13. The Cardiovascular System

Authors: Corwin, Elizabeth J.

Title: Handbook of Pathophysiology, 3rd Edition

Copyright 2008 Lippincott Williams & Wilkins

> Table of Contents > Unit IV - Oxygen Balance and Deficiencies > Chapter 13 - The Cardiovascular System

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Chapter 13

The Cardiovascular System

According to the American Heart Association, in the year 2004 nearly one million deaths in the United States were cardiovascular-related, accounting for 35% of all deaths in the U.S. that year. It is critical that health care providers and lay persons alike learn the concepts of cardiovascular disease, prevention, and health maintenance.

The cardiovascular system begins with the heart, a muscular pump that beats rhythmically and repeatedly 60 to 100 times a minute. Each beat causes blood to surge from the heart and travel throughout the body in a closed network of arteries, arterioles, and capillaries and return to the heart through venules and veins. The purpose of the cardiovascular system is to pick up oxygen in the lungs and nutrients absorbed across the gut and deliver them to all cells of the body. At the same time, the cardiovascular system removes the metabolic waste products produced by each cell and delivers them to the lungs or the kidneys to be excreted.

Physiologic Concepts

Anatomy of the Heart

The heart is a four-chambered, muscular organ that lies in the chest cavity, under the protection of the ribs, slightly to the left of the sternum. The heart sits within a loose, fluid-filled sac, called the pericardium. The four chambers of the heart include the left and right atria and the left and right ventricles. The atria sit next to each other above the ventricles. The atria and ventricles are separated from each other by one-way valves. The right and left sides of the heart are separated by a wall of tissue called the


septum. There is normally no mixing of blood between the two atria, except during fetal life, and there is never mixing of blood between the two ventricles in a healthy heart. Connective tissue surrounds all chambers. The heart is extensively innervated.

Two Circulations of the Cardiovascular System

The left side of the heart pumps blood through the systemic circulation, which reaches all cells of the body except those involved with gas exchange in the lungs. The right side of the heart pumps blood through the pulmonary circulation, which delivers blood only to the lungs to be oxygenated.

Systemic Circulation

Blood enters the left atrium from the pulmonary vein. Blood in the left atrium flows into the left ventricle through the atrioventricular (AV) valve located at the juncture of the left atrium and ventricle. This valve is called the mitral valve. All cardiac valves open when pressure in the chamber or vessel above them is greater than pressure in the chamber or vessel below.

Blood from the left ventricle outflows into a large, muscular artery, called the aorta, through the aortic valve. Blood in the aorta is delivered throughout the systemic circulation, through arteries, arterioles, and capillaries, which then rejoin to form veins. The veins from the lower part of the body return the blood to the largest vein, the inferior vena cava. The veins from the upper body return blood to the superior vena cava. The venae cavae empty into the right atrium.

Pulmonary Circulation

Blood in the right atrium moves into the right ventricle through another AV valve, called the tricuspid valve. Blood leaves the right ventricle and travels through a fourth valve, the pulmonary valve, into the pulmonary artery. The pulmonary artery branches into left and right pulmonary arteries, which travel to the left and right lungs, respectively. In the lungs, the pulmonary arteries branch many times into arterioles and then capillaries. Each capillary perfuses past an alveolus, the unit of respiration. All capillaries reform to become venules, and the venules become veins. The veins join to form the pulmonary veins.

Blood flows in the pulmonary veins back to the left atrium, completing the blood flow cycle. The heart and the systemic and pulmonary circulations are shown in Figure 13-1.

Functions of the Systemic and Pulmonary Circulations

As blood passes each cell of the body in the systemic circulation, carbon dioxide and other cellular waste products are added to the blood, while


oxygen and nutrients are delivered from the blood to the cells. In the pulmonary circuit, the opposite occurs: carbon dioxide is eliminated from the blood and oxygen is added. By continual cycling of the blood through the pulmonary and systemic circulations, oxygen supply and waste removal are ensured for all cells.

Figure 13-1. Anatomy of the heart.

Coronary Artery Blood Flow

Two large arteries, called the left and right coronary arteries, branch off the aorta as soon as it leaves the left ventricle and supply blood to the heart. The left coronary artery quickly branches into the left anterior descending artery and the circumflex artery. The left anterior descending artery travels down the anterior portion of the septal groove between the right and left ventricles and branches several more times to supply blood to the anterior portion of the septum and the anterior muscle mass of the left ventricle.

The left circumflex artery travels in the area between the left atrium and the left ventricle and supplies blood to the lateral wall of the left ventricle.

The right coronary artery travels in the groove between the right atrium and the right ventricle and branches off to supply blood to the posterior portions of the heart, including the posterior interventricular septum. In most people, the right coronary artery supplies blood to important electrical sites of the heart: the sinoatrial (SA) node and the AV node.


Cardiac Muscle

Cardiac muscle is composed of highly specialized muscle fibers. Not only do these fibers contract in response to action potentials produced from neural stimulation, but many cardiac muscle fibers are capable of spontaneously firing action potentials that can initiate their own contractions. Excitation-contraction of cardiac muscle is described in the next several sections, beginning with a description of the cardiac muscle fibers and finishing with an outline of how an action potential leads to the contraction and beating of the heart.

Cardiac Muscle Fibers

As described fully in Chapter 10, cardiac muscle fibers are made up of bands of protein filaments, called myofilaments, lying in series with each other. Each band is called a sarcomere. A cardiac sarcomere is shown in Figure 13-2. Sarcomeres in cardiac muscle are fused together at their borders to form areas called intercalated disks. These are areas of low resistance across which electrical currents can pass.


Each cardiac sarcomere is made up of thick and thin filaments. Thick filaments consist of the contractile protein myosin. Thin filaments include the second contractile protein, actin, and two regulatory proteins, tropomyosin and troponin. Cross-bridges extend from the myosin filaments to the actin filaments. In the absence of calcium ion, tropomyosin is attached to each actin molecule in such a way that tropomyosin covers the binding site for myosin on actin, and thus inhibits cross-bridge connection. The troponin complex, which includes troponin-I, -T, and -C, is attached to the tropomyosin filament. When calcium is available, troponin-C binds the tropomyosin filament in such a way that the myosin cross-bridges are now exposed and able to bind actin.

At this point, energy stored from a previous myosin-based reaction, in which adenosine triphosphate (ATP) was split into adenosine diphosphate


(ADP) and a phosphate molecule, is released and is used to swing the cross-bridges. This causes the myosin and actin filaments to slide past each other and muscle contraction to occur. Because all cardiac muscle cells are connected to each other at the intercalated disks, depolarization of one group of cardiac muscle cells spreads to neighboring cells and all cells contract as a unit. Each contraction represents a heartbeat.

Figure 13-2. A sarcomere.

Cardiac Muscle Depolarization and Action Potential Firing

An action potential in a cardiac muscle cell is triggered as a result of a depolarizing current reaching it from a neighboring muscle cell. Although in some ways similar to a skeletal muscle action potential, the cardiac action potential is unique due to its plateau phase and long duration.

Just like a skeletal muscle cell, a cardiac muscle cell fires an action potential when the inside of the cell becomes significantly more positively charged than the outside. As in skeletal muscle, this occurs when voltage-sensitive sodium channels open in the cell membrane, resulting in an in-rush of positively charged sodium ions. This is called Phase 0 of the cardiac action potential and is characterized by a rapid change in the membrane potential, from about -80 mV intracellularly to a positive intracellular value of approximately 20 25 mV (Fig. 13-3). Very quickly, closure of the sodium channels occurs, marking the end of Phase 0. Next begins Phase 1, a repolarizing phase. During Phase 1, potassium channels close in the cell membrane and positively charged potassium ions accumulate in the cell, preventing the return of the membrane potential toward its resting (negative) value. Closure of the potassium channels immediately following the onset of the action potential does not happen in skeletal muscle; in cardiac


muscle, it contributes to the slowing of repolarization. Prolongation continues during the next phase, Phase 2, as calcium ions begin to enter the cell through calcium channels present in the cell membrane. This increase in intracellular calcium triggers the opening of other, slow calcium channels located in the membrane of the sarcoplasmic reticulum, a storage compartment for intracellular calcium. This process, called calcium stimulated calcium release, results in a further rise in intracellular calcium levels, reaching levels that effectively move the troponin off the tropomyosin molecule and thus trigger the muscle cell to contract. The slow inward movement of calcium also prolongs cellular depolarization. Phase 3 is the final repolarization phase, and it occurs when the influx of calcium decreases and the outflow of potassium ions through delayed rectifier channels begins, finally bringing the membrane potential back to its negative resting value. Intracellular levels of calcium decrease, by means of calcium moving out membrane channels as well as via active transport of calcium back into the sarcoplasmic reticulum storage sites. As calcium falls, the cell relaxes and the heart enters diastole. The cell remains in Phase 4, the resting potential phase, until it is again stimulated to undergo an action potential. Prolongation of the action potential is significant because it makes it impossible to fire a second action potential before the first is completed, ensuring that cardiac cells will not undergo summation and tetany of contractions: If cardiac cells underwent tetany, the heart would stop pumping out blood because it would not be able to relax and fill with blood between beats.

Figure 13-3. The cardiac action potential.

Cardiac Muscle Relaxation

Adenosine diphosphate (ADP) releases from the cross-bridge after it swings, and another ATP molecule binds to the myosin protein, causing the myosin cross-bridges to separate from actin. As long as calcium ion still is available intracellularly to bind troponin, this new ATP will be split, and its energy will be released when a new cross-bridge connection forms, thereby repeating the cycle and ensuring that the muscle will continue to contract. Many cross-bridge cycles and sliding of the filaments occur during one action potential. The contraction ultimately stops when intracellular calcium levels fall. Without calcium, tropomyosin again blocks the site on actin to which the cross-bridges bind, and no further connection between myosin and actin can be made.

In skeletal muscle, there is always enough calcium released with each action potential to fully saturate all troponin sites and thus cause all cross-bridges to swing. In cardiac muscle, however, less than maximal amounts of calcium are usually released with a single action potential. This means that under certain circumstances, cardiac contractile strength may be increased if necessary.

The Pacemaker

Most cardiac muscle cells have the capacity to fire action potentials independently. However, certain cells are more permeable to sodium ions at


rest than others, and therefore start off more positively charged than other cells. These slightly depolarized cells reach action potential threshold and fire sooner than other cells. The fast-firing cells pass their excitation easily to other cells through the connections between each cell. The fastest depolarizing cells of the heart control the rate, or pace, of contraction. The cells that normally depolarize fastest make up the SA node. The SA node, located in the wall of the right atrium, is the primary pacemaker of the heart.

Spread of Electrical Depolarization Through the Myocardium

From the SA node, depolarization spreads rapidly through both atria and soon reaches the AV node, which is located in the lower right atrium near the juncture of the atria and ventricles. When the depolarization reaches the AV node, the electrical signal is delayed shortly before it is passed to the ventricles. During this delay, the atria reach action potential threshold and begin to contract, pumping their last bit of blood into the ventricles. While contraction of the atria is occurring, the electrical depolarization spreads through the AV node down specialized muscle fibers to an area of the ventricles called the bundle of His. Depolarization then spreads rapidly through the left and right bundle branches of the interventricular septum, and from there, down an extensive, wide-reaching group of specialized conducting fibers called Purkinje's fibers. In a normal heart, the apex of the ventricle depolarizes first, after which the wave of depolarization spreads up toward the atria. This wave allows for the efficient ejection of blood from the ventricle.

The Cardiac Cycle

Until the ventricles contract, the AV valves are open and blood flows from the atria into the relaxed, low-pressure ventricles. The aortic and pulmonary valves are closed because pressures are greater in the aortic and pulmonary arteries than in the relaxed ventricles. This allows blood to accumulate in the ventricles. This period of ventricular relaxation is called diastole. Blood volume in the ventricle immediately before ventricular contraction is called end-diastolic volume. When the ventricles contract, pressure inside the ventricles becomes greater than in the atria, and the AV valves snap shut. For a brief period of time, pressure in the aorta and pulmonary arteries is still higher than in the ventricles, so the aortic and pulmonary valves remain closed. With increasing pressure in the ventricles, the aortic and pulmonary valves burst open and blood flows out of the ventricles at high speed and pressure. This period of ventricular contraction is called systole.

With the end of systole, the ventricles relax again. As pressure in the relaxing ventricles falls below that in the aortic and pulmonary arteries, the aortic and pulmonary valves snap shut. Blood entering the atria from the venae cavae and pulmonary veins causes pressure to rebuild in the atria, opening the AV valves. The cycle of filling and emptying begins again.


Arterial Pressures

The pulmonary artery and aorta are muscular vessels that expand with the surge of blood they receive from the ventricles. They hold this blood before releasing it into the rest of the vascular system, not in big pulses followed by ebbs of flow, but in a steady stream. Pressure generated in the arteries at the peak of ventricular contraction is much greater than pressure in the arteries when the ventricles are relaxed. Both of these pressures are frequently measured. Systolic pressure is the arterial blood pressure generated during ventricular contraction. Diastolic pressure is the arterial blood pressure generated when the ventricles are relaxed.

Heart Sounds

Heart sounds are produced when the AV valves (mitral and tricuspid valves) and the pulmonary and aortic valves snap shut. At least two (and sometimes four) heart sounds can be heard.

The first heart sound is heard when the AV valves snap shut during ventricular contraction. This sound is somewhat prolonged and low in pitch, and occurs with the onset of systole when pressure in the ventricles becomes greater than in the atria. The second heart sound is shorter and occurs when outlet valves from the ventricles, the pulmonary and aortic valves, snap shut. This happens during diastole, when the ventricles relax and pressures in the pulmonary artery and aorta which have just received the surging blood are greater than pressures in the right and left ventricles. Third and fourth heart sounds are sometimes heard and are related to the sound of blood reverberating in the ventricles during rapid filling (third sound) or entering a ventricle that is stiff (fourth sound), for example, in conditions such as ventricular hypertrophy.

Cardiac Output

Repeated contractions of the myocardium are the heartbeats. Each beat pumps blood out of the heart. The amount of blood pumped per beat is the stroke volume. Cardiac output (CO), the volume of blood pumped per minute, depends on the product of the heart rate (HR; in beats per minute) and the stroke volume (SV; in milliliters of blood pumped per beat) as shown in Equation 13-1:

Cardiac output of an adult male ranges from 4.5 to 8 L/minute. Increased cardiac output is possible with increased heart rate or stroke volume.

The cardiac index is often calculated clinically and offers input on heart performance in an individual. The cardiac index is found by dividing the measured cardiac output by the body surface area of the individual.

Cardiac output can increase or decrease as a result of forces acting intrinsically or extrinsically to the heart; that is, with or without external


input. Intrinsic control of cardiac output is determined by the length of the cardiac muscle fibers. Extrinsic control refers to the effect of neural stimulation on the heart.

Intrinsic Control of Cardiac Output

The length of cardiac muscle fibers affects the tension they can produce because of the anatomic arrangement of muscle contractile proteins. In the resting heart, the muscle fibers are stretched to a degree less than that required to produce maximum tension. When cardiac muscle fibers are stretched, more myosin cross-bridges can reach their actin binding sites, causing an increase in cross-bridge swinging and an increase in cardiac tension and cardiac contractility. This results in an increase in stroke volume and cardiac output (Equation 13-1). Increased stretch of the myofibrils occurs when there is increased filling of the heart; therefore, the tension that is produced by the heart is proportional to the volume of blood in the heart immediately before ventricular contraction: the end-diastolic volume. Because of this response, the heart has reserve capacity to pump more forcefully when the volume of blood flow is increased for example, with exercise and volume loading.

Because an increase in venous return will increase end-diastolic volume, the length-tension relationship of the heart ensures that under most conditions, increased blood flow into the heart will be matched by increased blood pumped out. This serves to return the end-diastolic volume back toward normal, making this response typically of short duration. This intrinsic response of the heart to its own muscle fiber stretch is called Starling's law of the heart, after Frank Starling, the physiologist who first described it. The length-tension relationship of a normal heart under nonstimulated control conditions is shown in the lower curve of Figure 13-4.


Note that, unlike in the skeletal muscle length-tension curve, the normal heart does not fall off the curve at higher fiber length. The words under most conditions in the preceding paragraph refer to the fact that in a damaged heart, overstretch of the ventricle will not improve contractility, and the heart will not be able to pump out the extra blood. Therefore, a damaged heart continues to overfill and eventually becomes overstretched. This situation is characteristic of heart failure, which is described later.

Figure 13-4. Length tension curve: Starling's law of the heart.

A second reason why the stretch of cardiac muscle fibers determines cardiac output is that with increased venous return, the wall of the right atrium is stretched. This stretch causes an increased firing rate of the SA node and an increased heart rate of up to 20%. This increase in heart rate, coupled with an increase in stroke volume as a result of extra filling, can dramatically increase cardiac output. However, as mentioned earlier, because an increase in end-diastolic volume increases stroke volume, the intrinsic response to excess volume is usually temporary.

Extrinsic Control of Cardiac Output

Heart rate and stroke volume are affected by the sympathetic and parasympathetic nervous systems and by circulating hormones.

Sympathetic nerves travel in the thoracic spinal nerve tracts to the SA node and release the neurotransmitter norepinephrine. Norepinephrine binds to specific receptors called 1 adrenergic receptors, present on the cells of the SA node. When this happens, activation of a second messenger system causes increased firing rate of the node, leading to an increase in heart rate. The heart rate is decreased if the activation of the sympathetic nerves and the release of norepinephrine are reduced. An increase or decrease in the heart rate is called a positive or negative chronotropic effect.

