The Cardiovascular System - Heart PDF

Chapter 14 The Cardiovascular System: The Heart =============================================== ### Introduction The cardiovascular system comprises three interrelated components: the heart, blood vessels, and blood (Figure 14.1). The heart is a pump that generates the pressure to circulate blood...

Chapter 14 The Cardiovascular System: The Heart =============================================== ### Introduction The cardiovascular system comprises three interrelated components: the heart, blood vessels, and blood (Figure 14.1). The heart is a pump that generates the pressure to circulate blood to the body\'s tissues. To accomplish this, the heart beats about 100,000 times daily, up to 35 million beats per year, and about 3 billion beats in an average lifetime. Blood vessels are tubular structures through which blood flows from the heart to body tissues and back to the heart. Blood is a fluid that delivers oxygen and nutrients to cells and removes carbon dioxide and other wastes from cells. It also regulates pH and body temperature and protects against disease. 14.1 Basic Design of the Cardiovascular System ---------------------------------------------- ### The Pulmonary and Systemic Circulations With each beat, the heart pumps blood into two closed circuits---pulmonary and systemic (Figure 14.2). Pulmonary circulation consists of blood vessels that carry blood from the right side of the heart to the lungs' alveoli (air sacs) and then back to the left side of the heart. The systemic circulation consists of blood vessels that carry blood from the left side of the heart to all organs and tissues of the body except the alveoli and then back to the right side of the heart. In both circuits, blood is carried away from and then returned to the heart in the following way: - Large blood vessels called arteries carry blood away from the heart. - Arteries branch to form smaller vessels called arterioles. - Arterioles give rise to even smaller vessels called capillaries. - From capillaries, blood enters larger vessels called venules. - Venules give rise to even larger vessels called veins, which carry blood back to the heart. Capillaries are the smallest blood vessels of the body; they serve as the sites of gas, nutrient, and waste exchange between blood and surrounding tissues. In pulmonary capillaries, the blood becomes oxygenated as it picks up oxygen (O2) from inhaled air in the lungs\' alveoli and drops off some molecules of carbon dioxide (CO2) exhaled from the body. Oxygenated blood is bright red. In systemic capillaries, the blood becomes deoxygenated as it drops off some of its O2 to cells and picks up CO2, a waste product of cellular metabolism. Deoxygenated blood is dark red. By convention, blood vessels that contain oxygenated blood are colored red, and blood vessels that contain deoxygenated blood are colored blue. Because of gas exchange in the pulmonary and systemic capillaries, blood in pulmonary veins, the left side of the heart, and systemic arteries are oxygenated. In contrast, blood in systemic veins, the right side of the heart, and pulmonary arteries are deoxygenated. ### Parallel Flow Through the Systemic Circulation In the systemic circulation, blood flows through parallel pathways, a design feature known as parallel flow. In most of these pathways, a given portion of blood flows through an artery to only one organ and enters one set of capillaries before returning to the heart through a vein. Because of this arrangement, the same portion of blood does not flow from one organ to the next. The parallel flow of blood through systemic circulation is essential for two reasons: (1) It allows each organ to receive its supply of freshly oxygenated blood, and (2) it allows blood flow to different organs to be regulated independently. There are a few exceptions to parallel flow. In some organs, blood flows between two sets of capillaries arranged in series (one right after the other). You are already familiar with the hypothalamic--hypophyseal portal system that delivers hormones in blood from the hypothalamus to the anterior pituitary gland capillaries. Recall that in a portal system, blood flows from one capillary network into a portal vein and then into a second capillary network before returning to the heart. Another example of a portal system is the hepatic portal circulation, which carries absorbed nutrients in blood from gastrointestinal organs\' capillaries to the liver via the hepatic portal vein. This arrangement allows the liver to store or modify some of the absorbed nutrients before they pass into the general circulation. A final exception to parallel flow in the systemic circulation occurs in the kidneys, where an arteriole connects two sets of capillaries (the glomerulus and peritubular capillaries). The functional roles of the glomerulus and peritubular capillaries are described in the discussion of the urinary system in Chapter 19. 14.2 Organization of the Heart ------------------------------ The heart is a hollow, muscular organ about the size of a closed fist. It is in the thoracic (chest) cavity, with most of its mass lying to the left of the body's midline. The heart is bordered by the sternum (breastbone) anteriorly, the lungs laterally, the vertebral column posteriorly, and the diaphragm inferiorly. You can visualize the heart as a cone lying on its side: The upper, broad portion of the cone is known as the base; the lower, pointed tip of the cone is referred to as the apex. ### Pericardium and Heart Wall The heart is enclosed in a membranous sac called the pericardium, which confines the heart to its position in the thoracic cavity while allowing sufficient freedom of movement for vigorous and rapid contraction. The pericardium comprises an outer parietal layer and an inner visceral layer. The parietal layer is surrounded by a harsh fibrous coat of connective tissue that anchors the heart in place by attaching to nearby structures in the thoracic cavity. The visceral layer, also called the epicardium, adheres to the surface of the heart. Between the parietal and visceral layers of the pericardium is a space called the pericardial cavity that is filled with a thin film of lubricating fluid. This fluid, known as pericardial fluid, reduces friction within the pericardium as the heart moves. The wall of the heart consists of three layers: the epicardium (outer layer), the myocardium (middle layer), and the endocardium (inner layer). The epicardium, also known as the visceral layer of the pericardium, consists of epithelium and connective tissue. The myocardium forms the bulk of the heart wall. It consists of cardiac muscle and is responsible for the heart\'s pumping. The endocardium is a thin layer of epithelium that lines the heart chambers and covers heart valves. It is also continuous, with the epithelial cells lining the blood vessels attached to the heart. Epithelial cells line the body's heart, blood vessels, and lymphatic vessels are endothelial cells or endothelium. ### The Chambers of the Heart The heart has four chambers: two upper atria (singular is atrium) and two lower ventricles. Functionally, the heart can be divided into right and left sides, each consisting of an atrium and a ventricle. The right side of the heart serves as the pump for the pulmonary circulation, and the left serves as the pump for the systemic circulation. Therefore, the heart comprises two separate pumps located within the same organ. A muscular partition, or septum, separates the right and left sides of the heart. The septum prevents blood from mixing between the two sides of the heart. The part of the septum located between the two atria is called the interatrial septum; the part between the two ventricles is known as the interventricular septum. The thickness of the myocardium of the chambers varies according to the amount of work each chamber must perform. The atria have thin walls because they deliver blood under less pressure into the ventricles. The ventricles have thicker walls because they pump blood out of the heart under higher pressure and over greater distances. Although the right and left ventricles act as two separate pumps that simultaneously eject equal volumes of blood, the right side has a much smaller workload. It pumps blood a short distance to the lungs\' alveoli at lower pressure, and the resistance to blood flow is minor. The left ventricle pumps blood great distances to all other body parts at higher pressure, and the resistance to blood flow is larger. Therefore, the left ventricle works much harder than the right ventricle to maintain the same blood flow rate. The structure of the two ventricles confirms this functional difference---the muscular wall of the left ventricle is considerably thicker than the right ventricle wall. The heart chambers are associated with several large or