CARDIOVASCULAR PHYSIOLOGY CONCEPTS 2ND EDITION PDF

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Includes bibliographical references and index. ISBN 1. Cardiovascular system—Physiology. I. Title. [DNLM: 1. Cardiovascular Physiological. raudone.info 6/25/11 AM Page x. CARDIOVASCULAR PHYSIOLOGY CONCEPTS SECOND EDITION raudone.info i 6/11/ AM. download Cardiovascular Physiology Concepts: Read 37 Books Reviews - site. com.


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Richard raudone.infode. Here you can find archives of the magazine Cardiovascular Physiology Concepts 2nd Edition. 2nd edition. Baltimore, Md.: Lippincott Williams & Wilkins/Wolters Kluwer, pages, , English, Book; Illustrated, Cardiovascular physiology concepts. Title, Cardiovascular Physiology Concepts. Author, Richard Klabunde. Edition, illustrated. Publisher, Lippincott Williams & Wilkins, ISBN.

These Figure 2. By convention, the action Phase 1 represents an initial repolariza- potential is divided into five numbered phases. L-type calcium channels mV 0 3 are the major calcium channels in cardiac and —50 vascular smooth muscle. They are opened by membrane depolarization they are voltage- 4 4 operated and remain open for a relatively — long duration.

Ventricular Cell During phases 0, 1, 2, and part of phase 3, the cell is refractory i. ERP, effective refractory period. The long ERP also prevents site to take over as the pacemaker for the heart. At the end of the ERP, the cell is in SA nodal action potentials are divided into its relative refractory period.

Early in this three phases: When the sodium channels. Because the stimuli can elicit new, rapid action potentials.

As the action potentials. Unlike most other cells that calcium channels open and the membrane exhibit action potentials e. Other pacemaker cells exist Ion within the AV node and ventricular conduction system, but their firing rates are driven by the higher rate of the SA node because the intrinsic pacemaker activity of the secondary pacemak- If ers is suppressed by a mechanism termed over- drive suppression.

Hyperpolarization occurs because the action potential. Heart rate, however, can vary zation as shown in the following equation: These changes Eq. At low resting Depolarization causes voltage-operated, delayed heart rates, vagal influences are dominant rectifier potassium channels to open, and the over sympathetic influences.

The tion in heart rate is a negative chronotropic phase of repolarization is self-limited because response or negative chronotropy. The ionic mechanisms responsible for the 1 changing the slope of phase 4; 2 altering the spontaneous depolarization of the pacemaker threshold voltage for triggering phase 0; and 3 potential phase 4 are not entirely clear, but altering the degree of hyperpolarization at the probably involve multiple ionic currents. First, end of phase 3.

Second, in threshold. Sympathetic activation of the SA node the repolarized state, a pacemaker current If , increases the slope of phase 4 Fig.

This depolarizing current involves, frequency positive chronotropy. Fourth, nels, both of which increase the rate of depolari- as the depolarization begins to reach threshold, zation. Vagal stimulation has the opposite effects, and it hyperpolarizes the cell. Horizontal dashed lines represent threshold and maximal hyperpolarization potentials for normal cell. Acetylcholine also released by sympathetic nerves. Hyperthyroid- activates a special type of potassium channel ism induces tachycardia, and hypothyroidism KACh channel that hyperpolarizes the cell by induces bradycardia abnormally low heart increasing potassium conductance.

Changes in the serum concentration of Nonneural mechanisms also alter pacemaker ions, particularly potassium, can cause changes activity Table For example, circulating in SA node firing rate. Hyperkalemia induces catecholamines epinephrine and norepineph- bradycardia or can even stop SA nodal firing, rine cause tachycardia abnormally high heart whereas hypokalemia increases the rate of rate by a mechanism similar to norepinephrine phase 4 depolarization and causes tachycar- dia, apparently by decreasing potassium con- ductance during phase 4.

Increased body temperature e. Sympathetic Parasympathetic Various drugs used to treat abnormal heart stimulation stimulation rhythm i. Drugs affecting autonomic control echolamines or autonomic receptors e. Furthermore, like SA nodal pacemakers, these cells may display spontaneous depolarization during ischemia, digoxin toxicity, and excessive during phase 4. This abnormal automaticity catecholamine stimulation.

Nonpacemaker cells may undergo spread throughout the atria primarily by cell- spontaneous depolarizations either during phase to-cell conduction Fig. When a single 3 or early in phase 4, triggering abnormal action potentials.

Cardiac type of afterdepolarization, delayed afterdepo- cells are connected together by low-resistance larization, occurs at the end of phase 3 or early gap junctions between the cells, forming a in phase 4. It, too, can lead to self-sustaining functional syncytium. When one cell depolarizes, depolarizing currents can pass through the gap action potentials and tachycardia. This form of junctions red arrows and depolarize adjacent triggered activity appears to be associated with cells, resulting in a cell-to-cell propagation of elevations in intracellular calcium, as occurs action potentials.

Because see Chapter 3. Action potentials calated disks see Chapter 3 , ionic currents normally have only one pathway available to can flow between two adjoining cells.

When enter the ventricles, a specialized region of these ionic currents are sufficient to rapidly cells called the AV node. The AV node, located depolarize the adjoining cell to its threshold in the inferior—posterior region of the intera- potential, an action potential is elicited in trial septum separating the left from the right the second cell. This is repeated in every cell, atrium, is a highly specialized conducting tis- thereby causing action potentials to be propa- sue cardiac, not neural in origin that slows gated throughout the atria.

Action potentials in the impulse conduction velocity to about the atrial muscle have a conduction velocity of 0. This is one-tenth the velocity found about 0. Although the con- in atrial or ventricular myocytes see Fig. First, it allows sufficient time for existence of specialized myocytes that serve as complete atrial depolarization, contraction, and conducting pathways within the atria, termed emptying of atrial blood into the ventricles prior internodal tracts e.

As to ventricular depolarization and contraction action potentials originating from the SA node see Chapter 4. Conduction velocities of different regions are noted in parentheses. The the ventricle. This is important in atrial flutter more rapidly one cell depolarizes, the more and fibrillation, in which excessively high atrial quickly an adjoining cell depolarizes. There- rates, if transmitted to the ventricles, can lead fore, conditions that decrease the availability to a very high ventricular rate.

This can reduce of fast sodium channels e. In enter the base of the ventricle at the bundle of AV nodal tissue in which slow inward calcium His and then follow the left and right bundle primarily determines phase 0 of the action branches along the interventricular septum potential, alterations in calcium conductance that separates the two ventricles.

These spe- alter the rate of depolarization and therefore cialized bundle branch fibers conduct action the rate of conduction between AV nodal cells. Autonomic nerve throughout the ventricles. The Purkinje fiber activity significantly influences the conduction cells connect with ventricular myocytes, of electrical impulses throughout the heart, par- which become the final pathway for cell-to- ticularly in the specialized conduction system.

The activation of parasym- tion of ventricular myocytes, which is essen- pathetic vagal nerves decreases conduction tial to generate pressure efficiently during velocity via the action of acetylcholine on M2 ventricular contraction. If the conduction receptors. This is most prominent at the AV system becomes damaged or dysfunctional, as node, which has a high degree of vagal inner- can occur during ischemic conditions or myo- vation.