Sympathetic nerves also innervate cells throughout the myocardium, causing an increase in the force of each contraction (i.e., the contractility) at any given muscle fiber length. This causes an increase in stroke volume and is called a positive inotropic effect, as shown by the upper curve in Figure 13-4.

Parasympathetic nerves travel to the SA node and throughout the heart through the vagus nerve. Parasympathetic nerves release the neurotransmitter acetylcholine, which slows the rate of depolarization of the SA node and leads to a decrease in heart rate a negative chronotropic effect. Parasympathetic stimulation to other sites in the myocardium appears to reduce contractility and therefore stroke volume, producing a negative inotropic effect.

Hormonal control of cardiac output mainly involves the adrenal medulla, an extension of the sympathetic nervous system. With sympathetic stimulation, the adrenal medulla releases norepinephrine and epinephrine into the circulation. These hormones travel to the heart and produce positive chronotropic and inotropic responses.


Arteries and Veins

All blood vessels except the capillaries are composed of three layers: the tunica adventitia, the tunica media, and the tunica intima.

The tunica adventitia is the outermost layer of the blood vessel, away from the lumen of the tube. It is primarily connective tissue and provides the vessels with physical support.

The tunica media is the middle layer of the vessel and is composed of vascular smooth muscle. This layer always has some basal tone, or tension, which can be increased or decreased. An increase in tension of the tunica media results in constriction of the vessel and a narrowing of its lumen, leading to an increase in the resistance to blood flow through the vessel. Relaxation of the smooth muscle causes dilation of the vessel and decreased resistance to flow. Increases or decreases in the radius of the vessels occur through neural, hormonal, and local mediators of blood flow. Because of their capacity to change their resistance through contraction or relaxation of the smooth muscle, the arterioles in particular are called the resistance vessels of the circulatory system.

The third layer of the blood vessels is the tunica intima, the innermost layer. This single-cell layer is made up of endothelial cells and is surrounded by a basement membrane.

Special Characteristics of Veins

The veins, although composed of the tunicae adventitia, media, and intima, have much less smooth muscle than the arteries and arterioles. They are thin vessels that can easily expand to accommodate large volumes of blood and are easily collapsed. Because of their capacity to hold large volumes of blood, the veins are called the capacitance vessels of the circulatory system. This reservoir of venous blood can be called on in times of need when blood volume or pressure is low.

One-way valves are located periodically in the veins. These one-way valves allow blood to proceed toward the heart, but not back the other way. Blood is returned to the heart through the veins as a result of the pressure gradient that exists between the veins and the heart. Surrounding skeletal muscles contribute to returning venous blood to the heart by contracting and thus squeezing the veins. The valves prevent the blood squeezed up toward the heart from falling back down when the muscles relax. If one stands for a long period of time, the muscles relax and the valves don't close entirely, allowing blood to pool in the feet and ankles.


The smallest of the blood vessels are the capillaries, with a diameter between 4 and 9 m, barely large enough for a red blood cell to flow through. The capillaries are composed only of endothelial cells. Lipid-soluble


substances, such as oxygen and carbon dioxide, pass out of the capillaries into the interstitial space by diffusing across the endothelial cells. Substances that are not lipid soluble, such as small ions and glucose, may move between the endothelial cells through intercellular clefts or pores to reach the interstitial space. Because the diameter of the capillary pores is much smaller than the diameter of the plasma proteins and red blood cells, and because neither is lipid soluble, proteins and red cells are prohibited from moving out of the vascular system into the interstitial space.

Precapillary Sphincter

Immediately proximal to the capillaries are the meta-arterioles, which deliver blood to the capillaries through a precapillary sphincter. The precapillary sphincter is a smooth muscle fiber encircling the entrance to the capillary. This fiber is not innervated by nerves, but responds to hormonal and local mediators of blood flow.

Bulk Flow Across the Capillary

Bulk flow is the movement of a fluid as a result of a pressure gradient from high to low. In the vascular system, fluid moves back and forth between the capillaries and the interstitial fluid. Interstitial fluid is a plasma-like filtrate surrounding all cells. It can store fluid in times of high plasma volume, or resupply the vascular system in times of plasma loss.

There are four forces affecting the bulk flow of fluid across a capillary into the interstitial space. They include capillary pressure, interstitial hydrostatic pressure, plasma colloid osmotic pressure, and interstitial fluid colloid osmotic pressure.

Capillary pressure is the remainder of the mean arterial pressure generated by the heart. For most capillaries, this pressure averages approximately 18 mmHg over the length of the capillary (Fig. 13-5), with pressure at the arteriolar end significantly greater than the pressure at the venous end. Capillary pressure is a reflection of mean blood pressure. Therefore, if blood pressure increases, capillary pressure increases. If blood pressure decreases, capillary pressure decreases. Capillary pressure favors filtration of plasma out of the capillary into the interstitial space. Interstitial hydrostatic pressure is the pressure exerted by fluid in the interstitial space. Interstitial hydrostatic pressure is primarily caused by water. If positive, it opposes filtration of plasma out of the capillary; if negative, it draws fluid out of the capillary. Recent research suggests that the pressure is negative in most tissues, averaging approximately 3 mmHg. In some tissues, it may be positive and oppose filtration.

Plasma colloid osmotic pressure refers to osmotic pressure exerted by plasma proteins. Plasma colloid pressure opposes filtration of plasma out of the capillary. This pressure develops when water is pushed out of the capillary by the hydrostatic pressure and the proteins are too large and too charged to follow. The concentration of protein left behind increases,


causing an increase in osmotic pressure. This pressure serves to draw water back into the capillary. Plasma colloid osmotic pressure in most capillaries averages approximately 28 mmHg.

Figure 13-5. Forces of filtration and reabsorption across a capillary.

Interstitial fluid colloid osmotic pressure is normally a small force. Few proteins escape across the capillary into the interstitial compartment. Those that do are rapidly taken up into vessels of the lymph system. The lymph vessels return the proteins to the bloodstream by delivering them into the vena cava and the right atrium. Interstitial fluid colloid osmotic pressure averages approximately 8 mmHg.

Adding up the forces, filtration (18 mmHg + 3 mmHg + 8 mmHg = 29 mmHg) nearly balances reabsorption (28 mmHg) and little net movement of fluid across the capillary occurs (see Fig. 13-5). Extra fluid in the interstitial space is reabsorbed by the lymph flow.

Blood Flow

Blood travels in the vascular system by bulk flow, the movement of a fluid through a tube based on the pressure difference between one end of the tube and the other. The pressure of the blood as it leaves the heart (P1) minus the pressure in a downstream vessel (P2), divided by the resistance offered by the blood vessels (R), determines the blood flow (F) through the vascular system, as expressed in Equation 13-2:

Blood Pressure

Pressure at the beginning of the aorta is generated by the left ventricle. This pressure varies between approximately 120 mmHg during systole and


80 mmHg during diastole. Because diastole lasts longer than systole, the average, or mean, blood pressure equals approximately 40% of systolic pressure plus 60% of diastolic pressure.

As blood moves through the large and small arteries, some pressure is lost. Much more is lost as blood traverses the arterioles and capillaries. By the time blood flow reaches the capillary, blood pressure at the arteriole end of the capillary has decreased to approximately 35 mmHg for most capillary beds. With movement through the capillary, this pressure decreases to 10 mmHg at the venous end, resulting in a mean blood pressure in the capillary of approximately 18 mmHg. By the time the blood reaches the vena cava, the pressure is zero.

Thus, the pressure gradient affecting flow is large between the aorta and the vena cava (90 mmHg to 0 mmHg). This is the force that drives the blood through the systemic circulation.


Resistance to flow through a vessel depends on the length and radius of the vessel, and on the viscosity of the fluid. In the body, the length of the blood vessels is essentially fixed. Although potentially variable, blood viscosity is also fixed. Therefore, when discussing resistance to blood flow in the vascular system, one usually considers only the radius of the blood vessels. Because of the dynamics of flow through a tube, a small decrease in the radius causes an enormous increase in resistance to flow. This is true both for blood flowing through a blood vessel and for water flowing through a hose or a pipe.

The smaller the vessel, the greater the effect narrowing that vessel has on blood flow. Varying the radius of the large arteries does not significantly affect blood flow. Likewise, because veins are so distensible, they offer little resistance to flow. Instead, resistance to blood flow is determined by the radius of the arterioles. As mentioned earlier, this makes the arterioles the resistance vessels of the cardiovascular system.

Narrowing an arteriole decreases blood flow downstream into the capillaries and veins fed by that arteriole, backing up the blood upstream. Because blood pressure depends on blood flow, narrowing the arterioles decreases blood pressure downstream and increases blood pressure upstream.

In contrast, if the arterioles are dilated, flow increases, resulting in increased downstream pressure and decreased pressure upstream. Control of arteriole diameter is an intricate balance between local effects and nervous and hormonal stimulation.

Capillary Resistance to Blood Flow

The capillaries offer a great deal of resistance to blood flow because they are so narrow. However, because they have no smooth muscle, their diameter cannot be varied, so changes in capillary diameter cannot cause an increase or decrease in blood flow. The meta-arterioles immediately


preceding the capillaries do change in diameter and affect capillary blood flow. Because of the extensive surface area covered by all the capillaries, blood flow through them is slow, allowing ample time for the diffusion of oxygen and carbon dioxide to occur.

Total Peripheral Resistance

Resistance in the systemic vascular system is referred to as total peripheral resistance (TPR). It is impossible to measure resistance directly. Resistance in the cardiovascular system is calculated by measuring flow and pressure. The resistance equals pressure divided by flow. Resistance to flow in the pulmonary vascular system is much less than in the systemic system.

Control of Mean Arterial Blood Pressure

From the previous discussion, it should be apparent that in the vascular system it is difficult to discuss blood flow without referring to blood pressure. The variable regulated by the body, and usually measured clinically, is the systemic arterial blood pressure (BP). Equation 13-3 is used to describe the variables controlling systemic mean arterial blood pressure:

where, for the cardiovascular system,

  • BP is the mean arterial blood pressure,

  • CO is the cardiac output (which equals HR SV). Note: CO replaces F from Equation 13-2.

  • TPR is the total peripheral resistance.

Blood pressure control depends on sensors that continually measure blood pressure and send the information to the brain. The brain integrates all incoming information and responds by sending efferent (outgoing) stimulation to the heart and vasculature through the autonomic nerves. Various hormones and locally released chemical mediators add to the control of blood pressure.


Blood pressure is continually monitored by sensors called baroreceptors (pressure receptors). There are baroreceptors in the carotid artery (in the neck) and in the aortic arch where the aorta leaves the heart; these sensors are called the carotid and aortic baroreceptors, respectively. There are baroreceptors located in the arterioles supplying the kidney nephrons. Receptors in both atria and in the pulmonary artery also respond to changes in pressure. Because the atrial and pulmonary artery receptors are in low-pressure areas of the vasculature, they are called low-pressure receptors.

All baroreceptors act as stretch receptors that respond to changes in blood pressure. Their stretch increases with increased blood pressure. This


stretch increase causes afferent neurons receiving information from the receptors to increase their rate of firing. These neurons travel to the brain and innervate its cardiovascular center. A decrease in blood pressure decreases the stretch of the baroreceptors, which reduces the firing of the afferent nerves innervating the cardiovascular center.

Integrating Center for the Control of Blood Pressure

The cardiovascular center in the brain is part of the reticular formation and is located in the lower medulla and pons. The signals concerning blood pressure are integrated here. If a change in blood pressure has occurred, the cardiovascular center activates the autonomic nervous system, leading to changes in sympathetic and parasympathetic stimulation to the heart and sympathetic stimulation to the entire vascular system. Resistance of the vasculature is altered and blood flow and blood pressure are affected.

Efferent Neural Innervation of the Vascular System

Sympathetic nerves stimulate heart rate and contractility by binding to 1 receptors in the heart. Parasympathetic nerves decrease heart rate by binding to cholinergic receptors. In addition, sympathetic nerves traveling in the thoracic and upper lumbar spinal tracts influence blood pressure by exerting control over virtually the entire peripheral vascular system (except the capillaries) through innervation of the tunica media (the smooth muscle).

At most blood vessels, sympathetic nerves release norepinephrine, which binds to specific receptors on the smooth muscle cells, called alpha ( ) receptors. Stimulation of the receptors causes the smooth muscle to contract, constricting the vessel, which increases TPR and therefore increases blood pressure.

Blood vessels supplying skeletal muscle have a different type of receptor, called beta 2 ( 2) receptors, which, when stimulated by norepinephrine, cause the vessels to relax. It appears that this sympathetic vasodilatory response plays a significant role only in the anticipatory response to exercise, perhaps serving to prime the skeletal muscle with oxygen and nutrient support before exercise onset.

Skeletal muscle blood vessels also possess receptors for acetylcholine. These receptors are called muscarinic receptors and do not appear to be innervated by parasympathetic neurons. However, they respond to acetylcholine released by certain sympathetic cholinergic neurons. These neurons also supply the vascular smooth muscle in skeletal muscle and cause relaxation of the vessels, thus increasing blood flow through these vessels.

Hormonal Control of the Vascular System

There are several hormones that control the resistance of the vascular system. These hormones are released directly in response to changes in blood pressure, in response to neural stimulation, or both.


Norepinephrine and Epinephrine

Norepinephrine and epinephrine are released from the adrenal medulla in response to activation of the sympathetic nervous system. Both substances act like norepinephrine released from nerve terminals and bind to receptors to cause vasoconstriction, or to 2 receptors to cause vasodilation of arterioles supplying skeletal muscles. Norepinephrine and epinephrine from the adrenal medulla also bind to 1 receptors and increase heart rate.

Renin-Angiotensin System

Changes in blood pressure are sensed by the renal baroreceptors. If blood pressure is high, release of the hormone renin is decreased. If blood pressure decreases, renin release increases. Renin release is also stimulated by sympathetic nerves to the kidney. Renin controls the production of another hormone, angiotensin II.

Renin circulates in the blood and acts as an enzyme to convert the protein angiotensinogen to angiotensin I. Angiotensin I is a 10 amino acid protein, which is immediately split by angiotensin-converting enzyme (ACE) into the 8 amino acid peptide, angiotensin II. ACE is the same enzyme that breaks down (and inactivates) the vasodilator hormone bradykinin. Blocking the action of ACE blocks the production of angiotensin II and the breakdown of bradykinin.

Angiotensin II is a powerful vasoconstrictor that primarily causes constriction of the small arterioles. This causes an increase in resistance to blood flow and an increase in blood pressure. The increase in blood pressure then acts in a negative feedback manner to reduce the stimulus for further renin release. Angiotensin II also circulates to the adrenal gland and causes cells of the adrenal cortex to synthesize another hormone, aldosterone.


Aldosterone circulates to the kidney and causes cells of the distal tubule to increase sodium reabsorption. Under many circumstances, reabsorption of water follows that of sodium, leading to an increase in plasma volume. An increase in plasma volume increases stroke volume, and hence cardiac output. It also causes increased blood pressure.

Renin-angiotensin-aldosterone feedback cycle

It should be emphasized that the stimuli causing the release of renin decreased blood pressure and decreased plasma sodium concentration are reversed by the actions of angiotensin II and aldosterone. This is an excellent example of a negative feedback cycle.

Antidiuretic Hormone

Antidiuretic hormone (ADH), also called vasopressin, is released from the posterior pituitary in response to increased plasma osmolality (decreased water concentration) or decreased blood pressure.


ADH is a potent vasoconstrictor with the potential to increase blood pressure by increasing the resistance to blood flow. Under most circumstances, except perhaps during severe hemorrhage, levels of circulating ADH are too low to affect the arterioles. However, ADH controls the reabsorption of water across the collecting ducts of the kidney back into the bloodstream. This effect influences blood pressure by increasing plasma volume and therefore cardiac output. Without ADH, water does not follow sodium reabsorption in the kidney and severe dehydration may occur. Reabsorption of water in response to ADH reduces the stimuli (increased plasma osmolality and decreased blood pressure) for ADH release.

Atrial Natriuretic Peptide

Atrial natriuretic peptide (ANP) is a hormone released from cells of the right atrium in response to an increase in blood volume. ANP acts on the kidney to increase the excretion of sodium ion (natriuresis). Because water will follow sodium in the urine, ANP serves to decrease blood volume and blood pressure.

Summary of Blood Pressure Control

With a decrease in blood pressure, baroreceptor information is transmitted to the cardiovascular center in the brain. This causes the stimulation of sympathetic output to the heart and vascular system, increasing heart rate and TPR. Parasympathetic output is decreased, also increasing heart rate. Renin release increases, causing increased angiotensin II, which directly increases TPR and aldosterone synthesis. Increased aldosterone increases sodium reabsorption and, in the presence of ADH, water reabsorption. Increased plasma volume, stroke volume, and cardiac output result. Capillary pressure decreases directly with blood pressure and indirectly from sympathetic constriction of the arteriole feeding the capillary. This serves to decrease filtration of fluid out of the capillary. All of these responses serve to increase blood pressure toward normal, by increasing heart rate, stroke volume, and TPR (Fig. 13-6).

In contrast, if blood pressure increases, baroreceptor responses cause a decrease in sympathetic stimulation to the heart and vascular smooth muscle, and heart rate and TPR decrease. Increased parasympathetic stimulation to the heart contributes to the decrease in heart rate. There is a decrease in renin and ADH release, reducing TPR and plasma volume. ANP release increases. All these responses serve to decrease blood pressure toward normal.

