Chapter 4: Cardiovascular Physiology

Overview

The cardiovascular system consists of the heart, blood vessels, and blood. Its primary function is to transport materials to and from all parts of the body. The heart pressurizes blood and provides the driving force for its circulation through the blood vessels. Blood is propelled away from the heart in the arteries and returns to the heart in the veins. Substances transported throughout the cardiovascular system can be categorized as (1) materials entering the body from the external environment (e.g., O₂ and nutrients); (2) materials moving between cells within the body (e.g., hormones and antibodies); and (3) waste products, from cells, requiring elimination (e.g., heat and CO₂). The exchange of materials between blood and interstitial fluid occurs across capillaries in the microcirculation.

Anatomic Organization of the Cardiovascular System

The heart has four chambers. The two atria serve as reservoirs for blood returning to the heart. The two ventricles are pumps that propel blood through the circulation (Figure 4-1). A septum divides the heart into right and left sides. The right atrium is the reservoir serving the right ventricle, which pumps blood to the pulmonary circulation via the pulmonary artery. Blood returns from the lungs to the left atrium via the pulmonary veins. The left ventricle propels blood, via the aorta, to all other organs in the body through the systemic circulation.

Circulation of blood is completed as the blood from the systemic circulation drains into the right atrium via the superior and inferior venae cavae. The term “right side” of the circulation refers to the pulmonary circulation, which is served by the right ventricle. The term “left side” of the circulation refers to the systemic circulation, which is served by the left ventricle. The right side of the heart propels deoxygenated blood to the lungs, and the left side of the heart propels oxygenated blood to the tissues.

Heart failure results from conditions that impair the ability of the heart to fill with, or to pump out, sufficient blood. Either side of the heart may be affected, or both sides may be affected in some patients. In right-sided heart failure, there is a buildup of pressure that begins with the failing right ventricle and then moves to the right atrium and back to the systemic veins. Clinical signs include jugular venous distention and peripheral edema. The most common cause of right-sided heart failure is preexisting left-sided heart failure. In left-sided heart failure, pressure begins to build in the left ventricle, then back to the left atrium and into the lungs. Clinical signs include pulmonary edema and shortness of breath. The most common cause of left-sided heart failure is myocardial infarction.

The pulmonary and systemic circulations are in series with each other, and all blood passing through one system must flow through the other system. In the pulmonary circulation, blood normally flows at low pressure and receives the entire output of the right ventricle. In pulmonary hypertension, which can cause right-sided heart failure, pressure in the pulmonary artery is elevated, resulting in strain on the right ventricle.

Blood flow from the left ventricle is the same as that from the right ventricle because the two sides operate in series. Output from the left ventricle is distributed at higher pressure through organ systems arranged in parallel. One-way valves between the atria and the ventricles, between the ventricles and their receiving arteries, and within the systemic veins ensure that blood flows in one direction around the circulation.

Blood flow around the circulation is driven by a difference in pressure between the arteries and the veins. The amount of blood flow produced for a given pressure gradient depends on how much resistance to flow is offered by the vascular system.

Pressure

Pressure is defined as a force exerted per unit area. Units of mm Hg are used clinically—1 mm Hg is equivalent to a pressure exerted by a 1 mm Hg column of mercury acting on an area of 1 cm². Flow of fluid occurs as the result of a difference in pressure between two points. In a closed system of fluid-filled tubes, such as the cardiovascular system, the difference in pressure between the aorta and the large central veins drives blood flow through the systemic circulation. Blood is an incompressible fluid, and its volume cannot decrease when the ventricles contract. Instead, blood is pressurized, creating the potential energy for blood flow. Blood pressure decreases over distance as potential energy is lost through friction between blood and blood vessel walls and between blood cells. For a given pressure difference between two points, the amount of flow that occurs depends on resistance.

According to Ohm's law, flow is proportional to the driving pressure gradient (ΔP) and inversely proportional to resistance (R):

Ohm's law may be applied in many situations. For example, stenosis (severe narrowing) of the aortic valve increases resistance to ejection of blood from the left ventricle. According to Ohm's law, left ventricular pressure must increase significantly to maintain sufficient cardiac output. Chronically high left ventricular pressures can result in left ventricular hypertrophy and heart failure.

Resistance

A tube will offer greater resistance (R) to fluid flow if its length (L) increases or if the radius (r) is decreased. Resistance is also greater if the fluid moved has a higher viscosity (η).

Poiseuille's law describes the determinants of resistance:

Radius is the dominant variable that determines resistance because radius is raised to the fourth power, as indicated in ^eq002 . Figure 4-2 applies the principles of ^eq001 and ^eq002 and shows that doubling the vessel radius increases flow by a factor of 16. Physiologic control of vascular resistance is achieved by altering the blood vessel diameter through vasoconstriction and vasodilatation.

Poiseuille's law is also applied when selecting an appropriate sized intravenous catheter to achieve rapid fluid infusion. For example, when attempting resuscitation of a hemodynamically unstable patient, a catheter is selected that maximizes radius and minimizes length to reduce its resistance. In this situation, a large bore intravenous catheter placed in a peripheral vein is preferable to placing a long central venous line.

Resistance in the circulation can occur in series or in parallel. When resistances are arranged in series, the total resistance (R_T) is the sum of individual resistances: R_T = R₁ + R₂ + R₃ + R_n. When resistances are arranged in parallel, such as in organ systems in the systemic circulation, individual resistances contribute as reciprocals: 1/R_T = 1/R₁ + 1/R₂ + 1/R₃ +1/R_n, and the total resistance is much less than for serial resistances.

Compliance

Compliance describes the distensibility of a structure. Changes in the compliance of cardiac muscle affect the ability of the heart to fill with blood. Altered compliance of blood vessel walls changes the volume and pressure of blood.

Compliance is defined as the volume change produced by a given pressure change:

If a structure has low compliance (i.e., it is stiff), applying a normal pressure change (ΔP) will produce a small volume change (ΔV). Alternatively, delivering a normal volume will be associated with a large pressure change.

Low compliance is the central pathology in diastolic heart failure. Chronic hypertension renders the left ventricle thickened and noncompliant, impairing relaxation and diastolic filling. Ventricular compliance may be improved by treatment with calcium channel blockers to aid relaxation of the cardiac myocytes during diastole.

Atria and ventricles are composed of cardiac muscle cells, together with supporting connective tissue. A fibrous ring perforated by four valve openings electrically isolates the atria from the ventricles.

1. The tricuspid valve permits blood flow from the right atrium to the right ventricle.

2. The pulmonic valve conveys blood from the right ventricle to the pulmonary artery.

3. The mitral valve allows blood to flow from the left atrium into the left ventricle.

4. The aortic valve conducts blood from the left ventricle into the aorta.

The mitral and tricuspid valves are termed atrioventricular (AV) valves; the pulmonic and aortic valves are referred to as semilunar valves. The relationships between heart valves, heart chambers, and blood vessels are shown in Figure 4-3.

To understand the clinical implications of congenital heart diseases, it is necessary to have a knowledge of the structure and function of a normal (healthy) heart. Congenital heart diseases can be divided into cyanotic versus noncyanotic. Cyanosis is a bluish coloration of the skin due to the presence of deoxyhemoglobin. In cyanotic heart disease, a right-to-left shunt occurs, whereby deoxygenated blood returning to the right side of the heart bypasses the lungs and reenters the systemic circulation. Structural anomalies responsible for non­cyanotic heart disease allow deoxygenated blood to reach the lungs and become oxygenated.

Cellular Anatomy of Ventricular Muscle

• Cardiac muscle is striated and has an intracellular sarcomere structure that is very similar to that of skeletal muscle (see Chapter 1). Figure 4-4 shows that cardiac muscle cells (myocytes) form a highly branched network.

• Myocytes are surrounded by a sarcolemma (plasma membrane), with transverse tubules (T tubules) that extend into the cell interior.

• Sarcoplasmic reticulum is associated with every T tubule.

• Myocyte connections occur at structures called intercalated disks. The presence of gap junctions in intercalated disks accounts for high electrical conductance (low resistance) between myocytes.

• A single adequate stimulus for action potential in one myocyte results in the rapid spread of excitation to all myocytes via gap junctions. This is known as the all-or-none electrical response of the heart.

In the patient with coronary ischemia, areas of heart muscle can begin to randomly depolarize. These myocytes are referred to as “irritable.” Depolarization of one irritable myocyte rapidly propagates via the all-or-none principle, which can lead to a fatal arrhythmia (ventricular fibrillation or ventricular tachycardia). Fatal arrhythmias are the most common cause of sudden death during a myocardial infarction.

Excitation-Contraction Coupling

Cardiac muscle cells contract without nervous stimulation. Pacemaker cells spontaneously generate action potentials, which spread through gap junctions. Action potentials conducted along T tubules are associated with opening of the voltage-gated Ca²⁺ channels and entry of extracellular Ca²⁺ into the cells. Ca²⁺-induced Ca²⁺ release is triggered from internal sarcoplasmic reticulum stores. Almost all Ca²⁺ that interacts with troponin C to initiate contraction is derived from internal stores. Contraction occurs via the same sliding filament mechanism as described in Chapter 1. Relaxation of cardiac muscle depends on the removal of free cytosolic Ca²⁺. In cardiac muscle, Ca²⁺ is moved back into the extracellular fluid via the Na⁺/Ca²⁺ exchangers in the sarcolemma, which couple the inward transport of 3Na⁺ from the extracellular fluid to the outward transport of one intracellular Ca²⁺. In addition, Ca²⁺-ATPase is used by all types of muscle and pumps Ca²⁺ back into the sarcoplasmic reticulum. Table 4-1 compares the properties of cardiac muscle with those of skeletal and smooth muscle. Differences in the excitation-contraction coupling process, the control of force development, and other factors are highlighted.

Drugs that increase the availability of intracellular free Ca²⁺ cause an increase in myocardial contractility. Digitalis is a cardiac glycoside with multiple cardiac effects, one of which is to increase myocardial contraction via greater loading of intracellular Ca²⁺ stores. This is accomplished via the following steps:

• Digitalis blocks the Na⁺/K⁺-ATPase on the myocyte of the cardiac cell membrane, yielding an increase in intracellular [Na⁺].

• Increased intracellular [Na⁺] alters the electrochemical driving force for Na⁺/Ca²⁺ exchange and results in the reversal of the normal transport direction, bringing Ca²⁺ into the cell.