The functional con- in Chapter 3 see Fig. A number of drugs can ventricles to generate pressure. Intrinsic factors include the electrical tor antagonists agonists resistance between cells and the nature of the b-Adrenoceptor b-Blockers action potential, particularly in the initial rate agonists of depolarization phase 0.

It is especially useful in diagnos- body because the tissues surrounding the ing rhythm disturbances, changes in electrical heart are able to conduct electrical currents conduction, and myocardial ischemia and generated by the heart. When these electri- infarction. The remaining sections of this cal currents are measured by an array of elec- chapter describe how the ECG is generated trodes placed at specific locations on the body and how it can be used to examine changes in surface, the recorded tracing is called an ECG cardiac electrical activity.

An enlargement of one of the repeating waveform units in the rhythm strip shows the P wave, QRS complex, and T wave, which represent atrial depolarization, ventricular depolarization, and ventricular repolarization, respectively. The PR interval represents the time required for the depolarization wave to transverse the atria and the AV node; the QT interval represents the period of ventricular depolarization and repolarization; and the ST segment is the isoelectric period when the entire ventricle is depolarized.

Each small square is 1 mm. The repeating waves of the ECG aberrant conduction, or it can occur when an represent the sequence of depolarization and ectopic ventricular pacemaker drives ventric- repolarization of the atria and ventricles.

The ular depolarization. Such ectopic foci nearly ECG does not measure absolute voltages, but always cause impulses to be conducted over voltage changes from a baseline isoelectric slower pathways within the heart, thereby voltage. It represents the wave ventricle is depolarized and roughly corre- of depolarization that spreads from the SA node sponds to the plateau phase of the ventricular throughout the atria; it is usually 0.

The ST segment is impor- onds in duration Table No distinctly vis- tant in the diagnosis of ventricular ischemia, ible wave represents atrial repolarization in the in which the ST segment can become either ECG because it is masked by ventricular depo- depressed or elevated, indicating nonuniform larization and is of relatively small amplitude.

The The brief isoelectric zero voltage period after T wave represents ventricular repolarization the P wave represents the time in which the phase 3 of the action potential and lasts atrial cells are depolarized and the impulse is longer than depolarization. The period of time depolarization and repolarization occur.

This from the onset of the P wave to the beginning interval roughly estimates the duration of of the QRS complex, the PR interval, normally ventricular action potentials. The QT interval ranges from 0. This interval can range from 0. At high heart rates, ventricular depolarization and the onset of ventricular action potentials are shorter, decreasing the QT depolarization.

Because prolonged QT intervals can be onds, a conduction defect usually within the diagnostic for susceptibility to certain types of AV node is present e.

In prac- depolarization. This calculation allows the QT interval within the ventricles. Impairment can occur to be assessed independent of heart rate. Nor- with defects e. Atrial and ven- tricular rates of depolarization can be deter- Atrial Flutter mined from the frequency of P waves and QRS complexes by recording a rhythm strip. This correspond- ence indicates that ventricular depolarization is being triggered by atrial depolarization.

Under these normal conditions, the heart is said to be in sinus rhythm, because the Second-Degree AV Block 2: The resting sinus rhythm, as previously described, is highly dependent on vagal tone. AV, atrioventricular. In atrial each P wave. Conditions exist, however, when fibrillation, the SA node does not trigger the the frequency of P waves and QRS complexes atrial depolarizations.

Instead, depolarization may be different Fig. At any given instant, many individual the ectopic site are not conducted through instantaneous electrical vectors exist; each normal pathways.

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An instantaneous mean Volume Conductor Principles and electrical vector can be derived by summing the individual instantaneous vectors. ECG Rules of Interpretation In the heart, the mean electrical vector The previous section defined the components changes its orientation as different regions of of the ECG trace and what they represent in the heart undergo depolarization or repolariza- terms of electrical events within the heart.

The direction of the mean electrical vec- This section examines in more detail how the tor relative to the axis between positive and appearance of the recorded ECG waveform negative recording electrodes determines the depends on 1 location of recording electrodes polarity and influences the magnitude of the on the body surface; 2 conduction pathways recorded voltage as illustrated in Figure 2.

To interpret the significance of depolarization within the ventricles by show- changes in the appearance of the ECG, we ing four different mean vectors representing must first understand the basic principles of different times during depolarization.

In this how the ECG is generated and recorded. At a given bundle branches divide. To help understand this concept, The placement of the positive recording elec- Figure 2. Before the ventricles spreading into the atrial muscle.

When the SA undergo depolarization Panel A , there are node fires, many separate depolarization waves no electrical vectors so the voltage recording emerge from the SA node and travel throughout in either lead will be zero. Early during ven- the atria.

These separate waves can be depicted tricular activation Panel B , the first region as arrows representing individual electrical to depolarize is the interventricular septum, which normally depolarizes from left to right as depicted by the mean electrical vector. The SA Node vector is small because the tissue mass is small. The Vector same mean vector, however, when recorded using lead II will not show a change in volt- age no Q wave because the mean vector is oriented perpendicular to the lead II axis.

Individual of the heart begins to depolarize. The mean electrical vector red toward the apex and is heading roughly per- arrow represents the sum of the individual vec- pendicular to the aVL lead axis, thereby gener- tors at a given instant in time. Ventricles prior to depolarization; isoelectric zero voltage recorded by electrodes aVL and II. Ventricles depolarized; isoelectric voltage in aVL and II; red arrow represents mean electrical axis.

In contrast, the mean vector is heading almost electrode and is almost perpendicular to the directly towards the lead II positive electrode, lead II axis. Therefore, this vector produces a which results in a very tall, positive deflection large positive voltage in lead aVL and a rela- R wave of the QRS. After another 20 milli- tively small positive voltage in lead II. The last seconds Panel D , the apex and most of the regions of the left ventricle to depolarize Panel right ventricular free wall are completely depo- E result in a mean vector that is heading some- larized.

At this time, the left ventricular free what toward lead aVL, and away from lead II. Three basic zero. It is important to note that the placement types of ECG leads are recorded by these elec- of the recording electrode determines the shape trodes: These electrode leads are If the four mean vectors in Figure 2. The limb The mean electrical axis represents the aver- leads are sometimes referred to as bipolar leads age of all of the instantaneous mean electrical because each lead uses a single pair of positive vectors occurring sequentially during ven- and negative electrodes.

The augmented leads tricular depolarization. The determination and chest leads are unipolar leads because of mean electrical axis is of particular signifi- they have a single positive electrode with the cance for the ventricles and is used diagnosti- other electrodes coupled together electrically cally to identify left and right axis deviations, to serve as a common negative electrode.

Based on the previous discussion, the follow- Standard limb leads are shown in Figure 2. Lead I has the positive electrode on the left arm and the negative electrode on the right arm, 1.

A wave of depolarization instantaneous therefore measuring the potential difference mean electrical vector traveling toward across the chest between the two arms. In this a positive electrode results in a posi- and the other two limb leads, an electrode on tive deflection in the ECG trace.

Corol- the right leg is a reference electrode for record- lary: A wave of depolarization traveling ing purposes. In the lead II configuration, the away from a positive electrode results in a positive electrode is on the left leg and the negative deflection.

A wave of repolarization traveling toward a positive electrode results in a negative deflection. A wave of depolarization or repolariza- tion oriented perpendicular to an elec- trode axis produces no net deflection. The instantaneous amplitude of the measured potentials depends upon the ori- entation of the positive electrode relative to the mean electrical vector.

