamin A/C, and δ-sarcoglycan).16 exercise or stress, however, the sympathetic neural influence becomes more prominent. Parasympathetic innervation of the heart is through the vagal nerve. Supraventricular tissue receives signifi- CONTROL OF CARDIAC FUNCTION cantly more intense vagal innervation than do the ventricles. The principal parasympathetic target neuroeffectors NEURAL REGULATION OF CARDIAC 47,48 FUNCTION are the muscarinic receptors in the heart. Activation of muscarinic receptors reduces pacemaker activity, slows The two limbs of the autonomic nervous system provide AV conduction, directly decreases atrial contractile force, opposing input to regulate cardiac function.45 The neu- and exerts inhibitory modulation of ventricular contrac- rotransmitter of the sympathetic nervous system is nor- tile force. A total of five muscarinic receptors have been 49 epinephrine, which provides positive chronotropic (heart cloned. M2 receptors are the predominant subtype rate), inotropic (contractility), and lusitropic (relaxation) found in the mammalian heart. In the coronary circula- effects. The parasympathetic nervous system has a more tion, M3 receptors have been identified. Moreover, non– direct inhibitory effect in the atria and has a negative M2 receptors have also been reported to exist in the heart. modulatory effect in the ventricles. The neurotransmitter In general, for intracellular signaling, M1, M3, and M5 of the parasympathetic nervous system is acetylcholine. receptors couple to Gq/11 protein and activate the phos- Both norepinephrine and acetylcholine bind to seven- pholipase C–diacylglycerol–inositol phosphate system. transmembrane–spanning G protein–coupled receptors On the other hand, the M2 and M4 receptors couple to to transduce their intracellular signals and affect their the pertussis toxin–sensitive G protein, Gi/o, to inhibit 46 + functional responses (Fig. 20-15). At rest, the heart has adenylyl cyclase. M2 receptors can couple to certain K 2+ channels and influence the activity of Ca channels, If current, phospholipase A2, phospholipase D, and tyrosine kinases. α In contrast to vagal innervation, sympathetic inner- β vation of the heart is more predominant in the ventricle γ than in the atrium. Norepinephrine released from sym- Receptor G Protein Effector pathetic nerve terminals stimulates adrenergic receptors (adrenoreceptors [AdRs]) located in the heart. The Figure 20-15. General scheme for a G protein–coupled receptor two major classes of ARs are and , both of which are consisting of receptor, the heterotrimeric G protein, and the effec- α β tor unit. (Reprinted with permission from Bers DM: Cardiac excitation- G protein–coupled receptors that transduce their intra- contraction coupling, Nature 415:198-205, 2002. Copyright MacMillan cellular signals by means of specific signaling cascades Magazines Ltd.) (Fig. 20-16).

Adrenoceptors

α1-adrenoceptors α2-adrenoceptors β-adrenoceptors

α1A α1B α1D α2A α2B α2C β1 β2 β3

Gq /11 Gq /11 Gi Gi Gi Gi Gs Gs/Gi Gs/Gi

PLC-β PLC-β PLC-β AC AC AC AC/iCA AC/iCA AC

cAMP/PKA cAMP/PKA DAG/IP3, PKC, MAPK cAMP/PKA cAMP/PKA/MAPK

Figure 20-16. Adrenoceptor signaling cascades involving G proteins and effectors are adenylyl cyclase (AC), L-type calcium current (iCA), and phospholipase β (PLC-β) in the heart. The intracellular signals are diacylglycerol (DAG), inositol 1,4,5-triphosphate (IP3), protein kinase C (PKC), cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), and mitogen-activated protein kinase (MAPK). Gq/11, Heterotrimeric G protein; Gi, inhibitory G protein; Gs, stimulatory G protein.

