Atrioventricular Valves

The valve between the right atrium and right ventricle is made up of three cusps (tricuspid valve), whereas the valve between the left atrium and left ventricle has two cusps (mitral valve). The total area of the cusps of each AV valve is approximately twice that of their respective AV orifices, so that there is considerable overlap of the leaflets in the closed position (see Figures 4-5 and 4-6). Attached to the free edges of these valves are fine, strong ligaments (chordae tendineae), which arise from the powerful papillary muscles of the respective ventricles and prevent eversion of the valves during ventricular systole.

Semilunar Valves

The valves between the right ventricle and the pulmonary artery and between the left ventricle and the aorta consist of three cuplike cusps attached to the valve rings (see Figures 4-5 and 4-6). At the end of the reduced ejection phase of ventricular systole, there is a brief reversal of blood flow toward the ventricles (shown as a negative flow in the phasic aortic flow curve in Figure 4-13) that snaps the cusps together and prevents regurgitation of blood into the ventricles. During ventricular systole the cusps do not lie back against the walls of the pulmonary artery and aorta but float in the bloodstream approximately midway between the vessel walls and their closed position. Behind the semilunar valves are small outpocketings of the pulmonary artery and aorta (sinuses of Valsalva), where eddy currents develop that tend to keep the valve cusps away from the vessel walls. The orifices of the right and left coronary arteries are behind the right and the left cusps, respectively, of the aortic valve. Were it not for the presence of the sinuses of Valsalva and the eddy currents developed therein, the coronary ostia could be blocked by the valve cusps.

The Pericardium Is an Epithelized Fibrous Sac That Invests the Heart

The pericardium consists of a visceral layer that adheres to the epicardium and a parietal layer that is separated from the visceral layer by a thin layer of fluid. This fluid provides lubrication for the continuous movement of the enclosed heart. The pericardium strongly resists a large, rapid increase in cardiac size because its distensibility is small. The pericardium plays a role in preventing sudden overdistention of the chambers of the heart because of this characteristic. However, with congenital absence of the pericardium or after its surgical removal, cardiac function is within physiological limits. Nevertheless, with the pericardium intact, an increase in diastolic pressure in one ventricle increases the pressure and decreases the compliance of the other ventricle.

Preload Determines the Strength of Cardiac Contraction

For an isolated strip of ventricular cardiac muscle or an isolated papillary muscle in an experimental situation (Figure 4-9), preload is the force (load) on the muscle prior (or pre-) to its being activated to contract. The preload applies tension to the muscle and stretches it passively to a new length. In the heart, preload is the stress exerted on the ventricle during diastole and can be represented by the Laplace equation for a thick-walled sphere. Thus muscle can be characterized by a passive length-tension relationship, obtained by measuring length at different preloads. Preload also determines the strength of an active, isometric contraction that begins from a particular length. The muscle may be forced to contract isometrically by the addition of a very large afterload that the muscle will not be able to lift (Figure 4-9). (The further lengthening of the muscle that would be caused by the afterload is prevented with a physical stop.) Then, upon electrical stimulation, the muscle contracts isometrically (i.e., without shortening) and develops the maximum active force of which it is capable, from that initial length. Increasing preload always stretches the muscle further, causing both increased initial length (Figure 4-10A) and, up to a point, greater active force development. The total tension within the muscle at the peak of the contraction is the sum of the passive tension and active tension (Figure 4-10, B). When contractility is increased, as by norepinephrine (see Figure 4-8), the active tension and total tension are greatly increased (Figure 4-10C). The passive tension is largely unaffected when contractility increases, and thus the increase in total tension is due entirely to greater active tension. Conversely, a reduction in contractility, as might be caused by pharmacologic block of L-type Ca⁺⁺ channels, results in reduced total tension, largely accounted for by decreased active tension development. The fact that active tension generated by cardiac muscle rises steeply with increasing initial muscle length is critical to the performance of the heart, allowing the heart to contract more strongly if it is stretched by a greater volume of blood prior to contraction.

FIGURE 4-9 A simple experiment to determine the effect of preload on the strength of isometric cardiac muscle contraction. A, a: A strip of cardiac muscle, such as an isolated ventricular papillary muscle is attached to a lever and a fixed point. b: The other end of the lever is loaded, stretching the muscle. This load is the preload. c: A stop is placed against the lever, such that no further lengthening of the muscle can occur. d: Another weight is added (the afterload). Because of the stop, the muscle is not lengthened by this load. Only after it would begin to contract would this load exist on the muscle (hence the term afterload). In this case, the afterload is chosen to be so large that the muscle will not be able to lift it, and will therefore be forced to contract isometrically. e: The muscle is stimulated electrically to contract. f: The muscle contracts, generating force, but does not shorten. The contraction is isometric. B, The length of the muscle and the tension developed throughout the experiment in A are shown. The preload is a passive force that lengthens the muscle. When the muscle contracts, active tension is developed, but shortening cannot occur.