great blood vessels. The right atrium receives deoxygenated blood through two major veins: the superior vena cava, which brings blood mainly from the body above the heart, and the inferior vena cava, which brings blood mostly from parts below the heart. The right atrium then delivers the deoxygenated blood into the right ventricle, which pumps it into an artery called the pulmonary trunk. The pulmonary trunk divides into the pulmonary arteries, carrying deoxygenated blood to the lungs. Meanwhile, the blood becomes oxygenated in the lungs\' alveoli by picking up oxygen (O2) and unloading some carbon dioxide (CO2). The oxygenated blood is then carried to the left atrium via pulmonary veins. From the left atrium, the oxygenated blood passes into the left ventricle, which pumps the blood into a large artery called the aorta---the aorta branches into several smaller arteries carrying oxygenated blood to all body parts except the alveoli. Meanwhile, blood becomes deoxygenated in the body\'s tissues as it drops off some of its O2 and picks up CO2. ### Heart Valves As each chamber of the heart contracts, it pushes a volume of blood into a ventricle or out of the heart into an artery. The heart has four valves to prevent the blood from flowing backward: two atrioventricular valves and two semilunar valves. The heart\'s valves are composed of connective tissue covered by the endocardium, and they open and close in response to pressure changes as the heart contracts and relaxes. Each of the four valves helps ensure the one-way blood flow by opening to let blood through and then closing to prevent its backflow. #### Atrioventricular Valves As the name implies, atrioventricular (AV) valves lie between the atria and ventricles. The right AV valve is between the right atrium and the right ventricle. The tricuspid valve is also called because it consists of three cusps or flaps. The left AV valve is between the left atrium and the left ventricle. Because it consists of two cusps, also known as the bicuspid valve, another name for the left AV valve is the mitral valve because it resembles a bishop's miter (hat), which is two-sided. The cusps of the AV valves are connected to tendon-like cords called chordae tendineae (KOR-dē ten-DIN-ē-ē), which in turn are connected to papillary muscles, cone-shaped muscle projections located on the inner surface of the ventricles. The chordae tendineae prevent the valve cusps from everting (opening into the atria) when the ventricles contract and are aligned to allow the valve cusps to close the valve tightly. The AV valves open when the pressure in the atria exceeds the pressure in the ventricles. When the ventricles are relaxed, the papillary muscles are relaxed, the chordae tendineae are slack, and blood pushes the AV valves open, moving from a higher pressure in the atria to a lower pressure in the ventricles. When the ventricles contract, the blood pressure drives the cusps upward until their edges meet and close the opening. At the same time, the papillary muscles contract, which pulls on and tightens the chordae tendineae. This prevents the valve cusps from swinging upward and opening into the atria in response to the high ventricular pressure. If the AV valves or chordae tendineae are damaged, blood may regurgitate (flow back) into the atria when the ventricles contract. #### Semilunar Valves The two semilunar (SL) valves of the heart are the pulmonary valve between the right ventricle and the pulmonary trunk and the aortic valve between the left ventricle and the aorta. These valves are referred to as semilunar because they are both made up of three cusps shaped like half-moons (semi- = half; -lunar = moon-shaped). The cusps are attached to the walls of the pulmonary trunk and aorta and project into the lumen of each of these arteries. The SL valves allow the ejection of blood from the heart into arteries but prevent the backflow of blood into the ventricles. When the ventricles contract, pressure builds up within the chambers. The semilunar valves open when the pressure in the ventricles exceeds the pressure in the arteries, permitting the ejection of blood from the ventricles into the pulmonary trunk and aorta. As the ventricles relax, blood starts to flow back toward the heart. This backflowing blood fills the valve cusps, which causes the semilunar valves to close tightly. Surprisingly, no valves guard the junctions between the vena cavae and the right atrium or the pulmonary veins and the left atrium. As the atria contract, a small amount of blood flows backward from them into these vessels. However, backflow is minimized by a different mechanism: As the atrial muscle contracts, it compresses and nearly collapses the venous entry points. ### Fibrous Skeleton of the Heart In addition to cardiac muscle, the heart wall contains connective tissue that forms the fibrous skeleton of the heart. The fibrous skeleton consists of four dense connective tissue rings that surround the heart\'s valves, fuse, and merge with the interventricular septum. In addition to forming a structural foundation for the heart valves, the fibrous skeleton prevents overstretching of the valves as blood passes through them. It also serves as an attachment for bundles of cardiac muscle fibers. During atrial contraction, the two atria are pulled downward toward the fibrous skeleton; during ventricular contraction, the fibrous skeleton stabilizes the lower chambers as they contract. The connective tissue of the fibrous skeleton also acts as an electrical insulator between the atria and ventricles. ### Coronary Circulation Nutrients could not possibly diffuse from blood in the heart\'s chambers through all the layers of cells that make up the heart wall. For this reason, the heart wall has its network of blood vessels, the coronary or cardiac circulation (coronary = crown). The coronary arteries branch from the aorta and encircle the heart like a crown encircles the head (Figure 14.10a). While the heart is contracting, little blood flows through the coronary arteries because they are squeezed shut. When the heart relaxes, however, the high blood pressure in the aorta propels blood through the coronary arteries, into capillaries, and then into coronary (cardiac) veins. The blood from the coronary veins drains into a large vein called the coronary sinus, which empties into the right atrium. 14.3 Cardiac Muscle Fibers and the Cardiac Conduction System ------------------------------------------------------------ ### Organization of Cardiac Muscle Fibers Cardiac muscle consists of numerous cardiac muscle fibers. A typical cardiac muscle fiber is 50--100 μm long and has a diameter of about 14 μm. Compared to skeletal muscle fibers, most cardiac muscle fibers are shorter in length and smaller in diameter. They also exhibit branching, which gives individual cardiac muscle fibers a stair-step appearance. A cardiac muscle fiber usually has one nucleus, although an occasional cell may contain two nuclei. Like skeletal muscle fibers, cardiac muscle fibers are striated due to repeating sarcomeres of thick and thin filaments with a regular overlap pattern. In addition, the sarcomeres of cardiac muscle fibers have the same zones and bands as those of skeletal muscle fibers due to the arrangement of the thick and thin filaments. The thick filaments contain myosin, and the thin filaments contain actin, troponin, and tropomyosin. The dense and thin filaments\' proteins function similarly to skeletal muscle fibers. Transverse (T) tubules and sarcoplasmic reticulum (SR) are also present in cardiac muscle fibers; compared to skeletal muscle, the T tubules are less abundant, and the SR is somewhat smaller. Unlike skeletal muscle fibers, the ends of cardiac muscle fibers are connected by irregular transverse thickenings of the sarcolemma called intercalated discs (in-TER-kā-lāt-ed). An intercalated disc contains two cell junctions: desmosomes and gap junctions. Desmosomes mechanically bind cardiac muscle fibers together. They resist mechanical stress, a property that prevents cardiac muscle fibers from pulling apart during contraction. Gap junctions electrically couple cardiac muscle fibers to each other. They allow action potentials from one cardiac muscle fiber to its neighbors. Because gap junctions interconnect cardiac muscle fibers, when an action potential is generated in a mass of cardiac muscle fibers, the action potential quickly spreads to all the muscle fibers in that mass, and then the muscle fibers contract together. Such a mass of interconnected muscle fibers acts as a single, coordinated unit or functional syncytium (sin-SISH-ē-um; plural is syncytium or syncytia). Because the fibrous skeleton of the heart electrically insulates the atria from the ventricles, the atria and ventricles behave as two distinct functional syncytia and, therefore, contract independently