Autoregulation of Blood Flow

In general, blood pressure is controlled through neural and hormonal influences. However, individual tissues have mechanisms that regulate their own blood flow. This is accomplished by local vasodilation or vasoconstriction of meta-arterioles and precapillary sphincters. This local control of blood flow is called autoregulation, and is the means by which


some organs can maintain constant blood flow over a wide range of blood pressure, from approximately 70 to 180 mmHg.

Figure 13-6. Flow diagram: reflex response to a fall in blood pressure.

Theories of Autoregulation

Several theories are proposed to explain local control of blood flow. The most widely accepted is that chemical mediators are released by metabolizing cells that bind to meta-arterioles or precapillary sphincters, causing them to open or shut to blood flow.

Chemical mediators that control local blood flow include adenosine (a metabolite of ATP), carbon dioxide, histamine, lactic acid, potassium ions, and hydrogen ions. All of these substances except histamine are byproducts of metabolism; as cell metabolism increases, so do their concentrations. This serves to match increased metabolic activity with increased blood flow. Mast cells present throughout the interstitial space release histamine in response to immune stimulation or local injury. Adenosine appears to particularly regulate local blood flow in the heart.

An alternative theory concerning local control suggests that the meta-arterioles and capillary sphincters sense an oxygen or nutrient deficit that causes them to relax, thereby increasing blood flow to the surrounding cells.

Other Chemical Mediators Influencing Blood Flow

Various other chemicals are released by the blood vessels or by mediators of inflammation or healing, which affect blood flow to an area.


Nitric Oxide

Endothelial cells of the small arteries and arterioles respond to the binding of various vasoactive substances such as acetylcholine with the production of the vasodilator nitric oxide (previously called endothelial-derived relaxing factor). Nitric oxide diffuses through endothelial cells to underlying smooth muscle cells, causing endothelial-dependent relaxation of the smooth muscle. Nitric oxide release also occurs with increased blood flow through a vessel, allowing local dilation of the microvasculature to be matched by dilation of the small arteries and arterioles. Drugs that boost nitric oxide synthesis or prevent its breakdown are used to improve blood flow in a variety of clinical situations.


Endothelial cells also release endothelin, a 21 amino acid peptide that acts as a potent constrictor of vascular smooth muscle. Endothelin release is stimulated by angiotensin II, ADH, thrombin, cytokines, reactive oxygen species, and shearing forces acting on the vascular endothelium. Its release is inhibited by prostacyclin and nitric oxide. Deleterious effects of overproduction of endothelin on vascular smooth muscle include extended vasoconstriction, vascular hypertrophy, cell proliferation, and fibrosis. In addition, by binding to receptors on endothelial cells that are different from the ones on vascular smooth muscle, endothelin increases capillary permeability and contributes to inflammation. Endothelin has a long half-life (length of presence in the circulation or interstitial fluid), so even small changes in its production or clearance have significant impact on the vascular system. Overproduction of endothelin is implicated in numerous pathologies, including pulmonary hypertension and heart failure. Drugs to block endothelin receptors are being tested in a variety of clinical situations.


Serotonin (5-hydroxytryptamine) is primarily released by platelets drawn to an area of injury or inflammation. Effects of serotonin may be vasodilatory or vasoconstricting, depending on the site of release. Serotonin's ability to vasoconstrict and decrease blood flow appears to be one mechanism whereby platelets control or reduce bleeding.


Bradykinin, like all members of the kinin family, is a small polypeptide that acts as a potent vasodilator of arterioles and as a mediator to increase capillary permeability. Bradykinin is produced in the plasma or interstitial fluid by enzymatic splitting of a serum globulin in response to vascular or tissue injury or inflammation. The half-life of bradykinin is short. Normally, it is broken down rapidly by circulating ACE or another enzyme, carboxypeptidase.

The effects of bradykinin are increased local blood flow, increased capillary permeability, and decreased vascular resistance. These effects


allow delivery of mediators of the inflammatory and immune systems to a site of injury. Blockage of angiotensin-converting enzyme by various pharmaceutical agents prolongs the half-life of bradykinin and its effects.


There are many different types of prostaglandins. Some cause dilation of the vascular system and some cause constriction. Prostaglandins are derived from the metabolism of arachidonic acid by cyclooxygenase (COX) enzymes one (COX1) and two (COX2). Arachidonic acid is present in all cell membranes and is released with tissue injury. Prostaglandins work to control local blood flow. They may circulate to affect distant cells.

One main group of prostaglandins, those of the E series, cause local vasodilation and increased blood flow, which makes them important mediators of inflammation. Prostaglandins of the I series, especially PGI2, called prostacyclin, also are vasodilatory. PGI2 inhibits platelet aggregation and blood clotting. Thromboxane A2 is an important prostaglandin that causes vasoconstriction and blood clotting.

Prostaglandin synthesis is inhibited by drugs that block the function of the COX enzymes, including aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), and by specific COX enzyme inhibitors. Low concentration of aspirin particularly appears to cause a long-lasting block in production of thromboxane A2. Glucocorticoids, including endogenously released cortisol and dexamethasome provided therapeutically, block prostaglandin synthesis at an early stage after membrane injury, prior to the formation of arachidonic acid, and are potent anti-inflammatory agents.

The Lymph System

The lymph system consists of closed-end vessels that course through almost the entire interstitial fluid space. Lymph fluid is derived from interstitial fluid and is therefore very similar in composition to plasma.

Lymph Flow

The lymph system consists of small capillaries that drain into larger lymph vessels. Like blood vessels, these larger vessels are composed of smooth muscle and endothelial cells. Lymph from the lower body flows up the thoracic duct and empties into the left jugular and subclavian veins. Lymph flow from the left arm, shoulder, and left side of the head travels through the thoracic duct and then into the left jugular and subclavian arteries. Lymph flow from the right arm and right side of the neck and head empties into the right jugular and subclavian veins.

Movement of lymph results from contraction of the smooth muscle lining the lymph vessels in response to its stretch, and the pumping action of the surrounding skeletal muscles. Valves present in lymph vessels prevent backflow.


Role of the Lymph System

The lymph system has three essential roles in the body, all of which depend on the greater permeability of lymph capillaries compared to blood capillaries.

First, lymph capillaries retrieve any proteins that escape from the capillaries into the interstitial fluid. These proteins move easily into lymph vessels and are then returned to the blood circulation via the thoracic duct. This is essential because it allows interstitial colloid osmotic pressure to remain low. If proteins were allowed to accumulate in the interstitial space, interstitial colloid osmotic pressure would increase. This would result in increased forces favoring filtration into the interstitial fluid, which would soon cause massive interstitial edema. Death of the individual could occur from circulatory collapse.

The second essential role played by the lymph system involves the absorption of fats from the small intestine. In the small intestine, fats and fat-soluble vitamins are absorbed into small lymph vessels called lacteals, and are then delivered to the general circulation. Fat and the fat-soluble vitamins are required for life.

The third essential role played by the lymph system involves immune function. Because of the high permeability of the lymph capillaries, bacteria and other microorganisms enter the lymph system from infected areas and are transported to and through lymph nodes, where they become trapped and removed from the circulation. Lymph nodes are an intertwining meshwork of vessels filled with tissue macrophages and T and B cells; bringing bacteria and other cellular debris to the lymph nodes allows the immune and inflammatory cells an opportunity to protect the host from widespread infection. Lymph nodes are spaced intermittently along the lymph vessels.

Fetal Circulation

There are several major differences between fetal circulation and the circulation of infants, children, and adults. While in utero, a fetus does not receive oxygen through its own lungs. Rather, maternal oxygen is delivered across the placenta into the umbilical vein. The umbilical vein delivers oxygen-rich blood to the right side of the fetal heart through the vena cava. Because of the maternal source of oxygen, the fetal lungs and most of the blood vessels supplying them are collapsed, causing high resistance to blood flow through the fetal lungs, especially when compared to flow through the fetal systemic circulation, which offers low resistance because of the wide-open vessels of the placenta.

There are also structural differences that characterize fetal circulation. In the fetus, there are two connections (shunts) that exist to take advantage of the maternal oxygen source and the high resistance of the pulmonary circulation. The first of these connections is an opening between the right atrium and the left atrium, called the foramen ovale.


Because resistance is so high in the pulmonary circuit leaving the right ventricle, fetal blood travels in the direction of lower resistance: from right atrium to left through the foramen ovale. Because blood entering the vena cava in the fetus has already been oxygenated by passage through the placenta, this right to left shunting is an efficient adaptation. Well-oxygenated blood is delivered to the systemic (left-side) circulation without the need to send blood through the collapsed, nonfunctioning pulmonary system.

The second shunting system between the right and left sides of circulation in the fetus is a vascular connection between the pulmonary artery and the aorta. This connection, called the ductus arteriosus, allows oxygenated blood leaving the right side of the heart to bypass the fetal lungs and flow directly into the low resistance of the systemic circulation. It should be noted that the fetal lungs do receive a small amount of blood flow through the pulmonary artery, allowing for their continued growth and development.

Newborn Circulation

With birth, the situation changes dramatically and suddenly. The newborn is no longer supplied with oxygen from the placenta because the low-resistance vessels of the placenta are no longer connected to the fetus. At birth, the newborn separates from the placenta, fluid in the lungs is squeezed out, and the newborn takes a deep breath, opening up the lungs and the blood vessels flowing through them. Immediately at birth, resistance of the pulmonary circulation falls while resistance of the systemic circulation increases. Blood flow no longer shunts right to left through the foramen ovale or the ductus arteriosus because those directions now offer higher resistance to flow. These shunt passages normally begin to close within a few hours after birth.

Tests of Cardiovascular Functioning

The Electrocardiogram

The electrocardiogram (ECG) is the measurement of the electrical currents of the heart. Contraction of the atria and ventricles results from action potentials occurring simultaneously in all muscle cells of the atria, followed by all muscle cells of the ventricles. Electrodes placed in specific locations on the body can detect these action potential currents. The currents can then be graphically displayed and interpreted.

Currents Measured by the Electrocardiogram

There are three currents produced in the normal ECG, as shown in Figure 13-7. The P wave corresponds to atrial depolarization. The QRS complex (beginning of Q wave to end of S wave) corresponds to depolarization of the ventricles. The T wave corresponds to repolarization of the ventricles.


Repolarization of the atria occurs during the QRS complex and is nondistinguishable. The U wave is an inconsistent finding that may represent slow repolarization of the papillary muscles involved in opening and closing the AV valves. Normal sinus rhythm is the expected rhythm of the heart, driven by the SA node and passed along the normal, intact conduction system.

Figure 13-7. The electrocardiogram (ECG) depiction.

Patterns of the Electrocardiogram

Several patterns in the normal ECG stand out. First, the pattern of the three waves repeats itself with each beat. A time scale is usually shown on the recording, allowing one to determine the heart rate by counting any one of the waves over time. The P wave or the QRS complex can be counted.

Second, the QRS complex always follows the P wave in a normal beating pattern because the atria undergo an action potential and contract first. Their action potential subsequently spreads to the ventricles. The time between the end of the P wave and the beginning of the QRS complex reflects the time during which the action potential is delayed at the AV node.

Third, the size of the atrial depolarization, as measured by the height of the P wave, is less than the depolarization of the ventricles, as measured by the height of the QRS complex. This reflects the much greater muscle mass of the ventricles compared to the atria. The ventricular depolarization is a rapid spike, as shown by the narrow displacement of the QRS complex, indicating that conduction throughout the ventricle is rapid, and that the entire ventricle contracts as one quick-firing unit. Increased horizontal spread of the QRS complex occurs with prolonged conduction of the electrical impulse through the ventricles, indicating ventricular hypertrophy. A bizarre QRS complex may indicate cardiac cell death.


Measurement of Cardiac Enzymes

When cardiac muscle cells die during a myocardial infarct (MI), they release their intracellular contents. Specific proteins and enzymes normally present only inside cardiac cells can be measured in the blood. This allows one to accurately diagnose the existence and frequently the extent of myocardial cell death. Because different enzyme levels are elevated at different times after infarction, the timing of the infarct can be determined.

Proteins released after injury to the myocardial cells include myoglobin, normally found only in skeletal and cardiac muscle cells, and the cardiac-specific contractile proteins, troponin T, C, and I. Highly sensitive bedside laboratory kits, capable of measuring the presence of very low amounts of serum troponin T and I within a short time of a suspected infarct, have the capacity to revolutionize early detection of an MI. Enzymes released with cardiac cell death include myocardial creatine kinase (CK-MB), lactic acid dehydrogenase (LDH), and serum glutamic oxaloacetic transaminase (SGOT). The plasma concentration of each of these enzymes and proteins varies depending on the time since injury and the extent of the cell damage.

Stress Testing

Cardiac stress testing involves having an individual exercise up to his or her maximal capacity while observers monitor physical symptoms and the ECG. In a simple exercise stress test, the patient is asked to either walk on a treadmill or ride an exercise bike. The pattern of the ECG is observed for alterations in rhythm, the presence of AV blocks, and evidence of ST-segment changes indicative of hypoxia. Onset of physical symptoms, such as chest pain and extreme shortness of breath, is monitored.

Nuclear Stress Testing

Sometimes, an intravenous infusion of a radiolabeled isotope that has specific cardiac affinity is given during the exercise to monitor myocardial perfusion. An isotope commonly used is radioactive thallium-201, which can be substituted for potassium by cells and is infused during the peak portion of the exercise test. After a short delay, a nuclear scan of the heart is performed. Areas of the heart that have been perfused by blood will be labeled with the thallium. Areas of the heart that are poorly or not perfused by blood during the exercise test will be identified as cold spots, that is, without radiolabel. If the ischemia is temporary, the cold spots will disappear over time. Often patients are tested twice, once while at rest and once during exercise, and comparisons are made. Thallium-201 may be used alone in patients unable to exercise.


Echocardiography involves ultrasound waves directed at the chest wall that are analyzed by a computer as they bounce back from the chest. The computer generates an image that is used to calculate the size and


movement of the heart chambers, the performance of the valves, and the flow of blood through the heart. This test is highly sensitive and non-invasive and provides a visual image of the beating heart.

Cardiac Catheterization

In cardiac catheterization, also called coronary angiogram, a flexible tube (catheter) is inserted through a peripheral vein (femoral or brachial) into the right side of the heart, or through a peripheral artery (femoral or brachial) into the left side of the heart. Through the catheter, the chambers of the heart can be visualized and chamber pressures and oxygen content measured. A radiolabeled dye may be injected through the catheter, and the ability of the dye to move through the heart chambers and vessels may be monitored using x-ray techniques. Valve movement can be observed. Because cardiac catheterization is invasive, complications are possible, including tearing of the vessel wall. After the procedure, patients must lie still for 4 to 6 hours until leg vessels seal.

Computed Tomography Scan

The computed tomography (CT) scan is a combination of an x-ray scan of the heart coupled with multiple CT that produces highly detailed images of the arteries of the heart. Patients are given a radiolabeled dye to highlight the blood vessels, and then are exposed to a series of x-rays that create images of the heart in slices. These slices are reassembled by a computer to provide an image that can detail arterial narrowing, including that due to arterial calcium and fatty deposits. Risks include radiation exposure.

In a slightly different technique, called PET/CT scan, positron emission tomography (PET) is used in addition to the CT to provide even more detailed information than available by CT alone. Because a PET scan is expensive and not available at all facilities, it typically is used after specific vessels are identified by CT scan as being of concern.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) utilizes a powerful magnet that sets the nuclei of atoms in the heart cells vibrating at specific, recognized frequencies. The signals are analyzed by a computer to produce a detailed 3-D image. MRI is non-invasive and very sensitive, but cannot be used on patients with pacemakers or metal implants such as stents. They also cannot identify calcium deposits in the coronary arteries.

Pathophysiologic Concepts


A thrombus is a blood clot that can develop anywhere in the vascular system, causing the narrowing of a vessel. With a decrease in vessel diameter, blood


flow can be occluded (reduced or totally blocked). A thrombus can develop from any injury to the vessel wall because endothelial cell injury draws platelets and other mediators of inflammation to the area. Many of these substances stimulate clotting and activation of the coagulation cascade. Thrombus formation can occur when blood flow through a vessel is sluggish, which is why most thrombi develop in the low-pressure venous side of the circulation, where platelets and clotting factors can accumulate and adhere to vessel walls. Similarly, when blood flow is irregular or erratic for instance, during periods of irregular heartbeat or cardiac arrest thrombus formation is enhanced.


An embolus is a substance that travels in the bloodstream from a primary site to a secondary site, becomes trapped in the vessels at the secondary site, and causes blood flow obstruction. Most emboli are blood clots (thromboemboli) that have broken off from their primary site (usually deep leg veins). Other sources of emboli include fat released during the break of a long bone or produced in response to any physical trauma, and amniotic fluid, which may enter maternal circulation during the intense pressure gradients generated by labor contractions. Air and displaced tumor cells also may act as emboli to obstruct flow.

Usually emboli are trapped in the first capillary network they encounter. For instance, emboli traveling from deep leg veins are delivered in the venous system to the vena cava and the right side of the heart. From there, they enter the pulmonary artery and arterioles, encounter pulmonary capillaries, and become trapped. Arterial thromboemboli usually develop in the heart, following a myocardial infarction or an episode of dysrhythmia. Thromboemboli from the heart can become trapped in the coronary vessels or any of the organs downstream, including the brain, kidneys, and lower extremities.