FIGURE 4-10 The effect of preload on passive tension in a strip of cardiac muscle and on the active tension it develops. A, Recordings of muscle length and isometric tension, from experiments like those shown in Figure 4-9. Dashed and dotted lines show the response of the muscle to different preloads; increasing preload results in greater passive tension and greater active tension, until very high preloads, at which point peak active tension begins to decrease from that elicited by smaller preloads. B, Graph of results from experiments like those shown in A. The curve labeled “Passive” represents the passive force in the muscle produced by the preload, and the passive force is plotted as a function of the length of the muscle. Preload sets the initial muscle length, before it is stimulated to contract and produce active tension. The curve labeled “Total: Active plus Passive” represents the peak tension in the muscle during active contraction, as a function of its initial length. C, Increasing contractility, as produced by norepinephrine, causes increased active and total tension at any given initial muscle length. Decreased contractility, as might be caused by pharmacologic block of cardiac voltage–dependent Ca⁺⁺ channels (see Figure 4-8) causes reduced active and total tension. Passive tension is largely unaffected.

The detailed relationship between sarcomere length and tension (passive and active) has also been examined (Figure 4-11). Cardiac sarcomere length has been determined with electron microscopy in papillary muscles and intact ventricles rapidly fixed during systole (contracted) or diastole (relaxed). The developed force is maximal when cardiac muscle begins its contractions at initial sarcomere length of 2.2 µm. At this length, there is optimal overlap of thick and thin filaments, and a maximal number of possible cross-bridge attachments. Although skeletal and cardiac muscles show somewhat similar length-tension relationships (see Figure 4-11), the two types of muscle are distinctly different with respect to the normal operating range of sarcomere lengths. Cardiac muscle does not normally operate at very short (<1.8 µm) or very long (>2.2 µm) sarcomere lengths. Furthermore, the ascending limb of the cardiac muscle length-tension relation is very steep over the range of 1.8 µm to 2.0 µm, and this steepness cannot be accounted for entirely by more effective myofilament overlap, as it is in skeletal muscle. The active length-tension relation of skeletal muscle (see Figure 4-11) is obtained with constant levels of contractile activation, produced by tetanic stimulation, over the whole range of sarcomere lengths. Cardiac muscle, however, cannot be tetanized, and in cardiac muscle the level of contractile activation increases significantly over the range of 1.8 µm to 2.0 µm sarcomere length, thus accounting for the steep rise in active force. One mechanism, not present to the same extent in skeletal muscle, is that stretch of cardiac cells enhances the affinity of troponin C for Ca⁺⁺, thus resulting in the binding of a greater amount of Ca⁺⁺ to troponin C and the formation of a greater number of cross-bridges. The mechanism responsible for this greater affinity of troponin C for Ca⁺⁺ remains to be determined. One concept is that the thick and thin filaments are brought closer to each other as the diameter of the muscle fiber narrows during stretch, because the cell maintains constant volume. The protein, titin, may help in this process, in that it forms a scaffold to which actin and myosin filaments bind. Finally—another feature different from that of skeletal muscle—the amount of Ca⁺⁺ released from the SR in cardiac muscle increases with increasing sarcomere length. This is a time-dependent phenomenon, developing slowly over many beats, after the sarcomere length has been increased. Thus, three cellular mechanisms contribute to the length dependence of cardiac muscle contraction from 1.8 µm to 2.2 µm: (1) changes in myofilament overlap, similar to those in skeletal muscle; (2) increased activation as a result of greater chemical affinity of troponin C for Ca⁺⁺; and (3) increased activation as a result of greater release of Ca⁺⁺ from the sarcoplasmic reticulum.

FIGURE 4-11 Sarcomere length-tension relations for cardiac and skeletal muscle. Active tension (total tension − passive tension) is plotted as a function of initial sarcomere length. The diagrams of the myofilaments show the extent of overlap between thick and thin filaments at five specific sarcomere lengths in skeletal muscle. In skeletal muscle, maximum tension occurs at sarcomere lengths between 2.0 and 2.2 µm (between points B and C). Tension decreases between 2.2 and 3.65 µm of sarcomere length (between points A and B) because there is a decrease in the overlap between thick and thin filaments (between points C and D). In cardiac muscle, active tension falls steeply with sarcomere lengths greater or less than 2.2 µm. The increase in passive tension occurs at much shorter sarcomere lengths in cardiac muscle than in skeletal muscle.

(Redrawn from Gordon AM, Huxley AF, Julian FJ: Tension development in highly stretched vertebrate muscle fibres. J Physiol 184:143, 1966; and Braunwald E, Ross J Jr: Mechanisms of contraction of the normal and failing heart, Boston, 1976, Little Brown.)

Developed force of cardiac muscle is less than the maximal value when the sarcomeres are stretched beyond the optimal length, because the myofilaments overlap less and hence reduce cross-bridge cycling. At very short sarcomere lengths, the thin filaments overlap each other in the central region of the sarcomere. This ‘double overlap’ of the thin filaments diminishes contractile force.