Voltage amplitude positive or negative is directly related to the mass of tissue under- going depolarization or repolarization. RA, right arm; LA, left arm; face. Conventionally, electrodes are placed on RL, right leg; LL, left leg. Lead III lead III when the depolarization wave travels has the positive electrode on the left leg and the parallel to the axis between the left arm and negative electrode on the left arm. These three left leg. Whether the trode for lead I is defined as being at zero limb leads are attached to the end of the limb degrees relative to the heart along the hori- wrists and ankles or at the origin of the limbs zontal axis; see Fig.

This new construction of the electri- When using the ECG rules described in cal axis is called the axial reference system. With this axial electrode is on the left arm. A wave of depolarization axis between the right and left arms. In addition, and III. In the latter case, lead I shows no net a wave of repolarization moving away from deflection because the wave of depolarization the left arm is seen as a positive deflection. II and III, with which the positive electrode Three augmented limb leads exist in addi- is located on the left leg.

For example, a wave tion to the three bipolar limb leads described. The positive elec- both leads is on the left leg. Similarly, In practice, these are the same positive elec- a maximal positive deflection is obtained in trodes used for leads I, II, and III. For example, altered conduction can result in exaggerated Q waves in specific leads following some types of myocardial infarction.

Posterior Ischemia can also damage conduction path- ways, leading to arrhythmias or changes in the shape of the QRS complex. We do know, however, that tissue hypoxia caused by ischemia results in membrane depolarization. These electrodes inactivates fast sodium channels as previously record electrical activity in the horizontal plane, described, thereby decreasing action poten- which is perpendicular to the frontal plane of the limb leads.

One result is decreased conduction velocity. Changes in refractory period and conduction velocity can lead to and V6 overlies the left ventricular lateral wall. Membrane The rules of interpretation are the same as for the depolarization also alters pacemaker activity limb leads.

For example, a wave of depolarization and can cause latent pacemakers to become traveling toward a particular electrode on the active, leading to changes in rhythm and chest surface elicits a positive deflection. Normal ectopic beats. Finally, cellular hypoxia results electrical activation of the ventricles results in a in the accumulation of intracellular calcium, net negative deflection in V1 and a net positive which can lead to afterdepolarizations and deflection in V6 as shown in Figure 2.

These changes in might improve AV nodal conduction and phase 0 would reduce the conduction velocity thereby decrease the PR interval to within the within the ventricle. Blockade of fast sodium normal range 0. The QRS complex has no net voltage in lead I i. Because the ing the ERP of these cells, the action poten- QRS is positive in leads II and III, the mean tial emerging from adjacent pathways may electrical axis must be oriented toward the encounter tissue that is still refractory and positive electrode on the left leg, which is used therefore unexcitable, thereby preventing or for leads II and III.

Therefore, the mean elec- abolishing reentry. CASE Both aVL and aVR leads would have net negative Sympathetic nerve activity increases conduc- QRS voltages because the direction of the mean tion velocity within the AV node positive electrical axis is away from these two leads, dromotropic effect. Pathophysiology of Heart Disease. Dubin D. Rapid Interpretation of EKGs. Cover Publishing, Opie LH. The Heart: Physiology of the Heart. Wilkins, Therefore, if one the cell volume see Fig.

Thick fila- cardiac myocyte is electrically stimulated, ments are comprised of myosin, whereas thin cell-to-cell conduction ensures that the elec- filaments contain actin and other associated trical impulse will travel to all of the intercon- proteins. Chemical interactions between the nected myocytes. This arrangement allows actin and myosin filaments during the pro- the heart to contract as a unit i. In contrast, individual skeletal mus- the next section cause the sarcomere to cle cells are innervated by motor neurons, shorten as the myosin and actin filaments which utilize neuromuscular transmission to slide past each other, thereby shortening the activate individual muscle fibers to contract.

Within the sar- No cell-to-cell electrical conduction occurs in comere, a large, filamentous protein called skeletal muscle. It connects the myosin filament to The cardiac myocyte is composed of bun- the Z-lines, which helps to keep the thick fila- dles of myofibrils that contain myofilaments ment centered within the sarcomere.

Because Fig. When myocytes are viewed micro- of its elastic properties, titin plays an impor- scopically, distinct repeating lines and bands tant role in the passive mechanical properties can be seen, each of which represents differ- of the heart see Chapter 4. In addition to ent myofilament components.

The segment titin, myosin, and actin, a number of other between two Z-lines represents the basic con- proteins form the cytoskeleton of myocytes, tractile unit of the myocyte, the sarcomere.

As described later Within each sarcomere, myosin molecules and in Chapter 4, the length of the sarcomere are bundled together so that there are about is an important determinant of the force of molecules of myosin per thick filament.

Myosin is anchored to the Z-line by the protein titin. The sarcomere, or basic contractile unit, lies between two Z-lines. ATP is required for the cross-bridge ing excitation—contraction coupling; and formation between the thick and thin fila- troponin-I TN-I , which inhibits myosin ments. The troponin complex holds binding site on actin Fig. Regulatory tropomyosin in position to prevent binding subunits myosin light chains that can alter of myosin heads to actin.

Actin head for binding. Interdigitated between the actin inhibiting myosin—actin binding. Each tropomyosin molecule is asso- diagnostic markers for myocardial infarction ciated with seven actin molecules. Attached to because of their release into the circulation the tropomyosin at regular intervals is the tro- when myocytes die. The sarcolemmal membrane of the myocyte surrounds the bundle of myofibrils and has deep invaginations called transverse T tubules Fig.

Within proteins troponin complex, TN having three sub- the cell, and in close association with the units: TN-T binds to tropomyosin , TN-C binds to calcium ions , and TN-I inhibitory troponin, which T tubules, is an extensive, branching tubular inhibits myosin binding to actin.

Calcium binding network called the sarcoplasmic reticulum to TN-C produces a conformation change in the that surrounds the myofilaments. The pri- troponin—tropomyosin complex that exposes a mary function of this structure is to regulate myosin-binding site on the actin, leading to ATP hydrolysis.

Between the terminal cisternae release channels associated with the termi- and the T tubules are electron-dense regions nal cisternae. This triggers the subsequent called feet that are believed to sense calcium release of large quantities of calcium stored in between the T tubules and the terminal cister- the terminal cisternae through the calcium- nae.

Therefore, the calcium cyte contraction. When myosin-binding site on the actin molecule. This T tubules see Fig. The actin enters the cell during depolarization. By itself, and myosin filaments slide past each other, this calcium influx does not significantly thereby shortening the sarcomere length this increase intracellular calcium concentrations is referred to as the sliding filament theory except in local regions just inside the sarco- of muscle contraction Fig.

Ratcheting lemma. As intracellular calcium concentra- 2. Myosin heads bind to actin, leading to leads to troponin—tropomyosin inhibition of cross-bridge movement requires ATP the actin-binding site.

At the end of the cycle, hydrolysis and reduction in sarcomere a new ATP binds to the myosin head, displac- length. In the absence sin unbinds from actin requires ATP ; of sufficient ATP as occurs during cellu- this allows the sarcomere to resume its lar hypoxia, cardiac muscle contraction and original, relaxed length. Regulation of Contraction ultimately affect calcium handling by the cell.