• Increased intracellular [Ca²⁺] causes more Ca²⁺ to be stored in the sarcoplasmic reticulum.

• Subsequent excitation releases more Ca²⁺, resulting in increased myocardial contraction (a positive inotropic effect).

The Conducting System

The sinoatrial (SA) node is the normal pacemaker of the heart and the origin of each normal heartbeat. The SA node is a collection of specialized myocytes near the site where the superior vena cava enters in the wall of the right atrium. Spontaneous depolarization of the SA node occurs, resulting in the generation of action potentials. Figure 4-5 illustrates the pathway by which excitation (depolarization) spreads through the heart. Action potentials from the SA node spread rapidly throughout the atria via gap junctions between adjacent myocytes.

The atrioventricular (AV) node is the only electrical communication between the atria and the ventricles. It is characterized by very slow electrical conduction, ensuring that atrial contraction is completed before the ventricles are activated. The AV node is continuous with the ventricular conducting system, which consists of the atrioventricular bundle (bundle of His), the left and right bundle branches, and the Purkinje fiber system.

The ventricular conducting system is composed of columns of specialized myocytes containing a small amount of contractile protein. The large diameter of cells reduces electrical resistance and promotes rapid conduction. A thick connective tissue sheath insulates the ventricular conducting system, ensuring that the first electrical connection with working ventricular muscle occurs through Purkinje fibers. Action potentials spread rapidly through the ventricular muscle via gap junctions between the adjacent myocytes. The typical sequence of ventricular activation is from the left side of the ventricular septum near the apex of the heart, and then to the inner surface of the myocardium in both ventricles in the region of the apex. The general spread of excitation is from the inner (endo-) myocardium to the outer (epi-) myocardium and from the apex toward the base.

In Wolff-Parkinson-White syndrome, there is an accessory conduction pathway that creates a bidirectional link between the atria and the ventricles. A normal impulse that conducts from the atria down the AV node to the ventricles can travel up the accessory pathway to reexcite the atria. Alternatively, an atrial impulse can first conduct down the accessory pathway, depolarizing the ventricles, and then travel up the AV node (retrograde) and reactivate the atria. Either possibility can lead to paroxysmal supraventricular tachycardia, which manifests as palpitations, syncope, hypotension, and sometimes heart failure.

Ventricular Muscle Action Potential

Action potentials arriving at the ventricular muscle from the ventricular conducting system trigger the rapid spread of action potentials in all ventricular myocytes. The ventricular muscle action potential has a very long duration (250 ms). Figure 4-6 illustrates the following five phases of the ventricular muscle action potential, 0 through 4:

• Phase 4 is the interval between action potentials when the ventricular muscles are at their stable resting membrane potential.

• Phase 0 is the initial rapid upstroke that occurs immediately after stimulation. Membrane potential moves from its resting value of about −90 mV to a peak of about +30 mV during phase 0.

• Phase 1 is a partial repolarization of the membrane potential from its peak value of +30 mV to about 0 mV.

• Phase 2, also known as the plateau phase, is a dramatic slowing of repolarization.

• Phase 3 is the repolarization of membrane potential back to the resting value.

SA Node Action Potential

Figure 4-7 illustrates the SA node action potential. SA nodal cells are pacemakers because their membrane potential difference depolarizes spontaneously during phase 4, which is called the pacemaker potential or diastolic depolarization. The maximum membrane potential difference in pacemaker cells is about −60 mV, but there is no stable period of resting membrane potential. When the pacemaker potential reaches a threshold voltage of about −40 mV, the action potential is triggered in the cells of the SA node. When compared with ventricular muscle, phase 0 in the SA node is slow and the action potential duration is shorter. Action potential generation in the AV node is qualitatively the same as in the SA node but has a significantly slower phase 4 depolarization. Table 4-2 contrasts the ionic basis of nodal and ventricular muscle action potentials.

A knowledge of the ventricular action potential helps in the understanding of the mechanism of antiarrhythmic agents. There are four classes of antiarrhythmics, based on their site of action: class I, sodium channel blockers; class II, beta blockers; class III, potassium channel blockers; and class IV, calcium channel blockers. The SA node and AV node action potential upstroke (phase 4) is Ca²⁺ dependent, whereas the ventricular upstroke (phase 0) is Na⁺ dependent. As such, class I antiarrhythmics are effective in the treatment of ventricular ectopy (additional heart beats of ventricular origin), and class II and class IV antiarrhythmics are effective in slowing conduction in the SA and AV nodes.

Hierarchy of Pacemakers

The SA node is the normal pacemaker of the heart because it has the most rapid rate of phase 4 (diastolic) depolarization. A person is in normal sinus rhythm when cardiac excitation progresses from the SA node through the entire conduction pathway. The intrinsic rate of SA node firing is about 100 beats/min. Normal parasympathetic tone reduces the SA node firing rate to about 70 beats/min at rest. Endurance athletes have enhanced parasympathetic tone, which results in the classic finding of a slow resting heart rate in trained individuals. The AV node becomes the pacemaker if the SA node fails or transmission to the AV node fails. These patients are in nodal rhythm and typically have resting heart rates of 45–55 beats/min.

In patients with complete heart block (see normal and abnormal heart rhythm), there is no transmission through the AV node; the His-Purkinje fibers pace the heart between 20 and 40 beats/min. Slower pacemaker activity in distal parts of the conducting system allows the heart to continue beating if the SA node fails. However, these patients are likely to have bradycardia (slow heart rate) and reduced cardiac output. For example, sick sinus syndrome occurs when the SA node becomes fibrotic and loses its ability to spontaneously depolarize. Patients have bradycardia and symptoms of hypo­perfusion such as dizziness, syncope, weakness, and fatigue. Abnormal heart rhythms can be diagnosed by observing an electrocardiogram (ECG).

Refractory Periods

The normal mechanical pumping cycle of the heart requires a single excitation event. Any additional action potentials spread rapidly through coupled myocardial cells and produce additional arrhythmias (inappropriate heart beats). If the ventricular rate is excessive, there is insufficient time between beats for the ventricles to fill.

Figure 4-8 shows that ventricular muscle cells have a long, effective (absolute) refractory period from the onset of phase 0 to midway through phase 3. This protects against circular (reentry) conduction, in which control by the pacemaker fails and each spread of excitation through the ventricles triggers the next. Treatment with drugs such as beta blockers and calcium channel blockers, which extend the refractory period, can be effective at preventing reentry arrhythmias. The long refractory period of the AV nodal cells also protects against conduction of rapid atrial arrhythmias to the ventricles. For example, in atrial fibrillation, the atrial rate is between 350 and 500 impulses per minute. Without the refractory properties of the AV node, the ventricular rate would correspond with the atrial rate, which would be incompatible with life.

Autonomic Regulation of Heart Rate

If the autonomic nerves to the heart are cut (such as may occur during a heart transplant), the spontaneous heart rate at rest is approximately 100 beats/min. Parasympathetic tone reduces the typical resting heart rate to approximately 70 beats/min, and parasympathetic stimulation reduces the heart rate further and produces a negative chronotropic effect. Parasympathetic nerves release acetylcholine, which acts via the muscarinic receptors on the nodal cells. The muscarinic receptor antagonist atropine can be used to treat symptomatic bradycardia. Atropine blocks parasympathetic tone, allowing sympathetic tone to continue unchecked. Sympathetic nerve stimulation or circulating catecholamines increase the heart rate and produce a positive chronotropic effect. Sympathetic nerves release norepinephrine, acting on the β₁-adrenergic receptors. Figure 4-9 contrasts the parasympathetic and sympathetic nerve stimulation of the SA node, which underlies the effects on heart rate.

Activation of the sympathetic nervous system occurs in response to stress. Signs include tachycardia as well as pale cool skin, sweating, and dilation of the pupils. It is important to identify the cause of sympathetic drive, which may be intrinsic or extrinsic. Examples of intrinsic activation include pain, fear, anxiety, or hypotension; examples of extrinsic activation include the use of drugs such as caffeine, cocaine, methamphetamines, or ephedrine.

The ECG

The collective spread of action potentials through the myocytes produces small voltages that can be measured on the surface of the body with an ECG. A standard ECG is obtained by placing an electrode on each limb and at six specific locations on the anterior chest wall. In a lead, one electrode is regarded as the positive side of a voltmeter and another is the negative side. A lead reports changes in voltage difference between the positive and negative electrodes. By varying which electrode is regarded as positive or which is negative, a standard set of 12 leads provides a range of views of electrical events in the heart. Figure 4-10 illustrates the major waves on an ECG, together with standard intervals and segments and standard calibrations of time and voltage. Electrical activity in nodal and conducting tissue is not seen on an ECG because the amount of tissue is too small to produce measurable voltage differences at the body surface.

ECG waveforms are produced by momentary changes in voltage differences during the spread of cardiac excitation.

• The P wave represents atrial depolarization.

• The QRS complex is produced by ventricular depolarization.

• The T wave results from ventricular repolarization.

• Atrial repolarization is obscured by the QRS complex.

The QT interval is mostly determined by the duration of phase 2 of the ventricular action potential (Figure 4-6). A longer phase 2 is represented on the ECG as a prolonged QT interval, which may set up a dangerous form of ventricular tachycardia called torsade de pointes. Class III antiarrhythmic drugs cause a prolonged phase 2 of the action potential because repolarization is delayed when the K⁺ channels are blocked. Careful monitoring of the QT interval is a must when initiating therapy with a class III drug (e.g., amiodarone).

Heart muscle mass is depicted as amplitude on the ECG. For example, the P wave is smaller than the QRS complex because atria have less mass than ventricles. Left ventricular hypertrophy is identified if the sum of voltage deflections for the S wave in lead V₁ and the R wave in leads V₅ or V₆ ≥ 35 mm. Similarly, right ventricular hypertrophy is characterized by an R wave that is larger than the S wave in V₁.

Lead Systems

ECG signals are vector quantities, since charge movement through the heart has both direction and magnitude. Two lead systems have been devised as follows (Table 4-3):

1. The frontal (vertical) plane is defined by six limb leads.

2. The transverse plane is perpendicular to the frontal plane and is defined by six precordial chest leads.

Table 4-3 lists the placement of standard ECG electrodes. Every lead has a unique axis within its plane. Frontal plane leads are composed of three bipolar limb leads (I, II, and III), in which the positive electrode placed on one limb is compared to a negative electrode placed on another limb. These electrode connections to the left arm, the right arm, and the left leg form an equilateral triangle with the heart at its center, called Einthoven's triangle (Figure 4-11A). Three augmented unipolar limb leads (aV_R, aV_L, and aV_F) are defined by using each limb electrode as a positive electrode referenced to a null point obtained by adding the potential from the other two limb leads.