An aneurysm is a dilation of the arterial wall caused by a congenital or developed weakness in the wall. Weakness in the wall may develop as a result of an infection, from trauma, or, more commonly, from lesions produced by atherosclerosis. Aneurysms may burst with increased pressure, leading to massive internal hemorrhage.

Alterations in Capillary Forces of Filtration or Reabsorption

Occasionally, forces favoring filtration from the capillary into the interstitial fluid are greater than forces favoring reabsorption of fluid into the capillary from the interstitial space. The result is net filtration. Net filtration across the capillary results in interstitial edema.


The opposite occurs when forces favoring reabsorption of fluid from the interstitial space into the capillary are greater than those favoring filtration. This results in net reabsorption, which leads to increased plasma volume, stroke volume, and cardiac output. Blood pressure may be increased significantly.

Causes of Increased Capillary Filtration

Causes of increased capillary filtration include increased capillary pressure, caused by high blood pressure, and increased capillary leakage, caused by injury or inflammation. An increase in protein concentration in the interstitial fluid caused by increased capillary breakdown or decreased lymph flow to the area would also cause net filtration, leading to edema and swelling of the interstitial space. Similarly, decreased production or increased loss of plasma proteins would reduce the reabsorption of fluid back into the capillary. This can occur with liver disease or loss of protein in the urine.

Causes of Increased Capillary Reabsorption

Causes of increased reabsorption of fluid from the interstitial space include decreased blood pressure in the capillary due to a decrease in systemic pressure or constriction of the arteriole or precapillary sphincter. Increased plasma colloid osmotic pressure also draws fluid back into the capillary. Plasma colloid osmotic pressure increases with dehydration, leading to a return of fluid from the interstitium to the plasma, which helps return plasma volume toward normal. Finally, increased interstitial fluid pressure increases reabsorption by opposing further accumulation of fluid.


Stenosis is a narrowing of any vessel or opening. In the cardiovascular system, stenosis of the heart valves may occur. Stenosis of any valve usually occurs as a result of a congenital defect or an inflammatory process (e.g., after rheumatic fever).

Results of Cardiac Valve Stenosis

Stenosis of a cardiac valve results in the chamber upstream of the stenosis pumping more forcefully to expel its blood through the narrowed orifice. After years of this extra work, cardiac muscle can hypertrophy (increase in size). If the chamber cannot pump forcefully enough to overcome the stenosis, blood flow out of the chamber will be reduced. Because of the chamber hypertrophy and the extra work it must do to pump through the narrowed orifice, the chamber increases its oxygen consumption and energy demands. The coronary arteries supplying the muscle may be unable to supply adequate oxygen to meet this demand.


As it becomes increasingly difficult for the upstream chamber to empty against the narrowed orifice, blood may accumulate in the chamber and stretch its muscle fibers. If this is significant or prolonged, a decrease in muscle contractility can result.

Examples of Cardiac Valve Stenosis

Any cardiac valve may become stenosed. Mitral stenosis is narrowing of the valve between the left atrium and left ventricle. Aortic stenosis is narrowing of the valve between the left ventricle and the aorta. Tricuspid stenosis is narrowing of the valve between the right atrium and the right ventricle. Pulmonary stenosis is narrowing of the valve between the right ventricle and the pulmonary artery.

Valve Incompetence

An incompetent valve is one that does not close completely, allowing blood to move in both directions through that valve when the heart contracts (valve regurgitation). Any of the cardiac valves may be incompetent. Each chamber may hypertrophy.

Cardiac Shunts

In the cardiovascular system, a shunt is a connection between the pulmonary vascular system and the systemic vascular system. During fetal life, shunts between the right and left sides of the heart and between the aorta and pulmonary artery are normal. After birth, any shunting across the heart or between the pulmonary and systemic circulations is abnormal.

The direction blood flows through a shunt is determined by resistance to flow in each direction. Blood will flow in the direction of least resistance.

Right-to-Left Shunt

A right-to-left shunt is the flow of blood from the right side of the heart to the left, or from the pulmonary artery to the systemic circulation. After birth, right heart and pulmonary artery blood is poorly oxygenated. Therefore, a right-to-left shunt delivers poorly oxygenated blood to the systemic circulation. A right-to-left shunt is called a cyanotic shunt because delivery of poorly oxygenated blood to the systemic circulation causes cyanosis (bluish tinge to the skin). This is caused by deoxygenation of hemoglobin, as described in Chapter 14.

Fatigue results because cells of the muscles, brain, and other organs are not receiving adequate delivery of oxygen and nutrients. Respiratory rate increases as the body tries to compensate for the reduced oxygenation of the blood. Individuals with a cyanotic shunt may develop clubbing of the tips of the fingers, related to poor tissue perfusion.

ediatric Consideration

An infant with a right-to-left shunt may assume a knee-to-chest position, which increases flow through the pulmonary system and results in improved blood oxygenation. In older children, this maneuver is performed by squatting.


Left-to-Right Shunt

A left-to-right shunt is the flow of blood from the left side of the heart to the right side, or from the aorta to the pulmonary circulation. Left heart blood is well oxygenated. Therefore, a left-to-right shunt overdelivers well-oxygenated blood directly into the right side of the heart, or it immediately returns the blood to the pulmonary artery and lungs. Blood going to the lungs from the left side of the heart recirculates to the left atrium and left ventricle. Because the blood is well-oxygenated, this shunt is acyanotic.

A left-to-right shunt can be life-threatening because of the risk of hypertrophy of pulmonary vasculature as blood is continually recirculated through the lungs. Right heart failure may develop if there is a high volume of blood entering the right side of the heart from the left side of the heart. In addition, left heart failure may develop because of continual recycling of blood back into the left side of the heart from the lungs.

Alterations in the Electrocardiogram

Many conditions result in ECG alterations. Alterations in the ECG are associated with increased or decreased rate of contraction or changes in the force of contraction.

Ectopic Pacemaker

An ectopic pacemaker is a site in the heart capable of automaticity that takes over control of the heart rate from the SA node. An ectopic pacemaker may occur if the SA node begins to depolarize very slowly, or if conduction of the signal from the SA node to the AV node is blocked. Usually, cells in the AV node or conducting cells of Purkinje's fibers assume the pacemaker role.

If the SA node no longer controls the heart rate, an ECG will usually demonstrate a reduced heart rate and ventricular depolarization that does not follow atrial depolarization.

Sinus Node Dysrhythmia

Sinus node dysrhythmia occurs when the SA node sets the heart rate too slow (fewer than 60 beats/minute, called sinus bradycardia), or too fast (from 100 to 160 beats/minute, called sinus tachycardia). Sinus bradycardia may occur in a well-trained athlete. It may also occur with fever or exercise.


Sinus Arrhythmia

Sinus arrhythmia is an irregular rate of beating, usually varying with respiratory patterns. It is common in children and young adults.

Sinus Arrest

Sinus arrest occurs when the SA node stops depolarizing and firing action potentials. This leads to an ectopic site taking control of the heart rate.

Atrial Dysrhythmias

Atrial dysrhythmias disrupt normal contraction of the atria. They may include ectopic pacemakers or irritation of the SA node. There are several types of atrial dysrhythmias.

Premature atrial contraction (PAC) is an atrial dysrhythmia that occurs when an area of the atrium other than the SA node fires an action potential earlier than expected. This discharge may pass down to the AV node and back up the conduction fibers to the SA node. A PAC interrupts the pattern of SA node firing. The ventricles usually depolarize after a PAC, but occasionally are in a refractory period and resist depolarization.

Atrial flutter is an atrial dysrhythmia that occurs when the atria begin to contract at a rate of 160 to 350 beats/minute. The ventricles may not be able to keep up. With very rapid flutter, the ventricle may beat once for every five atrial beats. On an ECG, one would see many P waves, followed by an occasional QRS complex. Atrial flutter leads to hemodynamic instability.

Atrial fibrillation is an atrial dysrhythmia that occurs when the atria beat at more than 350 (up to 600) beats/minute. Ventricular depolarizations become irregular and may not follow atrial depolarization. Ventricular filling does not totally depend on organized atrial contractions; therefore, blood flow in and out of the ventricles is usually sufficient to meet normal energy needs, but not those encountered at high demand times such as during exercise.

Atrioventricular Blocks

Blocks of action potential spreading from the AV node may occur anywhere in the conducting system of Purkinje's fibers or the bundle of His. A block may cause an extra long delay between the P wave and the QRS complex, or may totally uncouple the P wave from the QRS. Blocks are described as first degree (each QRS follows a P but with an extended delay), second degree (occasionally, a P wave fails to cause a QRS complex), or third degree (complete block, in which the link between the P wave and the QRS complex is lost).

Blocks in Ventricular Conducting Branches

Conduction of the electrical signal from the AV node into and throughout the ventricle proceeds first through transitional fibers that join to form the


bundle of His. The bundle of His enters the ventricles and immediately separates into left and right bundle branches. These branches supply the entire heart and terminate as very fine Purkinje fibers. Interruption of the signal anywhere in any of the conducting passages results in the entire ventricle taking longer to depolarize, spreading out the QRS complex. If some areas of the myocardium are completely blocked from receiving the excitation, the ventricular beat will be abnormal and inefficient. Cardiac output will decrease.

Ventricular Dysrhythmias

Ventricular dysrhythmia is an alteration in ventricular beating rate. A ventricular dysrhythmia can directly affect cardiac output; therefore, it is usually a more serious problem than an atrial dysrhythmia. Although an increase in heart rate can increase cardiac output, cardiac output also depends on stroke volume. An abnormally high heart rate can cause a significant decrease in stroke volume because if the heart rate increases too much, filling time for the ventricle will be inadequate. There are several types of ventricular dysrhythmia.

Premature ventricular contraction (PVC) is a ventricular dysrhythmia that occurs when an ectopic site in the ventricle depolarizes spontaneously, causing ventricular contraction. This usually occurs when an area of the ventricle becomes irritated or injured, often because of lack of oxygen. Because the PVC can occur at any time in the cardiac cycle, the ventricle is usually not completely filled with blood before contraction occurs, so stroke volume will be reduced.

Ventricular tachycardia is a ventricular dysrhythmia that occurs when the ventricle is beating at a rate of 160 to 250 beats/minute. With this degree of limited filling time, stroke volume will be reduced or nonexistent.

Ventricular fibrillation is the most extreme example of ventricular dysrhythmia and occurs when the ventricle is depolarizing so erratically and rapidly that it does not contract at all as a unit, but rather quivers ineffectively. Cardiac output is zero and pulse and blood pressure are nonexistent. Without intervention, death will occur.

Some ECG changes are shown in Figure 13-8.

Conditions of Disease or Injury


Atherosclerosis, or hardening of the arteries, is a condition of the large and small arteries characterized by accumulation of fatty deposits, platelets, neutrophils, monocytes and macrophages throughout the tunica intima (endothelial cell layer) and eventually into the tunica media (smooth muscle layer). Arteries most often affected include the coronaries, the aorta, and the cerebral arteries.

Figure 13-8. Electrocardiogram (ECG) depiction of a normal tracing (A); sinus bradycardia (B); premature atrial contraction (C); and premature ventricular contraction (D).


The development of atherosclerosis begins with dysfunction of the endothelial cells lining the lumen of the artery. This may occur following injury to the endothelial cells, or from other stimuli. Injury to the endothelial cells increases their permeability to various plasma components, including fatty acids and triglycerides, allowing these substances access to the inside of the artery. Oxidation of fatty acids produces oxygen free radicals that further damage the vessel. Injury to the endothelial cells also initiates inflammatory and immune reactions, including the attraction of white blood cells, especially neutrophils and monocytes, and platelets to the area. The white cells release potent proinflammatory cytokines that further aggravate the situation, drawing even more white cells and platelets to the area, stimulating clotting, activating T and B cells, and releasing chemicals that act as chemoattractants to perpetuate the cycle of inflammation, clotting, and fibrosis. Once drawn to the area of injury, the white blood cells are caught there by activation of endothelial adhesion factors that act like Velcro to make the endothelium especially sticky to white cells. Once attached to the endothelial layer, the monocytes and neutrophils begin to emigrate between the endothelial cells, into the


interstitial space. In the interstitium, the monocytes mature into macrophages and, along with the neutrophils, continue to release cytokines, which further the inflammatory cycle. The proinflammatory cytokines also stimulate smooth muscle cell proliferation, causing smooth muscle cells to grow into the tunica intima. Additional plasma cholesterol and fats gain access to the tunicae intima and media as permeability of the endothelial layer increases. An early indication of damage is the presence of a fatty streak in the artery. With continued injury and inflammation, platelet aggregation increases and a blood clot (thrombus) begins to form. Scar tissue replaces some of the vascular wall, changing the structure of the wall. The end results are cholesterol and fat buildup, scar tissue deposits, platelet-derived clots, and smooth muscle cell proliferation.

Even without direct injury to the endothelial cells, changes in the endothelial adhesion factors may occur, resulting in the accumulation of white cells and the release of inflammatory mediators and clot-forming substances. Why some individuals have especially active adhesion factors is unclear. It is likely that both genetic and environmental factors are involved.

Regardless of the precipitating event, atherosclerosis leads to a decrease in the diameter of the artery and an increase in its stiffness. The atherosclerotic area of an artery is called a plaque. The development of a plaque is shown in Figure 13-9.

Figure 13-9. The formation of an atherosclerotic plaque with dysfunction of the endothelial cell (A) followed by white blood cell (WBC) migration and deposits of fat (foam) cells and calcium (B).


Causes of Atherosclerosis

There are several hypotheses as to what first initiates dysfunction of the endothelial cells, thereby activating this cascade. It is likely that different initiating events are involved to different degrees in different people. Five hypotheses are presented.

High Serum Cholesterol

The first hypothesis suggests that high serum cholesterol and high levels of circulating triglycerides can cause development of atherosclerosis. Fatty deposits, called atheromas, are found throughout and inside the tunica media in persons with atherosclerosis.

Cholesterol and triglycerides are carried in the blood encased in fat-carrying proteins called lipoproteins. High-density lipoprotein (HDL) carries fat away from cells to be degraded and is known to be protective against atherosclerosis. Low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) carry fat to the cells of the body, including the endothelial cells of the arteries. Especially at risk of atherosclerosis are persons who carry a defect in a specific apolipoprotein E protein normally involved in efficient hepatic uptake of lipoprotein particles, stimulation of cholesterol efflux from macrophages in the atherosclerotic lesion, and the regulation of immune and inflammatory responses. In the arterial wall, oxidation of cholesterol and triglycerides leads to inflammation and production of free radicals known to damage delicate endothelial cells.

According to this hypothesis, the oxidative-modification hypothesis of atherosclerosis, the initial oxidation of LDL in the subendothelial layer of the arteries turns on various inflammatory reactions, which ultimately attract monocytes and neutrophils to the area. These white blood cells become anchored to the endothelial layer by the adhesion molecules, and release additional inflammatory mediators that attract more white cells to the area and further stimulate LDL oxidation. Eventually, the monocytes move into the wall of the artery, where they mature into macrophages and internalize the LDL as fatty foam cells. Oxidized LDL is cytotoxic to vascular cells, further promoting inflammatory responses. According to this hypothesis, the higher the circulating level of LDL, the more frequently damage occurs.

Patients with diabetes mellitus often exhibit atherosclerosis caused by high cholesterol. Diabetes mellitus is a major risk factor for atherosclerosis. Persons with diabetes have high plasma cholesterol and triglycerides. Poor circulation to most organs causes hypoxia and tissue injury, also stimulating inflammatory reactions that contribute to atherosclerosis.

High Blood Pressure

The second hypothesis proposed for development of atherosclerosis is based on the finding that chronically high blood pressure produces shear


forces that scrape away at the endothelial layer of the arteries and arterioles, initiating their injury. Shear forces especially occur in sites of arterial bifurcation (splitting) or bending, a trait characteristic of the coronary arteries, aorta, and cerebral arteries. With shearing of the endothelial layer, damage can occur repeatedly, leading to a cycle of inflammation, accumulation and adhesion of white blood cells and platelets, and clot formation. Any thrombus that develops can be sheared off the artery, leading to a thromboembolus downstream, or may grow large enough to obstruct blood flow. It also may weaken the artery, causing it to burst under the maintained high blood pressure.


A third hypothesis to explain how atherosclerosis develops suggests that some endothelial cells become infected by a circulating microorganism. Infection directly produces cell-damaging free radicals; it also initiates the cycle of inflammation, a process associated with free radicals and adhesion factor activation. White blood cells and platelets arrive in the area and cause clots and scarring. A specific organism that has been implicated in this theory is Chlamydia pneumoniae, a common respiratory pathogen.

High Blood Iron Levels

A fourth hypothesis concerned with atherosclerosis of the coronary arteries is that high serum iron levels damage the coronary arteries or magnify damage from other insults. Iron is rapidly oxidized and capable of producing artery-damaging free radicals. This theory is suggested by some to explain the high incidence of coronary artery disease in men compared with premenopausal women, who typically have lower levels of iron.

High Blood Homocysteine Levels

A fifth hypothesis suggests that persons with elevated plasma homocysteine levels have increased vascular disease. Homocysteine is an amino acid formed by the metabolism of methionine. Research suggests that hyperhomocysteinemia is associated with endothelial dysfunction, specifically manifested by a decreased availability of endothelium-derived nitric oxide, a local vasodilator. Hyperhomocysteinemia also increases susceptibility to arterial thrombosis and accelerates the development of atherosclerosis in apolipoprotein E deficient mice. Homocysteine may also increase oxidation of LDL. Nutritional deficiencies in folic acid and the B vitamins are associated with elevated homocysteine.