of each other. You will soon learn that the atria contract before the ventricles. This allows the ventricles to fill with blood from the atria before the ventricles eject blood out of the heart to the rest of the body. Mitochondria are larger and more numerous in cardiac muscle fibers than skeletal ones. In a cardiac muscle fiber, they take up 25% of the volume of the sarcoplasm; in a skeletal muscle fiber, only 2% of the volume of the sarcoplasm is occupied by mitochondria. This structural feature means cardiac muscle depends largely on aerobic respiration to generate ATP and requires a constant oxygen supply. ### Autorhythmic Cardiac Muscle Fibers: The Conduction System Cardiac muscle does not require external stimulation to contract. Contractions occur because action potentials within the cardiac muscle are spontaneously generated periodically. This built-in rhythm is termed autorhythmicity. Cardiac muscle, as a functional syncytium, consists of two muscle fibers: autorhythmic and contractile fibers. Autorhythmic fibers, also known as pacemaker cells, spontaneously generate action potentials. They account for only a minimal number of cells in the functional syncytium and are usually grouped. Because autorhythmic fibers contain essentially no myofibrils, they are unable to contract. Contractile fibers constitute the great majority of cells in the functional syncytium. They have the necessary myofibrils to contract but cannot initiate action potentials. Instead, they become excited and then contract together in response to action potentials conducted to them from autorhythmic fibers via gap junctions. - The following components of the heart contain autorhythmic fibers: - Sinoatrial (SA) node in the wall of the right atrium close to the opening of the superior vena cava. - Atrioventricular (AV) node in the interatrial septum. - The atrioventricular (AV) bundle, also known as the bundle of His, is in the upper part of the interventricular septum. - Right and left bundle branches in the interventricular septum. - Purkinje fibers in the ventricular wall. The autorhythmic fibers of the heart have two critical functions: 1. They act as a pacemaker, setting the rhythm of electrical excitation that causes heart contraction. 2. They form the conduction system, the pathway that rapidly delivers action potentials throughout the heart muscle. The conduction system can conduct action potentials throughout the heart because gap junctions connect the conduction system\'s components to the heart\'s contractile fibers. The conduction system ensures that cardiac chambers become stimulated to contract in a coordinated manner, which makes the heart an effective pump. As you will see later in the chapter, problems with the conduction system can result in arrhythmias (abnormal rhythms) in which the heart beats irregularly, too fast, or too slowly. Cardiac action potentials propagate through the conduction system in the following sequence: 1. Cardiac excitation typically begins in the SA node when SA node cells spontaneously depolarize to the threshold by producing a pacemaker potential (described shortly). Once the threshold is reached, an action potential is generated and propagates throughout both atria. Following the action potential, the atria contract. 2. The action potential propagates from the atria to the atrioventricular (AV) node. 3. The action potential enters the AV bundle (bundle of His) from the AV node. This bundle is the only site where action potentials can be conducted from the atria to the ventricles. Recall that elsewhere, the fibrous skeleton of the heart electrically insulates the atria from the ventricles. 4. After propagating along the AV bundle, the action potential enters the right and left bundle branches. 5. From the bundle branches, the action potential propagates to the Purkinje fibers, which in turn conduct the action potential beginning at the apex of the heart to the remainder of the ventricular myocardium. Then, the ventricles contract, pushing the blood upward toward the semilunar valves. Autorhythmic fibers can initiate their action potentials because they have unstable resting membrane potentials. The membrane potential starts at about −60 mV and then spontaneously depolarizes to the threshold (−40 mV), generating an action potential. After repolarization, the membrane potential again depolarizes, and the cycle repeats. The spontaneous depolarization to the threshold in an autorhythmic fiber of cardiac muscle is known as a pacemaker potential. The first half of the pacemaker potential is caused by (1) the closure of voltage-gated K+ channels that were open during the repolarizing phase of the previous action potential and (2) the opening of F-type channels (so-named because they have funny or unusual properties), which are mainly permeable to Na+ ions. Closure of the voltage-gated K+ channels decreases the movement of K+ out of the cell (K+ has a higher concentration in the sarcoplasm than in extracellular fluid); the opening of the F-type channels increases the movement of Na+ from the extracellular fluid (which has a higher Na+ concentration) into the sarcoplasm. The combined effects of these channel activities cause the membrane potential to start drifting slowly above −60 mV. However, before the membrane potential reaches a threshold, the F-type channels close, and a new set of channels open: T-type voltage-gated Ca2+ channels (T for transient because they remain open for a relatively short period). Opening the T-type voltage-gated Ca2+ channels causes the second half of the pacemaker potential. When these channels open, Ca2+ enters the cell because the Ca2+ concentration is higher in extracellular fluid than in the sarcoplasm. The influx of Ca2+ depolarizes the membrane even further, eventually bringing it to the threshold. Once the threshold is reached, an action potential occurs. In an autorhythmic cardiac muscle fiber, an action potential consists of depolarizing and repolarizing phases. The depolarizing phase of the action potential is caused by the opening of L-type voltage-gated Ca2+ channels (L for long-lasting because they open for a relatively long period). When these channels open, additional Ca2+ enters the cell, and the membrane potential rises above the threshold to a positive value. (Recall that in neurons and skeletal muscle fibers, the depolarizing phase of the action potential is due to the influx of Na+ through voltage-gated Na+ channels.) The repolarizing phase of the action potential in an autorhythmic cardiac muscle fiber is caused by (1) the closure of L-type voltage-gated Ca2+ channels and (2) the opening of voltage-gated K+ channels. Opening the voltage-gated K+ channels allows K+ ions to leave the cell, decreasing the membrane potential to around −60 mV. Once an action potential is generated in an autorhythmic fiber, it spreads to the contractile fibers of cardiac muscle via gap junctions. Autorhythmic fibers in the SA node would initiate an action potential about every 0.6 seconds or 100 times per minute. This rate is faster than that of any other autorhythmic fibers. Because action potentials from the SA node spread through the conduction system and stimulate different areas before the other regions can generate an action potential at their own slower rate, the SA node acts as the heart\'s natural pacemaker. Action potentials from the autonomic nervous system (ANS) and blood-borne hormones (such as epinephrine) modify the timing and strength of each heartbeat. Still, they do not establish the fundamental rhythm. In a person at rest, for example, acetylcholine released by the parasympathetic division of the ANS slows SA node pacing to about every 0.8 seconds or 75 action potentials per minute. Hence, the resting heart rate is about 75 beats per minute. If the SA node becomes damaged or diseased, the AV node can take over the pacemaking task. However, with pacing by the AV node, the heart rate is slower, at only 40 to 60 beats per minute. If both node activity is suppressed, the AV bundle, a bundle branch, or Purkinje fibers may maintain the heartbeat. These fibers generate action potentials very slowly, about 20 to 35 times per minute. At such a low heart rate, blood flow to the brain is inadequate. ### Action Potentials in Contractile Cardiac Muscle Fibers Unlike autorhythmic fibers, contractile cardiac muscle fibers have a stable resting membrane potential of about −90 mV. This value results from resting contractile fibers being highly permeable to K+ ions and not very permeable to other ions. So, the resting membrane potential stabilizes around the K+ equilibrium potential of −90 mV. When a contractile cardiac muscle fiber is depolarized to the threshold by an action potential initiated by an autorhythmic fiber, it produces its action potential. The action potentials in contractile cardiac muscle fibers