β-Adrenergic agonist Ca2+ Although traditional teaching is that both β1-ARs and β2-ARs are coupled to the Gs-cAMP pathway, more recent experimental evidence indicates that β2-ARs also couple to the inhibitory G protein (Gi) to activate non–cAMP- γ β dependent signaling pathways. Additionally, β2-ARs can SL couple to G protein–independent pathways to modulate α5 Adenylyl P cardiac function. -AR stimulation increases both con- cyclase β β- traction and relaxation, as summarized in Figure 20-17. Receptor Ca2+ GTP The two major subpopulations of α-ARs are α1 and α2. + + SR α1-ARs and α2-ARs can be further subdivided into differ- cAMP ent subtypes. α1-ARs are G protein–coupled receptors and via protein kinase A + include the α1A, α1B, and α1D subtypes. The α1-AR subtypes P are products of separate genes and differ in structure, G Metabolism protein coupling, tissue distribution, signaling, regula- •Glycolysis tion, and function. Both -ARs and -ARs mediate •Lipolysis α1A α1B •Citrate cycle Ca2+ positive inotropic responses. However, the positive inotropic effect mediated by -ARs is believed to be of minor ADP+Pi α1 importance in the heart. α1-ARs are coupled to phospho- + lipase C, phospholipase D, and phospholipase A2; they ATP + Troponin C increase iCa2+ and myofibrillar sensitivity to Ca2+. − Cardiac hypertrophy is primarily mediated by α1A- Myosin cAMP 51,52 2 ARs. Cardiac hypertrophic responses to 1-AR agonists ATPase via TnI α ADP+Pi − involve activation of protein kinase C and mitogen-acti- cAMP 1 vated protein kinase through Gq-signaling mechanisms. Increased β via PL Three subtypes of α2-ARs are recognized: α2A, α2B, and α2C. 1. Rate of contraction In the mammalian heart, -ARs in the atrium play a role β 2. Peak force + α2 3. Rate of relaxation 3 in the presynaptic inhibition of norepinephrine release. Control These prejunctional α2-ARs are believed to belong to the α2C subtype. Neural regulation of cardiac function involves a Pattern of contraction complex interaction between the different classes and Figure 20-17. The β-adrenoceptor signaling system leads to an subpopulations of adrenoceptors and their signaling increased rate and force of contraction and increased relaxation. ADP, pathways. Targeted therapeutics in cardiovascular medi- adenosine diphosphate; ATP, adenosine triphosphate; ATPase, adenos- cine involve the clinical application and manipulation of ine triphosphatase; cAMP, cyclic adenosine monophosphate; GTP, guanosine triphosphate; Pi, phosphatidylinositol; PL, phospholipase; SL, a basic understanding of adrenoceptor pharmacology. sarcolemma; SR, sarcoplasmic reticulum; TnI, troponin I. (From Opie LH: Receptors and signal transduction. In The heart. Physiology from HORMONES AFFECTING CARDIAC cell to circulation, ed 3. Philadelphia, 1998, Lippincott-Raven, p 195.) FUNCTION Many hormones have direct and indirect actions on the β-ARs can be further divided into subpopulations of β1, heart (Table 20-1). Hormones with cardiac actions can be 50 β2, and β3. Although most mammalian hearts contain synthesized and secreted by cardiomyocytes or produced β1-ARs and β2-ARs, β3-ARs also exist in many mamma- by other tissues and delivered to the heart. They act on lian ventricular tissues. The relative contribution of each specific receptors expressed in cardiomyocytes. Most of β-AR subtype to modulation of cardiac function varies these hormone receptors are plasma membrane G pro- among species. In humans, β1-ARs are the predominant tein–coupled receptors (GPCRs). Non-GPCRs include subtype in both the atria and ventricles, but a substantial the natriuretic peptide receptors, which are guanylyl proportion of β2-ARs are located in the atria, and approxi- cyclase–coupled receptors, and the glucocorticoid and mately 20% of β2-ARs are found in the LV. Much less is mineralocorticoid receptors, which bind androgens and known about β3-ARs, but they do exist in the human ven- aldosterone and are nuclear zinc finger transcription tricle. Despite the fact that the β1-AR population is more factors. Hormones can have activity in normal cardiac intense than the β2-AR population, the cardiostimulant physiologic function or are active only in pathophysi- effect is not proportional to the relative densities of these ologic conditions, or both situations can apply. Most of two subpopulations, which is largely attributable to the the new information regarding the action of hormones tighter coupling of β2-ARs than β1-ARs to the cyclic ade- in the heart has been derived from the endocrine changes nosine monophosphate (cAMP) signaling pathway. Both associated with chronic heart failure.53 β1-ARs and β2-ARs activate a pathway that involves the Cardiac hormones are polypeptides secreted by cardiac stimulatory G protein (Gs), activation of adenylyl cyclase, tissues into the circulation in the normal heart. Natri- accumulation of cAMP, stimulation of cAMP-dependent uretic peptides,54,55 aldosterone,56 and adrenomedullin57 protein kinase A, and phosphorylation of key target pro- are hormones secreted by cardiomyocytes. Angioten- teins, including L-type Ca2+ channels, phospholamban, sin II, the effector hormone in the renin-angiotensin and TnI. system, is also produced by cardiomyocytes.58,59 The