In summary, the passive and active length-tension relations of cardiac muscle (see Figure 4-10B) arise from the mechanisms discussed above and, in the whole heart, are reflected in the relationship between volume of the heart and its actively developed pressure, as discussed later.

Afterload Determines the Velocity of Cardiac Muscle Shortening

A strip of cardiac muscle, and the intact heart, also experiences an additional load (force) against which it must contract, after it is activated (Figure 4-12). This load, known as afterload, determines the velocity with which the muscle can shorten. In the intact heart, this situation represents left ventricular ejection into the aorta. During ejection, the afterload is represented by the impedance due to aortic and intraventricular pressures, which are virtually equal to each other. Thus, the afterload is the stress applied to the ventricle during ejection of blood.

FIGURE 4-12 The velocity of shortening of cardiac muscle depends on the afterload. Velocity of shortening is increased by norepinephrine (NE). A and B, Experiment to measure the effect of afterload on shortening velocity. a: A preload, stop, and small afterload are added. b: The muscle is stimulated to contract. It contracts isometrically at first, until it generates enough force to lift the afterload. c: When the muscle generates sufficient force to lift the afterload, muscle shortening can occur. The velocity of shortening is the slope of the initial length change. C, Force-velocity (F/V) curve. Velocity of shortening decreases monotonically as the afterload is increased, up to a level, F0, that the muscle cannot lift. The velocity of shortening is increased at all forces by increasing contractility, as through the action of norepinephrine (NE).

Experimentally, the effects of afterload may be examined in experiments (see Figure 4-12) similar to those for preload. If the afterload is such that the muscle can generate enough force to lift the load, then the muscle contracts isometrically until it generates enough force to lift the afterload, after which it can begin to shorten. The velocity of shortening is maximal (V₀) for no afterload and decreases monotonically to zero when the force (load) is too great for the muscle to lift at all (i.e., an isometric contraction). Norepinephrine increases the velocity of shortening at every level of afterload.

Isovolumic Contraction

The onset of ventricular contraction coincides with the peak of the R wave of the electrocardiogram and the initial vibration of the first heart sound. It is indicated on the ventricular pressure curve as the earliest rise in ventricular pressure after atrial contraction. The phase between the start of ventricular systole and the opening of the semilunar valves (when ventricular pressure rises abruptly) is termed isovolumic contraction because ventricular volume is constant during this brief period (see Figure 4-13).

The increment in ventricular pressure during isovolumic contraction is transmitted across the closed valves. Isovolumic contraction has also been referred to as “isometric contraction.” However, some fibers shorten and others lengthen, as evidenced by changes in ventricular shape; it is, therefore, not a true isometric contraction.

Ejection

Opening of the semilunar valves marks the onset of the ejection phase, which may be subdivided into an earlier, shorter phase (rapid ejection) and a later, longer phase (reduced ejection). The rapid ejection phase is distinguished from the reduced ejection phase by (1) the sharp rise in ventricular and aortic pressures that terminate at the peak ventricular and aortic pressures; (2) a more abrupt decrease in ventricular volume; and (3) a greater aortic blood flow (see Figure 4-13). The sharp decrease in the left atrial pressure curve at the onset of ejection results from the descent of the base of the heart and stretch of the atria. During the reduced ejection period, blood flow from the aorta to the periphery exceeds ventricular output, and therefore aortic pressure declines. Throughout ventricular systole, the blood returning to the atria produces a progressive increase in atrial pressure. Note that during approximately the first third of the ejection period, left ventricular pressure slightly exceeds aortic pressure and flow accelerates (continues to increase), whereas during the last two thirds of ventricular ejection, the reverse holds true. This reversal of the ventricular-aortic pressure gradient in the presence of continued flow of blood from the left ventricle to the aorta (caused by the momentum of the forward blood flow) is the result of the storage of potential energy in the stretched arterial walls, which produces a deceleration of blood flow into the aorta (see Chapter 7). The peak of the flow curve coincides in time with the point at which the left ventricular pressure curve intersects the aortic pressure curve during ejection. Thereafter, flow decelerates (continues to decrease) because the pressure gradient has been reversed.

With right ventricular ejection, there is shortening of the free wall of the right ventricle (descent of the tricuspid valve ring) and lateral compression of the chamber. However, with left ventricular ejection, there is very little shortening of the base-to-apex axis, and ejection is accomplished chiefly by compression of the left ventricular chamber.

The effect of ventricular systole on left ventricular diameter is shown in an echocardiogram in Figure 4-14. During ventricular systole, the septum and the free wall of the left ventricle become thicker and move closer to each other.