The frontal plane is a circle in which each lead occupies one axis. The hexaxial reference system produced by the six frontal plane leads is shown in Figure 4-11B. This system provides a means of describing the direction of an electrical vector produced by the spread of electrical activity in the heart. The direction of the mean QRS vector is used most often because it is affected by common pathology (e.g., ventricular hypertrophy; bundle branch block). Each precordial chest electrode is a positive electrode terminal and can be compared to the virtual center of the heart, estimated electronically from the average of the limb leads.

Electrical Vectors

Figure 4-12 illustrates the concept of an electrical vector and how one may appear on different ECG leads. The ECG is an extracellular recording that views cells from the outside. Resting myocytes have a negative voltage on the inside of the cell membrane or, stated differently, they have a positive voltage on the outside of the cell membrane. A region of myocytes that has depolarized is negative on the outside when compared to neighboring cells at rest. This creates a voltage difference between adjacent regions, which is a vector quantity.

Vectors are represented using an arrow to illustrate their size and direction. By convention, the head of the vector (arrow) points toward the positive voltage (toward tissue not yet depolarized). The average vector changes momentarily in size and direction, producing the waves seen on an ECG. All 12 leads simultaneously report the spread of excitation through the heart when viewed from different angles. The waveform is different on each lead because each lead has a different orientation to the heart.

A major event is recorded by a lead when the vector direction is parallel to the axis of the lead. No net deflection is recorded by a lead if the vector is perpendicular to the axis of the lead. This concept is used to estimate the direction of vectors by assessing the ECG. The largest net deflection occurs in the lead that is roughly parallel to the electrical event. If a lead shows no net deflection (i.e., the event is isoelectric), then the electrical vector is perpendicular to the axis of that lead. Knowledge of the orientation of leads in the frontal plane is necessary to estimate vector direction in this way.

Mean Electrical Axis of Ventricular Depolarization

In principle, the axis (vector direction) of any part of the ECG can be determined. The mean axis of ventricular depolarization is most commonly evaluated by analyzing the QRS complex. The mean QRS axis has a normal range of −30° to +90° on the hexaxial reference system. Axes in the range of −30° to −90° are termed left axis deviation; axes in the range of +90° to +150° are termed right axis deviation.

Ventricular hypertrophy is the thickening (or enlargement) of the myocardium and is a common cause of axis deviation. An increased left ventricular mass biases the direction of the net QRS vector toward the left. Similarly, patients with right ventricular hypertrophy usually have a right axis deviation. Left axis deviation can also occur when the abdomi­nal contents physically push the heart up and to the left, such as occurs in patients who are obese or pregnant.

Mean electrical axis usually can be estimated from an ECG by inspection alone. Figure 4-13 shows an example of left axis deviation. The sum of all deflections (net deflection) in the QRS complex of lead aV_R is near zero. The mean axis is, therefore, approximately perpendicular to this lead, corresponding to the axis of lead III. As expected, there is a large net QRS deflection recorded in lead III, confirming that the electrical vector in this case is roughly parallel to lead III (and perpendicular to aV_R). Because the net deflection is negative in lead III, the QRS vector is directed at the negative end of lead III at an angle of approximately −60° on the hexaxial reference system.

Normal and Abnormal Heart Rhythm

An ECG is routinely used to record heart rate and rhythm. Figure 4-14 compares a normal lead II record with several common arrhythmias. In normal sinus rhythm, a P wave is followed at normal intervals by a QRS complex and a T wave (see Figure 4-14A). Heart rate, in beats/min, is calculated by dividing the R-R interval (expressed in seconds) into 60. Heart rate above 100 beats/min is described as tachycardia; a heart rate below 60 beats/min is described as bradycardia.

A premature atrial beat is revealed when a P wave occurs earlier than expected and is followed by the usual QRS complex and T wave (see Figure 4-14B). Paroxysmal atrial tachycardia is a rapid run of heart beats that begins suddenly and ends abruptly; P waves precede each QRS complex, showing that beats originate in the atria (see Figure 4-14C). In atrial fibrillation (see Figure 4-14D), there is chaotic electrical activity; no P waves can be defined, and QRS complexes occur at irregular intervals, reflecting random depolarization of the AV node. The resulting pulse is classically described as “irregularly irregular.” In atrial fibrillation, stasis of blood often occurs in the atrial appendages due to the loss of atrial contraction. Anticoagulation therapy may be needed to counter the risk of thromboembolism.

Heart block is a group of abnormalities characterized by varying degrees of impaired conduction through the AV node.

• In first-degree heart block, the PR interval is abnormally long at a normal heart rate, indicating delayed conduction through the AV node (see Figure 4-14E).

• Second-degree heart block is characterized by intermittent failure of the AV node so that not every P wave is followed by a QRS complex. There are two types of second-degree heart block: Mobitz type I (Wenckebach) block is a benign rhythm whose origin is the AV node (see Figure 4-14F). It is characterized by progressive lengthening of the PR interval on consecutive beats, followed by a dropped QRS complex. Mobitz type II second-degree heart block is a more ominous rhythm and has its origin in the distal His-Purkinje system. It is characterized by dropped ventricular beats that are not preceded by PR interval lengthening (see Figure 4-14G). The block may persist for two or more beats, yielding an atrial to ventricular ratio of 2:1, 3:1, and so on. Type II heart block may progress quickly to complete heart block.

• Third-degree (complete) heart block occurs when the atrial rhythm is completely dissociated from the ventricular rhythm (see Figure 4-14H). There is no relation between P waves and QRS-T complexes. Complete AV block may come and go. When a period of block begins, there is often an interval of 5–30 seconds before the ventricular conducting system takes over as the pacemaker. During this period, the patient faints due to lack of cerebral blood flow. This pattern of periodic fainting is called Stokes-Adams syndrome. Treatment of third-degree heart block includes implanting a pacemaker to maintain an adequate heart rate and blood pressure.

Arrhythmias that impact the timing and performance of ventricular contraction may arise from within the ventricles rather than being the result of abnormalities of atrial rhythm or AV node. Premature ventricular contractions (PVCs) occur with no preceding P wave (see Figure 4-14I). The origin of the ventricular excitation is within the ventricular conducting system or from a ventricular muscle focus. The QRS complex is often an irregular shape, reflecting a pattern of electrical spread that differs from a normal pacemaker source. Abnormal ventricular pacemakers, which are often damaged or unstable areas of ventricular myocardium, can drive ventricular tachycardia. This is a dangerous type of arrhythmia because the beating frequency may be too high to allow adequate ventricular filling. Ventricular tachycardia may degenerate into ventricular fibrillation associated with random chaotic electrical activity (see Figure 4-14J). Ventricular fibrillation is fatal within a short period of time due to lack of coordinated ventricular contraction.

PVCs are either asymptomatic or are sensed as palpitations. They occur in most of the normal population and are benign. However, in the setting of a current or past myocardial infarction (MI), PVCs may become more frequent. Two episodes of PVCs coupled together are known as couplets; three or more episodes of PVCs coupled together are known as ventricular tachycardia and are associated with increased mortality. The most common cause of death during an MI is fatal arrhythmia (ventricular fibrillation or ventricular tachycardia).

Arrhythmias are often caused by electrolyte abnormalities. For example, as plasma K⁺ concentration increases, hyperkalemia produces the following sequence of cardiotoxic effects: peaked T waves, prolonged PR interval, widening of the QRS complex, blockage of the AV node, loss of P waves, and eventual merging of the QRS complex with the T wave, which produces a “sine wave” pattern that can degenerate into ventricular fibrillation or asystole.

The cardiac cycle is described as the repetitive electrical and mechanical events that occur with each beat of the heart. Electrical events precede mechanical events, which result from the entry of Ca²⁺ into the myocytes during cardiac action potentials. ECG waves can be correlated with mechanical events. The P wave precedes atrial contraction. During the PR segment, there is no apparent electrical activity in the ECG. During this time, there is conduction through the AV node and the ventricular conducting system. The QRS complex precedes contraction of the ventricle. The T wave of ventricular repolarization precedes ventricular relaxation.

Blood is pressurized by ventricular contraction and then ejected into the circulation during systole. Muscle relaxation is followed by ventricular filling during diastole. Mechanical events of the cardiac cycle occur in five phases (Figure 4-15):

1. Ventricular diastole. Throughout most of ventricular diastole, the atria and ventricles are relaxed. The AV valves are open, and the ventricles fill passively.

2. Atrial systole. During atrial systole, a small amount of additional blood is pumped into the ventricles.

3. Isovolumic ventricular contraction. Initial contraction increases ventricular pressure, closing the AV valves. Blood is pressurized during isovolumic ventricular contraction.

4. Ventricular ejection. The semilunar valves open when ventricular pressures exceed pressures in the aorta and pulmonary artery. Ventricular ejection (systole) of blood follows.

5. Isovolumic relaxation. The semilunar valves close when the ventricles relax and pressure in the ventricles decreases. The AV valves open when pressure in the ventricles decreases below atrial pressure. Atria fill with blood throughout ventricular systole, allowing rapid ventricular filling at the start of the next diastolic period.

Wiggers Diagram

Several variables can be measured to assess the electrical and mechanical events that occur with each beat of the heart. Electrical events can be followed using an ECG. Pressure changes in each chamber of the heart and in the central blood vessels can be measured by cardiac catheterization. Volume changes can be derived by echocardiography. Heart sounds can be recorded as a phonocardiogram. The Wiggers diagram, shown in Figure 4-16, integrates all of these variables and allows correlation of the following electrical and mechanical events during the cardiac cycle:

• Left ventricular pressure is normally 0–10 mm Hg at the end of diastole but increases rapidly as the ventricles contract. The mitral valve closes when the left ventricular pressure exceeds left atrial pressure. The mitral and tricuspid valves are not forced back into the atria during ventricular contraction because they are anchored to the papillary muscles via the fibrous chordae tendineae. The aortic valve opens when the left ventricular pressure increases to a value just higher than the aortic diastolic pressure, typically about 80 mm Hg. Forceful contraction during early ventricular ejection increases the left ventricular pressure to a peak value of about 120 mm Hg, corresponding to the aortic systolic blood pressure. As the ventricular contraction weakens, the left ventricular pressure decreases. When the left ventricular pressure decreases just below the aortic blood pressure, the aortic valve closes. Left ventricular pressure decreases rapidly as the muscle relaxes; when the pressure decreases just below the left atrial pressure, the mitral valve opens. Ventricular filling occurs at low pressures, reflecting the left atrial pressure.