consist of four phases: a depolarizing phase, an initial repolarizing phase, a plateau phase, and a final repolarizing phase. #### Depolarizing Phase During the depolarizing phase, fast voltage-gated Na+ channels open. These channels are called fast because they open rapidly in response to a threshold-level depolarization. They are the same type of voltage-gated Na+ channels present in neurons and skeletal muscle fibers. Opening these channels increases the membrane permeability to Na+ ions, allowing Na+ to flow into the cell. This rapid depolarization increases the membrane potential to about +20 mV. #### Initial Repolarizing Phase The fast Na+ channels automatically inactivate within a few milliseconds, reducing the membrane permeability to Na+. As a result, Na+ inflow decreases. Of the several different types of voltage-gated K+ channels present in a contractile cardiac muscle fiber, a subset known as fast voltage-gated K+ channels\* opens at this time, allowing K+ ions to leave the cell. The closure of fast voltage-gated Na+ channels and the opening of fast voltage-gated K+ channels cause the initial repolarizing phase of the action potential. During this phase, the membrane potential begins to decrease. #### Plateau Phase The next phase of the action potential is the plateau, a period of sustained depolarization. It is due in part to the opening of L-type voltage-gated Ca2+ channels. When these channels open, calcium ions move from the extracellular fluid into the cell. While this is occurring, fast voltage-gated K+ channels close, and slow voltage-gated K+ channels begin to open. The slow voltage-gated K+ channels† are so-named because they are activated when the membrane initially depolarizes but are slow to open. They are the same voltage-gated K+ channels in neurons and skeletal muscle fibers. Because the fast voltage-gated K+ channels are entirely closed and the slow voltage-gated K+ channels are only partially open, the membrane permeability to K+ is relatively low. However, there is just enough efflux of K+ through the slow voltage-gated K+ channels to balance the Ca2+ influx through the L-type voltage-gated Ca2+ channels, causing the action potential curve to flatten out like a plateau. The plateau phase lasts about 0.2 sec, and the membrane potential of the contractile fiber is close to 0 mV. By comparison, depolarization in a neuron or skeletal muscle fiber is much briefer, about 1 msec, because it lacks a plateau phase. #### Final Repolarizing Phase During the final repolarizing phase of the action potential, the slow voltage-gated K+ channels fully open. This increases the membrane permeability to K+, accelerating K+ outflow. At the same time, the L-type voltage-gated Ca2+ channels close. This decreases the membrane permeability to Ca2+, reducing Ca2+ inflow. The increase in K+ outflow and decrease in Ca2+ inflow rapidly restores the membrane potential to −90 mV. Once the membrane potential reaches the resting level, the slow voltage-gated K+ channels close. ### Excitation-Contraction Coupling in Contractile Cardiac Muscle Fibers Once an action potential is generated in a contractile cardiac muscle fiber, it ultimately causes the muscle fiber to contract by increasing the Ca2+ concentration in the sarcoplasm. The sequence of events that connects the muscle action potential to muscle contraction is known as excitation-contraction (EC) coupling. EC coupling in cardiac muscle involves L-type voltage-gated Ca2+ channels in the membrane of transverse (T) tubules and nearby Ca2+ release channels in the terminal cisternal membrane of the sarcoplasmic reticulum (SR) (Figure 14.15). As the cardiac muscle action potential travels along the sarcolemma and into the T tubules, L-type voltage-gated Ca2+ channels open, allowing Ca2+ to move from extracellular fluid into the sarcoplasm. The entering Ca2+ functions as trigger Ca2+ that binds to Ca2+ release channels in the sarcoplasmic reticulum (SR), causing the channels to open and release an even more significant amount of Ca2+ into the sarcoplasm. The process by which extracellular Ca2+ triggers the release of additional Ca2+ from the SR is called Ca2+-induced Ca2+ release (CICR). About 90% of the calcium needed to contract a cardiac muscle fiber comes from the sarcoplasmic reticulum via CICR, and the remaining 10% of the requisite Ca2+ comes from extracellular fluid. After the Ca2+ concentration in the sarcoplasm increases, cardiac muscle fibers contract in the same way as skeletal muscle fibers: Ca2+ binds to troponin, which in turn undergoes a conformational change that causes tropomyosin to move away from myosin-binding sites on actin (Figure 14.15). Once the binding sites are exposed, myosin binds to actin, and the thick and thin filaments begin sliding past one another (sliding filament mechanism). Cardiac muscle can produce graded contractions (contractions that vary in strength). These graded contractions do not involve the recruitment of more muscle fibers because cardiac muscle is a functional syncytium. All muscle fibers in the syncytium contract simultaneously, so no other muscle fibers can be added to increase the tension generated. Instead, cardiac muscle produces graded contractions by increasing the strength of contraction of the existing muscle fibers in the syncytium. This occurs by adding more Ca2+ to the sarcoplasm, increasing crossbridge formation. Relaxation of cardiac muscle fibers involves decreasing the Ca2+ concentration in the sarcoplasm to resting levels. A cardiac muscle fiber's sarcoplasmic reticulum (SR) contains Ca2+--ATPase pumps that actively transport Ca2+ from the sarcoplasm into the SR. In addition, the sarcolemma of a cardiac muscle fiber contains Na+--Ca2+ exchangers that actively transport Ca2+ out of the cell in exchange for Na+ movement into the cell. As the Ca2+ concentration in the sarcoplasm drops, Ca2+ dissociates from troponin, tropomyosin covers the myosin-binding sites on actin, and the cardiac muscle fiber relaxes. ### Refractory Period of Cardiac Muscle Fibers Cardiac muscle fibers, like neurons and skeletal muscle fibers, have a refractory period, the period after an action potential begins when an excitable cell temporarily loses its excitability. The refractory period occurs because voltage-gated Na+ channels that are initially activated during the depolarizing phase of the action potential quickly become inactivated and must wait until the membrane repolarizes and returns to the resting state before they are capable of being activated again. Recall that in skeletal muscle fibers, the refractory period is about 1 msec, much shorter than the duration of contraction (20--200 msec). Because the refractory period is so short, a skeletal muscle fiber can be re-excited before its previous contraction is over. Consequently, skeletal muscle contractions can summate (add together in strength) and produce tetanus, a sustained contraction in which the muscle relaxes only slightly between stimuli (incomplete tetanus) or does not relax at all between stimuli (complete tetanus). In contractile cardiac muscle fibers, however, the refractory period is long (about 250 msec) due to the prolonged plateau phase of the action potential. The refractory period of these fibers lasts almost as long as the duration of contraction (300 msec). As a result, a contractile cardiac muscle fiber cannot be re-excited until its previous contraction is almost over. For this reason, summation of contractions and tetanus do not occur in cardiac muscle. The advantage is apparent if the heart\'s pumping action depends on alternating contraction (when the heart ejects blood) and relaxation (when the heart refills). If cardiac muscle could undergo tetanus, the heart would no longer be able to function as a pump because it would not have a chance to relax and refill with blood---a situation that would be fatal. ### ATP Production in Cardiac Muscle In contrast to skeletal muscle, cardiac muscle produces little of the ATP it needs by anaerobic glycolysis. Instead, it relies almost exclusively on aerobic respiration in its numerous mitochondria. The required oxygen diffuses from blood in the coronary circulation and is released from myoglobin inside cardiac muscle fibers. Cardiac muscle fibers use several fuels to power mitochondrial ATP production. In a person at rest, cardiac muscle's ATP comes mainly from the catabolism of fatty acids (60%) and glucose (35%), with smaller contributions from lactic acid, amino acids, and ketone bodies. During exercise, cardiac muscle's use of lactic acid, produced by actively contracting skeletal muscles, rises. Like skeletal muscle, cardiac muscle also produces some ATP from creatine phosphate. One sign that a myocardial infarction has occurred is the presence in the blood of creatine kinase (CK), the enzyme that catalyzes the transfer of a phosphate