FIGURE 4-14 Two-dimensional echocardiographic images of a normal human heart (young adult male) taken from the parasternal long-axis view. A, During diastole, the left atrium (LA) communicates freely with the cavity of the left ventricle (LV). The anterior leaflet (ALMV) and the posterior leaflet (PLMV, shown in B) of the mitral valve (MV) are open; the leaflets of the aortic valve (AV) are closed. B, During systole, the left ventricular (LV) interventricular septum (IVS), and posterolateral wall (LVPW) wall thicken; the LV cavity diminishes in volume. The LV cavity is open to the ascending aorta (aAo); the AV is open and the MV is closed. Also evident in the echocardiograms are the descending aorta (dAo), the coronary sinus (CS), the right ventricle cavity (RV), and the RV free wall. The pericardium (Peri) is evident as a very bright structure; a reverberation artifact is present.

(Courtesy of Dr. Peter Schulman.).

The venous pulse curve shown in Figure 4-13 has been taken from a jugular vein. The a wave is caused by atrial contraction, the c wave by the impact of the adjacent common carotid artery and to some extent by transmission of a pressure wave produced by the abrupt closure of the tricuspid valve in early ventricular systole, and the v wave by the pressure of blood returning from the peripheral vessels and the abrupt opening of the tricuspid valve. Note that except for the c wave, the venous pulse closely follows the atrial pressure curve.

At the end of ejection, a volume of blood approximately equal to that ejected during systole remains in the ventricular cavities. This residual volume (end-systolic volume) is fairly constant in normal hearts but is smaller with increased heart rate or reduced outflow resistance and larger when the opposite conditions prevail.

In addition to serving as a small adjustable blood reservoir, the residual volume to a limited degree can permit transient disparities between the outputs of the two ventricles.

Ventricular Diastole

The Indicator Dilution Technique is a Useful Method for Measuring Cardiac Output

The indicator dilution technique for measuring cardiac output is also based on the law of conservation of mass and is illustrated by the model in Figure 4-20. Let a liquid flow through a tube at a rate of Q mL/s, and let q mg of dye be injected as a bolus into the stream at point A. Let mixing occur at some point downstream. If a small sample of liquid is continually withdrawn from point B farther downstream and passed through a densitometer, a curve of the dye concentration, c, may be recorded as a function of time, t, as shown in the lower half of Figure 4-20.

FIGURE 4-20 Indicator dilution technique for measuring cardiac output. In this model (upper section), in which there is no recirculation, q mg of dye is injected instantaneously at point A into a stream flowing at Q mL/min. A mixed sample of the fluid flowing past point B is withdrawn at a constant rate through a densitometer. The resulting dye concentration curve at point B has the configuration shown in the lower section of the figure.

If no dye is lost between points A and B, the amount of dye, q, passing point B between times t₁ and t₂ will be

     (6)

where is the mean concentration of dye. The value of may be computed by dividing the area of the dye concentration by the duration (t₂ − t₁) of that curve; that is

     (7)

Substituting this value of into equation 6 and solving for Q yields

     (8)

Thus flow may be measured by dividing the amount of indicator injected upstream by the area under the downstream concentration curve.

This technique had been widely used to estimate cardiac output in humans. A measured quantity of some indicator (a dye or isotope that remains within the circulation) is injected rapidly into a large central vein or into the right side of the heart through a catheter. Arterial blood is continuously drawn through a detector (densitometer or isotope rate counter), and a curve of indicator concentration is recorded as a function of time.

The most popular indicator dilution technique is thermodilution. The indicator is cold saline. The temperature and volume of the saline are measured accurately before injection. A flexible catheter is introduced into a peripheral vein and advanced so that the tip lies in the pulmonary artery. A small thermistor at the catheter tip records the changes in temperature. The opening in the catheter lies a few inches proximal to the tip. When the tip is in the pulmonary artery, the opening lies in or near the right atrium. The cold saline is injected rapidly into the right atrium through the catheter. The resultant change in temperature downstream is recorded by the thermistor in the pulmonary artery.

The thermodilution technique has the following advantages: (1) an arterial puncture is not necessary; (2) the small volumes of saline used in each determination are innocuous, allowing repeated determinations to be made; and (3) recirculation is negligible. Temperature equilibration takes place as the cooled blood flows through the pulmonary and systemic capillary beds, before it flows by the thermistor in the pulmonary artery the second time.

Metabolism of ATP and its Relation to Mechanical Function

The chemical energy that fuels cardiac contractile work and relaxation is derived from ATP hydrolysis (Figure 4-21). The healthy heart has a relatively constant level of ATP (~5 µmol/g wet weight) despite an extremely high rate of ATP hydrolysis (≈0.3 µmol g⁻¹ second⁻¹). The tissue content of ATP is low relative to the rate of breakdown and production, with a complete turnover of the myocardial ATP content approximately every 12 seconds (s) in the heart at rest. The hydrolysis of ATP provides energy for contractile work (actin-myosin interaction and cell shortening), pumping Ca⁺⁺ back into the sarcoplasmic reticulum at the end of systole, and maintaining normal ion gradients (low Na⁺ and high K⁺ in the cell).