• Aortic pressure increases in concert with the left ventricular pressure during ventricular ejection. Vibration caused by closure of the aortic valve causes a deviation in the aortic pressure, called the dicrotic notch. The aortic pressure decreases between ventricular beats as blood continues to flow from the aorta into the circulation. Diastolic blood pressure is the aortic pressure minimum recorded just before the next ventricular ejection.

• Left atrial pressure normally is no greater than 10 mm Hg at any time during the cardiac cycle. Three small peaks, or waves, are identified and denoted as a, c, and v. The a wave is produced by atrial systole. The c wave occurs when the mitral valve bulges into the left atrium during ventricular contraction. The v wave reflects passive atrial filling during ventricular systole.

Although the Wiggers diagram includes left-sided events, similar atrial pressure waves occur on the right side of the heart. Inspection of the external jugular vein during physical examination provides information about right atrial pressure. A “cannon” a wave is seen in jugular venous pulsations if the atria contract when the AV valves are closed. This occurs in complete heart block when the atria and the ventricles contract independently. Similarly, a prominent v wave can be seen in the jugular vein during tricuspid regurgitation as additional blood enters the right atrium from the right ventricle.

Right-sided heart failure results in increased right-sided heart pressures and jugular venous distention. The abdominojugular reflux test can assist in the clinical diagnosis of right-sided heart failure. This test is performed by pressing on the liver to increase venous return to the right side of the heart while observing jugular venous distention. In a healthy patient, there is a slight rise in jugular distention that quickly returns to its previous level. In a patient with right-sided heart failure, jugular distention is pronounced and remains pronounced because the failing right ventricle is unable to accommodate increased venous return.

• The Wiggers diagram includes changes in left ventricular volume during the cardiac cycle. Left ventricular end-diastolic volume is about 140 mL in a normal heart at rest. Ventricular systole ejects about half of the end-diastolic volume at rest, producing a typical end-systolic volume of about 70 mL. Ventricular filling is rapid in early diastole. Ventricular volume reaches a plateau during passive filling, called diastasis, because ventricular compliance decreases as the chamber fills. Atrial systole produces a final boost to achieve end-diastolic volume. The stroke volume ejected during ventricular systole is the difference between end-diastolic volume and end-systolic volume.

• The Wiggers diagram includes a phonocardiogram, which is a recording of sounds that occur during the cardiac cycle. The first heart sound (S₁) is caused by closure of the atrioventricular valves, and the second heart sound (S₂) is caused by closure of the pulmonic and aortic valves. The third (S₃) and fourth (S₄) heart sounds may be normal sounds associated with ventricular filling. Abnormal heart sounds are most commonly recorded when the heart valves are defective.

Atrial systole normally contributes about 10% of ventricular filling at rest. As the heart rate increases, the amount of time necessary for passive ventricular filling decreases, and the contribution of atrial systole can increase to over 30% of end-diastolic volume. Patients with atrial fibrillation lack this “atrial kick” and may have inadequate ventricular filling, particularly during physical activity. Patients with cardiovascular disease may rely on the atrial kick to maintain adequate cardiac output; without it, they may develop heart failure.

Normal Heart Sounds

Heart valves prevent reverse blood flow. AV valves prevent backflow of blood into the atria during ventricular contraction, and semilunar valves prevent backflow of blood from the aorta and pulmonary artery to the ventricles during diastole. Heart valves open and close passively in response to pressure differences across the valves. Valve opening is silent in the normal heart. Closure of the valves produces vibrations that are heard as heart sounds. Figure 4-17 shows timing of the heart sounds in relation to events seen on an ECG.

The first heart sound (S₁), a “lub,” is generated by the closing of the mitral (M₁) and tricuspid (T₁) valves. Closure of the tricuspid valve follows so closely after mitral valve closure that these sounds are perceived as a single sound. The larger diameter of the AV valves produces a low-pitched sound that is best heard with the bell of a stethoscope. The anatomic complexity of the AV valve apparatus contributes to the longer duration of the first heart sound compared to the second.

The second heart sound (S₂), a “dup,” occurs when the semilunar valves snap closed at the onset of diastole. The S₂ has a crisper, higher pitch and shorter duration, and is best heard with the diaphragm of a stethoscope because the pressure gradients producing valve closure are larger. The second sound is composed of aortic (A₂) and pulmonic (P₂) valve closures. During inspiration, A₂ and P₂ are often heard as separate sounds (Figure 4-17). The splitting of S₂ is caused by delayed closure of the pulmonic valve and earlier closure of the aortic valve. Decreased intrathoracic pressure on inspiration allows the distensible pulmonary circulation to receive a greater stroke volume from the right ventricle, prolonging right ventricular systole and delaying the P₂ sound. Increased pulmonary vascular capacitance during inspiration also reduces venous return to the left atrium, which shortens left ventricular systole and produces an earlier A₂ sound.

Paradoxical splitting of S₂ occurs when closure of the aortic valve is delayed, causing P₂ to occur first, followed by A₂. The most notable causes are aortic stenosis (which prolongs left ventricular systole) and left bundle branch block (which delays the onset of left ventricular contraction).

A third heart sound (S₃) is sometimes heard in normal persons. It is a low-pitched, early diastolic sound heard best at the apex of the heart, and is caused by vibrations due to rapid ventricular filling. S₃ may be normal in children and in adults after exercise.

A fourth heart sound (S₄) can be caused by atrial systole. It is a low-pitched, late diastolic or presystolic sound. S₄ may be heard normally in young children but is usually associated with cardiovascular pathology in adults. In atrial fibrillation, there is no atrial kick; these patients, therefore, cannot have an S₄. In patients with tachycardia, S₄ may be fused with an S₃ sound, producing a summation gallop.

Common Valvular Abnormalities

Sounds in the vascular system are produced by turbulent blood flow. Blood flow through blood vessels is normally silent because flow is laminar in nature. Laminar flow means that the blood flow is smoothly distributed throughout the vessel, with the fastest flow in the center of the lumen and the slowest flow where blood is in contact with the walls of the blood vessel. The likelihood of noisy turbulent flow increases with high blood flow velocity. Velocity of flow is accelerated across narrow areas of blood vessels or heart valves. This creates turbulence, leading to noises known as bruits in blood vessels and as murmurs in the heart. Murmurs are best heard “downstream” from their origin along the course of the turbulent blood flow.

There are two types of valve abnormalities that produce heart murmurs. Stenosis is a narrowing of the valve that creates higher velocity blood flow through the partially constricted opening and produces a murmur when the valve is normally open. Insufficiency (also called incompetence or regurgitation) is failure of a valve to close completely. When valves do not close properly, there is some backflow of blood at a time when the valve should be closed. For example, failure of the AV valve to close completely results in the flow of blood back into the atrium during ventricular contraction.

Figure 4-18 illustrates the murmur of aortic stenosis. This is a systolic murmur that occurs when the velocity of blood flow accelerates through the narrowed valve. The murmur is loudest in the middle of systole when the pressure gradient across the valve is greatest. Aortic stenosis leads to reduced stroke volume and a decrease in systolic pressure in the aorta. Pressure in the left ventricle is increased above normal to eject the stroke volume. Aortic stenosis is most common in elderly patients and is caused by calcification of the valve. Three cardinal symptoms of aortic stenosis are angina, syncope, and congestive heart failure.

Figure 4-19 illustrates the murmur of mitral insufficiency. This is a systolic murmur produced by blood flowing backward through the valve when it is normally closed. This produces a soft, holosystolic (throughout systole) murmur. Mitral insufficiency results in an increased volume load to the left atrium and ventricle. Forward flow into the aorta usually does not change significantly unless congestive heart failure occurs late in the course of the disease. Increased left atrial pressure and large atrial v waves should be predicted due to the backflow of blood from the left ventricle during systole, but they often are absent due to increasing compliance of the left atrium during the course of the disease.

Mitral valve prolapse is billowing of floppy, redundant mitral leaflets back into the left atrium during ventricular systole. Sudden tensing of floppy leaflets produces the classic auscultatory finding of midsystolic click. Mitral valve prolapse can be accompanied by mitral insufficiency. If the prolapsing leaflets do not come together properly, then a late systolic murmur can be heard, corresponding to regurgitant flow back into the atrium.

Figure 4-20 illustrates the murmur of aortic insufficiency. A normal aortic valve controls the large pressure difference between the aortic diastolic blood pressure and the left ventricular diastolic pressure. A leaking aortic valve allows regurgitation of flow backward through the valve during diastole, when it should normally be closed. The murmur decreases in intensity as the pressure gradient across the valve decreases in late diastole. Retrograde flow from the aorta into the left ventricle during diastole increases the ventricular end-diastolic volume. This subsequently increases the stroke volume and the aortic systolic blood pressure. An abnormal blood flow from the aorta into the ventricle during diastole causes the aortic diastolic pressure to decrease. Increased systolic pressure and decreased diastolic pressure produce a large arterial pulse that is the basis of several physical findings, including (1) Corrigan's pulse, the “water-hammer pulse” that collapses rapidly; (2) Quincke's pulse, when pulsations are noted in the root of the fingernail bed while lightly pinching the tip of the fingernail; and (3) de Musset's sign, when the head bobs with each pulsation. Aortic insufficiency may result from valve disease (e.g., rheumatic heart disease) or aortic root dilation (e.g., syphilis or Marfan's syndrome).

Figure 4-21 illustrates the murmur of mitral stenosis. High resistance across the mitral valve produces turbulent blood flow into the left ventricle, causing a soft crescendo murmur. There may also be an “opening snap”, created by rapid movement of the contracted mitral valve apparatus and heard as a sharp sound immediately after S₂. Systemic blood pressure may be reduced in mitral stenosis because of decreased filling of the left ventricle, resulting in a decrease in stroke volume. Left atrial pressure is often elevated, causing pulmonary congestion.