group from creatine phosphate to ADP to make ATP. Usually, CK and other enzymes are confined within cells. Injured or dying cardiac or skeletal muscle fibers release CK into the blood. ### Electrocardiogram As action potentials propagate through the heart, they generate electrical currents that can be detected at the body\'s surface. An electrocardiogram (e-lek′-trō-KAR-dē-ō-gram), abbreviated either ECG or EKG (from the German word elektrokardiogram), is a recording of these electrical signals. The ECG is a composite record of action potentials all heart muscle fibers produce during each heartbeat. In a typical ECG, three recognizable waves appear with each heartbeat. The first, the P wave, is a slight upward deflection on the ECG. The P wave represents atrial depolarization, which spreads from the SA node through contractile fibers in both atria. The second wave, called the QRS complex, begins as a downward deflection, continues as a large, upright, triangular wave, and ends as a downward wave. The QRS complex represents ventricular depolarization, as the action potential spreads through ventricular contractile fibers. The third wave is a dome-shaped upward deflection called the T wave. It indicates ventricular repolarization and occurs just as the ventricles are starting to relax. The T wave is more petite and broader than the QRS complex because repolarization occurs more slowly than depolarization. During the plateau phase of steady depolarization, the ECG tracing is flat. In reading an ECG, the size of the waves can provide clues to abnormalities. More giant P waves indicate enlargement of an atrium; an enlarged Q wave may indicate a myocardial infarction; and an enlarged R wave generally indicates enlarged ventricles. The T wave is flatter than usual when the heart muscle receives insufficient oxygen, such as in coronary artery disease. The T wave may be elevated in hyperkalemia (high blood K+ level). Analysis of an ECG also involves measuring the time spans between waves, called intervals or segments. For example, the P--Q interval, also known as the P--R interval, is the time from the beginning of the P wave to the beginning of the QRS complex. It represents the conduction time from the beginning of atrial excitation to the beginning of ventricular excitation. Put another way, the P--Q interval is the time required for the action potential to travel through the atria, AV node, and the remaining fibers of the conduction system. The P- Q interval lengthens when the action potential is forced to detour around scar tissue caused by disorders such as coronary artery disease and rheumatic fever. The S--T segment, which begins at the end of the S wave and ends at the beginning of the T wave, represents the time when the ventricular contractile fibers are depolarized during the plateau phase of the action potential. The S--T segment is elevated (above the baseline) in acute myocardial infarction and depressed (below the baseline) when the heart muscle receives insufficient oxygen. The Q--T interval extends from the start of the QRS complex to the end of the T wave. It is the time from the beginning of ventricular depolarization to the end of ventricular repolarization. The Q--T interval may be lengthened by myocardial damage, myocardial ischemia (decreased blood flow), or conduction abnormalities. ### Correlation of ECG Waves with the Timing of Atrial and Ventricular Diastole and Systole As you have learned, the atria and ventricles depolarize and contract at different times because the conduction system routes cardiac action potentials along a specific pathway. The term systole (SIS-tō-lē = contraction) refers to the phase of contraction; the phase of relaxation is diastole (dī-AS-tō-lē = dilation or expansion). The ECG waves predict the timing of atrial and ventricular systole and diastole. At a heart rate of 75 beats per minute, the timing is as follows: 1. A cardiac action potential arises in the SA node. It propagates throughout the atrial muscle and down to the AV node in about 0.03 sec. The P wave appears on the ECG as the atrial contractile fibers depolarize. 2. After the P wave begins, the atria contract (atrial systole). Conduction of the action potential slows at the AV node because the fibers have much smaller diameters and fewer gap junctions. (Traffic slows as a four-lane highway narrows to one lane in a construction zone!) The resulting 0.1-sec delay gives the atria time to contract, thus adding to the blood volume in the ventricles before ventricular systole begins. 3. The action potential propagates rapidly again after entering the AV bundle. About 0.2 sec after the onset of the P wave, it propagated through the bundle branches, Purkinje fibers, and the entire ventricular myocardium. Depolarization progresses down the septum, upward from the apex, and outward from the endocardial surface, producing the QRS complex. At the same time, atrial repolarization occurs, but it is not usually evident in an ECG because the giant QRS complex masks it. 4. Contraction of ventricular contractile fibers (ventricular systole) begins shortly after the QRS complex appears and continues during the S--T segment. As contraction proceeds from the apex toward the base of the heart, blood is squeezed upward toward the semilunar valves. 5. Repolarization of ventricular contractile fibers begins at the apex and spreads throughout the ventricular myocardium. This produces the T wave in the ECG about 0.4 sec after the onset of the P wave. 6. Shortly after the T wave begins, the ventricles relax (ventricular diastole). By 0.6 sec, ventricular repolarization is complete, and ventricular contractile fibers are relaxed. During the next 0.2 sec, contractile fibers in the atria and ventricles are relaxed. At 0.8 sec, the P wave appears again on the ECG, the atria begin to contract, and the cycle repeats. 14.4 The Cardiac Cycle ---------------------- A single cardiac cycle includes all the events associated with one heartbeat. Thus, a cardiac cycle consists of diastole (relaxation) and systole (contraction) of the atria plus diastole and systole of the ventricles. ### Phases of the Cardiac Cycle The cardiac cycle is divided into five phases: (1) passive ventricular filling, (2) atrial contraction, (3) isovolumetric ventricular contraction, (4) ventricular ejection, and (5) isovolumetric ventricular relaxation. Figure 14.19 shows the various phases of the cycle, as well as the relationship between the heart's electrical signals and changes in pressure and volume during each phase. The pressures in Figure 14.19 apply to the left side of the heart; pressures on the right side are considerably lower. Each ventricle expels the same blood volume per beat, and the same pattern exists for both pumping chambers. #### Passive Ventricular Filling Our discussion of the cardiac cycle begins when the atria and ventricles are in diastole. Atrial pressure is higher than ventricular pressure because the atria fill with blood and return it to the heart through veins. As a result of the pressure difference, the atrioventricular (AV) valves open, and blood flows from the atria into the ventricles. This phase of the cardiac cycle is known as passive ventricular filling. The term passive is used because no muscle contractions are involved. About 80% of ventricular filling occurs during this phase; the remaining 20% occurs during atrial contraction. It is worth mentioning that the semilunar (SL) valves are closed at this time because aortic pressure is higher than left ventricular pressure, and pulmonary trunk pressure is higher than proper ventricular pressure. At the end of atrial diastole, an action potential arises in the SA node and then propagates throughout the atria, causing the atria to depolarize. The P wave on the ECG indicates atrial depolarization. #### Atrial Contraction Atrial depolarization causes atrial systole. While the atria are in systole, the ventricles remain in diastole. As the atria contract, atrial pressure increases, and more blood is forced through the open AV valves into the ventricles. Atrial contraction contributes 25 mL of blood to the volume already in each ventricle (about 105 mL). The end of atrial systole is also the end of ventricular diastole (relaxation). Thus, each ventricle contains about 130 mL at the end of its relaxation period (diastole). This blood volume is called the end-diastolic volume (EDV). Toward the end of the atria systole, the QRS complex appears on the ECG, marking the onset of ventricular depolarization. #### Isovolumetric Ventricular Contraction Ventricular depolarization causes ventricular systole. While the ventricles are in systole, the atria are in diastole. As ventricular systole begins, pressure rises inside the ventricles and pushes blood up against the AV valves, forcing them to shut. For a moment, both the AV and SL valves are