Summary of Causes Inducing Atherosclerosis

Atherosclerosis occurs as a result of dysfunction of the endothelial cells lining the arteries, an occurrence that turns on inflammatory reactions and, in many cases, free radical production. Damage may occur from physical injury, such as hypertension, or chemical injury, such as elevated LDL, infection, heavy metal exposure, or chemical insult.

ediatric Consideration

Autopsy studies of children who have died in accidents have shown that fatty streaks on the arteries may occur in children 10 years of age or younger. Even though these early indications of atherosclerosis may be asymptomatic, they may be predictive of later coronary disease. Children with risk factors for atherosclerosis, including high body mass index, elevated systolic and diastolic pressures, and elevated cholesterol, show a larger percentage of fatty streaks than do children with few risk factors. Smoking in the teen years also increases incidence of fatty streaks.


Clinical Manifestations

Clinical manifestations of atherosclerosis usually occur late in the course of the disease.

  • Intermittent claudication, an aching, cramping feeling in the lower extremities, occurs, especially during or after exercise. Intermittent claudication is caused by poor blood flow through atherosclerotic vessels supplying the lower limbs. When oxygen demand of the leg muscles increases, the limited flow cannot supply the extra oxygen required, and pain from muscle ischemia develops. As atherosclerosis worsens, intermittent pain can progress to pain during rest because even normal demands for oxygen cannot be met.

  • Cold sensitivity occurs with inadequate blood flow to the extremities.

  • Skin color changes occur as blood flow decreases to an area. With ischemia, the area becomes pale. This is followed by local autoregulatory responses, resulting in hyperemia (increased blood flow) to the area, causing the skin to flush red.

  • Reduced arterial pulses may be felt downstream from an atherosclerotic lesion. If blood flow is inadequate to support metabolic needs, cell necrosis and gangrene may develop.

Diagnostic Tools

  • Elevated cholesterol and triglyceride levels may indicate a risk factor for atherosclerosis. Cholesterol levels higher than 180 mg/dL of blood are considered elevated, and the individual is considered especially at risk of coronary artery disease.

  • A non-invasive technique called reactive hyperemia peripheral arterial tonometry (RH-PAT) is being evaluated for the potential to identify individuals with early-stage atherosclerosis. Return of digital blood volume is measured following a brief period of imposed ischemia. A sluggish return of blood in the extremities is postulated to indicate similar endothelial dysfunction at the level of the coronary arteries.

  • Imaging of the arteries may allow visualization of atherosclerotic lesions. Identifying or monitoring atherosclerosis may be done using coronary or carotid artery CT, ultrasound, or MRI.



  • Hypertension may develop from long-standing atherosclerosis, just as hypertension and high shear forces can cause atherosclerosis. With thrombus formation, scar tissue, and smooth muscle cell proliferation, the lumen of the artery is reduced and the resistance to flow through the artery increases. The left ventricle must pump more forcefully to produce enough pressure to drive blood through the atherosclerotic vascular system, which can result in increased systolic and diastolic blood pressures.

  • A thrombus may dislodge by breaking off from an atherosclerotic plaque. This may lead to obstruction of blood flow downstream, causing a stroke if the blood vessels of the brain are occluded or a myocardial infarction if the blood vessels of the heart are affected.

  • Development of an aneurysm, a weakening of the artery, may result from atherosclerosis. The aneurysm may burst, causing a stroke if it is located in the cerebral vasculature.

  • Vasospasm may develop in atherosclerotic vessels. Normal endothelial cells act to block various vasoactive substances from directly binding to and acting on smooth muscle cells of the tunica media. If the endothelial layer is not intact, certain peptides such as serotonin and acetylcholine can diffuse directly to the underlying smooth muscle layer, causing the smooth muscle cells to constrict. This response may be involved in coronary artery spasm, or in the spasm of cerebral arteries known as a transient ischemic attack. Damage to the endothelial layer may also be a cause of male erectile dysfunction, since vasodilation of the penile arteries is required for an erection to develop.


  • Diet modification can lower LDL and improve HDL levels. High-fiber foods (fruits, vegetables, whole grains), fatty fish (omega 3 fatty acids), soy products (isoflavones), and garlic have been shown to lower LDL cholesterol.

  • Drug therapy is frequently used to lower total cholesterol and triglyceride levels and improve HDL. Drugs known as statins are especially effective, although contraindications to their use exist and side effects may be serious.

  • Aspirin or anti-clotting drugs reduce risk of thrombus formation.

  • A well-planned exercise program may reduce LDL, increase HDL concentrations, and lower body weight. Exercise may also stimulate development of collateral vessels around occluded sites.

  • Good control of plasma glucose level is essential in diabetic patients.

  • Cessation of smoking is essential for patients with atherosclerosis because of the damaging effects of smoke-related compounds on the endothelial cell wall.

  • Antihypertensive medications will decrease shearing of the endothelial wall.

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  • Nitric oxide or nitroglycerin may be administered to patients experiencing vasospasm to relax the vessel wall.

  • Antimicrobial therapy may offer protection against infectious injury to the endothelial layer.

  • Blood donation by a man three times a year should reduce his iron levels to those seen in menstruating women, thereby reducing oxidative injury.


Hypertension is abnormally high blood pressure measured on at least three different occasions from a person who has been at rest at least 5 minutes. Normal blood pressure varies with age, thus any diagnosis of hypertension must be age specific. The 7th Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure has published revised guidelines on optimal and hypertensive values of systolic and diastolic pressures. In general, optimal pressures are considered less than 120 mmHg systolic and 80 mmHg diastolic, while pressures considered hypertensive are higher than 140 mmHg systolic, and higher than 90 mmHg diastolic. A state of prehypertension includes blood pressures between 120 and 139 mmHg systolic and 80 and 89 mmHg diastolic. For those with especially significant cardiovascular risk factors, including a strong family history of myocardial infarct or stroke, or a personal history of diabetes, even these prehypertensive values are too high.

Causes of Hypertension

Because blood pressure depends on heart rate, stroke volume, and TPR, an uncompensated increase in any of these variables can cause hypertension.

Increased heart rate may occur with abnormal sympathetic or hormonal stimulation to the SA node. Chronically increased heart rate frequently accompanies conditions of hyperthyroidism. However, increased heart rate is usually compensated for by decreases in stroke volume or TPR, and thus does not cause hypertension.

Chronically increased stroke volume may occur if there is a prolonged increase in plasma volume, since increased plasma volume is reflected as an increase in end diastolic volume, and hence increased stroke volume and blood pressure. Increased end diastolic volume is referred to as an increase in the preload of the heart. Increased preload is usually associated with an increased systolic blood pressure reading.

A prolonged increase in plasma volume may occur as a result of renal mishandling of salt and water, or it may result from excess salt consumption. Epidemiological, migration, and genetic studies in humans and animals provide compelling evidence of a relationship between high salt intake and elevated blood pressure. From an evolutionary perspective, humans are adapted to ingest and excrete less than 1 gram of salt per day, which is at least ten times less than the average salt consumption in industrialized countries.


Besides excess dietary intake of salt, abnormally increased renin or aldosterone levels or decreased blood flow to the kidneys also may alter renal handling of salt and water.

Chronically increased TPR may occur with increased sympathetic or hormonal stimulation to the arterioles, or with an overresponsiveness of the arterioles to normal stimulation, both of which would cause a narrowing of the vessels. With increased TPR, the heart has to pump more forcefully, and therefore exert more pressure, to drive the blood through the narrow vessels. This is referred to as an increase in the afterload of the heart, and is usually associated with an increased diastolic pressure reading. With a prolonged increase in afterload, the left ventricle may begin to hypertrophy (increase in size). As a result, the ventricle's own oxygen demands increase further, causing it to pump even more forcefully to meet those demands.

Each of the possible causes of hypertension mentioned may result from increased sympathetic nervous system activity. For many people, increased sympathetic nerve stimulation, or perhaps overresponsiveness of the body to normal sympathetic stimulation, may contribute to the development of hypertension. This may result from a prolonged stress response, which is known to involve sympathetic activation, or from a genetic excess of receptors for norepinephrine in the heart or vascular smooth muscle. Other genetic influences may be racially determined. For instance, there is evidence that African Americans, who generally report more frequent and more severe hypertension, demonstrate an alteration in sodium-calcium pumping such that calcium accumulates in the smooth muscle cells, increasing muscle contraction and resistance.

Types of Hypertension

Hypertension is often classified as either primary or secondary, based on whether a cause can be identified. Most cases of hypertension have no known cause and are called primary or essential hypertension. When a clear cause of hypertension can be identified, it is called secondary hypertension.

Secondary Hypertension

An example of secondary hypertension is renal vascular hypertension, which develops as a result of renal artery stenosis. This condition may be congenital or a result of atherosclerosis. Renal artery stenosis reduces blood flow to the kidney, leading to activation of renal baroreceptors, stimulation of renin release, and production of angiotensin II. Angiotensin II increases blood pressure directly by increasing TPR, and indirectly by increasing aldosterone synthesis and sodium reabsorption. If repair of the stenosis is possible or the affected kidney is removed, blood pressure returns to normal.

Other causes of secondary hypertension include pheochromocytoma, an epinephrine-secreting tumor of the adrenal gland, which causes


increased heart rate and stroke volume, and Cushing's disease, which causes increased stroke volume from salt retention and increased TPR as a result of hypersensitivity of the sympathetic nervous system. Primary aldosteronism (increased aldosterone with no known cause) and oral contraceptives may also cause secondary hypertension.

Hypertension in Pregnancy

Hypertension in a pregnant woman carries risk to both the mother and fetus. Four categories of hypertension in pregnancy have been identified by the National Institutes of Health Working Group on High Blood Pressure in Pregnancy: gestational hypertension, chronic hypertension, preeclampsia-eclampsia, and preeclampsia superimposed on chronic hypertension.

Gestational hypertension is a type of secondary hypertension because, by definition, the elevation in blood pressure ( 140 mmHg systolic; 90 mmHg diastolic) occurs after 20 weeks' gestation in a previously non-hypertensive woman, and reverses within 12 weeks postpartum. Gestational hypertension appears to result in part from a combination of increased cardiac output and increased TPR. If hypertension persists beyond 12 weeks postpartum, or was present before 20 weeks' gestation, it is categorized as chronic hypertension.

With preeclampsia, high blood pressure is accompanied by proteinuria (urinary excretion of at least 0.3 g protein in 24 hours). Preeclampsia typically develops after 20 weeks' gestation and is associated with decreased placental blood flow and the release of chemical mediators that cause dysfunction of vascular endothelial cells throughout the body. It is a very serious disorder, as is preeclampsia superimposed on chronic hypertension.

Clinical Manifestations

Most clinical manifestations occur after years of hypertension, and include:

  • Waking headache, sometimes with nausea and vomiting, caused by increased intracranial blood pressure.

  • Blurred vision caused by hypertensive damage to the retina.

  • Unsteadiness in the gait caused by central nervous system damage.

  • Nocturia caused by increased renal blood flow and glomerular filtration.

  • Dependent edema and swelling caused by increased capillary pressure.

Diagnostic Tools

  • Diagnostic measurement of blood pressure using a sigmoid cuff manometer will show elevated systolic and diastolic pressures in an individual before any symptoms of the disease are present.

  • Proteinuria is present in women with preeclampsia.



See page C9 for illustrations of common complications.

  • Stroke may result from a high-pressure hemorrhage in the brain or from an embolus broken off a noncerebral vessel exposed to high pressure. Strokes may occur with long-standing hypertension if arteries supplying the brain become hypertrophied and thickened, thereby reducing blood flow to areas of the brain that depend on them. The cerebral arteries that are atherosclerotic may become weak, increasing the likelihood of an aneurysm.

  • A myocardial infarct (MI) may occur if the atherosclerotic coronary arteries cannot supply adequate oxygen to the myocardium or if a thrombus develops that blocks flow through a vessel. With chronic hypertension and the development of ventricular hypertrophy, the oxygen demands of the myocardium may not be met, and cardiac ischemia leading to an infarct may occur. Likewise, ventricular hypertrophy may cause changes in the timing of electrical conductance through the ventricle, leading to dysrhythmia, cardiac hypoxia, and an increased risk of clot formation.

  • Renal failure may occur with progressive high-pressure damage to the renal capillaries, the glomeruli. With glomerular injury, blood flow to the functional units of the kidney, the nephrons, is impaired, and these can become hypoxic and die. With damage to the glomerular membranes, proteins will be lost in the urine, decreasing the plasma colloid osmotic pressure and contributing to edema, which is often seen with long-standing hypertension.

  • Encephalopathy (brain damage) may occur, especially with malignant (swiftly progressing, dangerous) hypertension. The dramatically high pressure seen in this condition causes increased cerebral capillary pressure and drives fluid into the interstitial space throughout the central nervous system. Surrounding neurons collapse, and coma and death may result.

  • Seizures may develop in women with preeclampsia. The infant may be born small for his or her gestational age because of poor placental perfusion, and may suffer hypoxia and acidosis if the mother develops a seizure before or during the birth process.


To treat hypertension, one can lower heart rate, stroke volume, or TPR. Pharmacologic and non-pharmacologic interventions may help an individual reduce his or her blood pressure.

  • Weight loss appears to reduce blood pressure in some people, perhaps by reducing the workload of the heart, and therefore heart rate and stroke volume.

  • Exercise, especially coupled with weight loss, reduces blood pressure by reducing resting heart rate and possibly TPR. Exercise increases HDL


    levels, which may reduce the development of atherosclerosis-associated hypertension.

  • Relaxation techniques may reduce heart rate and TPR by interrupting the sympathetic stress response.

  • Quitting smoking is important in reducing the long-term effects of hypertension because cigarette smoke is known to reduce blood flow to various organs and can increase the work of the heart.

  • Diuretics act by several different mechanisms to reduce cardiac output by causing the kidney to increase its excretion of salt and water. Some diuretics (thiazides) also decrease TPR.

  • Calcium channel blockers decrease cardiac or arterial smooth muscle contraction by interfering with the calcium influx needed for contraction. Some calcium channel blockers are more specific for cardiac muscle slow calcium channels; some are more specific for vascular smooth muscle calcium channels. Calcium channel blockers vary in their ability to preferentially reduce heart rate, stroke volume, and TPR.

  • Angiotensin II converting enzyme inhibitors (ACE inhibitors) act to decrease angiotensin II by blocking the enzyme needed to convert angiotensin I to angiotensin II. This decreases blood pressure directly by decreasing TPR, and indirectly by decreasing aldosterone secretion, thereby increasing loss of sodium in the urine and reducing plasma volume and cardiac output. Converting enzyme inhibitors also lower blood pressure by prolonging the effects of the vasodilator bradykinin, which is normally broken down by converting enzyme. ACE inhibitors are contraindicated in pregnancy.

  • Beta-receptor antagonists ( -blockers), especially selective 1-blockers, act on the beta receptors of the heart to decrease heart rate and cardiac output.

  • Alpha-receptor antagonists ( -blockers) block the vascular smooth muscle receptors that normally respond to sympathetic stimulation with vasoconstriction. This reduces TPR.

  • Direct arteriolar vasodilators may be used to decrease TPR.

  • Some individuals may benefit from a sodium-restricted diet.

  • Gestational hypertension and preeclampsia-eclampsia are reversed upon delivery of the infant.

Raynaud's Disease

Raynaud's disease is a primary vascular disease characterized by a temporary spasm of the small arteries and arterioles, usually in the fingers or, less frequently, the toes. Spasm of the blood vessels leads to tissue hypoxia, which is characterized by pallor (whiteness) or cyanosis (bluish tinge) of the digits, followed by rubor (redness) as the local mechanisms of vasodilatation take over. Usually, there is no lasting damage with an episode of spasm. However, if the spasms are extensive or very frequent, tissue injury and scarring can occur. The cause of Raynaud's disease is unknown, but is usually seen in young women in response to cold exposure.


Raynaud's phenomenon is a secondary disease that can occur following repeated exposure to vibration, such as would be experienced by a jackhammer operator. It might also develop in an individual who has suffered damage from previous cold exposure, or in an individual suffering from a systemic disease such as lupus erythematosus or scleroderma.

Clinical Manifestations

  • Color changes of the digits with cold exposure.

  • Numbness of the digits, then tingling and pain as the episode ends.

Diagnostic Tools

  • A good physical examination and history will assist diagnosis.


  • Gangrene may occur if episodes are extensive.

  • Late onset of Raynaud's may be an early indication of autoimmune disease.


  • Avoid unnecessary exposure to the cold and vibrations.

  • Treat underlying disease if present.

Varicose veins

Varicose veins are tortuous (twisted) distended veins occurring where blood has pooled, often in the legs. Since blood flow in the veins is driven by contraction of surrounding skeletal muscles that squeeze blood back to the heart, long episodes of standing without muscle contraction can lead to pooling of blood in the legs. Varicose veins may also develop if valves that normally prevent backflow of blood give way, thereby delivering even more blood to the next backstream valve. If this valve gives way as well, blood will continue to fill up the veins below.

Valve incompetence (weakness) can be a hereditary predisposition, or it may occur following trauma to the valves. Obesity may contribute to the risk of developing varicose veins because of the associated sedentary lifestyle and the increased volume of blood pressing on the valves. Similarly, pregnant women are at increased risk of developing varicose veins because of their increased blood volume and body weight.

Clinical Manifestations

  • Bulging, distended veins, showing prominent bluish streaks and pools in the legs.

Diagnostic Tools

  • Physical examination and family history will assist diagnosis.