Changes in contraction resulting from altered Inotropy calcium handling and myosin ATPase activity Several cellular mechanisms regulate contrac- are referred to as inotropic changes inotropy. Removal of calcium from the TN-C inhibits actin—myosin binding so that cross-bridge cycling ceases and the sarcomere resumes its relaxed length.

One important 2 calcium release by the sarcoplasmic reticu- site of phosphorylation is the L-type calcium lum; 3 calcium binding to TN-C; 4 myosin channel.

Phosphorylation increases the per- phosphorylation; 5 SERCA activity; and 6 meability of the channel to calcium, thereby calcium efflux across the sarcolemma. There- during depolarization Fig. L-type calcium channel. The primary mech- Another G-protein, the inhibitory G-protein anism for this regulation involves cyclic Gi-protein , inhibits adenylyl cyclase and adenosine monophosphate cAMP , the for- decreases intracellular cAMP.

This tors Fig. Norepinephrine released by pathway is coupled to muscarinic receptors sympathetic nerves, or circulating epineph- M2 that bind acetylcholine released by para- rine released by the adrenal glands, binds sympathetic vagal nerves within the heart.

This receptor is coupled to a the Gi-protein. Therefore, acetylcholine and specific guanine nucleotide-binding regula- adenosine are negative inotropic agents. The cAMP acts as a second messenger to activate protein Enhanced calcium release by the sarcoplasmic kinase A cAMP-dependent protein kinase, reticulum also can increase inotropy Fig. The bind- sarcoplasmic reticulum, leading to an increase ing of calcium to TN-C is determined by the in calcium release. This erated between actin and myosin.

Activation of these receptors hypoxia, has been shown to decrease TN-C stimulates phospholipase C to form inositol affinity for calcium. This may be one mecha- triphosphate IP3 from phosphatidylinositol nism by which acidosis decreases the force of 4,5-bisphosphate PIP2 , which stimulates cal- contraction. The mechanism by which is available to be taken up by the sarcoplasmic changes in length increase calcium affinity by reticulum and subsequently released.

TN-C is unknown. Cellular hypoxia also decreases the site 4. This leads to calcium accumulation in The physiologic significance of this mecha- the cell; however, inotropy is not increased, in nism, however, is uncertain. PK-A of calcium following its release by the phosphorylation of phospholamban, which sarcoplasmic reticulum. This reduction in removes the inhibitory effect of phospholamban intracellular calcium causes calcium that is on SERCA, increases the rate of calcium trans- bound to TN-C to be released, thereby permit- port into the sarcoplasmic reticulum.

SERCA ting the troponin—tropomyosin complex to activity can also be stimulated by increased resume its resting, inactivated conformation.

Enhanced sequestering of calcium by intracellular calcium concentrations. The rate at which calcium enters the cell reticulum, thereby increasing inotropy. Under ditions that reduce ATP production by the cell some pathologic conditions e. Inhibiting these transport systems pump and the ATP-dependent calcium pump can cause intracellular calcium concen- Fig. As described in Chapter 2, trations to increase sufficiently to impair these pumps transport calcium out of the cell, relaxation.

Blood vessels, except capillaries and small postcapillary venules, are composed of three layers: Capillaries and small postcapillary venules do not have media and adventitia. The primary components are given for each layer. In larger blood vessels vasa vasorum found in large vessels, a region of connective tissue also vessels , lymphatics, and autonomic nerves exists between the endothelial cells and the primarily sympathetic adrenergic.

The basal lamina. The media contains smooth smallest vessels, capillaries, are composed of muscle cells, imbedded in a matrix of col- endothelial cells and a basal lamina; they are lagen, elastin, and various glycoproteins. The smooth muscles cells are organized so that their contraction reduces Vascular smooth muscle cells are typically 5 to the vessel diameter. Numerous small invaginations cav- different elastic properties, determines the eolae found in the cell membrane significantly overall mechanical properties of the vessel.

For example, the aorta has a large amount of The sarcoplasmic reticulum is poorly devel- elastin, which enables it to passively expand oped compared with the sarcoplasmic reticu- and contract as blood is pumped into it from lum found in cardiac myocytes.

Contractile the heart. This mechanism enables the aorta proteins actin and myosin are present; how- to dampen the arterial pulse pressure see ever, the actin and myosin in smooth muscle are Chapter 5.

In contrast, smaller arteries and not organized into distinct bands of repeating arterioles have a relatively large amount of units as they are in cardiac and skeletal mus- smooth muscle, which is required for these cle. Instead, bands of actin filaments are joined vessels to contract and thereby regulate arte- together and anchored by dense bodies within rial blood pressure and organ blood flow.

The the cell or dense bands on the inner surface outermost layer, or adventitia, is separated of the sarcolemma, which function like Z-lines from the media by the external elastic lamina. N, nucleus. Similar hormones e. These low-resistance intercellular con- by the tissue surrounding the blood vessel.

For example, elec- can be initiated by electrical, chemical, and trical depolarization and contraction of a local mechanical stimuli. Electrical depolarization site on an arteriole can result in depolarization of the vascular smooth muscle cell membrane at a distant site along the same vessel, indicat- using electrical stimulation elicits contraction ing cell-to-cell propagation of the depolarizing primarily by opening voltage-dependent currents.

Vascular smooth ion channels, particularly calcium channels. In blood vessels, the smooth can elicit contraction. Each of these substances muscle is normally in a partially contracted binds to specific receptors on the vascular state, which determines the resting tone or smooth muscle cell.

Different signal transduc- diameter of the vessel. This tonic contraction tion pathways converge to increase intracellu- is determined by stimulatory and inhibitory lar calcium, thereby eliciting contraction. This probably therefore, are very important in regulating results from stretch-induced activation of smooth muscle contraction.

The concentra- ionic channels that leads to calcium influx. An increase in free intracellu- cium either back into intracellular storage lar calcium can result from either increased sites or out of the cell. Calcium is reseques- entry of calcium into the cell through L-type tered by the sarcoplasmic reticulum by an calcium channels or release of calcium from ATP-dependent calcium pump similar to the internal stores e.

SERCA pump found in cardiac myocytes. Cal- The free calcium binds to a special calcium- cium is removed from the cell to the external binding protein called calmodulin. The cal- environment by either an ATP-dependent cal- cium—calmodulin complex activates myosin cium pump or the sodium—calcium exchanger, light chain kinase, an enzyme that phospho- as in cardiac muscle see Chapter 2. Myosin light chains are regulatory subu- modulate intracellular calcium concentration nits found on the myosin heads.

Myosin light and therefore the state of vascular tone. This chain phosphorylation leads to cross-bridge section describes three different pathways: Dephosphorylation of myosin light chains by MLC phosphatase also produces relaxation. ATP, adenosine triphosphate; Pi, phosphate group. The activation of guanylyl cyclase Fig. Norepi- 3. Adenosine endothelin-I via ETA receptors , vasopressin and prostacyclin PGI2 also activate Gs-pro- via V1 receptors and acetylcholine via M3 tein through their receptors, leading to an receptors activate phospholipase C through increase in cAMP and smooth muscle relaxa- the Gq-protein, causing the formation of IP3 tion.