TABLE 20-1 ACTIONS OF HORMONES ON CARDIAC FUNCTION Increase (+) or Decrease (−) Hormone Receptor Cardiac Action With CHF Adrenomedullin GPCR +Inotropy/+chronotropy + Aldosterone Cytosolic or nuclear MR ? + Angiotensin GPCR + Inotropy/+ chronotropy + Endothelin GPCR ? + Natriuretic peptides GCCR ANP (ANF) + BNP + Neuropeptide Y* GPCR − Inotropy + Vasopressin GPCR + Inotropy/+ chronotropy + Vasoactive intestinal peptide† GPCR + Inotropy No Estrogen ERα/ERß Indirect No Testosterone AR Indirect No Progesterone PR Indirect No Thyroid hormones NR + Inotropy/+ chronotropy — Growth hormones IGF-1 + Inotropy/+ chronotropy —

ANF, Atrial natriuretic factor; ANP, atrial natriuretic peptide; AR, androgen receptor; BNP, B-type natriuretic peptide; CHF, congestive heart failure; ER, estrogen receptor; GCCR, guanylyl cyclase–coupled receptor; GPCR, G protein–coupled receptor; IGF-1, insulin growth factor 1; MR, mineralocorticoid receptor; NR, nuclear receptor; PR, progesterone receptor. *Data from Grundemar L, Hakanson R: Multiple neuropeptide Y receptors are involved in cardiovascular regulation. Peripheral and central mechanisms, Gen Pharmacol 24:785-796, 1993; and Maisel AS, Scott NA, Motulsky HJ, et al: Elevation of plasma neuropeptide Y levels in congestive heart failure, Am J Med 86:43-48, 1989 †Data from Henning RJ, Sawmiller DR: Vasoactive intestinal peptide: cardiovascular effects, Cardiovasc Res 49:27-37, 2001.