Mitral stenosis is the most common valvular lesion caused by rheumatic heart disease. However, proper treatment of streptococcal pharyngitis with penicillin can prevent the valvular complications of rheumatic fever.

Patent ductus arteriosus produces a characteristic continuous murmur in neonates. The ductus arteriosus is a normal fetal connection between the aorta and the pulmonary artery, which normally closes near the time of birth. When this connection remains open, blood flows from the high pressure in the aorta to the lower pressure in the pulmonary artery. The murmur is continuous because there is a pressure gradient from the aorta to the pulmonary artery throughout the entire cardiac cycle. The incidence of patent ductus arteriosus is high in premature infants.

Patent ductus arteriosus produces increased pulmonary blood flow and greater filling of the left atrium and ventricle. A large stroke volume increases systolic aortic blood pressure. Runoff of blood from the aorta through a patent ductus during diastole accounts for reduced aortic diastolic blood pressure. There is a large arterial pulse wave similar to that seen in aortic insufficiency in the adult. Prostaglandin E and low arterial partial pressure of O₂ (P_ao₂) maintain patency of the ductus, so that administering O₂ and prostaglandin inhibitors (e.g., indomethacin) promotes closure of the patent ductus arteriosus.

Flow murmurs can occur in a structurally normal vascular system. Anemia causes flow murmurs because cardiac output is increased to maintain delivery of O₂ to the tissues. There is increased velocity of blood flow and decreased blood viscosity in anemia, which can result in turbulent flow and cause vibrations. Turbulent flow occurs mostly at the cardiac valves and at bifurcations of the large and the medium-sized arteries.

Pressure-Volume Loops

Figure 4-22 shows the cardiac cycle of the left ventricle, represented by plotting pressure against volume to produce a loop. At point A, the ventricle contains the end-systolic blood volume, and the mitral valve opens. The ventricle fills until end-diastolic volume is achieved at point B, where the mitral valve is closed by the onset of ventricular contraction. Isovolumic contraction increases pressure to point C, which corresponds to diastolic blood pressure and opening of the aortic valve. Ventricular ejection propels pressure through its peak value at point D, corresponding to aortic systolic pressure, until the aortic valve closes at point E. Pressure decreases back to point A during isovolumic relaxation, completing one cardiac cycle. The width of the pressure-volume loop is the stroke volume (the difference between end-diastolic volume and end-systolic volume). The area within a pressure-volume loop is an index of stroke work.

Cardiac output is the volume of blood pumped by each ventricle per minute. Cardiac output (Q_T) is regulated by autonomic nerves and hormones through changes in heart rate (HR) or stroke volume (SV). In adults, cardiac output is usually expressed in liters per minute:

HR is measured by feeling a pulse in an artery that is close to the skin or it is seen on an ECG. SV can be estimated from an echocardiogram. Cardiac output is then calculated using ^eq004 .

Example

If resting SV is 70 mL and HR is 70 beats/min, then

Cardiac output can also be measured clinically in the cardiac catheterization laboratory, using a thermodilution method whereby a cold saline solution of known temperature and volume is injected into the right atrium. The reduction in blood temperature measured downstream in the pulmonary artery is a function of cardiac output.

The Fick Principle

A traditional physiologic method for calculating cardiac output applies the Fick principle, which derives blood flow from variables related to O₂ consumption. The O₂ consumption (Vo₂) of a specific organ is the product of blood flow and the decrease in O₂ content between the artery and the vein (Cao₂ — Cvo₂). In the Fick equation (^eq005 ), these terms are rearranged to determine blood flow. Cardiac output can be calculated by applying the Fick concept to the entire body, relating total body O₂ consumption to the difference in O₂ content between blood in the systemic arteries and the mixed venous blood sampled from the pulmonary artery or the right ventricle:

Example

A person consumes 250 mL of O₂ per min. Arterial O₂ content is 20 mL of O₂ per dL of blood, and the O₂ content of mixed venous blood is 15 mL of O₂ per dL of blood:

Hypovolemic and cardiogenic shock are classic examples of low cardiac output, which results in inadequate tissue perfusion (shock). Paradoxically, low cardiac output is not a universal finding in patients in shock. In septic shock, for example, there is inadequate tissue perfusion with high cardiac output. Release of inflammatory cytokines during sepsis, which results from an overwhelming systemic infection, has many effects, which together may cause shock:

• Decreased systemic vascular resistance (decreased afterload) to the point where increasing cardiac output cannot maintain blood pressure.

• Increased capillary permeability, causing edema and loss of effective circulating volume (decreased preload).

• Reduced cardiac contractility, caused by the release of myocardial depressant factors.

Ejection Fraction

Ejection fraction is a simple measurement of ventricular performance and describes the fraction of end-diastolic volume ejected from the ventricle during systole:

Example

A healthy man of average size is found to have a resting end-diastolic volume of 140 mL and a resting SV of 70 mL:

Congestive heart failure is classified as either systolic dysfunction (loss of contractility) or diastolic dysfunction (impaired compliance). The ejection fraction is decreased in patients with systolic dysfunction due to the loss of contractility, but it is maintained in patients with diastolic dysfunction.

Cardiac Index

The adequacy of cardiac output should be considered in relation to tissue metabolic demand, which varies by body size and activity. Therefore, cardiac output is expressed relative to the body surface area (BSA) as the cardiac index (CI):

Example

A 24-year-old woman is found to have a resting cardiac output of 4.0 L/min. Her body surface area is 1.40 m²:

The Frank-Starling Principle

The Frank-Starling principle, illustrated in Figure 4-23, describes the relationship between SV and end-diastolic volume. Increased diastolic filling produces greater stretch of heart muscle, resulting in a larger SV. The mechanism involves more optimal overlap between the thin and thick muscle filaments as preload increases and increased sensitivity of troponin C to Ca²⁺ as cardiac muscle is stretched. End-diastolic volume is the most important determinant of SV. Outputs from the left and right sides of the heart are also equalized as a result of the Frank-Starling principle because the output of one side becomes the venous return of the other side.

Assessment of Ventricular Function

SV is determined by three factors: preload, afterload, and contractility. Ventricular preload is the end-diastolic volume created by venous return. Ventricular afterload is the sum of factors that oppose ejection of blood during systole. Contractility is the intrinsic vigor of muscle contraction related to the biochemical state of the cell.

Preload

Preload is enhanced by several factors, including:

• Increased circulating blood volume.

• Rhythmic skeletal muscle contraction, which propels blood toward the heart due to the presence of one-way valves in veins.

• Deep inspiration, which decreases intrathoracic pressure and increases abdominal pressure, promoting venous return to the thorax.

• Atrial systole.

• Venoconstriction, which reduces venous pooling and promotes the return of blood to the central circulation.

Figure 4-24 shows representations of the effect of increased preload on SV, using either the Frank-Starling curve or a pressure-volume loop.

Preload can be quickly increased at the bedside by placing the patient in the Trendelenburg position (supine with the head lower than the feet), as well as by using drugs and intravenous fluids. Interventions that increase preload are often used to improve cardiac output, but this is not always beneficial. For example, during an acute MI, the O₂ supply to the myocardium is disrupted, and treatments that reduce myocardial O₂ consumption are desirable. Nitrates can be used to reduce preload, decreasing the ventricular wall tension and, as a result, decreasing the myocardial O₂ consumption.

Afterload

The second factor that determines SV is afterload. The major component of afterload is resistance to blood flow created by the circulation, with the small muscular arteries and arterioles offering the most vascular resistance. Blood pressure is used as an index of afterload because it is created by blood flow through vascular resistance.

Vascular resistance is only one source of ventricular afterload. Another source is low compliance of the ventricle or great vessels, which impedes the ejection of blood. Stenosis of the semilunar valves is a pathologic example of increased afterload. Afterload is represented using a pressure-volume loop, as shown in Figure 4-25 by a line drawn from the end-diastolic pressure-volume point (B) to the end-systolic pressure-volume point (E). The slope of this line represents all factors opposing the volume change that occurs in systole. If the slope of the line is increased, there is higher systolic pressure and/or reduced SV.

Afterload reduction is an important therapeutic approach in the treatment of heart failure to allow higher SV without increasing myocardial O₂ consumption. One of the main categories of the afterload-reducing drugs used in congestive heart failure is angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers. The effects of these drugs go beyond afterload reduction to include inhibiting the maladaptive neurohormonal effects of angiotensin II on cardiac remodeling in congestive heart failure.

Contractility

Contractility is the third factor that determines SV and is the intrinsic vigor of muscle contraction under defined loading conditions. Several graphic representations of altered contractility are shown in Figure 4-26. In isolated muscle, altered contractility is indicated as a change in the maximal velocity of shortening (V_max) (see Figure 4-26A). V_max is obtained by extrapolating the load-velocity relation to a theoretic zero load. An increase in V_max implies faster myosin cross-bridge cycling.

Contractility is more difficult to define in the intact heart than in isolated muscle. The rate of pressure change in the left ventricle at the onset of isovolumic contraction is one indicator of contractility (see Figure 4-26B). A left shift in the Frank-Starling relation also indicates greater contractility, whereas a right shift indicates depression of function (see Figure 4-26C).

Contractility can be assessed using a pressure-volume loop by examining the rate at which the end of systole is reached. The slope of a line drawn from a zero pressure point to the end-systolic pressure-volume point (E) is an index of contractility (see Figure 4-26D). For a given preload and afterload, an increase in the slope of this line yields greater SV and higher systolic pressure, indicating increased contractility.

Agents that increase contractility are called positive inotropes, and those that decrease contractility are called negative inotropes. Catecholamines are the most important physiologic examples of positive inotropes. The basis for increased contractility is increased Ca²⁺ entry into the myocytes. The rate of Ca²⁺ reuptake is also increased, causing more rapid muscle relaxation, which is necessary at faster heart rates. Catecholamines occupy myocardial β₁-adrenoceptors, causing the generation of intracellular cyclic adenosine monophosphate (cAMP) and activation of protein kinase A. Cellular mechanisms that underlie increased contractility are summarized in Table 4-4. “Sympathomimetic” drugs that are positive inotropes include dobutamine, dopamine, and isoproterenol. Using positive inotropes to treat heart failure increases mortality; therefore, these drugs must be used with caution.