IP3 then directly stimulates the relaxes vascular smooth muscle through the sarcoplasmic reticulum to release calcium. The formation of diacylglycerol from PIP2 A third important mechanism for regulat- activates protein kinase C, which can modu- ing vascular smooth muscle contraction is the late vascular smooth muscle contraction as NO—cGMP system. Many endothelial-depend- well via protein phosphorylation.

In vascular smooth stimulate the conversion of L-arginine to muscle, unlike cardiac myocytes, an increase NO by activating NO synthase. This activates the IP3 pathway of the NO—cGMP pathway dominates and stimulates calcium release by the over the actions of the IP3 pathway; sarcoplasmic reticulum, which leads to therefore, acetylcholine normally causes increased smooth muscle contraction.

Architecture of the vessel wall. Ultrastructure of the heart. Handbook of In: Handbook of Physiology, vol 2. American Physiological Physiology, vol 1. American Physiological Society, ; 1— Society, ; 3— Sanders KM. Invited review: Regulation of cardiac contraction Somlyo AV: Ultrastructure of vascular smooth by calcium. Handbook of Physiology, vol 1. American Handbook of Physiology, vol 2. American Physiological Society, ; — Physiological Society, ; 33— Physiology from Cell to Circulation.

The right atrium is a highly disten- that attach to papillary muscles located on sible chamber that can easily expand to accom- the respective ventricular walls.

The papillary modate the venous return at a low pressure 0 muscles contract when the ventricles con- to 4 mm Hg. Blood flows from the right atrium, tract. This generates tension on the valve leaf- across the tricuspid valve right atrioventricu- lets via the chordae tendineae, preventing the lar [AV] valve , and into the right ventricle. The valves from bulging back and leaking blood free wall of the right ventricle wraps around into the atria i.

The as the ventricles develop pressure. The semi- outflow tract of the right ventricle is the pulmo- lunar valves pulmonic and aortic do not nary artery, which is separated from the ven- have analogous attachments. Blood returns to the heart from the lungs via four pul- Autonomic Innervation monary veins that enter the left atrium. Blood flows from the left atrium, across the mitral Autonomic innervation of the heart plays an valve left AV valve , and into the left ventricle. The left ventricle has a thick muscular wall that The heart is innervated by parasympathetic allows it to generate high pressures during con- vagal and sympathetic efferent fibers see traction.

The left ventricle ejects blood across Chapter 6 for details on the origin of these the aortic valve and into the aorta.

Furthermore, the timing of mechanical node, whereas the left vagus nerve inner- events in the right side of the heart is very vates the AV node; however, significant over- similar to that of the left side.

The main differ- lap can occur in the anatomical distribution. For example, the right ventricu- sparsely innervated by vagal efferents. Sym- lar pressure typically changes from about 0 to pathetic efferent nerves are present through- 4 mm Hg during filling to a maximum of 25 to out the atria especially in the SA node and 30 mm Hg during contraction.

This catheter can also the heart. Vagal-mediated inotropic influences be used to inject a radiopaque contrast agent are moderate in the atria and relatively weak into the left ventricular chamber. This per- in the ventricles. Activation of the sympa- mits fluoroscopic imaging contrast ventricu- thetic nerves to the heart increases heart rate, lography of the ventricular chamber, from conduction velocity, and inotropy. Sympa- which estimates of ventricular volume can be thetic influences are pronounced in both the obtained; however, real-time echocardiogra- atria and ventricles.

The stretch cardiac cycle is defined as the cardiac events receptors are involved in feedback regula- initiated by the P wave in the electrocardio- tion of blood volume and arterial pressure, gram ECG and continuing until the next whereas the pain receptors produce chest pain P wave. The cardiac cycle is divided into two when activated during myocardial ischemia. Sys- tole refers to events associated with ventricu- lar contraction and ejection.

The cardiac cycle is further divided into seven phases, begin- Cardiac Cycle Diagram ning when the P wave appears. These phases To understand how cardiac function is regu- are atrial systole, isovolumetric contraction, lated, one must know the sequence of mechan- rapid ejection, reduced ejection, isovolumet- ical events during a complete cardiac cycle ric relaxation, rapid filling, and reduced fill- and how these mechanical events relate to ing.

The events associated with each of these the electrical activity of the heart. The cardiac phases are described below. Atrial Systole: AV Valves left side of the heart left ventricular pressure Open; Aortic and Pulmonic and volume, left atrial pressure, and aortic Valves Closed pressure as a function of time. Although not shown in this figure, pressure and volume The P wave of the ECG represents electrical changes in the right side of the heart right depolarization of the atria, which initiates atrium and ventricle and pulmonary artery contraction of the atrial musculature.

On the right side of the heart, ventricles. Isovolumetric occurs before the atria contract. Therefore, Contraction: All Valves Closed ventricular filling is mostly passive and depends on the venous return. However, at This phase of the cardiac cycle, which is the high heart rates e. As the ventricles depo- decreased , and the amount of blood that larize, myocyte contraction leads to a rapid enters the ventricle by passive filling is increase in intraventricular pressure.

The reduced. Under these conditions, the relative abrupt rise in pressure causes the AV valves to contribution of atrial contraction to ventricu- close as the intraventricular pressure exceeds lar filling increases greatly and may account atrial pressure. In addi- muscles with their attached chordae tendineae tion, atrial contribution to ventricular fill- prevents the AV valve leaflets from bulging ing is enhanced by an increase in the force back or prolapsing into the atria and becom- of atrial contraction caused by sympathetic ing incompetent i.

Closure of the nerve activation. Enhanced ventricular filling AV valves results in the First Heart Sound owing to increased atrial contraction is some- S1.

This leads to inadequate ven- a stethoscope overlying the heart. The left the aorta or pulmonary artery occurs. The right ventricular phase. During this phase, some individual fib- end-diastolic pressure is typically about ers shorten when they contract, whereas oth- 4 mm Hg. Ventricu- S4. The sound is caused by vibration of the lar chamber geometry changes considerably ventricular wall as blood rapidly enters the as the heart becomes more spheroid in shape, ventricle during atrial contraction.

This sound although the volume does not change. Early generally is noted when the ventricle com- in this phase, the rate of pressure develop- pliance is reduced i. Reduced Ejection: This causes ventricular active tension to decrease i.

Rapid Ejection: Ventricular pressure falls slightly below Valves Remain Closed outflow tract pressure; however, outward flow When the intraventricular pressures exceed still occurs owing to kinetic or inertial energy the pressures within the aorta and pulmonary of the blood that helps to propel the blood into artery, the aortic and pulmonic valves open and the aorta and pulmonary artery. Atrial pres- blood is ejected out of the ventricles. Ejection sures gradually rise during this phase owing to occurs because the total energy of the blood continued venous return into the atrial cham- within the ventricle exceeds the total energy bers.

The end of this phase concludes systole. The total energy of the blood is the sum of the pressure energy Phase 5. Isovolumetric and the kinetic energy; the latter is related to Relaxation: All Valves Closed the square of the velocity of the blood flow. In other words, ejection occurs because an energy As the ventricles continue to relax and intra- gradient is present mostly owing to pressure ventricular pressures fall, a point is reached at energy that propels blood into the aorta and which the total energy of blood within the ven- pulmonary artery.

During this phase, ventric- tricles is less than the energy of blood in the ular pressure normally exceeds outflow tract outflow tracts. When this total energy gradient pressure by only a few millimeters of mercury reversal occurs, the aortic and pulmonic valves mm Hg. Although blood flow across the to abruptly close. At this point, systole ends and valves is high, the relatively large valve open- diastole begins. Valve closure causes the Sec- ing i.