closed. This cardiac cycle phase is called isovolumetric ventricular contraction (iso- = same). During this interval, cardiac muscle fibers contract and exert force but are not shortening. Thus, the muscle contraction is isometric (same length). Moreover, because all four valves are closed, ventricular volume remains the same (isovolumic). #### Ventricular Ejection Continued contraction of the ventricles causes pressure inside the chambers to rise sharply. SL valves open when left ventricular pressure surpasses aortic pressure at about 80 mmHg and proper ventricular pressure rises above pulmonary trunk pressure (about 20 mmHg) (step   8   in Figure 14.19). At this point, the ventricular ejection phase of the cardiac cycle begins. During this phase, blood is pumped out of the heart. The left ventricle ejects about 70 mL of blood into the aorta, and the right ventricle ejects the same blood volume into the pulmonary trunk. The volume remaining in each ventricle at the end of systole, about 60 mL, is the end-systolic volume (ESV). Stroke volume, the volume ejected per beat from each ventricle, equals end-diastolic volume minus end-systolic volume: SV = EDV − ESV. At rest, the stroke volume is 130 − 60 mL = 70 mL (slightly more than 2 oz). The percentage of the end-diastolic volume that is ejected with each stroke volume is called the ejection fraction (EF): EF = SV/EDV × 100. Under normal resting conditions, EF is about 54% (70 mL/130 mL × 100). Changes in stroke volume alter the ejection fraction. Near the end of ventricular systole, the T wave appears on the ECG, marking the onset of ventricular repolarization. #### Isovolumetric Ventricular Relaxation Ventricular repolarization causes ventricular diastole. As the ventricles relax, pressure within the chambers falls, and blood in the aorta and pulmonary trunk begins to flow backward toward the regions of lower pressure in the ventricles. Backflowing blood catches in the valve cusps and closes the SL valves. The blood rebound off the aortic valve\'s closed cusps produces the dicrotic wave on the aortic pressure curve. After the SL valves close, there is a brief interval when ventricular blood volume does not change because all four valves are closed. This phase is known as isovolumetric ventricular relaxation. As the ventricles continue to relax, the pressure falls quickly. When ventricular pressure drops below atrial pressure, the AV valves open, and another cardiac cycle repeats as passive ventricular filling begins. ### Duration of the Cardiac Cycle At rest, when the heart rate is 75 beats per minute, a cardiac cycle lasts about 0.8 seconds. In one complete cycle, the atria are in diastole for 0.7 seconds and systole for 0.1 seconds, and the ventricles are in diastole for 0.5 seconds and systole for 0.3 seconds. When the heart beats faster, such as during exercise, the amount of time the heart chambers spend in either diastole or systole decreases, with the duration of diastole decreasing the most. ### Heart Sounds That Can Be Heard During the Cardiac Cycle During each cardiac cycle, two prominent heart sounds can be heard with a stethoscope. The first sound (S1), described as a 'LUB' sound, is louder and slightly longer than the second sound. S1 is caused by vibrations associated with the closure of the AV valves soon after ventricular systole begins. The second sound (S2), shorter and not as loud as the first, can be described as a 'DUP' sound. S2 is caused by vibrations associated with the closure of the SL valves at the beginning of ventricular diastole. Thus, the heartbeat is heard as 'LUP-DUP,' 'LUP-DUP,' 'LUP-DUP,' and so on. 14.5 Cardiac Output ------------------- ### Definition of Cardiac Output Although the heart has autorhythmic fibers that enable it to beat independently, its operation is governed by events occurring throughout the body. All body cells must receive a certain amount of oxygenated blood each minute to maintain health and life. When cells are metabolically active, as they are during exercise, they take up even more oxygen from the blood. During rest periods, the cellular metabolic need is reduced, and the heart\'s workload decreases. Cardiac output (CO) is the volume of blood ejected from each ventricle of the heart per minute. It equals the stroke volume (SV), the volume of blood ejected by the ventricle during each contraction, multiplied by the heart rate (HR), the number of heartbeats per minute. In a typical adult male at rest, cardiac output is about 5.25 L/min. This volume is close to the total blood volume of about 5 liters. Thus, your entire blood volume flows through your pulmonary and systemic circulations each minute. Factors that increase stroke volume or heart rate typically increase CO. During mild exercise, for example, stroke volume may increase to 100 mL/beat and heart rate to 100 beats/min. Cardiac output then would be 10 L/min. During intense (but still not maximal) exercise, the heart rate may accelerate to 150 beats/min, and stroke volume may rise to 130 mL/beat, resulting in a cardiac output of 19.5 L/min. Cardiac reserve is the difference between a person's maximum cardiac output and cardiac output at rest. The average person has a cardiac reserve of four or five times the resting value. Top endurance athletes may have a cardiac reserve of seven or eight times their resting CO. People with severe heart disease may have little or no cardiac reserve, which limits their ability to carry out even the simple tasks of daily living. ### Factors that Regulate Stroke Value A healthy heart pumps out the blood that entered its chambers during the previous diastole. In other words, if more blood returns to the heart during diastole, more blood is ejected during the next systole. At rest, the stroke volume is 50--60% of the end-diastolic volume because 40--50% of the blood remains in the ventricles after each contraction (end-systolic volume). Three significant factors regulate stroke volume and ensure that the left and right ventricles pump equal volumes of blood: (1) preload, the degree of stretch on the heart before it contracts; (2) contractility, the forcefulness of contraction of individual ventricular muscle fibers; and (3) afterload, the pressure that must be exceeded before ejection of blood from the ventricles can occur. #### Preload: Effect of Stretching A greater preload (stretch) on cardiac muscle fibers before contraction increases their force of contraction. Within limits, the more the heart fills with blood during diastole, the greater the force of contraction during systole. This relationship is known as the Frank-Starling law of the heart, in honor of the two physiologists (Otto Frank and Ernest Starling) who first described it. Preload is proportional to the end-diastolic volume (EDV) (the volume of blood that fills the ventricles at the end of diastole). Typically, the greater the EDV, the more forceful the next contraction. The Frank-Starling law manifests the length-tension relationship for cardiac muscle because EDV influences the length of the sarcomeres just before a contraction begins. Recall that resting sarcomeres are held close to their optimal lengths in the length-tension relationship for skeletal muscle. The zone of overlap between each sarcomere\'s thick and thin filaments is ideal, and the muscle fibers can develop maximum tension. When skeletal muscle fibers are stretched beyond their optimal lengths, there is less overlap between the thick and thin filaments. As a result, the tension that the fibers can produce decreases. In cardiac muscle, resting sarcomeres are held at a shorter length than the optimum. At such a length, the thin filaments from each side of the sarcomere overlap, reducing the interaction between the thick and thin filaments. This results in relatively low tension development during contraction, responsible for the average stroke volume. However, when an increase in EDV stretches cardiac muscle fibers, the stretch causes the sarcomeres to get closer to their optimal lengths, resulting in more significant tension development when the muscle fibers contract and an increase in stroke volume. Suppose cardiac muscle fibers are stretched beyond their optimal lengths. In that case, there are fewer interactions between the thick and thin filaments, the tension that the fibers can produce decreases, and stroke volume falls. In a healthy heart, cardiac muscle is usually prevented from stretching beyond its optimal length by connective tissues in the wall of the heart, the fibrous skeleton, and the pericardium. Thus, cardiac muscle almost always operates along the ascending portion of the length-tension curve. Two key factors determine EDV: (1) filling time, the duration of ventricular diastole, and (2) venous return, the volume of blood returning to the right ventricle. When heart rate increases, filling time is shorter. Less filling time means a smaller EDV and the ventricles may contract before they are adequately filled. By contrast, when venous return increases, a greater blood volume flows into the ventricles, and the EDV increases. When the heart rate exceeds 160 beats/min, stroke volume usually declines due to the short filling time. At such rapid heart rates, EDV is less, and the preload is lower. People with slow resting heart rates usually have large resting stroke volumes because filling time is prolonged, and preload is more significant. The Frank-Starling law of the heart equalizes the output of the right and left ventricles and keeps the same volume of blood flowing to both the systemic and pulmonary circulations. If the left side of the heart pumps more blood than the right side, the volume of blood returning to the right ventricle (venous return) increases. The increased EDV causes the right ventricle to contract forcefully on the next beat, returning the two sides to balance.  #### Contractility The second factor influencing stroke volume is myocardial contractility, the strength of contraction at any given preload. Agents that alter contractility are said to have an inotropic effect: Those that increase contractility have a positive inotropic effect, and those that decrease contractility have a negative inotropic effect. Thus, for a constant preload, a positive inotropic effect causes an increase in stroke volume, and a negative inotropic effect causes a decrease in stroke volume. Stimulation of the sympathetic nervous system, hormones such as epinephrine and norepinephrine, increased extracellular Ca2+ levels, and the drug digitalis all have positive inotropic effects. Positive inotropic agents enhance contractility by increasing the amount of Ca2+ in the sarcoplasm during cardiac action potentials. As an example, consider how an increase in contractility is caused by sympathetic stimulation: 1. Norepinephrine released from sympathetic nerve endings binds to β1-adrenergic receptors in the sarcolemma of contractile muscle fiber in the ventricular myocardium. 2. The binding of norepinephrine to the receptor activates a stimulatory G protein (Gs). 3. Activated Gs stimulates adenylyl cyclase to produce the second messenger cyclic AMP (cAMP). 4. cAMP binds to and activates a protein kinase (protein kinase A). The activated protein kinase, in turn, phosphorylates various proteins with effects that ultimately cause an increase in contractility. 5. Phosphorylation of L-type voltage-gated Ca2+ channels in the sarcolemma increases the duration of the open state of these channels, allowing more Ca2+ to move from the extracellular fluid into the sarcoplasm for contraction. 6. Phosphorylation of Ca2+ release channels in the sarcoplasmic reticulum (SR) membrane enhances Ca2+ release from the SR lumen into the sarcoplasm, providing additional Ca2+ for contraction. 7. Phosphorylation of phospholamban in the SR membrane increases Ca2+ uptake into the SR lumen by Ca2+-ATP-ase pumps. This speeds relaxation and makes more Ca2+ available to be released for the next contraction. Phospholamban is a regulatory protein that typically inhibits the Ca2+-ATPase. When phospholamban is phosphorylated, it is inactivated, and the inhibition of the Ca2+-ATPase is removed. 8. Phosphorylation of myosin heads of the thick filaments enhances myosin ATPase activity, increasing the cross-bridge cycling rate. In contrast to positive inotropic effects, adverse inotropic effects decrease contractility. Inhibition of the sympathetic nervous system, excess H+ ions (from acidosis), increased extracellular K+ levels, and drugs known as calcium channel blockers all have adverse inotropic effects. Harmful inotropic agents decrease contractility by reducing the amount of Ca2+ in the sarcoplasm. For example, calcium channel blockers inhibit the opening of L-type voltage-gated Ca2+ channels in the sarcolemma of contractile fibers, thereby reducing Ca2+ inflow. #### Afterload Ejection of blood from the heart begins when the pressure in the right ventricle exceeds the pressure in the pulmonary trunk (about 20 mmHg) and when the pressure in the left ventricle exceeds the pressure in the aorta (about 80 mmHg). At that point, the higher ventricle pressure causes blood to open the semilunar valves. The pressure must be overcome before a semilunar valve, which is the afterload, can open. An increase in afterload causes stroke volume to decrease so that more blood remains in the ventricles at the end of the systole. Conditions that can increase afterload include hypertension (elevated blood pressure) and narrowing of arteries by atherosclerosis. The effect of afterload on stroke volume can be predicted from the cardiac muscle\'s load--vessel relationship (Figure 14.24). As afterload increases, the shortening velocity of ventricular muscle fibers decreases. A decreased shortening velocity means that the ventricular muscle fibers eject less blood, reducing stroke volume. ### Factors that Regulate Heart Rate As you have just learned, cardiac output depends on stroke volume and heart rate. Adjustments in heart rate are necessary for the short-term control of cardiac output and blood pressure. The sinoatrial (SA) node initiates contraction and, if left to itself, would set a constant heart rate of about 100 beats/min. However, tissues require different volumes of blood flow under various conditions. During exercise, for example, cardiac output rises to supply working tissues with increased oxygen and nutrients. Stroke volume may fall if the ventricular myocardium is damaged or blood volume is reduced by bleeding. In these cases, homeostatic mechanisms maintain adequate cardiac output by increasing the heart rate and contractility. The two main factors that regulate heart rate are the autonomic nervous system and specific chemicals (including several hormones and ions). Other factors contributing to heart rate regulation include age, gender, physical fitness, and body temperature. Agents that alter the heart rate are said to have a chronotropic effect. Those that increase heart rate have a positive chronotropic effect; those that decrease heart rate have a negative chronotropic effect. ### Autonomic Regulation of Heart Rate The heart receives innervation from the autonomic nervous system\'s sympathetic and parasympathetic divisions (ANS). Sympathetic innervation of the heart begins with sympathetic preganglionic neurons, which extend from the thoracic spinal cord to the sympathetic trunk ganglia, where they synapse with sympathetic postganglionic neurons. In turn, axons of the sympathetic postganglionic neurons form sympathetic nerves known as cardiac accelerator nerves that extend to the SA node, AV node, and ventricular myocardium. Action potentials in cardiac accelerator nerves trigger the release of norepinephrine, which binds to β1-adrenergic receptors on cardiac cells. Parasympathetic innervation of the heart begins with parasympathetic preganglionic neurons, which extend from the brain stem via the vagus (X) nerves to synapse with parasympathetic postganglionic neurons in the heart wall. In turn, axons of the parasympathetic postganglionic neurons terminate mainly in the SA node and AV node, with essentially no inputs to the ventricles. Action potentials in parasympathetic postganglionic axons trigger the release of acetylcholine, which binds to muscarinic cholinergic receptors on cardiac cells. #### Sympathetic Regulation Stimulation of the sympathetic nervous system has three main effects on the heart: (1) it increases heart rate; (2) it increases the rate of action potential conduction from the atria to the ventricles; and (3) it increases contractility. Increase in heart rate. Sympathetic stimulation of the SA node causes an increase in heart rate. This occurs by increasing the rate of spontaneous depolarization in SA node cells so that the threshold for an action potential is reached more rapidly. The specific steps involved in this process are as follows: 1. Norepinephrine from sympathetic postganglionic neurons binds to β1-adrenergic receptors in the sarcolemma of an SA node cell. 2. Binding of norepinephrine to the receptor activates a stimulatory G protein (Gs). 3. Activated Gs stimulates the adenylyl cyclase to produce cyclic AMP (cAMP). 