  • A blood clot may develop, since the risk of clotting increases when blood pools or is sluggish in its flow.

  • Chronic venous insufficiency may occur if blood pooled in the vascular system is enough to significantly reduce cardiac output. Edema in the feet and ankles will be apparent.


  • Weight reduction.

  • Elevation of the legs to assist blood flow return to the heart.

  • Avoidance of tight-fitting clothes at the top of the legs or waist, which can restrict blood flow.

  • Elastic support hose for the lower legs to compress the veins, assisting blood flow return to the heart.

  • Walking and exercise to increase muscle strength and contraction of the leg muscles to increase blood flow return to the heart.

  • Sclerotherapy, the injection of a sclerosing agent into a collapsed superficial vein, will cause fibrosis of the vein.

  • Surgical stripping of the veins or cauterization may be performed.

Angina Pectoris

Angina pectoris is severe pain originating from the heart that occurs in response to an inadequate oxygen supply to the myocardial cells. The pain of angina may radiate down the left arm, to the back, to the jaw, or into the abdominal area.

When the workload of any tissue increases, oxygen demand goes up. If the oxygen demand increases in healthy hearts, the coronary arteries dilate and bring more blood flow and oxygen to the muscle. However, if the coronary arteries are stiffened or narrowed with atherosclerosis and cannot dilate in response to an increased demand for oxygen, myocardial ischemia (inadequate blood supply) occurs, and the myocardial cells begin to use anaerobic glycolysis to meet their energy requirements. This form of energy production is very inefficient and results in the production of lactic acid. Lactic acid decreases myocardial pH and causes the pain associated with angina pectoris. If the energy demands of the cardiac cells are lessened, the oxygen supply becomes adequate and the muscle cells revert to oxidative phosphorylation for energy production. This process does not produce lactic acid. With removal of the accumulated lactic acid, the pain of angina goes away. Angina pectoris is therefore a short-lived experience.

Types of Angina

There are three types of angina: stable, Prinzmetal's (variant), and unstable.

Stable angina, also called classic angina, occurs when atherosclerotic coronary arteries cannot dilate to increase flow when oxygen demand is increased. Increased work of the heart can accompany physical exercise


such as sports participation or climbing stairs. Exposure to the cold, especially in conjunction with work such as snow shoveling, increases the metabolic demands of the heart and is a strong stimulator of classic angina. Mental stress, such as that caused by anger or by mental tasks such as mathematics, may trigger classic angina. The pain of stable angina typically goes away when the individual stops the activity.

Prinzmetal's angina occurs without any obvious increase in the workload of the heart, and in fact frequently occurs during rest or sleep. In Prinzmetal's (variant) angina, a coronary artery undergoes a spasm, causing cardiac ischemia to occur downstream. Sometimes the site of spasm is related to atherosclerosis. Other times, the coronary arteries do not appear to be sclerotic. It is possible that even if no visible lesions are apparent on the artery, subtle damage to the endothelial layer may be present. This allows vasoactive peptides access directly to the smooth muscle layer, causing its contraction. Dysrhythmias are common with variant angina.

Unstable angina is a combination of classic and variant angina, and is seen in an individual with worsening coronary artery disease. It usually accompanies an increased workload of the heart. It appears to result from coronary atherosclerosis, characterized by a growing, spasm-prone thrombus. Spasm occurs in response to vasoactive peptides released from platelets drawn to the area of damage. The most potent constrictors released by the platelets are thromboxane, serotonin, and platelet-derived growth factors. As the thrombus continues to grow, episodes of unstable angina increase in frequency and severity, and the individual is at increased risk of suffering irreversible damage. Unstable angina is included along with myocardial infarction under the heading acute coronary syndrome and requires a thorough clinical workup, sometimes including hospitalization.

Clinical Manifestations

  • Constricting or squeezing pain in the pericardial or substernal area of the chest, possibly radiating to the arms, jaw, or thorax.

  • In stable and unstable angina, pain is typically relieved by rest. Prinzmetal's angina is unrelieved by rest but usually disappears in about 5 minutes.

Diagnostic Tools

  • Alteration in the ST segment of the ECG may occur.

  • Areas of reduced blood flow may be observed using radioactive imaging during an induced angina episode as part of an exercise stress test.

  • Cardiac enzymes and proteins may be measured to rule out MI.


  • Prevention: Aspirin is sometimes prescribed to prevent anginal symptoms. Also, individuals prone to angina are encouraged to avoid stressors known to precipitate attacks of classic angina, such as working in the cold. They are strongly encouraged not to smoke.

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  • Invasive techniques such as percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass surgery reduce episodes of classic angina. With PTCA, the atherosclerotic lesion is dilated by a catheter inserted through the skin into the femoral or brachial artery and fed into the heart. Once in the affected coronary vessel, a balloon in the catheter is inflated. This cracks the plaque and stretches the artery. With bypass surgery, the diseased piece of a coronary artery is tied off, and an artery or vein taken from elsewhere in the body is connected to nondamaged areas. Flow is reinstated through this new vessel. The vessels most frequently transplanted are the saphenous vein and the internal mammary artery. Initial response to PTCA appears good, but vessels frequently (20-40% of the time) become sclerotic again within a few months. Placing artificial tubes, or stents, into the artery to keep it open improves outcome. Drug-coated stents may reduce the rate of stent restenosis. Coronary bypass relieves the pain of angina, but does not appear to affect long-term mortality.

  • Since the cause of angina is insufficient oxygen to meet the energy demands of the heart, once angina does occur, treatment is geared at reducing energy demands:

    Rest allows the heart to pump out less blood (decreased stroke volume) at a slower rate (decreased heart rate). This reduces the work of the heart, and therefore its oxygen requirements. Sitting is the preferable posture for rest, since lying down increases blood return to the heart, leading to increased end-diastolic volume, stroke volume, and cardiac output.

    Nitroglycerin and other nitrates act as potent dilators of the venous system, decreasing venous return of blood to the heart. A decreased venous return decreases end diastolic volume, allowing the heart to decrease stroke volume. Nitrates dilate the arterial system as well, reducing the afterload against which the heart must pump, and increasing coronary blood flow. Dilation of a coronary artery undergoing spasm also may occur with nitrates. These effects reduce the inequalities of oxygen demand versus supply, and nitroglycerin given sublingually (under the tongue) usually reverses angina.

    Beta-adrenergic blockers reduce angina by reducing heart rate and contractility of the heart, thereby reducing its oxygen demands. Calcium channel blockers also reduce the afterload against which the heart must pump by dilating the arteries and arterioles downstream and are particularly effective in reducing the spasm of variant angina. Calcium channel blockers should not be used in patients at risk of heart failure.

    Oxygen therapy eases demands on the heart.

Myocardial Infarction

Myocardial infarction (MI) is the death of myocardial cells that occurs following prolonged oxygen deprivation. It is the culminating lethal response to unrelieved myocardial ischemia. Myocardial cells begin to die


after about 20 minutes of oxygen deprivation. After this period, the ability of the cells to produce ATP aerobically is exhausted, and the cells fail to meet their energy demands.

Without ATP, the sodium-potassium pump quits, and the cells fill with sodium ions and water, eventually causing them to lyse (burst). With lysis, cells release intracellular potassium stores and intracellular enzymes, which injure neighboring cells. Intracellular proteins gain access to the general circulation and the interstitial space, contributing to interstitial edema and swelling around the myocardial cells. With cell death, inflammatory reactions are initiated. At the site of inflammation, platelets accumulate and release clotting factors. Mast cell degranulation occurs, resulting in the release of histamine and various prostaglandins. Some are vasoconstrictive and some stimulate clotting (thromboxane).

Effect of an MI on Cardiac Depolarization, Cardiac Contractility, and Blood Pressure

With the release of potassium ion and the various intracellular enzymes, and with the accumulation of lactic acid, the electrical conduction pathways of the heart are altered. This can result in interruption of atrial or ventricular depolarization, or in initiation of a dysrhythmia.

With the death of muscle cells and changes in the heart's electrical patterns, the heart begins to pump in a less coordinated manner, causing contractility to decrease. Stroke volume falls, causing a fall in systemic blood pressure.

Reflex Responses to a Fall in Blood Pressure

Decreased blood pressure triggers the baroreceptor responses, leading to activation of the sympathetic nervous system and the renin-angiotensin system, and increasing the release of antidiuretic hormone. Stress hormones (ACTH and cortisol) are also released, which increases glucose production. Activity of the parasympathetic nervous system decreases.

With increased sympathetic and decreased parasympathetic nervous stimulation to the SA node, heart rate increases. Likewise, sympathetic and angiotensin stimulation of the arterioles causes an increase in TPR. Blood flow to the kidneys is reduced, reducing urine production and contributing to the stimulation of the renin-angiotensin system. Constriction of the arterioles causes a decrease in capillary pressure, reducing the capillary forces favoring filtration. Net reabsorption of interstitial fluid occurs, increasing the plasma volume and increasing venous return. Aldosterone synthesis stimulates sodium reabsorption which, in the presence of ADH, increases plasma volume further. Sympathetic simulation to the sweat glands and skin causes the individual to sweat and feel cool and clammy to the touch.

In summary, more blood (increased preload) is delivered to the heart, which is pumping at a faster rate against a narrowed arterial vasculature (increased afterload). The net result of activation of all the reflexes, which occur because of reduced cardiac contractility and fall in blood pressure, is


to increase the workload of the already damaged heart. Oxygen demands of the heart increase. This can be disastrous because the initial problem causing the myocardial infarct was insufficient oxygen supply to heart cells. As the reflexes further increase the demands on the damaged heart, more and more cardiac cells become hypoxic. When oxygen demands of more cells cannot be met, zones of injured and ischemic cells increase around the central necrotic (dead) zone. These injured and ischemic cells are at risk of dying. The pumping ability of the heart falls further, and hypoxia of all tissues and organs, including surviving areas of the heart, occurs. Finally, as blood is erratically or ineffectually pumped, it begins to move sluggishly through the vessels of the heart. This, along with accumulation of platelets and other clotting factors, increases the risk of blood clot development.

Causes of Myocardial Infarct

Myocardial infarct is usually the outcome of long-standing coronary artery disease (CAD). For example, a common cause of an MI is the rupture and dislodgement of an atherosclerotic plaque from one of the coronary arteries, and the subsequent obstruction of blood flow that occurs as it is trapped downstream. An MI might also occur if a thrombotic lesion adhering to a damaged artery becomes large enough to totally obstruct flow downstream, or if a heart chamber becomes so hypertrophied that it is unable to meet its oxygen demands, for example, in a patient with long-standing hypertension.

Risk factors for developing CAD and/or MI (CAD/MI) include a positive family history, hypertension, hypercholesterolemia, obesity, smoking, and diabetes. Particular genotype patterns also may place individuals at risk of CAD/MI. For example, recent studies of a few families with high rates of CAD/MI have identified mutations in a gene known as MEF2A, which codes for one of the transcription factors known as myocyte enhancer factor 2. In its normal expression, this protein is involved in the early stages of vasculogenesis (formation of new blood vessels); mutations may compromise its ability to perform this function, resulting in increased susceptibility to heart disease. Hormonal factors also may contribute to CAD/MI. Although previously thought to be protective against CAD/MI, recent results from the Women's Health Initiative suggest that estrogen, given either alone or with progesterone to postmenopausal women, may increase the risk of heart attack. Cortisol, associated with the acute response to stress, also is associated with an increased risk of MI. Some evidence suggests that African Americans have poorer outcomes following an MI due to late diagnosis, in addition to known risk factors including chronically high stress.

Clinical Manifestations

Although some individuals do not show any obvious signs of an MI (a silent heart attack), significant clinical manifestations usually occur:


  • Abrupt (usually) onset of pain, often described as severe and crushing in nature. The pain may radiate anywhere on the upper body, but most often radiates to the left arm, neck, or jaw. Nitrates and rest might relieve ischemia outside the necrotic zone by decreasing the workload of the heart but will not relieve the pain of infarct completely.

  • Nausea and vomiting, probably related to intense pain, are common.

  • Feelings of weakness related to decreased blood flow to the skeletal muscles occur. Studies have shown that, for women, fatigue may be the key or only symptom present with infarct.

  • The skin becomes cool, clammy, and pale due to sympathetic vasoconstriction.

  • Urine output decreases related to decreased renal blood flow and increased aldosterone and ADH.

  • Tachycardia develops, due to increased cardiac sympathetic stimulation and anxiety.

  • A mental state of great anxiety and a feeling of doom often develop, perhaps related to release of stress hormones and ADH (vasopressin).

Diagnostic Tools

  • A good history and physical, including family history of heart disease, are important, especially for diagnosing an MI in a patient who might otherwise be considered at low risk, such as a premenopausal woman.

  • Blood pressure may be decreased or normal depending on extent of myocardial damage and success of the baroreceptor reflexes. Heart rate is usually increased. A fourth heart sound may be heard.

  • The ECG may show acute changes with elevation in the ST segment and T wave inversion. Within 1 or 2 days of the infarct, deepening of the Q wave occurs. Although the ST and T wave changes will disappear over time, the Q wave changes remain and can be used to detect a past infarct.

  • Systemic signs of inflammation occur, including fever, elevated number of leukocytes, and increased sedimentation rate. These signs begin about 24 hours after the infarct and continue for up to 2 weeks.

  • Cardiac enzyme levels (creatinine phosphokinase, serum glutamic oxaloacetic transaminase, and lactic dehydrogenase) in the serum increase as a result of myocardial cell death. The increases occur in a characteristic pattern, beginning immediately after an infarct and continuing for about a week.

  • Troponin T and troponin I levels become detectable in the blood within 15 to 20 minutes. Myoglobin is detected within 1 hour, peaking within 4 to 6 hours of the infarct.


  • Thromboemboli may develop as myocardial contractility falls. These emboli can block blood flow to other regions of the heart not previously


    damaged during the original infarct. They may also travel to other organs, blocking their blood flow and causing infarction in those organs.

  • Congestive heart failure may occur when the failing heart cannot pump out all the blood it is receiving. Heart failure may develop soon after an infarct if the original infarct is very large, or may occur subsequent to activation of the baroreceptor reflexes. With activation of baroreceptor responses, there is increased blood returned to the damaged heart and constriction of the downstream arteries and arterioles. This causes blood to accumulate in the heart and leads to overstretch of the cardiac muscle cells. If the overstretch is severe enough, it can cause the contractility of the heart to decrease further as the muscle cells begin to fall down the length-tension curve.

  • Dysrhythmia, the most common complication of an infarct, may develop due to alteration in electrolyte balance and decreased pH. Hypoxic areas of the heart may become irritable and initiate action potentials, also leading to dysrhythmia. The SA or AV nodes, or the transduction pathways (Purkinje's fibers or the bundle of His), may be part of the necrotic or ischemic zones, thereby affecting signal initiation or passage. Fibrillation is the primary cause of death following a myocardial infarct outside the hospital setting.

  • Cardiogenic shock (collapse of blood pressure) may occur with a prolonged, severe decrease in cardiac output. Cardiogenic shock may be fatal at the time of the infarct, or may cause death or disability days or weeks later as a result of subsequent pulmonary or renal failure following ischemia. Cardiogenic shock usually follows at least a 40% loss of myocardial muscle mass.

  • Myocardial rupture may occur after a large infarct.

  • Pericarditis, an inflammation of the heart, may occur, usually a few days after the infarct. Pericarditis occurs as part of the inflammatory reaction following cardiac cell injury and death. Some types of pericarditis may occur weeks after the infarct and may represent an immune hypersensitivity reaction to tissue necrosis.

  • With healing after a myocardial infarct, scar tissue replaces dead myocardial cells. If this represents a large area of the myocardium, contractility of the heart may be permanently reduced. In some cases the scar tissue may be weak, leading to later myocardial rupture or development of an aneurysm.


Prevention of heart disease is vital. Prevention involves:

  • Reducing or eliminating modifiable risk factors. Since cardiovascular risk factors interact with each other, even moderate reductions in a few risk factors can be more effective than instituting a major reduction in any one risk factor. For example, a significant reduction in the risk of heart attack occurs with moderate levels of exercise (including walking), cessation of smoking, and moderate limitation of dietary fat. Cardiovascular


    risk management guidelines that integrate risk reductions should be used routinely.

  • Individuals under stress, and especially those with a family history of heart disease, should be educated to reduce risks and to seek medical attention quickly if signs of an MI develop.

For a patient with acute coronary syndrome, the following treatment guidelines, using the acronym ABCDE, have been proposed:

  • A for antiplatelet therapy, anticoagulation, angiotensin-converting enzyme inhibition, and angiotensin receptor blockade

  • B for beta-blockade and blood pressure control

  • C for cholesterol treatment and cigarette smoking cessation

  • D for diabetes management and diet

  • E for exercise.

For a patient suffering a heart attack, the following treatments are added:

  • Cessation of physical activity to reduce the workload of the heart helps to limit the area of damage.

  • Cardiopulmonary resuscitation (CPR) may be required if the heart is in fibrillation or arrest. Electrical defibrillation to restore electrical rhythm within the first minutes of cardiac arrest is especially helpful in surviving an MI. Recent community-wide efforts that focus on intensive training of the public in the use of defibrillators have been shown to double the survival rate of cardiac arrest victims.

  • Immediate intravenous or intracoronary infusions of thrombolytic (clot-busting) drugs break up a causative embolus. Rapid use of these drugs (preferably within an hour of the infarct) is associated with a dramatically increased survival rate and a limited extent of further myocardial injury. Drugs to prevent new clot development, such as heparin, are also required. Coronary angioplasty may be used to open coronary arteries instead of clot-busting drugs.