renin-angiotensin system is one of the most important guanosine monophosphate and represent part of the car- regulators of cardiovascular physiology. It is a key mod- diac endocrine response to hemodynamic changes caused ulator of cardiac growth and function. Angiotensin II by pressure or volume overload. They also participate in stimulates two separate receptor subtypes, AT1 and AT2, organogenesis of the embryonic heart and cardiovascu- 54,55 both of which are present in the heart. AT1 receptors are lar system. In patients with chronic heart failure, the predominant subtype expressed in the normal adult increases of serum ANP and BNP levels are a predictor of 69 human heart. Stimulation of AT1 receptors induces a posi- mortality. tive chronotropic and inotropic effect. Angiotensin II also Adrenomedullin is a recently discovered cardiac hor- mediates cell growth and proliferation in cardiomyocytes mone that was originally isolated from pheochromocy- and fibroblasts and induces the release of the growth fac- toma tissue. It increases the accumulation of cAMP and has tors aldosterone and catecholamines through the stim- direct positive chronotropic and inotropic effects.57,60,61 ulation of AT1 receptors. Activation of AT1 receptors is Adrenomedullin, with interspecies and regional varia- directly involved in the development of cardiac hypertro- tions, has also been shown to increase nitric oxide pro- phy and heart failure, as well as adverse remodeling of the duction, and it functions as a potent vasodilator. myocardium. In contrast, AT2 receptor activation is coun- Aldosterone is one of the cardiac-generated steroids, terregulatory and generally antiproliferative. Expression although its physiologic significance remains to be defined. of AT2 receptors, however, is relatively scant in the adult It binds to mineralocorticoid receptors and can increase the heart because they are most abundant in the fetal heart expression or activity (or both) of cardiac proteins involved and decline with development. In response to injury and in ionic homeostasis or the regulation of pH, such as cardiac + + + + − ischemia, AT2 receptors become upregulated. The precise Na /K -ATPase, the Na -K cotransporter, Cl -bicarbonate 2+ + + 56 role of AT2 receptors in the heart remains to be defined. (HCO3 ), and the Na -hydrogen (H ) antiporter. Aldoste- The beneficial effects of blockade of the renin-angio- rone modifies cardiac structure by inducing cardiac fibrosis tensin system with angiotensin-converting enzyme in both ventricular chambers and thereby leads to impair- inhibitors in the treatment of heart failure have been ment of cardiac contractile function. 70 attributed to an inhibition of AT1-receptor activity. In Other hormones such as the growth hormone, thy- addition to the renin-angiotensin system, other cardiac roid hormones,71 and sex steroid hormones (see the fol- hormones that have been shown to play pathogenic roles lowing text) can also have cardiac effects through direct in the promotion of cardiomyocyte growth and cardiac actions of nuclear receptors or indirect effects. fibrosis, development of cardiac hypertrophy, and progression of congestive heart failure include aldosterone,56 Sex Steroid Hormones and the Heart adrenomedullin,60-62 natriuretic peptides,54,55 angioten- Cardiac contractility is more intense in premenopausal sin,63-65 endothelin,66 and vasopressin.67,68 women than in age-matched men, and withdrawal Increased stretch of the myocardium stimulates the of hormone replacement therapy in postmenopausal release of atrial natriuretic protein (ANP) and B-type women leads to a reduction in cardiac contractile func- natriuretic protein (BNP) from the atria and ventricles, tion. The gender dimorphism in heart function and its respectively. Both ANP and BNP bind to natriuretic pep- adaptive responses to injury and disease states are partly tide receptors to generate the second messenger cyclic mediated by sex steroid hormones.