Maximal outflow before the pulmonic valve. Normally, little or velocity is reached early in the ejection phase, no blood flows backward into the ventricles as and maximal systolic aortic and pulmonary these valves close.

Valve closure is associated artery pressures are achieved, which are typi- with a characteristic notch incisura in the cally about and 25 mm Hg in the aorta aortic and pulmonary artery pressure tracings. Unlike in the ventricles, where pressure rapidly While blood is being ejected and ventric- falls, the decline in aortic and pulmonary artery ular volumes decrease, the atria continue to pressures is not abrupt because of potential fill with blood from their respective venous energy stored in their elastic walls and because inflow tracts.

Although atrial volumes are systemic and pulmonic vascular resistances increasing, atrial pressures initially decrease impede the flow of blood into distributing arter- x' descent as the base of the atria is pulled ies of the systemic and pulmonary circulations. Ventricular volumes remain constant iso- No heart sounds are ordinarily heard dur- volumetric during this phase because all valves ing ejection.

The opening of healthy valves are closed. The residual volume of blood that is silent. The presence of a sound during remains in a ventricle after ejection is called the ejection i.

For the left ven- valve disease or intracardiac shunts see tricle, this is approximately 50 mL of blood. Chapter 9.

Reduced Filling: Although ventricular vol- reduced filling phase is the period during dias- ume does not change during isovolumetric tole when passive ventricular filling is nearing relaxation, atrial volumes and pressures con- completion.

This is sometimes referred to as tinue to increase owing to venous return. As the ven- tricles continue to fill with blood and expand, they become less compliant i. Phase 6. Rapid Filling: AV Valves This causes the intraventricular pressures Open; Aortic and Pulmonic to rise, as described later in this chapter.

Valves Closed Increased intraventricular pressure reduces When the ventricular pressures fall below the pressure gradient across the AV valve the atrial pressures, the AV valves open and ven- pressure gradient is the difference between tricular filling begins. Initially, the ventricles the atrial and ventricular pressure so that the are still relaxing, which causes intraventricular rate of filling declines, even though atrial pres- pressures to continue to fall by several mm Hg sures continue to increase slightly as venous despite ongoing ventricular filling.

The rate of blood continues to flow into the atria. Aortic initial filling is enhanced by the fact that atrial pressure and pulmonary arterial pressure con- volumes are maximal just prior to AV valve tinue to fall during this period as blood flows opening. Once the valves open, the elevated into the systemic and pulmonary circulations. At low heart rates, results in rapid, passive filling of the ventri- the length of time allotted to diastole is rela- cles.

Once the ventricles are fully relaxed, their tively long, which lengthens the time of the pressure begins to rise as they fill. High heart rates reduce The opening of the AV valves causes a rapid the overall cycle length and are associated fall in atrial pressures. Without compen- blood leaves the atria. The v wave and y descent satory mechanisms, this cycle length reduc- are transmitted into the proximal venous ves- tion would lead to less ventricular filling i.

Compensatory mechanisms the heart and pulmonary veins on the left side. Summary of Intracardiac If the AV valves are functioning normally, no Pressures prominent sounds will be heard during filling. When a Third Heart Sound S3 is audible dur- It is important to know normal values of ing ventricular filling, it may represent tensing intracardiac pressures, as well as the pressures of chordae tendineae and the AV ring, which is within the veins and arteries entering and the connective tissue support for the valve leaf- leaving the heart, because abnormal pressures lets.

This S3 heart sound is normal in children, can be used to diagnose certain types of car- but it is considered pathologic in adults because diac disease and dysfunction. Figure 4. The area within the pressure—volume loop is the ventricular stroke work.

The higher of the two pressure values expressed in mm Hg in the right ventricle RV , left ventricle The maximal pressure that can be devel- LV , pulmonary artery PA , and aorta Ao rep- oped by the ventricle at any given left ventric- resent the normal peak pressures during ejection ular volume is described by the end-systolic systolic pressure , whereas the lower pressure pressure—volume relationship ESPVR. The values represent normal end of diastole pres- sure ventricles or the lowest pressure diastolic pressure—volume loop, therefore, cannot cross pressure found in the PA and Ao.

Note that the pressures on the right The changes in pressures and volumes side of the heart are considerably lower than described in the cardiac cycle diagram and those on the left side of the heart, and that by the pressure—volume loop are for normal the pulmonary circulation has low pressures adult hearts at resting heart rates.

Pressure— compared to the systemic arterial system. The volume loops appear very differently in the pressures shown for the right and left atria presence of valve disease and heart failure as indicate an average atrial pressure during the described in Chapter 9.

The primary function of the heart is to impart Ventricular Pressure—Volume energy to blood to generate and sustain an Relationship arterial blood pressure sufficient to adequately Although measurements of pressures and perfuse organs. The heart achieves this by con- volumes over time can provide important tracting its muscular walls around a closed insights into ventricular function, pressure— chamber to generate sufficient pressure to pro- volume loops provide another powerful tool pel blood from the left ventricle, through the for analyzing the cardiac cycle, particularly aortic valve, and into the aorta.

Each time the ventricular function. This SV, multiplied by the panel are generated by plotting left ventric- number of beats per minute heart rate, HR , ular pressure against left ventricular volume equals the cardiac output CO Equation In Figure 4. These changes in heart rate are brought about primarily by changes in In experimental settings, cardiac output can sympathetic and parasympathetic nerve activ- be measured by electromagnetic or Dop- ity at the SA node see Chapter 2.

Obviously, this approach cannot ily result in a proportionate change in cardiac be used in humans; therefore, indirect tech- output. The reason is that changes in heart niques are used.

The most commonly used is rate can inversely affect SV. A cold rate is elevated. This occurs because the ven- saline solution of known temperature and tricular filling time decreases as the length of volume is injected into the right atrium from a diastole shortens, thereby resulting in less ven- proximal port on the catheter. The cold injec- tricular filling. However, when normal physi- tate mixes into the blood and cools the blood, ological mechanisms during exercise cause the which then passes through the right ventricle heart rate to double, cardiac output more than and into the pulmonary artery.

The thermistor doubles because SV actually increases. This at the catheter tip measures the blood temper- increase in SV, despite the elevation in heart ature, and a cardiac output computer is used rate, is brought about by several mechanisms to calculate flow cardiac output. Doppler acting on the heart and systemic circulation echocardiography can be used to estimate see Chapter 9. When these mechanisms fail, real-time changes in flow within the heart, SV cannot be maintained at elevated heart rates.

Ventricles depolarized; isoelectric voltage in aVL and II; red arrow represents mean electrical axis. In contrast, the mean vector is heading almost directly towards the lead II positive electrode, which results in a very tall, positive deflection R wave of the QRS. After another 20 milliseconds Panel D , the apex and most of the right ventricular free wall are completely depolarized. At this time, the left ventricular free wall depolarizes from the endocardial inside to epicardial outside surface.

Therefore, this vector produces a large positive voltage in lead aVL and a relatively small positive voltage in lead II. The last regions of the left ventricle to depolarize Panel E result in a mean vector that is heading somewhat toward lead aVL, and away from lead II. It is important to note that the placement of the recording electrode determines the shape of the QRS complex that is recorded.