  • Oxygen is provided to increase oxygenation of the blood, reducing demands on the heart and increasing systemic perfusion.

  • Pain medications (usually morphine and meperidine [Demerol]) are used to make patients more comfortable, decrease mental stress and anxiety, and reduce the activity of the sympathetic nervous system, which raises heart rate and vascular resistance in response to acute pain. Morphine is also a vasodilator that works to decrease preload and afterload.

  • Nitrates may be provided to decrease venous return and relax the arteries, decreasing preload and afterload and increasing coronary blood flow.

  • Diuretics that increase blood flow may be provided. This preserves kidney function and prevents volume overload and development of congestive heart failure. Increased renal blood flow also reduces the release of renin.

  • Positive inotropic agents (digitalis) may be used to increase the contractility of the heart.

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  • Coronary artery bypass may be considered if the infarct was due to a thrombotic occlusion.

After an MI, additional considerations include:

  • Cardiac rehabilitation, involving a balance between rest and exercise and lifestyle modifications to reduce atherosclerotic risks and hypertension. Following the ABCDEs for acute coronary syndrome is essential. The family needs to be considered and involved.

  • New research has shown that the heart contains stem cells that can regenerate cardiac muscle cells, and so is capable of repairing itself. These findings may offer hope to patients who have experienced an MI.


Pericarditis is inflammation of the fluid-filled pericardial sac surrounding the heart. Pericarditis can occur with any cardiac trauma, including a myocardial infarct, blunt or penetrating trauma to the chest, infection, or neoplasm. Kidney disease, rheumatic fever, and other systemic diseases may also cause pericarditis.

With trauma, disease, or infection, inflammation of the pericardial tissues causes fluid to accumulate in the interstitial space. This exudate may be purulent if a bacterial infection is present. Acute pericarditis usually resolves on its own in 2 to 6 weeks. Chronic pericarditis is diagnosed if the condition does not resolve. It is usually associated with other symptoms of heart disease or systemic inflammation.

Clinical Manifestations

  • Sharp chest pain, usually with a rapid onset, that worsens when the individual breathes, coughs, or changes position. Pain is lessened when the individual sits up and leans forward.

  • Difficulty breathing and a dry cough.

  • Fever is usually present.

Diagnostic Tools

  • A friction rub can be heard with a stethoscope due to the inflamed sac rubbing over the heart with each beat.

  • Systemic signs of inflammation (fever, elevated sedimentation rate, and increased leukocyte count) may occur.

  • Cardiography can indicate fluid accumulation in the pericardial sac.


  • Cardiac tamponade, compression of the heart due to extensive buildup of fluid or blood in the pericardial sac, may occur if the pressure in the pericardial sac increases to a level equal to or greater than that of the


    diastolic pressure of the heart. This causes diastolic filling of the heart to cease, collapsing stroke volume and cardiac output.


  • Bed rest, with elevation of the head of the bed to improve breathing.

  • Oxygen therapy.

  • Antibacterial, antifungal, or antiviral therapy if an infectious cause is suspected.

  • Drainage of the pericardial fluid (pericardiocentesis) or removal of the pericardium (pericardectomy) may be performed.


Myocarditis is inflammation of the heart not related to coronary artery disease or myocardial infarct. Myocarditis most often is a result of a viral infection of the myocardium, but may be caused by a bacterial or fungal infection. Coxsackievirus is often implicated. Systemic disease such as lupus erythematosus may also cause the disorder.

Myocarditis results in weakening of the heart muscle and a decrease in cardiac contractility. The heart becomes flabby and dilated, with many foci of pinpoint hemorrhage developing in the endocardium, myocardium, and epicardial layers. Myocarditis is a major cause of heart transplantation in the United States.

Clinical Manifestations

  • Chest pain.

  • Fatigue and dyspnea.

Diagnostic Tools

  • Systemic signs of inflammation include elevated sedimentation rate and leukocytosis.

  • Elevated levels of antiviral antibodies, frequently against the coxsackievirus, are seen.

  • Echocardiography and coronary artery catheterization show normal arteries and cardiac valves. Biopsy of the muscle shows inflammation.


  • Heart failure.

  • Arrhythmia leading to sudden death.


  • Treatment of infectious cause or systemic disease.

  • Control of heart failure.

  • Heart transplantation.



Cardiomyopathy refers to any disease or injury of the heart not related to coronary artery disease, hypertension, or congenital malformations. Cardiomyopathy may occur following an infection of the heart, as a result of an autoimmune disease, or following the exposure of an individual to certain toxins, including alcohol and many anticancer drugs. Cardiomyopathy also may occur idiopathically.

Clinically, myopathies are divided into those resulting in ventricular dilation and those characterized by hypertrophy of the myocardium. With dilated cardiomyopathy, the ventricle stretches, leading to heart failure. With hypertrophic myopathy, cardiac muscle thickens, especially along the interventricular septum. This makes the ventricle stiff, resulting in reduced compliance and diastolic filling.

Clinical Manifestations

  • Dyspnea (difficulty breathing) and fatigue may occur if cardiac output is reduced.

  • Dysrhythmia may occur as a result of atrial stretching.

  • Emboli may develop as a result of sluggish coronary blood flow.

  • Chest pain may be present.

Diagnostic Tools

  • An ECG or echocardiogram will demonstrate a thickened myocardium.


  • A myocardial infarct may occur if oxygen demand of the thickened ventricle cannot be met.

  • Heart failure may occur in dilated cardiomyopathy if the heart cannot pump out as much blood as is entering.


  • Salt restriction and diuretics are used for dilated cardiomyopathy to reduce end diastolic volume. Other treatments for heart failure may be required.

  • Anticoagulants are provided to prevent the formation of emboli. Examples include warfarin, heparin, and a new therapy, ximelagatran. Recent findings show that ximelagatran has fewer side effects than the older drugs, and monitoring may not need to be as stringent. Ximelagatran has few known food or drug interactions.

  • -blockers are provided for hypertrophic cardiomyopathy in order to decrease the heart rate, allowing increased diastolic filling time. They also reduce ventricular stiffness.

  • Surgical resection of some areas of hypertrophied myocardium may be attempted.

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  • Calcium channel blockers are not used since they may further decrease contractility of the heart.

Heart Failure

Heart failure occurs when the heart is unable to pump enough blood out to meet the oxygen and nutrient demands of the body. Heart failure can result from either diastolic or systolic dysfunction.

Diastolic heart failure may develop alone or in conjunction with systolic heart failure. It often follows prolonged hypertension. When the ventricle must pump continually against a very high afterload (increased resistance), muscle cells hypertrophy and become stiff. Stiffness of the muscle cells causes a reduction in ventricular compliance, leading to decreased ventricular filling, abnormal diastolic relaxation, and decreased stroke volume. Left ventricular end-diastolic volume (LVEDV) and left ventricular end-diastolic pressure (LVEDP) are elevated and reflected back into the pulmonary circulation, causing pulmonary hypertension. Because stroke volume and hence blood pressure fall, baroreceptor reflexes are activated.

Systolic dysfunction as a cause of heart failure results from injury to the ventricle, usually from a myocardial infarct. The damaged muscle is unable to contract forcefully, and again, stroke volume falls. Decreased stroke volume leads to a decrease in blood pressure, quickly followed by the initiation of reflex responses geared to reverse the trend. Because the damaged ventricle is unable to bring stroke volume back up, the reflexes continue. In particular, sympathetic stimulation of cardiac 1-receptors becomes chronic. Research suggests that the chronically activated sympathetic response ultimately reduces calcium levels in, and release of calcium from, the myocardial cell's sarcoplasmic reticulum. Reduction in myocardial calcium causes defective excitation-contraction coupling, leading to diminished myocardial force production, dysrhythmia, and eventual contractile dysfunction and cardiac muscle cell remodeling.

Also worsening the path of heart failure is the effect the progressive increase in end-diastolic volume has on stretching the cardiac muscle cell well beyond its optimum length, causing less tension to be produced as the ventricle becomes more distended with blood. Heart failure becomes a worsening cycle: the more overfilled the ventricle becomes, the less blood it can pump out, leading to further accumulation of blood and additional stretch of the muscle fibers. As a result, stroke volume, cardiac output, and blood pressure all remain low. The body's reflex responses initiated in response to the fall in pressure continue unabated and significantly worsen the situation.

Reflexes Initiated During Heart Failure

Decreased blood pressure is sensed by the baroreceptors. Most reflex responses initiated by baroreceptor activation significantly advance heart failure progression as shown in Figure 13-10. This occurs because the


reflex responses either further increase ventricular filling (preload) or further reduce stroke volume by increasing the afterload against which the ventricle must pump. Increased preload and afterload serve to increase the workload and oxygen demand of the heart. If the increased oxygen demand cannot be met, the muscle fibers become increasingly hypoxic and contractility worsens. The downward spiral of heart failure continues.

Figure 13-10. Flow diagram of heart failure.


As each of these reflexes further fill and stretch the heart and/or increase afterload, blood pressure continues to be below normal, causing those same reflexes to be maintained and heightened. As described above, the chronically activated sympathetic response leads to diminished intracellular calcium release from the sarcoplasmic reticulum, and ultimately to contractile dysfunction. Heart failure continues unless the cycle of overfill, decreased stroke volume, and decreased blood pressure is broken.

One reflex response that is advantageous during heart failure is that which occurs from atrial over-filling. As blood is poorly pumped out of the ventricle, it soon begins to accumulate in the atria. Expansion of the atria leads to stretching of atrial baroreceptors and the release of the hormone atrial natriuretic peptide (ANP). ANP works on the kidney to increase the excretion of sodium ion (natriuresis). Since, under most circumstances, water excretion follows sodium excretion, production of ANP is one mechanism by which the body is able to rid itself of excess fluid volume. ANP also relaxes vascular smooth muscle, causing vasodilation. A second natriuretic peptide, called B-type natriuretic peptide (BNP), is released in the form of a precursor peptide, pro-BNP, from an over-stretched ventricle. Once in the circulation, pro-BNP is converted to BNP. Like ANP, BNP is natriuretic and vasodilatory. Serum levels of both of these hormones, especially BNP, are significantly correlated with heart failure severity and are excellent markers of disease progression.

Causes of Heart Failure

Heart failure may result from noncardiac causes such as long-standing systemic or pulmonary hypertension or, less commonly, disorders such as kidney failure or water intoxication, which increase plasma volume to such a degree that the ventricular fibers are stretched beyond their optimum length.

Cardiac causes of heart failure include myocardial infarct, cardiac myopathy, valvular defects, and congenital malformation. Pathways leading to heart failure following myocardial infarct and chronic hypertension are highlighted in Figure 13-10. As shown in the figure, if increased oxygen demand of a hypertrophied ventricle cannot be met by increased blood flow (usually because of coronary atherosclerosis), ventricular contractility will fall. In this case, diastolic dysfunction and systolic dysfunction are both present.

Progression of Heart Failure

Heart failure can begin on either the left or right side of the heart. For instance, longstanding systemic hypertension would cause the left ventricle to hypertrophy and fail. Long-standing pulmonary hypertension would cause the right ventricle to hypertrophy and fail. The site of a myocardial infarct would determine which side of the heart is first affected following a heart attack.


Because a failing left ventricle would cause blood to back up in the left atrium, and then to the pulmonary circuit, right ventricle, and right atrium, it is apparent that left heart failure can eventually lead to right heart failure. In fact, the main cause of right heart failure is left heart failure. As blood is poorly pumped out of the right side of the heart, it begins to pool in the peripheral venous system. The end result is a further reduction in circulating blood volume and blood pressure, and a worsening cycle of heart failure.

Clinical Manifestations

Clinical manifestations of heart failure are often separated into forward and backward effects, with the right or left side of the heart as the starting point. Forward effects are considered downstream from the failing myocardium. Backward effects are considered upstream from the failing myocardium.

Forward Effects of Left Heart Failure

  • Decreased systemic blood pressure

  • Fatigue

  • Increased heart rate

  • Decreased urine output

  • Plasma volume expansion

Backward Effects of Left Heart Failure

  • Increased pulmonary congestion, especially when lying down

  • Dyspnea (difficult breathing)

  • Right heart failure if the condition worsens

Forward Effects of Right Heart Failure

  • Decreased pulmonary blood flow

  • Decreased blood oxygenation

  • Fatigue

  • Decreased systemic blood pressure (due to decreased left heart filling), and all the signs of left heart failure

Backward Effects of Right Heart Failure

  • Increased venous pooling of blood, edema of the ankles and feet

  • Jugular venous distension

  • Hepatomegaly and splenomegaly

Diagnostic Tools

  • A third heart sound may be present.

  • Radiological identification of pulmonary congestion and ventricular enlargement may indicate heart failure.

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  • Magnetic resonance imaging (MRI) or ultrasound identification of ventricular enlargement may indicate heart failure.

  • Measurement of ventricular end-diastolic pressure with a catheter inserted into the pulmonary artery (reflecting left ventricular pressure) or into the vena cava (reflecting right ventricular pressure) can diagnose heart failure. Left ventricular pressure usually reflects left ventricular volume.

  • Echocardiography can demonstrate abnormal dilation of the cardiac chambers and abnormalities in contractility.

  • Measurement of serum BNP (and to a lesser extent, ANP) provides information on disease severity and progression. Normal levels vary with age (baseline increases with age) and gender (increased levels in women compared to men), so a patient's age and sex need to be considered when evaluating results.


  • Best-practice guidelines released by the American Heart Association have identified the use of beta blockers and angiotensin-converting enzyme (ACE) inhibitors as the most effective therapies for heart failure unless specific contraindications exist. Beta blockers reduce heart rate, allowing for improved stroke volume. ACE inhibitors reduce afterload (TPR) and plasma volume (preload). Angiotensin receptor blockers may be used in place of ACE inhibitors.

  • Diuretics are administered to decrease plasma volume, thereby decreasing venous return and removing some of the stretch on the cardiac muscle fibers.

  • Oxygen therapy may be used to reduce the demands of the heart.

  • Nitrates may be administered to reduce afterload and preload.

  • Clinical trials of nitric oxide boosting drugs (BiDil) for some patients with heart failure, in particular African Americans, suggest that such drugs both improve patients' quality of life and prolong survival.

  • Aldosterone blockers (epleronone) have been approved for the treatment of congestive heart failure following a heart attack.

  • Digoxin (digitalis) may be administered to increase contractility. Digoxin acts directly on the cardiac muscle fibers to increase the strength of each contraction regardless of the length of the muscle fibers. This increases cardiac output, relieving the ventricle of volume and lessening the stretch of the chamber. Digitalis is used less for the treatment of heart failure now than in the past.

Rheumatic fever

Rheumatic fever is a serious inflammatory disease that may occur in an individual 1 to 4 weeks following an untreated throat infection by the group A beta-hemolytic Streptococcus bacteria. The acute condition is characterized by fever and inflammation of the joints, heart, nervous system, and skin. In some cases, it can permanently affect the structure and function of the heart, especially the heart valves. Rheumatic fever is a relatively rare illness, however, affecting only 3% of those with untreated


streptococcal infections. Rheumatic fever is preventable with prompt antibiotic therapy.

Rheumatic fever can occur at any age, but mainly affects children between the ages of 5 and 15. It is likely that individuals who develop the disease, and those who experience repeated infections, have a genetic tendency to do so.

Rheumatic Heart Disease

Approximately 10% of individuals who acquire rheumatic fever develop rheumatic heart disease. Rheumatic heart disease is the major cause of acquired cardiac valve disease. Damage to the heart with rheumatic fever occurs as a result of a robust host immune response that, although produced against the streptococcal antigens, cross-reacts against self-antigens expressed on the heart valves. This immune response involves both humoral (B cell) and cell-mediated (T cell) immunity. The attack against self-antigens is likely related to an antigenic similarity between cardiac valves and antigens of the group A beta-hemolytic streptococcus, and/or to an error in the presentation of host antigens to the immune cells. Immune attack can occur against any of the four cardiac valves, but is usually seen against the mitral and aortic valves.

The course of rheumatic heart disease can be separated into acute and chronic stages. In the acute stage, the valves become swollen and red as the inflammatory reaction begins. Lesions may develop on the valve leaflets. As the acute inflammation subsides, scar tissue develops. Scar tissue may deform the valves and, in some cases, cause the leaflets to fuse together, narrowing the orifice. A chronic stage of the disease may follow, characterized by repeated inflammation and continued scarring.

Associated Effects of Rheumatic Fever

Besides affecting the heart, rheumatic fever has other systemic effects. These include migratory (moving) joint inflammation and pain, occurrence of skin nodules, and occasionally a rash. The central nervous system is affected, causing behavioral changes, awkwardness in walking and speech, and a type of movement called chorea, characterized by spontaneous, jerky motions. These nervous system manifestations usually regress over the course of a few weeks or months.

Clinical Manifestations

  • Throat culture is positive for group A beta-hemolytic streptococcus. History of the infection usually includes headache, fever, swollen lymph nodes along the jaw, and stomach pain or nausea.

  • Migratory polyarthritis occurs, with inflammation of the joints (swelling, redness, pain, heat). The large joints of the elbows, knees, ankles, and wrists are often affected.

  • Subcutaneous hard nodules develop over the muscles of affected joints. These nodules are painless and transitory.

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  • Erythema marginatum (a transitory rash) is seen, especially on trunk, inner arms, and thighs.