4. cAMP directly binds to F-type Na+ channels in the sarcolemma. Recall that F-type channels produce the pacemaker potential, the spontaneous depolarization to a threshold that occurs in pacemaker cells (see Figure 14.13). CAMP binding to F-type channels keeps the channels open for extended periods, allowing more Na+ ions to enter the cell. 5. The increased influx of Na+ through F-type channels increases the rate of spontaneous depolarization, allowing the threshold to be reached more quickly. As a result, the SA node generates action potentials at a higher frequency, and the heart rate increases. Increase in rate of action potential conduction from atria to ventricles. Sympathetic stimulation of the AV node speeds up conduction velocity through the AV node, which increases the rate at which action potentials are conducted from the atria to the ventricles. The effect of sympathetic stimulation of the AV node occurs because of enhanced opening of F-type Na+ channels, increasing Na+ inflow. This depolarizes the AV node membrane, making it easier for AV node cells to be excited by incoming action potentials from the atria. As a result, conduction velocity through the AV node increases, and action potentials travel from the atria to the ventricles faster. Increase in contractility. Sympathetic stimulation of the ventricular myocardium causes an increase in contractility. Recall that binding of norepinephrine to β1-adrenergic receptors in contractile ventricular fibers activates a G protein signaling pathway that ultimately increases the Ca2+ levels in the sarcoplasm, thereby increasing contractility. As a result, a greater volume of blood is ejected during systole. With a moderate increase in heart rate, stroke volume does not decline because the increased contractility offsets the decreased preload. With maximal sympathetic stimulation, however, heart rate may reach 200 beats/min in a 20-year-old person. At such a high heart rate, stroke volume is lower than at rest due to the short filling time. #### Parasympathetic Regulation Stimulation of the parasympathetic nervous system has two main effects on the heart: (1) it decreases heart rate, and (2) it decreases the rate of action potential conduction from the atria to the ventricles. Because only a few parasympathetic fibers innervate ventricular muscle, parasympathetic stimulation has little or no effect on the contractility of the ventricles. Decrease in heart rate. Parasympathetic stimulation of the SA node decreases heart rate by reducing the rate of spontaneous depolarization in SA node cells so that the threshold for an action potential is reached more slowly (Figure 14.27a). The specific steps involved occur as follows (Figure 14.27b): 1. Acetylcholine (ACh) released from parasympathetic postganglionic neurons binds to muscarinic receptors in the sarcolemma of an SA node cell. 2. The binding of ACh to its receptor activates an inhibitory G protein (Gi). 3. Activated Gi directly opens a subset of K+ channels known as acetylcholine-regulated K+ channels or K+ACh channels. Opening the K+ channels allows more K+ ions than usual to leave the cell. As a result, the cell membrane hyperpolarizes, causing the pacemaker potential of the SA node cell to start at a more negative value. 4. The activated Gi protein also inhibits adenylyl cyclase, causing the production of cyclic AMP (cAMP) to decrease. The decreased concentration of cAMP accelerates the closure of F-type Na+ channels. (Recall that binding of cAMP to F-type channels increases their duration of opening; when fewer cAMP molecules are available, the channels have a greater probability of closing.) Closure of the F-type Na+ channels reduces the entry of Na+ ions into the SA node cell during the pacemaker potential. 5. Hyperpolarization of the SA node membrane and decreased Na+ entry during the pacemaker potential both have the same effect on the SA node cell: They decrease the rate of spontaneous depolarization. As a result, the SA node generates action potentials at a lower frequency, and the heart rate decreases. Decrease in rate of action potential conduction from atria to ventricles. Parasympathetic stimulation of the AV node slows conduction velocity through the AV node, which decreases the rate at which action potentials are conducted from the atria to the ventricles. The effect of parasympathetic stimulation of the AV node is due to augmented opening of K+ACh channels, increasing K+ outflow. This hyperpolarizes the AV node membrane, making it more difficult for the AV node to be excited by action potentials from the atria. So, conduction velocity through the AV node decreases, and action potentials travel more slowly from the atria to the ventricles. #### Shifting Balance Between Sympathetic and Parasympathetic Regulation A continually shifting balance exists between sympathetic and parasympathetic stimulation of the heart. At rest, parasympathetic stimulation predominates. The resting heart rate---about 75 beats/min---is usually lower than the autorhythmic rate of the SA node (about 100 beats/min). With maximal stimulation by the parasympathetic division, the heart can slow to 20 or 30 beats/min or stop momentarily. ### Chemical Regulation of Heart Rate Certain chemicals influence both the basic physiology of cardiac muscle and the heart rate. For example, hypoxia (lowered oxygen level), acidosis (low pH), and alkalosis (high pH) all depress cardiac activity. Several hormones and ions have significant effects on the heart: - **Hormones.** Epinephrine and norepinephrine (from the adrenal medullae) enhance the heart's pumping effectiveness. These hormones affect cardiac muscle fibers like norepinephrine released by cardiac accelerator nerves---they increase heart rate, the rate of action potential conduction from the atria to the ventricles, and contractility. They achieve these functions by binding to the same β1 receptors in cardiac cells ---exercise, stress, and excitement cause the adrenal medullae to release more hormones. Thyroid hormones also enhance cardiac contractility and increase heart rate. - **Ions.** Given that differences between intracellular and extracellular concentrations of several ions (for example, Na+ and K+) are crucial to producing action potentials in all nerve and muscle fibers, it is not surprising that ionic imbalances can quickly compromise the pumping effectiveness of the heart. In particular, the relative concentrations of three ions---K+, Ca2+, and Na+---significantly affect cardiac function. Elevated blood levels of K+ or Na+ decrease heart rate and contractility. Excess Na+ blocks Ca2+ inflow during cardiac action potentials, thereby reducing the force of contraction, whereas excess K+ blocks the generation of action potentials. An increase in extracellular Ca2+ speeds up the heart rate and strengthens the heartbeat. ### Other Factors in Heart Rate Regulation Age, gender, physical fitness, and body temperature influence resting heart rate. A newborn will likely have a resting heart rate of over 120 beats/min, gradually declining throughout life. Adult females often have slightly higher resting heart rates than adult males, although regular exercise tends to bring resting heart rates down in both sexes. A physically fit person may exhibit bradycardia (a resting heart rate under 60 beats/min). This is a beneficial effect of endurance-type training because a slowly beating heart is more energy efficient than one that beats more rapidly. Increased body temperature, as occurs during a fever or strenuous exercise, causes the SA node to discharge action potentials more quickly, thereby increasing heart rate. Decreased body temperature decreases heart rate and strength of contraction. 14.6 Exercise and the Heart --------------------------- Regardless of current fitness level, cardiovascular fitness can be improved at any age with regular exercise. Some types of exercise are more effective than others for improving cardiovascular health. Aerobics, any activity that works large body muscles for at least 20 minutes, elevates cardiac output and accelerates metabolic rate. Three to five such sessions a week are usually recommended to improve cardiovascular system health. Examples of aerobic activities include brisk walking, running, bicycling, cross-country skiing, and swimming. Sustained exercise increases the muscles\' oxygen demand. Whether this demand is met depends mainly on the adequacy of cardiac output and proper respiratory system functioning. After several weeks of training, a healthy person increases maximal cardiac output, thereby increasing the maximal rate of oxygen delivery to the tissues. Oxygen delivery also rises because skeletal muscles develop more capillary networks in response to long-term training. During strenuous activity, a well-trained athlete can achieve a cardiac output double that of a passive person, partly because training causes heart hypertrophy (enlargement). Even though the heart of a well-trained athlete is more enormous, resting cardiac output is about the same as in a healthy, untrained person because stroke volume is increased while heart rate is decreased. The resting heart rate of a trained athlete is often only 40--60 beats per minute (resting bradycardia). Regular exercise also helps to reduce blood pressure, anxiety, and depression, control weight, and increase the body's ability to dissolve blood clots by increasing fibrinolytic activity.