If the four mean vectors in Figure 2. The mean electrical axis represents the average of all of the instantaneous mean electrical vectors occurring sequentially during ventricular depolarization. The determination of mean electrical axis is of particular significance for the ventricles and is used diagnostically to identify left and right axis deviations, which can be caused by a number of factors including conduction blocks in a bundle branch and ventricular hypertrophy.

Based on the previous discussion, the following rules can be used in interpreting the ECG: A wave of depolarization instantaneous mean electrical vector traveling toward a positive electrode results in a positive deflection in the ECG trace. A wave of depolarization traveling away from a positive electrode results in a negative deflection. A wave of repolarization traveling toward a positive electrode results in a negative deflection. A wave of repolarization traveling away from a positive electrode results in a positive deflection.

A wave of depolarization or repolarization oriented perpendicular to an electrode axis produces no net deflection. The instantaneous amplitude of the measured potentials depends upon the orientation of the positive electrode relative to the mean electrical vector.

Voltage amplitude positive or negative is directly related to the mass of tissue undergoing depolarization or repolarization. ECG Leads: Placement of Recording Electrodes The ECG is recorded by placing an array of electrodes at specific locations on the body surface.

Three basic types of ECG leads are recorded by these electrodes: These electrode leads are connected to a device that measures potential differences between selected electrodes to produce the characteristic ECG tracings. The limb leads are sometimes referred to as bipolar leads because each lead uses a single pair of positive and negative electrodes. The augmented leads and chest leads are unipolar leads because they have a single positive electrode with the other electrodes coupled together electrically to serve as a common negative electrode.

Lead I has the positive electrode on the left arm and the negative electrode on the right arm, therefore measuring the potential difference across the chest between the two arms. In this and the other two limb leads, an electrode on the right leg is a reference electrode for recording purposes.

If the three limbs of Einthoven triangle are broken apart, collapsed, and superimposed over the heart Fig. This new construction of the electrical axis is called the axial reference system. Three augmented limb leads exist in addition to the three bipolar limb leads described. Each of these leads has a single positive electrode that is referenced against a combination of the other limb electrodes. The ECG negative electrode is on the right arm.

Lead III has the positive electrode on the left leg and the negative electrode on the left arm. These three limb leads roughly form an equilateral triangle with the heart at the center , called Einthoven triangle in honor of Willem Einthoven who developed the ECG in Whether the limb leads are attached to the end of the limb wrists and ankles or at the origin of the limbs shoulder and upper thigh makes virtually no difference in the recording because the limb can be viewed as a wire conductor originating from a point on the trunk of the body.

When using the ECG rules described in the previous section, a wave of depolarization heading toward the left arm gives a positive deflection in lead I because the positive electrode is on the left arm.

Maximal positive deflection of the tracing occurs in lead I when a wave of depolarization travels parallel to the axis between the right and left arms. If a wave of depolarization heads away from the left arm, the deflection is negative. In addition, a wave of repolarization moving away from the left arm is seen as a positive deflection. Similar statements can be made for leads II and III, with which the positive electrode is located on the left leg.

For example, a wave of depolarization traveling toward the left leg gives a positive deflection in both leads II and III because the positive electrode for both leads is on the left leg. A maximal positive deflection is obtained in lead II when the depolarization wave travels parallel to the axis between the right arm and left leg. These electrodes record electrical activity in the horizontal plane, which is perpendicular to the frontal plane of the limb leads. The rules of interpretation are the same as for the limb leads.

For example, a wave of depolarization traveling toward a particular electrode on the chest surface elicits a positive deflection. Normal electrical activation of the ventricles results in a net negative deflection in V1 and a net positive deflection in V6 as shown in Figure 2. A lead ECG can identify the extent, location, and progress of damage to the heart following ischemic injury. For example, altered conduction can result in exaggerated Q waves in specific leads following some types of myocardial infarction.

Ischemia can also damage conduction pathways, leading to arrhythmias or changes in the shape of the QRS complex. Furthermore, ischemia can produce injury currents flowing from the depolarized ischemic regions to normal regions that can shift the isoelectric portions of the ECG, resulting in upward or downward shifts in the ST segment recorded by overlying electrodes.

The mechanisms by which ischemia and infarction alter the ECG are complex and not fully understood. We do know, however, that tissue hypoxia caused by ischemia results in membrane depolarization. This depolarization inactivates fast sodium channels as previously described, thereby decreasing action potential upstroke velocity. One result is decreased conduction velocity. Changes in refractory period and conduction velocity can lead to reentry currents and tachycardia.

Membrane depolarization also alters pacemaker activity and can cause latent pacemakers to become active, leading to changes in rhythm and ectopic beats.

Finally, cellular hypoxia results in the accumulation of intracellular calcium, which can lead to afterdepolarizations and tachycardia. These changes in phase 0 would reduce the conduction velocity within the ventricle.

Blockade of fast sodium channels is the primary mechanism of action of Class I antiarrhythmic drugs such as quinidine and lidocaine. The QRS complex has no net voltage in lead I i. Furthermore, the net negative deflections in these two augmented leads would be of equal magnitude because each lead axis differs from the mean electrical axis by the same number of degrees. Rapid Interpretation of EKGs.

Cover Publishing, Katz AM. Physiology of the Heart. Lilly LS. Pathophysiology of Heart Disease. Opie LH. The Heart: Physiology from Cell to Circula tion. CASE Reentry requires that cells can be prematurely reexcited by action potentials emerging from adjacent conducting pathways. By increasing the ERP of these cells, the action potential emerging from adjacent pathways may encounter tissue that is still refractory and therefore unexcitable, thereby preventing or abolishing reentry.

Therefore, if one cardiac myocyte is electrically stimulated, cell-to-cell conduction ensures that the electrical impulse will travel to all of the interconnected myocytes. This arrangement allows the heart to contract as a unit i. In contrast, individual skeletal muscle cells are innervated by motor neurons, which utilize neuromuscular transmission to activate individual muscle fibers to contract.

No cell-to-cell electrical conduction occurs in skeletal muscle. The cardiac myocyte is composed of bundles of myofibrils that contain myofilaments Fig. When myocytes are viewed microscopically, distinct repeating lines and bands can be seen, each of which represents different myofilament components. The segment between two Z-lines represents the basic contractile unit of the myocyte, the sarcomere. The length of each sarcomere under physiologic conditions ranges from about 1.

As described later and in Chapter 4, the length of the sarcomere is an important determinant of the force of myocyte contraction. Thick filaments are comprised of myosin, whereas thin filaments contain actin and other associated proteins. Chemical interactions between the actin and myosin filaments during the process of excitation—contraction coupling see the next section cause the sarcomere to shorten as the myosin and actin filaments slide past each other, thereby shortening the distance between the Z-lines.

Within the sarcomere, a large, filamentous protein called titin exists. It connects the myosin filament to the Z-lines, which helps to keep the thick filament centered within the sarcomere.

Because of its elastic properties, titin plays an important role in the passive mechanical properties of the heart see Chapter 4. In addition to titin, myosin, and actin, a number of other proteins form the cytoskeleton of myocytes, connecting the internal and external cell components.