  • Chorea (rapid, jerky movements) may occur, accompanied by clumsiness in movement.

  • Behavioral changes may become apparent.

Diagnostic Tools

  • Antistreptolysin O titer is increased in individuals after a streptococcal infection.

  • Signs of inflammation during the acute phase of rheumatic heart disease include fever, arthralgia (joint pain), elevated sedimentation rate, and increased number of leukocytes.

  • Elevated C-reactive protein is measurable in the serum. This protein is released by the liver as part of the immune system response to the streptococcal bacteria.

  • An Aschoff body, a fibrous area of tissue necrosis, may be present on the heart.


  • A heart murmur may develop in an individual without a previous murmur, or a worsening of a previous murmur may occur, if rheumatic heart disease develops.

  • Cardiomegaly (increased size of the heart), pericarditis, or congestive heart failure in a previously well individual may also occur.


  • The most important method available for reducing the harmful effects of rheumatic fever and rheumatic heart disease is to promptly identify the occurrence of a beta-hemolytic streptococcal infection and provide a full course of antibiotic therapy.

  • If rheumatic fever develops, interventions to limit the disease include administration of antibiotics and anti-inflammatory drugs. Restriction of activities to reduce cardiac demand is also suggested.

  • To prevent recurrence of rheumatic fever in susceptible individuals, prophylactic antibiotics (usually penicillin) are administered for at least 5 years after the most recent occurrence. Education on the signs and symptoms of a streptococcal infection, and the need for prompt treatment, should be provided to the entire family.

Mitral Valve Stenosis

Mitral valve stenosis is a narrowing in the opening of the valve between the left atrium and the left ventricle. Mitral valve stenosis usually occurs due to a buildup of scar tissue following rheumatic fever or another cardiac infection. It may also result from a congenital defect in valve structure.


In order to pump blood through the narrowed orifice, the left atrium must contract more forcefully. If the left atrium is unable to pump through the orifice, blood will pool in the atrium and back up into the lungs and right side of the heart. Right heart failure can result, especially if flow through the valve is so restricted that stroke volume and cardiac output are too low to maintain normal-range systemic blood pressure. If this occurs, baroreceptor reflexes initiating sympathetic and hormonal responses will be activated, leading to increased plasma volume and increased TPR in an attempt to raise blood pressure. If plasma volume increases, further overfilling of the left atrium will occur, worsening the situation.

Clinical Manifestations

  • Clinical manifestations may be absent or severe, depending on the level of stenosis.

  • Pulmonary congestion, with signs of dyspnea (difficulty breathing) and pulmonary hypertension, may occur.

  • Dizziness and fatigue due to decreased left ventricular output may occur. Heart rate may be elevated due to sympathetic stimulation.

Diagnostic Tools

  • A low-pitched murmur may be present during ventricular filling (diastole) as the blood reverberates through the constricted opening.

  • Echocardiography may be used to diagnose abnormal valve structure and motion.


  • Left atrial hypertrophy may cause atrial dysrhythmia or right heart failure.


  • Treatment for congestive heart failure may be required.

  • Valve replacement or surgical correction of the stenosis may be attempted.

Aortic valve stenosis

Aortic valve stenosis is a narrowing in the opening of the valve between the left ventricle and the aorta. Like mitral valve stenosis, aortic stenosis usually follows rheumatic fever or is a congenital malformation. With aortic stenosis, the left ventricle must pump more forcefully to expel blood through the narrow orifice. This causes ventricular hypertrophy and eventually reduces compliance. As blood backs up in the ventricle, atrial pressure increases and blood backs up into the pulmonary system and the right side of the heart. If the stenosis is severe, systemic blood pressure may fall, initiating baroreceptor reflexes geared toward increasing plasma volume and TPR. Heart failure may occur.


Clinical Manifestations

  • Clinical manifestations may be absent or severe, depending on the level of stenosis.

  • Pulmonary congestion, with signs of dyspnea and pulmonary hypertension, may occur if blood backs up into the pulmonary vascular system.

  • Dizziness and fatigue may occur due to decreased cardiac output and decreased stroke volume. Heart rate may be elevated via sympathetic stimulation.

Diagnostic Tools

  • A systolic heart murmur may be heard as blood rushes through the narrow orifice.

  • Echocardiography may be used to diagnose abnormal valve structure and motion.


  • Left ventricular hypertrophy may develop, leading to congestive heart failure.


  • Treatment for congestive heart failure may be required.

  • Valve replacement or surgical correction of the stenosis may be attempted.

Pulmonary Valve Stenosis

Pulmonary valve stenosis is a narrowing of the opening between the right ventricle and the pulmonary valve. Pulmonary valve stenosis most commonly occurs due to a congenital defect. With a narrow orifice, the right ventricle must pump more forcefully to expel blood. This can lead to right ventricular hypertrophy, backing up into the right atrium and causing dilation of the vena cava and blood accumulation in the systemic veins. Blood flow into the lungs and left side of the heart will be reduced if the stenosis is severe, leading to a decrease in blood pressure. Right heart failure may develop.

Clinical Manifestations

  • Clinical manifestations may be absent or severe depending on the level of stenosis.

  • Decreased pulmonary flow causes poor oxygenation of the blood and feelings of weakness and fatigue.

  • Venous distention and swelling of the ankles and feet are common.


Diagnostic Tools

  • Echocardiography may be used to diagnose abnormal valve structure and motion.



  • Right heart hypertrophy and subsequent right heart failure may occur.


  • Treatment for heart failure may be required.

  • Valve replacement or surgical correction of the stenosis may be attempted.

Mitral Valve Regurgitation

Mitral valve regurgitation is the return of blood into the left atrium from the left ventricle through the mitral valve, occurring especially when the ventricle contracts. Mitral valve regurgitation results from an incompetent mitral valve that fails to snap shut completely upon initiation of ventricular systole. Mitral valve regurgitation is usually caused by rheumatic fever or another bacterial infection of the heart, or by rupture of the valve with coronary artery disease.

With mitral valve regurgitation, some blood returns to the left atrium as the left ventricle contracts. This causes ventricular stroke volume and cardiac output to fall, leading to a decrease in blood pressure and activation of baroreceptor reflexes. Chronic dilation and filling of the ventricle and the atrium occur, leading to hypertrophy and, potentially, congestive heart failure. Blood backing into the pulmonary circulation causes pulmonary congestion and pulmonary hypertension.

Clinical Manifestations

  • Clinical manifestations may be absent or severe, depending on the level of stenosis.

  • Pulmonary congestion, with signs of dyspnea and pulmonary hypertension, may occur if blood backs up into the pulmonary vascular system.

  • Decreased cardiac output due to decreased stroke volume may cause dizziness and fatigue. Heart rate may be elevated via sympathetic stimulation.

Diagnostic Tools

  • A systolic heart murmur may be heard as blood is pushed through the orifice.

  • Echocardiography may be used to diagnose abnormal valve structure and motion.


  • Left ventricular and left atrial hypertrophy may develop, leading to congestive heart failure.


  • Treatment for congestive heart failure may be required.

  • Valve replacement or surgical correction of the incompetent valve may be attempted.

Aortic Valve Regurgitation

Aortic valve regurgitation is the return of blood into the left ventricle from the aorta during diastole. Incompetence of the aortic valve usually follows rheumatic fever. With blood flowing backward into the left ventricle during diastole, diastolic pressure in the aorta is reduced. A reduction in diastolic pressure in the aorta leads to a characteristic increase in the pulse pressure: the difference between the measured systolic and diastolic pressures. Aortic regurgitation also increases left ventricular diastolic volume because during diastole, blood is entering the left ventricle from both the left atrium and the aorta. This increases stroke volume and cardiac output. Aortic valve regurgitation leads to hypertrophy of the left ventricle, which can cause the development of congestive heart failure.

Clinical Manifestations

  • A wide pulse pressure can be measured.

  • Hyperkinetic (very strongly bounding) peripheral and carotid pulsations are typically present.

  • Symptoms of heart failure may develop.

Diagnostic Tools

  • A high-pitched diastolic heart murmur is frequently heard.

  • Echocardiography may be used to diagnose abnormal valve structure and motion.


  • Treatment for congestive heart failure may be required.

  • Valve replacement or surgical correction of the incompetent valve may be attempted.

Congenital Heart Defects

Congenital heart defects involve abnormal shunting between the left and right sides of the heart or between the aorta and pulmonary artery. The direction of blood flow in the shunt depends on the relative resistance of the pulmonary and systemic circulations.


Usually, pulmonary vascular resistance falls and systemic vascular resistance increases following birth. If a shunt is present under these conditions, the direction will be left to right. Well-oxygenated blood will flow from the left side of the heart into the right side or into the pulmonary circulation, resulting in overfilling of the pulmonary circuit and, since the blood is immediately delivered again into the left atrium, overfilling of the left side of the heart. Overfilling may lead to pulmonary congestion and left heart failure. If blood is delivered directly to the right side of the heart from the left through an opening in the septal wall, right heart failure may develop.

In a premature infant, resistance to flow in the pulmonary circulation may be greater than resistance in the systemic circulation due to immature development of the lungs, resulting in a right-to-left shunt. In a right-to-left shunt, poorly oxygenated blood is delivered into the systemic blood supply, causing cyanosis. A shunting pathway that causes cyanosis is called a cyanotic defect.

Types of Congenital Heart Defects

Congenital heart defects may involve the atria, the ventricles, any of the valves, or the great arteries.

Atrial Septal Defect

An atrial septal defect (ASD) is an abnormal opening between the left and right atria. It is a congenital disorder that occurs when the foramen ovale fails to close after birth, or when another opening between the left and right atria is present due to improper closure of the wall between the two atria during gestation.

Ventricular Septal Defect

A ventricular septal defect (VSD) is an abnormal opening between the left and right ventricles that occurs when the wall between the ventricles fails to close properly during gestation. VSD is the most common cardiac congenital defect. The size of the defect determines the severity of the symptoms.

Patent Ductus Arteriosus

Patent ductus arteriosus (PDA) occurs when the ductus arteriosus, the connection between the pulmonary artery and the aorta, remains open after birth. Normally, the ductus closes soon after birth as a result of increased oxygenation in the pulmonary circulation. If the ductus does not close, blood will shunt between the two main arteries. The direction of blood flow will depend on the relative resistance to flow of the pulmonary and systemic circulation.

Transposition of the Great Vessels

Transposition of the great vessels is a congenital heart defect in which the openings of the aorta and pulmonary artery are switched; that is, the aorta originates in the right ventricle and the pulmonary artery originates in the


left ventricle. This reversal results in separation of the left and right heart circulations.

Blood flows in the pulmonary vein to the left atrium. From there it flows to the left ventricle and back through the pulmonary artery to the lungs, to cycle again to the left atrium. This blood is oxygenated, but does not supply the systemic circulation.

At the same time, blood flows in the vena cava to the right atrium, to the right ventricle, through the aorta to the systemic circulation, and back again to the vena cava. This blood is not oxygenated. Obvious signs of cyanosis will be apparent.

Transposition of the great vessels is incompatible with life unless, as is frequently the case, a septal defect or a patent ductus arteriosus maintains communication between the two circulations. If no communication is present, surgical opening of the atrial septum is required until major surgery to redirect blood flow can be performed.

Coarctation of the Aorta

Coarctation of the aorta is a congenital defect that results in the narrowing of the aorta as it leaves the left ventricle. The narrowing can be proximal or distal to the ductus arteriosus.

Aortic coarctation that occurs proximal to the ductus arteriosus is called preductal coarctation. If the coarctation is severe, the major source of systemic blood flow will be pulmonary artery blood flowing through the ductus arteriosus. In order to keep infants with preductal coarctation alive until the stenosis can be surgically repaired, the ductus must remain open. This is accomplished by administering prostaglandin E intravenously or into the duct. Preductal coarctation is a cyanotic defect.

Postductal coarctation occurs if the narrowing is distal to the ductus arteriosus. In this case, the duct usually closes. However, blood leaves the aorta via subclavian arteries, which branch off before the coarctation, and travels to the upper body. The result is an obvious disparity in the upper and lower body pulses, depending on the degree of coarctation. Systemic signs of poor blood flow will be apparent. Collateral vessels that deliver blood to the systemic circulation frequently develop around the coarctation.

Tetralogy of Fallot

Tetralogy of Fallot is a congenital heart defect characterized by four presenting abnormalities: ventricular septal defect, pulmonary artery stenosis, right ventricular hypertrophy, and a shifting of the position of the aorta so that it opens into the right ventricle (an overriding aorta). Tetralogy of Fallot is a cyanotic defect.

Clinical Manifestations

  • With a right-to-left shunt, cyanosis, fatigue, and weakness occur. Knee-to-chest or squatting behavior may be observed. Clubbing of the digits may develop.

  • P.460

  • With a left-to-right shunt, pulmonary congestion and dyspnea may occur. Left heart failure may develop.

Diagnostic Tools

  • With an atrial septal defect, a splitting of the second heart sound is frequently heard because closure of the pulmonary valve may be prolonged.

  • With a ventricular septal defect, a systolic murmur is usually present.

  • Postductal coarctation causes disparity in upper and lower body pulses and blood pressure.


  • Some defects may be small, require no treatment, or close spontaneously.

  • Surgical correction of the defect is often required.

  • Treatment for congestive heart failure may be necessary.

  • Prostaglandin E is administered to maintain patency of the ductus arteriosus in preductal coarctation.

  • Administration of the prostaglandin inhibitor indomethacin will initiate closure of the ductus in patent ductuctus arteriosus.


Shock is the collapse of systemic arterial blood pressure. With a severe fall in blood pressure, blood flow does not adequately meet the energy demands of tissues and organs. In addition, the body responds by diverting blood away from most tissues and organs to ensure that vital organs that is, the brain, heart, and lungs receive blood. The tissues and organs that are deemed expendable are severely jeopardized, especially the kidneys, the gut, and the skin. If the individual survives the shock episode, renal failure, gastric ulcers, intestinal infarction, and a sloughing of the skin often follow.

The Baroreceptor Response to Shock

With the beginning of shock, baroreceptor reflexes are activated and the body tries to compensate for the drastically reduced blood pressure. If the cause of shock continues, compensation will become inadequate and deterioration of all organs, including the lungs, heart, and brain, will progress. As the heart and lungs deteriorate, a deadly cycle is initiated. Oxygenation and cardiac output progressively fall, and shock worsens, soon becoming irreversible. Irreversible shock results in death of the individual.

Causes of Shock

Blood pressure depends on the product of the cardiac output (heart rate stroke volume) and TPR. Therefore, anything that causes heart rate, stroke


volume, or TPR to plummet can cause shock. There are six major causes of shock.

Cardiogenic shock can occur following collapse of the cardiac output, which often results from a myocardial infarct, fibrillation, or congestive heart failure.

Hypovolemic shock can occur if there is a loss of circulating blood volume, causing a severe drop in cardiac output and blood pressure. Hemorrhage and dehydration can cause hypovolemic shock.

Anaphylactic shock can occur following a widespread allergic response associated with mast cell degranulation and the release of inflammatory mediators, such as histamine and prostaglandin. These inflammatory mediators cause widespread systemic vasodilatation and edema, which cause TPR and blood pressure to fall dramatically.

Septic shock can occur following a massive systemic infection and the subsequent release of vasoactive mediators of inflammation. These substances initiate widespread vasodilation and edema, causing TPR and blood pressure to collapse. Septic shock may occur with a blood-borne bacterial infection or result from the release of gut contents, for example, with gastrointestinal perforation or a burst appendix. Some bacteria seem to be superantigens capable of rapidly stimulating septic shock.

Neurogenic shock occurs following sudden loss of vascular tone throughout the body. Neurogenic shock may result from an injury to the cardiovascular center of the brain, a spinal cord injury, or deep general anesthesia. It may also occur as a result of a burst of parasympathetic stimulation to the heart that slows the heart rate, with a corresponding decrease in sympathetic stimulation to the blood vessels. This type of occurrence may explain sudden fainting during a severe emotional disturbance.

Burn shock occurs following a severe burn involving a substantial amount of total body surface area. Burn shock is an interesting combination of shock due to the systemic release of the vasodilatory mediators of inflammation causing a fall in TPR, and a collapse of the blood volume as plasma leaks across suddenly porous capillary membranes.

Clinical Manifestations

Specific manifestations will depend on the cause of shock, but all, except neurogenic shock, will include the following:

  • Cool, clammy skin.

  • Pallor.

  • Increased heart and respiratory rate.

  • Dramatically decreased blood pressure.

Individuals with neurogenic shock will have a normal or slow heart rate, and will be warm and dry to the touch.


Diagnostic Tools

  • A measured severe decrease in blood pressure.

  • Decreased or absent urine output.


  • Tissue hypoxia, cell death, and multi-organ failure following a prolonged decrease in blood flow.

  • Adult respiratory distress syndrome from hypoxic destruction of the alveolar-capillary interface.

  • Most patients who die of shock do so because of disseminated intravascular coagulation resulting from extensive tissue hypoxia and subsequent tissue death that leads to massive stimulation of the coagulation cascade.


  • The cause of shock must be identified and reversed if possible.

  • Plasma volume replacement is essential, except with cardiogenic shock. What is used for replacement depends on the cause of shock.

  • Supplemental oxygen or artificial ventilation may be required.

  • Vasopressor agents are given in order to return blood pressure toward normal.

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Handbook of Pathophysiology. Foundations of Health & Disease
Handbook of Pathophysiology
ISBN: 0781763118
EAN: 2147483647
Year: 2004
Pages: 26
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