FIGURE 4-21 Linkages between cardiac cell functions, adenosine triphosphate (ATP) hydrolysis, oxidative phosphorylation, and NADH (reduced form of nicotinamide adenosine dinucleotide) generation by dehydrogenases (DHases) in metabolism. ADP, adenosine diphosphate; ETC, electron transport chain; NAD⁺, nicotinamide adenosine dinucleotide; SR, sarcoplasmic reticulum.

Approximately two thirds of the ATP hydrolyzed by the heart is used to fuel contractile work, with the remaining third used for ion pumps and “housekeeping” functions like synthesis of proteins and nucleic acids. The sarcoplasmic reticulum Ca⁺⁺-ATPase is the primary ion pump consuming ATP. This process occurs during the end of systole, when cytosolic Ca⁺⁺ is rapidly sequestered into the sarcoplasmic reticulum to initiate diastolic relaxation (see Figure 4-8). In the healthy heart the rate of ATP hydrolysis (breakdown) is exquisitely matched to the rate of ATP resynthesis. There is no significant change in the concentrations of ATP or ADP even with the onset of heavy exercise. The primary means for ATP resynthesis is via oxidative phosphorylation in mitochondria (>98%) with a small amount from glycolysis (<2%). Oxidative phosphorylation requires O₂ and dihydrogen (H₂). The O₂ is delivered to the myocardium and consumed in the mitochondria at complex IV to make H₂O, whereas the H₂ is from the metabolism of carbon fuels (mainly fatty acids, glucose, and lactate) and the generation of NADH (reduced form of nicotinamide adenine dinucleotide) and FADH₂ (reduced form of flavin adenine dinucleotide). ATP is formed from ADP and inorganic phosphate when H⁺ is consumed by complex V (Figure 4-22). Importantly, the rates of ATP formation and breakdown depend on an adequate delivery of O₂ to the myocardium, which is a function of myocardial blood flow and oxygenation of arterial blood. An increase in ATP breakdown in the myocardium, such as occurs when heart rate, systolic blood pressure, and contractility are increased (as during exercise), requires an increase in O₂ delivery to the myocardium so that the mitochondria can generate sufficient ATP by oxidative phosphorylation to meet the demand for ATP. Thus, the rate of myocardial O₂ consumption is tightly linked to the work rate (or power) of the myocardium.

FIGURE 4-22 The electron transport chain. ADP, adenosine diphosphate; ATP, adenosine triphosphate; CAC, citric acid cycle; FAβO, fatty acid β-oxidation; FAD, flavin adenine dinucleotide; FADH₂, reduced form of FAD; I through IV, Complexes I through IV; NAD⁺, nicotinamide adenosine dinucleotide; NADH, reduced form of NAD; PDH, pyruvate dehydrogenase; Pi, inorganic phosphate; Q, ubiquinone; V, Complex V, or ATP Synthase.

There is also ATP resynthesis from the breakdown of creatine phosphate by the creatine phosphokinase (CPK) reaction:

This is a very fast reaction that acts to “buffer” the ATP concentration when the rate of ATP hydrolysis is suddenly increased, as with the onset of exercise, or when there is an abrupt decrease in oxidative phosphorylation, such as occurs with myocardial ischemia.

There is a stoichiometric link among the rate of oxidation of carbon fuels, NADH and FADH₂ reduction, flux through the electron transport chain, O₂ consumption, oxidative phosphorylation, ATP hydrolysis, actin-myosin interaction, and external contractile power produced by the heart (Figures 4-21 and 4-23). Thus an increase in contractile power results in a concomitant increase in all of the components in the system. The ATP concentration in the heart remains constant, even when the heart is stressed. Cardiac muscle has the highest mitochondrial content of any cell type (≈30% of cell volume is occupied by mitochondria). The citric acid or Krebs cycle provides reducing equivalents (NADH and FADH₂) for oxidative phosphorylation, resulting in the condensation of ADP and inorganic phosphate to regenerate ATP. The citric acid cycle is fueled by acetyl–coenzyme A (CoA) formed primarily from oxidation of pyruvate and fatty acids. Cardiomyocytes oxidize fatty acids derived from both the plasma and the breakdown of intracellular triacylglycerol stores, whereas pyruvate is derived from either lactate dehydrogenase or glycolysis. The rates of these metabolic pathways are tightly coupled to the rate of contractile work, and conversely, contractile work is coupled to the supply of O₂ and the rate of oxidative phosphorylation. After an overnight fast, fatty acids are the major oxidative fuel for the heart (60%-100% of the O₂ consumption), with a lesser contribution from lactate and glucose (0%-20% from each). The regulation of myocardial metabolism is complex in that it is linked to arterial substrate and hormone levels, coronary flow, inotropic state, and the nutritional status of the tissue.