Left Ventricular Failure

Ventricular failure can result from systolic or diastolic dysfunction, illustrated in Figure 4-27 using pressure-volume loops. Systolic dysfunction occurs when myocardial contraction is weak, most commonly following a MI. Patients have reduced SV despite normal preload; contractility is reduced (see Figure 4-27A) and tachycardia is present to maintain cardiac output. Treatment is aimed at afterload reduction to increase SV.

In diastolic dysfunction, there is low cardiac muscle compliance and poor filling. Patients have a right shift of the end-diastolic pressure-volume point (see Figure 4-27B). Increased ventricular diastolic pressure at any given volume indicates low compliance. Common causes include ischemic heart disease and ventricular hypertrophy from longstanding hypertension. Treatment is aimed at reducing blood volume and preload and promoting ventricular relaxation.

Blood flows through a circuit of vessels consisting of, in sequence, arteries, arterioles, capillaries, venules, and veins. Each of these vascular segments has different attributes and functions within the circulation.

• Large arteries (e.g., the aorta) are high pressure reservoirs that store energy in their elastic walls during ventricular ejection and release it during diastole to maintain blood flow.

• Small muscular arteries and arterioles are the site of greatest vascular resistance in the circulation. This accounts for the large decrease in blood pressure that occurs across this segment of the circulation (Figure 4-28). Neurohumoral regulation of arteriolar tone controls vascular resistance and has a major effect on arterial blood pressure.

• Capillaries are thin-walled vessels that provide a large surface area for the exchange of gases, nutrients, and wastes. Imbalances of hydrostatic and osmotic pressure gradients across the capillary walls are the most common causes of edema (swelling due to excess interstitial fluid volume).

• Venules and veins present little resistance to flow. The venous system is a high capacitance, low pressure reservoir. The largest blood volume in the cardiovascular system is in the systemic veins (the second largest blood volume is in the pulmonary vasculature). Small muscular veins assist in the regulation of venous return. Increased venous tone reduces the capacitance of veins, causing increased venous return. Larger cardiac preload results in increased cardiac output via the Frank-Starling mechanism.

Systemic Arterial Blood Pressure

The pressure difference across the circulation from the arteries to the veins drives blood flow. An adequate arterial blood pressure is necessary to sustain cardiac output. Arterial blood pressure is a major physiologic controlled variable subject to short-term and long-term negative feedback regulation. Several arterial pressure indices are discussed below (Figure 4-29):

• Systolic blood pressure is the peak pressure recorded in the central arterial system and occurs during ventricular ejection.

• Diastolic blood pressure is the minimum pressure recorded in the central arterial system and occurs just before the start of ventricular systole.

• Pulse pressure is the difference between systolic blood pressure and diastolic blood pressure. Pulse pressure is reflected by the strength of the arterial pulse wave palpated in the peripheral arteries.

• Mean arterial pressure (MAP) is a time-weighted average of systolic blood pressure and diastolic blood pressure. Systole occupies about one third of the cardiac cycle under resting conditions and diastole occupies about two thirds, giving rise to the following estimate of MAP:

  

Example

Blood pressure measured by cuff inflation in the upper arm of a healthy person is 120/80 mm Hg. Systolic blood pressure = 120 mm Hg; diastolic blood pressure = 80 mm Hg; and pulse pressure = 120 − 80 = 40 mm Hg.

Hypertension, or high blood pressure, is a risk factor associated with several diseases, including heart attack, stroke, and renal failure.

• Normal blood pressure is defined as a systolic blood pressure < 120 mm Hg but > 90 mm Hg, and diastolic blood pressure is < 80 mm Hg but > 60 mm Hg.

• Systolic blood pressure between 120–139 mm Hg and diastolic blood pressure between 80–89 mm Hg is considered prehypertension.

• Hypertension is defined as systolic blood pressure > 140 mm Hg or diastolic blood pressure > 90 mm Hg.

Hypertension causes end-organ damage and may be an asymptomatic disease for many years before being diagnosed. To assess the severity and duration of hypertension, the physician can examine the interior of the eye using an ophthalmoscope to assess the extent of retinal artery damage.

Determinants of Systemic Blood Pressure

MAP is proportional to cardiac output and vascular resistance. Factors that increase cardiac output or vascular resistance increase MAP. To understand specific determinants of blood pressure indices, it is necessary to interpret a patient's vital signs. Systolic blood pressure has three determinants:

1. SV. Increased SV increases systolic blood pressure and pulse pressure.

2. Aortic compliance. If compliance is low, the SV produces a large systolic blood pressure. Aortic compliance is not physiologically regulated but declines gradually in older persons. Systolic blood pressure typically increases 1 mm Hg for each year after age 60. This increase results from the loss of tissue elasticity in the aorta and atherosclerotic change in arterial walls.

3. Diastolic blood pressure. The absolute value of systolic blood pressure must be interpreted with respect to diastolic blood pressure because this is the baseline pressure before systole. For this reason, pulse pressure is also observed to assess SV.

Similar to systolic blood pressure, diastolic blood pressure has three determinants:

1. Vascular resistance is the main determinant of diastolic blood pressure. Blood flow through the circulation continues throughout diastole, although ventricular ejection is over. Flow is sustained because the arterial pressure exceeds the venous pressure. In addition, the elastic aorta stores energy during systole that is imparted to arterial blood during diastole. Diastolic blood pressure is determined by the size of arteriolar resistance encountered by blood flow. Higher arteriolar resistance (vasoconstriction) increases diastolic blood pressure.

2. Runoff of blood from the aorta. Diastolic blood pressure decreases if blood flow into the circulation during diastole is reduced. In aortic valve insufficiency, the aortic pressure rapidly decreases during diastole because backflow of blood into the left ventricle reduces forward flow into the circulation. This also occurs when a patent ductus arteriosus is present.

3. Diastolic time interval. Aortic pressure decreases with time between heart beats because blood continues to flow into the circulation from the aorta throughout diastole. The measured diastolic blood pressure is lower when the HR is slow because more time elapses between beats. Diastolic blood pressure is higher at faster HRs because there is less time for a decline in aortic pressure between beats. Figure 4-30 illustrates the effect of altered HR on diastolic blood pressure.

Isolated systolic hypertension is mainly a disease of elderly patients. It occurs because of a gradual decline in arterial compliance (a component of systolic blood pressure, not diastolic blood pressure), so that systolic blood pressure increases and diastolic blood pressure decreases. Treatment adds an additional challenge because reducing diastolic blood pressure further may increase cardiovascular events, which occur because most coronary perfusion occurs during diastole, not systole.

Regulation of Systemic Vascular Resistance

The collective resistance to blood flow presented by the systemic vasculature is called systemic vascular resistance, or total peripheral resistance. Systemic vascular resistance is mainly determined by changes in the diameter of the arterioles. These vessels exhibit partial constriction under normal physiologic conditions, called vascular tone, and are the sites of active regulation of blood flow in the circulation. Arteriolar tone is affected by many factors, including sympathetic tone and hormones and endothelial and metabolic factors. Systemic vascular resistance is increased by vasoconstriction and reduced by vasodilatation.

Venous Return

Venous return is the volume of blood returning to the central venous compartment (thoracic venae cavae and right atrium) per minute (i.e., it is a flow rate). It is helpful to think about properties of the venous circulation in isolation to understand processes that influence venous return, such as altered posture, ventilation, and skeletal muscle activity. Central venous pressure is the pressure of venous blood in the thoracic vena cava and the right atrium. Low central venous pressure promotes venous return into the central venous compartment, whereas high central venous pressure reduces venous return. Central venous pressure has a strong influence on cardiac preload and, through the Frank-Starling mechanism, determines ventricular SV.

Measuring or estimating central venous pressure in the hemodynamically unstable patient guides management. For example, in hypovolemia, a low central venous pressure indicates the need for aggressive intravenous fluid resuscitation prior to using drugs. Intravenous fluid replacement will increase preload, thereby increasing cardiac output, blood pressure, and tissue perfusion. Drugs such as phenylephrine, which is a potent arterial vasoconstrictor, will increase blood pressure at the expense of decreasing blood flow to certain tissues and organs. These drugs are used as a last line attempt to maintain blood pressure in a decompensating patient.

A change in posture from a supine to a standing position causes an initial decrease in central venous pressure because gravity causes an accumulation of blood in the veins of the lower limbs. Reduced thoracic venous blood volume results in a decrease in venous return and, therefore, in a decrease in the cardiac output and systemic arterial pressure. Blood pressure normally is restored by baroreceptor reflexes that mediate vasoconstriction and cardiac stimulation (see Neurohumoral Control of the Cardiovascular System).

During dynamic exercise, mechanisms to support venous return are essential because ventricular diastolic filling time is reduced by rapid HRs. Rhythmic contraction of skeletal muscles is one mechanism that promotes venous return during exercise by compressing veins in the limbs, forcing venous return back toward the thorax. Retrograde flow is prevented by one-way valves in the veins. The increased rate and depth of ventilation during exercise is another mechanism that causes greater venous return. Forceful inspiration causes intrathoracic pressure to become more negative to expand the lungs and achieve deeper inhalation. Figure 4-31 shows that the decrease in intrathoracic pressure acts as an external force on the venae cavae and the right atrium, causing them to distend. As more blood is drawn into the thoracic vena cava from the abdomen, more blood enters the right atrium. Effects such as these are often described in terms of transmural pressure changes.

Transmural pressure is the pressure exerted across the wall of a structure and is calculated by subtracting the external pressure from the internal pressure. Transmural pressure can be thought of as the pressure acting to distend or dilate a structure. In the example of deep inspiration increasing venous return, transmural pressure across the wall of the vena cava and right atrium increases because the external pressure becomes more negative during inspiration.

Kussmaul's sign occurs when there is an increase (instead of the normal decrease) in jugular venous distention during an inspiration, and is a sign of right-sided heart failure. In the healthy heart, a deep inspiration (i.e., more negative intrathoracic pressure) will collapse the jugular veins as the blood is pulled into the right side of the heart. However, in right-sided heart failure, the pressures on the right side of the heart are high and are unable to accommodate the increased volume coming from the venae cavae. This is detected clinically as increased jugular venous distention.

Cardiac and Systemic Vascular Function Curves

The factors discussed previously that affect venous return are important because in a closed system, such as the cardiovascular system, cardiac output must equal venous return. Blood flow through the system depends on both cardiac and vascular function. Viewing the systemic circulation as a whole, flow is indicated by the pressure difference between the aorta and the right atrium, divided by systemic vascular resistance. Factors such as cardiac excitation, blood volume, and vascular compliance and resistance all influence total blood flow. The effects of changes in these variables are often described using systemic vascular function curves and cardiac function curves.