The most extensively studied sex steroid hormones are vascular tone. In addition to sex steroid hormone stim- estradiol-17β (E2) and its bioactive metabolites. They bind ulation of nuclear or nonnuclear receptors, sex steroid and act on the two subtypes of estrogen receptors (ERs) hormone receptors could also induce rapid signaling of in the heart: ERα and ERβ. Progesterone and testosterone growth factor pathways in the absence of ligands. (two other sex steroid hormones) and the enzyme aroma- Gender differences exist in cardiac electrophysiologic tase, which converts testosterone to estrogen, are much function. The modulatory actions of estrogen on Ca2+ less well investigated. Progesterone and testosterone bind channels might be responsible for sex-based differences and act on their respective progesterone receptors and in repolarization of the heart, such as the faster resting androgen receptors in the heart. Sex steroid hormones heart rate of women, as well as the increased propensity interact with their receptors to affect postsynaptic target of women to have prolonged QT syndrome.74 Estrogen, cell responses and to influence presynaptic sympathoad- through the activation of ERβ, confers protection after renergic function. Cardiomyocytes are not only targets ischemia and reperfusion in murine models of myocardial for the action of sex steroid hormones, but they are also infarction. In contrast, testosterone, in the same model, the source of synthesis and the site of metabolism of has the opposite effect. Aromatase also has protective these hormones.72 effects, probably through its action to increase estrogen E2 is derived from testosterone and is primarily metab- and to decrease testosterone. olized in the liver to form hydroxyestradiols, catecho- Gender differences in cardiac physiology should lestradiols, and methoxyestradiols. Estradiol metabolism include consideration of the cellular physiology of sex also takes place in vascular smooth muscle cells, cardiac steroid hormones in males and females; intrinsic dif- fibroblasts, endothelial cells, and cardiomyocytes. Car- ferences in the physiology of cardiomyocytes, vascular diomyocytes express nuclear steroid hormone receptors smooth muscle cells, and endothelial cells between males that modulate gene expression and nonnuclear recep- and females; and gender-based differences in the auto- tors for the nongenomic effects of sex steroid hormones. nomic modulation of cardiac physiology. They interact with many different coregulators to con- fer tissue and temporal specificity in their transcriptional CARDIAC REFLEXES actions. These cell-specific coactivator and corepressor proteins are known as estrogen-related receptors.73 Sex Cardiac reflexes are fast-acting reflex loops between the steroid hormones can activate rapid signaling pathways heart and the central nervous system (CNS) that contrib- without changing gene expression (Fig. 20-18). One such ute to regulation of cardiac function and the maintenance example is stimulation of vascular endothelial nitric of physiologic homeostasis. Specific cardiac receptors oxide synthase to mediate vascular dilatation. Estrogen’s elicit their physiologic responses by various pathways. vasodilatory effect might explain the lower systolic blood Cardiac receptors are linked to the CNS by myelinated or pressures of premenopausal women when compared unmyelinated afferent fibers that travel along the vagus with age-matched men. In men, aromatase-mediated nerve. Cardiac receptors are in the atria, ventricles, peri- conversion of testosterone to estrogen maintains normal cardium, and coronary arteries. Extracardiac receptors