FIGURE 4-23 Regulation of the oxidation of glucose and lactate by pyruvate dehydrogenase (PDH). The activity of PDH is inhibited by product inhibition from acetyl-CoA (coenzyme A) and NADH (reduced form of nicotinamide adenosine dinucleotide) (dashed arrows). Also, PDH activity is inhibited when phosphorylated by PDH kinase and activated when dephosphorylated by PDH phosphatase. ADP, adenosine diphosphate; ATP, adenosine triphosphate; CPT-I, carnitine palmitoyltransferase; G-6-P, glucose-6-phosphate; GLUT, glucose transporter; Pi, inorganic phosphate; S.R., sarcoplasmic reticulum.

Fatty Acid Metabolism

The heart readily extracts free fatty acids from the plasma and either oxidizes it or converts it to triglyceride stores. The rate of uptake of free fatty acids depends mainly on their concentration in the plasma and the concentration of the fatty acid transporter (FAT) in the plasma membrane. Thus fatty acid uptake is increased when fatty acid levels are increased, as with fasting or diabetes and decreased when they are low, such as following ingestion of a meal.

Esterified fatty acids are transferred across the mitochondrial membrane into the mitochondrial matrix by the carnitine–fatty acyl transport system (see Figure 4-24). The first one in the sequence, carnitine palmitoyltransferase I (CPT I), catalyzes the formation of long-chain acylcarnitine from long-chain acyl-CoA in the compartment between the inner and outer mitochondrial membranes. The second enzyme, carnitine:acylcarnitine translocase, transports long-chain acylcarnitine across the inner mitochondrial membrane, whereas the last one in the sequence, CPT II, regenerates long-chain acyl-CoA in the mitochondrial matrix. Of the three enzymes involved in the transmitochondrial membrane transport, CPT I serves the key regulatory role. CPT I transfers the fatty acid moiety from acyl-CoA to carnitine to form long-chain acylcarnitine, which is then transported to the mitochondrion. CPT I activity is inhibited by malonyl-CoA. Once in the mitochondrial matrix, long-chain acyl-CoA passes through the β-oxidation to produce acetyl-CoA.

FIGURE 4-24 The pathways and regulatory points of myocardial substrate metabolism. Regulation of fatty acid oxidation, and fatty acid inhibition of flux through PDHa. CoA, coenzyme A; CPT, carnitine palmitoyltransferase; PDH, pyruvate dehydrogenase; PDHa, active dephosphorylated PDH.

Acetyl-CoA can also be formed from the oxidation of ketone bodies (acetoacetate and β-hydroxybutyrate), which are taken up by the myocardium from the plasma (see Figure 4-24). Normally the heart does not use a significant number of ketone bodies as a fuel simply because their plasma concentration is very low. In poorly controlled diabetes or during starvation, the concentration of ketone bodies increases dramatically and they become a significant source of fuel for the heart.

Carbohydrate Metabolism

Regulation of Glycolysis

Given a constant supply of G-6-P, the primary regulators of glycolytic rate are the activity of phosphofructokinase (PFK), and the ability to form NADH (Figure 4-25). Nicotinamide adenine dinucleotide (NAD⁺) is reduced to NADH by the conversion of glyceraldehyde 3-phosphate (GAP) to 3-phosphoglycerol phosphate by the enzyme GAP dehydrogenase (GAP-DH). Cytosolic NADH can be converted back to NAD⁺ through the conversion of pyruvate to lactate by lactate dehydrogenase (LDH), or the reducing equivalents can be shuttled into the mitochondria via the malate-aspartate shuttle. The rate of glycolysis in the myocardium is increased during exercise; however, the NADH and pyruvate are oxidized in mitochondria to CO₂, H₂O, and NAD⁺. Glycolysis is also increased when myocardial blood flow is below normal, a condition called myocardial ischemia. In this situation, mitochondrial oxidation of pyruvate and NADH is insufficient, and they are converted to lactate and NAD⁺ in the cytosol.

FIGURE 4-25 Regulation of the oxidation of glucose and lactate by pyruvate dehydrogenase (PDH). The activity of PDH is inhibited by product inhibition from acetyl-CoA (coenzyme A) and NADH (reduced form of nicotinamide adenosine dinucleotide), and by phosphorylation by PDH kinase and dephosphorylation by PDH phosphatase. Inhibition of myocardial fatty acid oxidation reduces inhibition on PDH and thus increases pyruvate oxidation. ADP, adenosine diphosphate; ATP, adenosine triphosphate; NAD⁺, nicotinamide adenosine dinucleotide.