Figure 4-32A illustrates a systemic vascular function curve showing venous return as a function of right atrial pressure. Venous return increases as the right atrial pressure is reduced because there is a larger pressure gradient favoring venous return into the atrium. At the point where venous return (flow) becomes zero, the right atrial pressure is typically between 6 mm Hg and 12 mm Hg. If blood flow in the circulation stops, the arterial pressure decreases and the venous pressure increases until the pressure equalizes at all points in the cardiovascular system. This pressure is called systemic function pressure (P_SF), or mean circulatory filling pressure, and is obtained from a systemic vascular function curve. Systemic function pressure is not measured clinically, but can be thought of as the amount of pressure in the vascular system that drives venous return.

Systemic function pressure is determined by the relationship between blood volume and vascular compliance. Systemic function pressure increases if blood volume is high or if vascular compliance is low. The overall compliance of the vascular system is determined by venous tone because the venous system is 10–20 times more compliant than the arterial system. Figure 4-32B shows that increasing blood volume or reducing venous compliance shifts the venous return curve upward to the right, thereby increasing the systemic function pressure and venous return.

Figure 4-32C shows the effect of arteriolar vasoconstriction and vasodilatation on venous return. Arteriolar vasoconstriction reduces venous return because blood flow into the microcirculation, and into the venous system beyond it, is reduced. Vasodilatation has the opposite effect. There is no change in the systemic function pressure when the arteriolar tone changes because the arterioles contribute little to overall vascular compliance.

The Frank-Starling relationship, shown in Figure 4-33A, dictates that an increase in the right atrial pressure, which drives more ventricular filling, increases SV and cardiac output. Cardiac and vascular function curves are plotted on a graph in Figure 4-33B, which reveals a single operational point where cardiac output is equal to venous return.

In physiologic states, cardiac output is limited mostly by factors that influence vascular function and venous return. During exercise, for example, there is activation of the sympathetic nervous system, resulting in simultaneous enhancement of cardiac function as well as venoconstriction. In dynamic exercise, systemic vascular resistance decreases due to arteriolar dilation in working muscles. In Figure 4-34A, a combination of vascular and cardiac function curves are used to show how increased cardiac output and venous return occurs during dynamic exercise.

Figure 4-34B illustrates how compensation occurs in patients with heart failure. There is increased blood volume and reduced venous compliance, which increases venous return and cardiac output. However, this occurs at the expense of higher right atrial pressure, which in turn increases the venous blood pressure. The risk of edema formation is increased when venous blood pressure increases (see Capillary Microcirculation).

The main homeostatic goal in cardiovascular regulation is to maintain adequate cardiac output. Wall stretch is determined at strategic locations in the cardiovascular system to provide information about blood pressures as an index of blood flow:

• Carotid sinus baroreceptors provide momentary feedback about arterial blood pressure.

• The renal juxtaglomerular apparatus senses effective circulating blood volume.

• Low pressure baroreceptors in the venous system and cardiac atria provide further information about blood volume.

The collective input from these sensors is coupled to changes in autonomic nervous tone and endocrine axes such as renin-angiotensin-aldosterone, atrial natriuretic peptide, and vasopressin (see Chapters 6 and 8). Changes in vascular resistance and compliance, cardiac performance, and renal handling of sodium and water are integrated to maintain normal blood pressure and blood flow. Integrated responses to blood volume and pressure changes are discussed in more detail in Chapter 6.

The Autonomic Nervous System

The primary site of cardiovascular control within the central nervous system is the medulla oblongata. Sensory inputs enter the nucleus tractus solitarius. Inhibitory interneurons project to networks of sympathetic nerve cell bodies, and excitatory interneurons project to parasympathetic nerve cell bodies. As a consequence, basal baroreceptor input results in tonic activation of parasympathetic outflow and suppression of sympathetic outflow.

Parasympathetic (vagal) fibers innervate the SA and AV nodes, the conduction pathways, and the cardiac myocytes. The principal neurotransmitter released is acetylcholine, which in most cases acts via the muscarinic (M₂) receptors. The main cardiovascular effects of the parasympathetic nerves are to slow HR and conduction velocity and to reduce the force of atrial contraction, with minor direct effect on ventricular function. Parasympathetic activation causes vasodilatation in erectile tissue but has no significant overall effect on systemic vascular resistance.

Extensive sympathetic innervation occurs in the heart and vasculature. The primary neurotransmitter released during sympathetic innervation is norepinephrine, which mediates responses through several different adrenergic receptors. Increased HR, increased conduction velocity, and increased contractility are all mediated via the β₁ receptors. Generalized vasoconstriction and venoconstriction are mediated via the α₁ receptors. Vascular beds such as skeletal muscle also express β₂ receptors, which mediate vasodilatation. The α₁ receptors are more widely expressed in vascular smooth muscle than the β₂ receptors, and norepinephrine has a higher affinity for α receptors; therefore, the net effect of sympathetic nerve stimulation is vasoconstriction and an increase in systemic vascular resistance.

Activation of the sympathetic nervous system causes simultaneous secretion of catecholamine hormones from the adrenal medulla. Epinephrine is the primary hormone secreted, which has actions similar to norepinephrine but produces less change in systemic vascular resistance. This difference is because epinephrine has a higher affinity for β₂ receptors and, at low doses, produces a mixture of vasoconstriction and vasodilatation in different parts of the circulation.

The Baroreceptor Reflex

The baroreceptor reflex is the main acute response that protects against changes in the systemic arterial blood pressure. The primary stretch sensors are located in the carotid sinus, with secondary sensors in the aortic arch. Afferent nerve impulses are carried from the carotid sinus nerve to the brainstem via the glossopharyngeal nerves. Increased stretch of the carotid sinus, caused by a rise in MAP or pulse pressure, increases the action potential frequency in the carotid sinus nerve. In the medulla oblongata, this input increases inhibition of sympathetic outflow and stimulates parasympathetic outflow. The opposite occurs when MAP or pulse pressure decreases and carotid sinus stretch is reduced. Activation of the baroreceptor reflex can be used to terminate supraventricular tachycardia. Carotid massage or an intravenous fluid bolus both increase wall stretch in the carotid sinus, activating parasympathetic outflow, which can terminate supraventricular tachycardia.

The adequacy of the baroreceptor reflex can be assessed by the tilt-table test. Figure 4-35 shows the expected baroreflex response when a patient is moved from a supine to a standing position while blood pressure and HR are being monitored. The normal response is an initial decrease in MAP due to venous pooling in the lower limbs, which reduces venous return and cardiac output. Decreased action potential frequency in the carotid sinus nerve results in reduced parasympathetic tone and increased sympathetic tone.

Several effector mechanisms restore MAP to prevent reduced brain perfusion and fainting:

• HR is increased by withdrawal of vagal tone and by increased sympathetic stimulation of the SA node.

• Ventricular contractility and SV are increased by sympathetic stimulation of cardiac myocytes.

• Vasoconstriction, mediated by the sympathetic nerves, increases the systemic vascular resistance and thereby increases the diastolic blood pressure and MAP.

• Venoconstriction, due to sympathetic stimulation, reduces vascular compliance, increasing venous return and restoring cardiac preload.

Patients with poor vascular or neural tone or low blood volume may sustain a decrease in MAP of more than 20 mm Hg when moving to a standing position; this is defined as postural (orthostatic) hypotension. Patients with diabetes mellitus may develop neuropathy, causing autonomic nervous system dysfunction. When moving from a supine to a standing position, these patients do not combat postural hypotension with reflex tachycardia—they will have a decrease in blood pressure and a slow to normal HR.

Blood flow is not distributed equally to all organs and tissues and depends on the control of relative vascular resistance between organs. In some organs, there is considerable variation in blood flow; this occurs, for example, in the gastrointestinal tract during digestion of a meal or in muscle during exercise. In other organs, such as the brain and the kidney, blood flow is relatively constant. Table 4-5 summarizes the distribution of blood flow to various organs at rest.

Coronary Blood Flow

Unlike blood flow to other organs, blood flow to the myocardium is higher during diastole than during systole (Figure 4-36). The higher rate of flow to the myocardium occurs because contraction of the myocardium during systole compresses coronary blood vessels, limiting coronary blood flow. Tachycardia may present a problem for coronary perfusion because most blood flow occurs during the diastolic period, which becomes shorter as HR increases.

Coronary perfusion pressure is estimated clinically as the difference between diastolic blood pressure and left ventricular end-diastolic pressure. Therefore, patients with low diastolic blood pressure or high filling pressures in the heart have a reduced driving force for coronary perfusion.

The extraction of O₂ from arterial blood in the myocardium is maximal at rest. Increased O₂ demand in other organs is supplied by a combination of increased blood flow and increased O₂ extraction. The only means of increasing O₂ supply to the heart is to increase coronary blood flow. This can only be achieved by increasing coronary perfusion pressure or by reducing coronary vascular resistance. Coronary arteriolar resistance is affected most by metabolic demand of myocytes. An increase in myocardial metabolism causes a local release of vasodilator metabolites such as adenosine and CO₂, K⁺, and H⁺ into the interstitial fluid.

When cardiac activity increases, nitric oxide is produced by the vascular endothelial cells. The stimulus for nitric oxide release is mechanical distortion (shearing forces) acting on the vascular endothelial cells. Nitric oxide diffuses into nearby vascular smooth muscle cells, where it acts through soluble cyclic guanosine monophosphate (cGMP) to produce vasodilatation. Nitric oxide donors (e.g., nitroglycerin) are used to provide relief from angina pectoris.

Increases in cardiac activity are often associated with stimulation of the heart by the sympathetic nervous system. The autonomic nerves have little direct effect on coronary vascular resistance. However, sympathetic stimulation (e.g., injection of epinephrine) results in coronary vasodilatation. The mechanism is indirect and is due to increased cardiac work, causing greater production of local vasodilator metabolites.

Cardiac O₂ consumption is closely related to the amount of ventricular wall tension developed during contraction. Patients with dilated cardiomyopathy have an increased myocardial O₂ demand because a dilated heart must develop more wall tension to pressurize the blood. This is a consequence of Laplace's law (P = 2T/r), which states that the amount of wall tension (T) in a sphere is proportional to both the amount of luminal pressure developed (P) and the radius (r).