NO E2

caveatin NOS Ca2+, K+ GPR-30 EGFR ER

Figure 20-18. Signaling mecha- GPR-30 nism of nuclear and nonnuclear localized estrogen receptor (ER) NCX NHE and the estrogen-binding recep- Intracellular responses: Ca2+ tor, GPR-30. Nuclear ER influences •Kinase activation the transcription of target genes by •Signaling cascade 2+ binding to an ER-response element •Ca transient SR (ERE) within the promotor region •Protein interaction of target genes. E2, Estrogen; EGFR, epidermal growth factor receptor; NCX, Na+-Ca2+ exchanger; NHE, Na+-H+ exchanger; NO, nitric oxide; NOS, nitric oxide synthase, SR, sar- ER coplasmic reticulum. (From Du XJ, Protein ER ER mRNA Fang L, Kiriazis H: Sex dimorphism in synthesis cardiac pathophysiology: experimen- ERE tal findings, hormonal mechanisms, and molecular mechanisms, Pharma- Nucleus col Ther 111:434-475, 2006.) Mitochondria

are located in the great vessels and carotid artery. Sym- decrease in cardiac contractility, heart rate, and vascu- pathetic and parasympathetic nerve input is processed in lar tone. In addition, activation of the parasympathetic the CNS. After central processing, efferent fibers to the system further decreases the heart rate and myocardial heart or the systemic circulation will provoke a particu- contractility. Reverse effects are elicited with the onset lar reaction. The response of the cardiovascular system to of hypotension. efferent stimulation varies with age and duration of the The baroreceptor reflex plays an important benefi- underlying condition that elicited the reflex in the first cial role during acute blood loss and shock. However, instance. the reflex arch loses its functional capacity when arterial blood pressure is less than 50 mm Hg. Hormonal Baroreceptor Reflex (Carotid Sinus Reflex) status and therefore sex differences may alter barorecep- The baroreceptor reflex is responsible for the mainte- tor responses.77 Furthermore, volatile anesthetics (par- nance of arterial blood pressure. This reflex is capable of ticularly halothane) inhibit the heart rate component of regulating arterial pressure around a preset value through this reflex.78 Concomitant use of Ca2+-channel blockers, a negative-feedback loop (Fig. 20-19).75,76 In addition, angiotensin-converting enzyme inhibitors, or phosphodi- the baroreceptor reflex is capable of establishing a pre- esterase inhibitors will lessen the cardiovascular response vailing set point for arterial blood pressure when the of raising blood pressure through the baroreceptor reflex. preset value has been reset because of chronic hyperten- This lessened response is achieved by either their direct sion. Changes in arterial blood pressure are monitored effects on the peripheral vasculature or, more impor- by circumferential and longitudinal stretch receptors tantly, their interference with CNS signaling pathways located in the carotid sinus and aortic arch. The nucleus (Ca2+, angiotensin).79 Patients with chronic hyperten- solitarius, located in the cardiovascular center of the sion often exhibit perioperative circulatory instability as medulla, receives impulses from these stretch receptors a result of a decrease in their baroreceptor reflex response. through afferents of the glossopharyngeal and vagus nerves. The cardiovascular center in the medulla consists Chemoreceptor Reflex of two functionally different areas; the area responsible Chemosensitive cells are located in the carotid bodies and for increasing blood pressure is laterally and rostrally the aortic body. These cells respond to changes in pH sta- located, whereas the area responsible for lowering arte- tus and blood O2 tension. At an arterial partial O2 pressure rial blood pressure is centrally and caudally located. The (PaO2) of less than 50 mm Hg or in conditions of acidosis, latter area also integrates impulses from the hypothala- the chemoreceptors send their impulses along the sinus mus and the limbic system. Typically, stretch recep- nerve of Hering (a branch of the glossopharyngeal nerve) tors are activated if systemic blood pressure is greater and the tenth cranial nerve to the chemosensitive area of than 170 mm Hg. The response of the depressor system the medulla. This area responds by stimulating the respi- includes decreased sympathetic activity, leading to a ratory centers and thereby increasing ventilatory drive.

Cardiovascular control center

Pressure 240 receptors in wall of Arterial pressure carotid 200 sinus 160 Normal 120

80 Figure 20-19. Anatomic configura-

Blood pressure (mm Hg) 40 tion of the baroreceptor reflex. Pres- sure receptors in the wall of the carotid sinuses and aorta detect changes in arterial pressure in the circulation. Aortic These signals are conveyed to affer- baroreceptors ent receptive regions of the medulla through the Hering and vagus nerves. Aorta Nerve activity Output from effector portions of the medulla modulates peripheral tone and heart rate. The increase in blood pressure results in increased activation of the reflex right( ), which affects a decrease in blood pressure. (From Cam- pagna JA, Carter C: Clinical relevance of the Bezold-Jarisch reflex, Anesthesiology 98:1250-1260, 2003.)

In addition, activation of the parasympathetic system Oculocardiac Reflex ensues and leads to a reduction in heart rate and myo- The oculocardiac reflex is provoked by pressure applied cardial contractility. In the case of persistent hypoxia, the to the globe of the eye or traction on the surrounding CNS will be directly stimulated, with a resultant increase structures. Stretch receptors are located in the extraocular in sympathetic activity. muscles. Once activated, stretch receptors will send afferent signals through the short- and long-ciliary nerves. Bainbridge Reflex The ciliary nerves will merge with the ophthalmic divi- The Bainbridge reflex80-82 is elicited by stretch receptors sion of the trigeminal nerve at the ciliary ganglion. The located in the right atrial wall and the cavoatrial junc- trigeminal nerve will carry these impulses to the gasserian tion. An increase in right-sided filling pressure sends ganglion, thereby resulting in increased parasympathetic vagal afferent signals to the cardiovascular center in the tone and subsequent bradycardia. The incidence of this medulla. These afferent signals inhibit parasympathetic reflex during ophthalmic surgery ranges from 30% to activity, thereby increasing the heart rate. Acceleration 90%. Administration of an antimuscarinic drug such as of the heart rate also results from a direct effect on the glycopyrrolate or atropine reduces the incidence of bra- SA node by stretching the atrium. The changes in heart dycardia during eye surgery (also see Chapter 84). rate are dependent on the underlying heart rate before stimulation. Complete references available online at expertconsult.com Bezold-Jarisch Reflex References The Bezold-Jarisch reflex responds to noxious ventricular stimuli sensed by chemoreceptors and mechano- 1. Berne RM, Levy MN: The cardiac pump. 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