Interrelation Between Fatty Acid and Carbohydrate Metabolism

High rates of fatty acid oxidation feed back to inhibit uptake of glucose and lactate. In humans, there is a strong negative correlation between the concentration of free fatty acids in the arterial plasma and the extraction of glucose and lactate by the heart. Fatty acid oxidation inhibits the oxidation of lactate and glucose by a variety of mechanisms. The phenomenon of fatty acid inhibition of glucose uptake and oxidation is called the glucose–fatty acid cycle. First, high rates of fatty acid oxidation result in an increase in citrate content in the mitochondria, which then leads to an higher citrate content in the cytosol and inhibition of PFK activity and decreased rate of glycolysis. High rates of fatty acid oxidation also inhibit PDH activity. Raised mitochondrial levels of acetyl-CoA and NADH activate PDH kinase that then phosphorylates and inhibits PDH (see Figure 4-25). Also, it has been shown in isolated heart mitochondria that elevated rates of fatty acid oxidation inhibit flux through PDH for any given PDH phosphorylation state. Pharmacologic inhibition of CPT I inhibits fatty acyl-CoA transport into the mitochondria and its subsequent oxidation to acetyl-CoA and results in greater pyruvate oxidation by lowering acetyl-CoA levels and relieving tonic inhibition of PDH.

Effects of Plasma Substrate and Insulin Levels

Under most conditions, plasma free fatty acid levels are a primary regulator of myocardial glucose and lactate oxidation. High plasma free fatty acid levels (>0.8 mM) inhibit both the uptake and oxidation of glucose and lactate in human myocardium, whereas pharmacologic lowering of plasma free fatty acid levels (<0.3 mM) results in an increase in myocardial glucose and lactate uptake. This increase is primarily related to the release of product inhibition on PDH and glycolysis as free fatty acid concentration decreases in the perfusate. Arterial lactate concentration is not a key regulator of lactate uptake and oxidation under normal resting conditions in humans, when levels are rather constant at about 0.6 to 1.2 mM. However, during and after exercise, arterial lactate levels increase and arterial lactate concentration becomes the major regulator of lactate oxidation. Plasma glucose concentration is not a major regulator of glucose uptake and oxidation under well-perfused conditions, in which plasma insulin and free fatty acid are held constant.

Plasma insulin levels regulate directly myocardial carbohydrate metabolism by stimulating glucose transport into cardiomyocytes and indirectly by inhibiting lipolysis in adipocytes and thus lowering plasma free fatty acid levels. The direct action of insulin on glucose uptake occurs by increasing the incorporation of GLUT 4 and GLUT 1 into the sarcolemmal membrane. Insulin also results in stimulation of hexokinase and glycogen synthetase activities, resulting in increased glucose phosphorylation and glycogen synthesis; the mechanism for this effect in the heart is unclear but could be at least partially due to the increase in glucose and G-6-P that occurs secondary to insulin-stimulated glucose transport. In addition to these direct effects, insulin indirectly increases flux through glycolysis and PDH by decreasing plasma free fatty acid levels and thereby releasing fatty acid inhibition, causing an increase in glucose and lactate uptake and oxidation.

What is the significance of insulin in terms of substrate use in the human heart? With fasting, insulin levels are reduced, resulting in less insulin inhibition of fatty acid release from adipocytes, an increase in plasma free fatty acid concentration (>0.8 mM), a high rate of fatty acid oxidation by the heart, and inhibition of glucose and lactate uptake and oxidation by the heart. In contrast, after a meal, insulin levels increase dramatically and the free fatty acid levels fall, resulting in greater glucose and lactate uptake and oxidation by the heart. Diabetes is similar to fasting in that there are frequently periods of low insulin and high fatty acid concentrations in the plasma and low rates of glucose and lactate uptake and oxidation.

Cardiac O₂ Consumption and the Link between Ventricular Function and Cardiac Metabolism

The rates of ATP hydrolysis and synthesis under nonischemic conditions are coupled to the mechanical power output of the left ventricle (see Figure 4-21). The rate of citric acid cycle flux and O₂ consumption by the myocardium (_O2) varies proportionately with ventricular power output because almost all of the ATP synthesis occurs by oxidative phosphorylation. The _O2 is the amount of O₂ consumed by the myocardium each minute and is the difference between the amount of O₂ that flows into the myocardium and the amount that flows out.

Estimation of cardiac work is important in clinical practice because cardiac work determines the O₂ needs of the heart. Cardiac work has external and internal components. External mechanical work, W, (force times distance) is that done by the heart on moving the blood within it and can be written as

     (9)

The first term on the right side of Equation 9 is P-V work; that is, each small increment of volume that is pumped, dV, is multiplied by the associated pressure, P, and the products, PdV, are integrated over the duration of the stroke volume, t₂ − t₁. The second term is kinetic work due to the speed at which the blood moves, where ρ is the density of blood and v is its velocity. At resting levels of cardiac output, the kinetic energy component is less than 5% in the left ventricle. However, at high cardiac outputs, as in strenuous exercise, the kinetic energy component can account for up to 50% of total cardiac work in the right ventricle. This follows because work in the right ventricle is about 15% of that in the left ventricle inasmuch as the pulmonary vascular resistance is much less than systemic vascular resistance.