Coronary Artery Disease

Patients with atherosclerotic coronary artery disease have maximal arteriolar dilation at rest and are unable to further increase coronary blood flow. These patients are at risk of developing cardiac ischemia when local O₂ demand increases. Myocardial O₂ consumption is increased by increased HR, increased contractility, and increased afterload (aortic blood pressure). The severity of coronary artery disease can be assessed using a treadmill stress test, which may produce angina pectoris and changes that can be seen on an ECG that indicate coronary ischemia. The phenomenon of “coronary steal” can be used to show coronary ischemia in some patients by administering a vasodilator such as dipyridamole. The vessel distal to the stenosis is already maximally dilated; vasodilatation of collateral coronary vessels “steals” blood flow from the stenotic segment, causing it to become hypoperfused.

Cerebral Blood Flow

The brain requires a constant supply of O₂, and its blood flow is relatively independent of MAP and autonomic nervous system activity. Cerebral blood flow is mainly determined by myogenic autoregulation, in which blood flow is relatively constant over a wide range of MAP, from approximately 60 mm Hg to 130 mm Hg, as shown in Figure 4-37A. Cerebral arterioles respond directly to the degree of distention by varying smooth muscle tone. When MAP decreases, there is less wall distention on arterioles; thus, smooth muscle relaxes and increases vessel diameter, which reduces resistance and restores blood flow.

In patients with chronic hypertension, the autoregulation curve shifts to the right. When these patients are treated with antihypertensive drugs to restore blood pressure to normal, the corrected blood pressure may be below their range of autoregulation, in which case cerebral blood flow decreases, causing dizziness or altered cognitive function (see Figure 4-37A).

Cerebral blood flow responds to changes in local metabolic demand. Increased neuronal activity and O₂ consumption cause local vasodilation. Blood gases, particularly the arterial CO₂ partial pressure (Paco₂), strongly influence cerebral blood flow (see Figure 4-37B). For example, dizziness associated with hyperventilation is caused by cerebral vasoconstriction resulting from increased CO_2­ excretion and reduced Paco₂. Conversely, increased Paco₂ causes cerebral vasodilatation. Variations in Pao₂ have little effect unless severe hypoxemia (low Pao₂) occurs, resulting in pronounced cerebral vasodilatation.

The brain is the only circulation encased in bone, which limits the total volume of brain tissue, cerebrospinal fluid, and blood. Intracranial pressure increases if there is a tumor, bleeding, or cerebral edema, in which case compression of the blood vessels increases vascular resistance and reduces blood flow. Cerebral perfusion pressure is estimated as the difference between MAP and intracranial pressure. Reducing intracranial pressure in the patient with a head injury is critical. Hyperventilation reduces intracranial pressure by decreasing Paco₂, causing reflexive cerebral vasoconstriction and reducing cerebral blood volume and pressure.

Renal Blood Flow

Among the major organs, the kidneys have one of the highest rates of blood flow, which is necessary to supply enough plasma for glomerular filtration. Despite high O₂ consumption rates per gram of kidney tissue, usually renal perfusion far exceeds the needs of local cellular metabolism. As a result, the kidney has the lowest O₂ extraction of the major organs. Unlike cerebral blood flow, blood flow to the kidneys is not controlled by metabolic factors.

Renal perfusion pressure is the difference between MAP and venous pressure and is therefore similar to most other organs. High renal blood flow is achieved with normal perfusion pressure because vascular resistance is low. Vascular resistance is shared equally by afferent and efferent glomerular arterioles (see Chapter 6).

Renal blood flow is most strongly influenced by autoregulation and sympathetic tone. Under most circumstances, renal blood flow is relatively constant because myogenic autoregulation operates over a MAP range of 60 mm Hg to 160 mm Hg. Increases in sympathetic tone occur during exercise or if the baroreceptor reflex is stimulated by reduced MAP, resulting in renal vasoconstriction. The kidney is susceptible to ischemic damage (e.g., acute tubular necrosis) in states of shock associated with profound sympathetic vasoconstriction.

Splanchnic Blood Flow

The splanchnic circulation receives the highest proportion of cardiac output at rest and is shared among the liver, the spleen, and the digestive organs (see Chapter 7). The sympathetic nervous system exerts dominant control over splanchnic blood flow, causing vasoconstriction and venoconstriction. Local metabolism increases blood flow after a meal. Parasympathetic stimulation of multiple digestive organs indirectly causes vasodilation through increased local metabolism.

Cutaneous Blood Flow

Most blood flow to skin is regulated in response to both thermo­regulatory signals and general cardiovascular control of MAP. Activation of efferent norepinephrinergic sympathetic nerves by such means as pain, cold, fear, or low MAP leads to cutaneous vasoconstriction, directing blood to more vital organs. On the other hand, increased core body temperature causes hypothalamic activation of cholinergic sympathetic efferents, resulting in sweating and cutaneous vasodilatation to increase heat loss. During a fever, body temperature is regulated at a higher set point. When a fever is developing, shivering and vasoconstriction increase body temperature. When a fever “breaks,” the set point returns to normal. Body temperature is returned to normal by sweating and cutaneous vasodilation (see Chapter 2).

Skeletal Muscle Blood Flow

Skeletal muscle has a large flow reserve compared to that of resting blood flow. At rest, there is relatively high vascular tone and a high proportion of capillaries are not perfused. Blood flow to resting muscle is strongly influenced by norepinephrinergic sympathetic vasoconstriction. During dynamic exercise, more than 75% of cardiac output may be directed to working skeletal muscle. Local metabolism exerts dominant control over vascular resistance in working skeletal muscle, and there is marked recruitment of capillaries that were not perfused at rest.

Capillaries have the largest collective surface area for the exchange of nutrients and wastes. Diffusion is the most important mechanism for exchange across capillary walls. Lipid-soluble substances and gases diffuse readily. Lipid-insoluble substances such as peptides have low permeability and are restricted to openings between adjacent endothelial cells or transport through cells using vesicular pathways. The time available for diffusion as blood flows through the microcirculation is maximized by slow velocity of blood flow. The velocity of flow is least in the capillaries because blood flow is shared among many parallel vessels, with a large collective cross-sectional area.

Transcapillary Fluid Flux

Bulk fluid flow occurs between plasma and interstitium. Understanding factors that determine transcapillary fluid movement is clinically important as the basis for understanding edema formation (tissue swelling caused by excessive accumulation of interstitial fluid). For example, brain edema is dangerous because it increases intracranial pressure, leading to brain compression. Pulmonary edema is dangerous because it presents a diffusion barrier for O₂ uptake into the blood. In almost all other organs, a large amount of edema fluid can accumulate before organ function is compromised.

Fluid moves readily across the capillary walls of most tissues by filtration. Net fluid movement is a function of the driving pressure for filtration and the capillary permeability. The net driving force for filtration consists of a gradient of hydrostatic pressure that pushes fluid out of plasma and is opposed by a gradient of oncotic pressure:

^eq009 is known as the Starling equation, and the individual components of the net driving pressure are referred to as Starling's forces:

• Capillary hydrostatic pressure (P_c) is a force pushing fluid out of the capillaries. Hydrostatic pressure is usually about 35 mm Hg at the arteriolar end of a capillary, decreasing to about 15 mm Hg at the venous end of a capillary.

• Interstitial fluid hydrostatic pressure (P_i) is usually near zero or is slightly subatmospheric, favoring fluid movement into the interstitial space.

• Capillary oncotic pressure (π_c) is an osmotic force exerted by plasma proteins, and pulls fluid into the plasma from the interstitium and is approximately 25 mm Hg.

• Interstitial fluid oncotic pressure (π_i) is normally low because proteins have reflection coefficients of 0.8–1.0 and interstitial protein concentration is low (see Chapter 1 for a discussion of reflection coefficient).

Example

The following Starling forces were measured in a systemic capillary:

• Capillary hydrostatic pressure = 30 mm Hg

• Interstitial hydrostatic pressure = 1 mm Hg

• Capillary oncotic pressure = 25 mm Hg

• Interstitial oncotic pressure = 2 mm Hg

  

Figure 4-38 shows that the balance of forces changes along the length of a typical capillary as capillary hydrostatic pressure decreases. Net fluid filtration out of plasma occurs at the arterial end of capillary beds, and net fluid reabsorption into plasma occurs toward the venous end.

Lymphatics

Blind-ended lymphatic capillaries consisting of single-layered endothelial plates are found in all tissues except the brain and the heart. These capillaries are permeable to fluid and to protein. There is net formation of 3–4 L daily of interstitial fluid, which enters the lymphatic capillaries and is delivered back to the venous system through larger lymph vessels, lymph nodes, and lymphatic ducts. Uptake of lymphatic fluid resists edema formation and can increase as interstitial fluid hydrostatic pressure (P_i) increases. Proteins that enter the interstitium from plasma are removed by the lymphatic system.

Causes of Edema

Most causes of edema can be explained in terms of changes in one or more of the variables noted in ^eq009 and are described as follows:

• The most common causes of edema result from increased venous pressure due to heart failure or venous obstruction (Table 4-6).

• Generalized edema may also result from low serum protein concentration due to reduced capillary oncotic pressure (π_c). This can occur in liver failure when insufficient albumin is synthesized and in nephrotic syndrome when plasma protein is excreted in the urine.

• In inflammation or sepsis, generalized edema may occur because inflammatory mediators reduce protein reflection coefficient (σ) and proteins leak into the interstitium, thereby increasing interstitial fluid oncotic pressure.

• Lymphatic blockage causes edema because the tissue fluid that has formed is trapped in the interstitium when the outflow pathway is blocked.

Pulmonary capillaries are normally surrounded by negative intrathoracic pressures, which promote net filtration. Patients with acute respiratory distress syndrome may develop pulmonary edema. The edema occurs because the patient must inspire forcefully to breathe, causing intrathoracic pressure and interstitial fluid oncotic pressure to become more negative.

Assessing whether edema is unilateral or bilateral is important in determining the cause. For example, congestive heart failure typically results in bilateral edema (e.g., bilateral pulmonary edema, pleural effusions, and ankle swelling). In contrast, edema caused by blockage of lymphatic drainage that occurs from parasitic infection (e.g., Wuchereria bancrofti) is often unilateral.