The internal work of the heart can be written as

     (10)

where α is proportionality constant that converts Tdt into units of work, that converts Tdt into units of energy. T is tension, and dt is time. Clinically, _O2 and left ventricular power are difficult to measure; however, they are both closely related to the rate-pressure product, which is the heart rate times the systolic arterial blood pressure, P_sys. Such measurements are important because internal work is a large determinant of myocardial O₂ need.

The magnitude and duration of the left ventricular pressure and wall tension, as well as heart rate and contractility, are related to left ventricular O₂ consumption (_O2). An alternative approach to evaluate cardiac work and its relation to has been developed. With this method, P-V loops (see Figure 4-17) are examined under conditions with varied preload and afterload; contractility is maintained constant. Integration of the area subtended by the end-systolic and end-diastolic P-V relations and by the systolic component of the P-V loop trajectory (Figure 4-26A, shaded area) yields a product, the P-V area (mm Hg × mL). This includes the external work (EW) and potential energy (PE) underlying cardiac function and represents the total mechanical energy of the ventricle. The relation between O₂ consumption and the P-V area is measured experimentally under varied preload and afterload conditions. When O₂ consumption (_O2, mL O₂/beat/g left ventricle) is plotted against the P-V area (mm Hg × mL/g left ventricle), as shown in Figure 4-26B, a positive linear relation is obtained. The intercept of the _O2-P-V area relation is the _O2 for unloaded contractions. The area below the intercept (P-V area–independent _O2) comprises the basal metabolic O₂ consumption and the O₂ consumed for excitation-contraction coupling. The area above the intercept gives the P-V area–dependent _O2; this is the O₂ consumed by the contractile proteins during cross-bridge cycling. The inverse of the slope gives the thermodynamic efficiency of the utilization of O₂ for the total mechanical energy of contraction. In the human heart, this amounts to 0.35 or 35%. The efficiency of O₂ utilization does not change with agents that increase contractility, but the O₂ consumed for excitation-contraction coupling increases. Thus, during exercise, the slope does not change but the linear relation is shifted upward, an indication of the extra O₂ needed to sustain the increased cardiac output.

FIGURE 4-26 A, Pressure-volume loop from left ventricle (LV) with areas corresponding to external work (EW) and mechanical potential energy (PE) integrated and summed to yield pressure-volume area (PVA). The end-systolic pressure-volume relation (ESPVR) is an index of contractility; EDPVR is the end-diastolic pressure-volume relation. B, Plot of myocardial O₂ consumption (MV_O2; mL/beat per gram LV) as a function of the PVA (mm Hg • mL per gram LV). The linear regression slope gives the O₂ consumption dependent on PVA. The area below the intercept with the ordinate indicates the O₂ consumption that is independent of PVA.

(Redrawn from Suga H: Ventricular energetics. Physiol Rev 70:247, 1990).

Simultaneously halving the aortic pressure and doubling the cardiac output, or vice versa, results in the same value for cardiac work. However, the O₂ requirements are greater for any given amount of cardiac work when a major proportion of the work is pressure work, as opposed to volume work. An increase in cardiac output at a constant aortic pressure (volume work) is accomplished with only a small increase in left ventricular _O2, whereas increased arterial pressure at constant cardiac output (pressure work) is accompanied by a large increase in _O2.

At rest, the _O2 of the two ventricles is about 9 mL O₂/100 g/min. The healthy human heart can increase the _O2, coronary blood flow, and left ventricular external power approximately fourfold to fivefold over resting conditions to maximal exercise (see also Chapter 13). In other words, in the absence of coronary artery disease, there is a “reserve” of approximately 400% in the capacity of the myocardium to increase its blood flow, rates of citric acid cycle flux, oxidative phosphorylation, _O2, and rate of external power generation. The power generation by the left ventricle is the product of the heart rate and the area contained within the PV loop. This “loop area” is the amount of external work generated by the left ventricle by a single heart beat.

Physical exercise requires a greater cardiac output to deliver O₂ to the working skeletal muscles. This is accomplished by increasing both heart rate and stroke volume (see Chapter 13; Figure 13-3). An increase in the amount of cardiac work is generated with each heartbeat, as illustrated in Figure 4-27. Physical exercise causes an increase in myocardial contractility, preload, and afterload; thus the LV P-V loop area increases because of a greater end-diastolic volume, a greater peak systolic pressure, and a decrease in end-systolic volume. The power generation (power = work/time) of the left ventricle increases because of the greater loop area and heart rate.

FIGURE 4-27 Pressure-volume loop indicating the pressure-volume area (PVA) of the left ventricle (LV) at rest (area bounded by black lines) and during exercise (area bounded by blue lines). The end-systolic pressure-volume relation (ESPVR) slope is increased because contractility is greater. The increased area during exercise shows the increased PVA or work done by the left ventricle; this necessitates an increased O₂ consumption. EDPVR, end-diastolic pressure-volume relation.

(Redrawn from Suga H: Ventricular energetics. Physiol Rev 70:247, 1990).