Myosin is a large molecular weight protein. Within each sarcomere, myosin molecules are bundled together so that there are about molecules of myosin per thick filament. Myosin is anchored to the Z-line by the protein titin. The sarcomere, or basic contractile unit, lies between two Z-lines. ATP is required for the cross-bridge formation between the thick and thin filaments. Regulatory subunits myosin light chains that can alter the ATPase activity when phosphorylated are associated with each myosin head.

Each thick filament is surrounded by a hexagonal arrangement of six thin filaments. The thin filaments are composed of actin, tropomyosin, and troponin Fig.

Actin is a globular protein arranged as a chain of repeating globular units, forming two helical strands. Interdigitated between the actin strands are rod-shaped proteins called tropomyosin.

Each tropomyosin molecule is associated with seven actin molecules. Attached to the tropomyosin at regular intervals is the troponin regulatory complex, made up of three 43 subunits: The troponin complex holds tropomyosin in position to prevent binding of myosin heads to actin. As a clinical aside, both TN-I and TN-T are used as diagnostic markers for myocardial infarction because of their release into the circulation when myocytes die.

Calcium binding to TN-C produces a conformation change in the troponin—tropomyosin complex that exposes a myosin-binding site on the actin, leading to ATP hydrolysis.

To understand this process, the internal structure of the myocyte needs to be examined in more detail. The sarcolemmal membrane of the myocyte surrounds the bundle of myofibrils and has deep invaginations called transverse T tubules Fig. The T tubules, being a part of the external sarcolemma, are open to the external environment of the cell. This permits ions to exchange between extracellular and intracellular compartments to occur deep within the myocyte during electrical depolarization and repolarization of the myocyte.

Within the cell, and in close association with the T tubules, is an extensive, branching tubular network called the sarcoplasmic reticulum that surrounds the myofilaments.

The primary function of this structure is to regulate intracellular calcium concentrations, which is involved with contraction and relaxation. Between the terminal cisternae and the T tubules are electron-dense regions called feet that are believed to sense calcium between the T tubules and the terminal cisternae.

Closely associated with the sarcoplasmic reticulum are large numbers of mitochondria, which provide the energy necessary for myocyte contraction.

When the myocyte is depolarized, calcium ions enter the cell during the action potential through long-lasting L-type calcium channels located on the external sarcolemma and T tubules see Fig.

It is important to note that a relatively small amount of calcium enters the cell during depolarization. By itself, this calcium influx does not significantly increase intracellular calcium concentrations except in local regions just inside the sarcolemma. This induces a conformational change in the regulatory complex such that the troponin—tropomyosin complex moves away from and exposes a myosin-binding site on the actin molecule.

The binding of the myosin head to the actin results in ATP hydrolysis, which supplies energy so that a conformational change can occur in the actin—myosin complex. The actin and myosin filaments slide past each other, thereby shortening the sarcomere length this is referred to as the sliding filament theory of muscle contraction Fig. Ratcheting cycles will occur as long as the cytosolic calcium remains elevated. As intracellular calcium concentration declines, calcium dissociates from TN-C, which causes a conformational change in the troponin—tropomyosin complex; this again leads to troponin—tropomyosin inhibition of the actin-binding site.

At the end of the cycle, a new ATP binds to the myosin head, displacing the adenosine diphosphate, and the initial sarcomere length is restored.

Thus, ATP is required both for providing the energy of contraction and for relaxation. In the absence of sufficient ATP as occurs during cellular hypoxia, cardiac muscle contraction and relaxation will be impaired. The events associated with excitation—contraction coupling are summarized in Table Regulation of Contraction Inotropy Several cellular mechanisms regulate contraction Fig. Myosin heads bind to actin, leading to cross-bridge movement requires ATP hydrolysis and reduction in sarcomere length.

Changes in contraction resulting from altered calcium handling and myosin ATPase activity are referred to as inotropic changes inotropy.

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Removal of calcium from the TN-C inhibits actin—myosin binding so that cross-bridge cycling ceases and the sarcomere resumes its relaxed length. This receptor is coupled to a specific guanine nucleotide-binding regulatory protein stimulatory G-protein; Gs-protein , that activates adenylyl cyclase, which in turn hydrolyzes ATP to cAMP.

One important site of phosphorylation is the L-type calcium channel. Phosphorylation increases the permeability of the channel to calcium, thereby increasing calcium influx during action potentials. This increase in trigger calcium enhances calcium release by the sarcoplasmic reticulum, thereby increasing inotropy. Therefore, norepinephrine and epinephrine are positive inotropic agents. Therefore, activation of this pathway decreases inotropy.

This pathway is coupled to muscarinic receptors M2 that bind acetylcholine released by parasympathetic vagal nerves within the heart. Adenosine receptors A1 also are coupled to the Gi-protein. Therefore, acetylcholine and adenosine are negative inotropic agents. This second pathway involves a class of G-proteins Gq-proteins; Fig. Activation of these receptors stimulates phospholipase C to form inositol triphosphate IP3 from phosphatidylinositol 4,5-bisphosphate PIP2 , which stimulates calcium release by the sarcoplasmic reticulum.

The binding of calcium to TN-C is determined by the free intracellular concentration of calcium and the binding affinity of TN-C to calcium. The greater the intracellular calcium concentration, the more the calcium that is bound to TN-C, and the more the force that is generated between actin and myosin.

Increasing the affinity of TN-C for calcium increases binding at any given calcium concentration, thereby increasing force generation. Acidosis, which occurs during myocardial hypoxia, has been shown to decrease TN-C affinity for calcium. This may be one mechanism by which acidosis decreases the force of contraction. Changes in calcium sensitivity may explain in part how increases in sarcomere length also known as preload; see Chapter 4 leads to an increase in force generation.

The mechanism by which changes in length increase calcium affinity by TN-C is unknown. Increased cAMP is known to be associated with increased phosphorylation of the myosin heads, which may increase inotropy. The physiologic significance of this mechanism, however, is uncertain. PK-A phosphorylation of phospholamban, which removes the inhibitory effect of phospholamban on SERCA, increases the rate of calcium transport into the sarcoplasmic reticulum.

SERCA activity can also be stimulated by increased intracellular calcium caused by increased calcium entry into the cell or decreased cellular efflux. Enhanced sequestering of calcium by the sarcoplasmic reticulum increases subsequent release of calcium by the sarcoplasmic reticulum, thereby increasing inotropy.

Because the SERCA pump requires ATP, hypoxic conditions that reduce ATP production by the cell can diminish the pump activity, thereby reducing subsequent release of calcium by the sarcoplasmic reticulum and decreasing inotropy.

As described in Chapter 2, these pumps transport calcium out of the cell, thereby preventing the cell from becoming overloaded with calcium. This leads to calcium accumulation in the cell; however, inotropy is not increased, in part, because the lack of ATP decreases myosin ATPase activity. Regulation of Relaxation Lusitropy The rate of myocyte relaxation lusitropy is determined by the ability of the cell to rapidly reduce the intracellular concentration of calcium following its release by the sarcoplasmic reticulum.

This reduction in intracellular calcium causes calcium that is bound to TN-C to be released, thereby permitting the troponin—tropomyosin complex to resume its resting, inactivated conformation. Several intracellular mechanisms help to regulate lusitropy, most of which influence intracellular calcium concentrations.

The rate at which calcium enters the cell at rest and during action potentials influences intracellular concentrations. Under some pathologic conditions e. Inhibiting these transport systems can cause intracellular calcium concentrations to increase sufficiently to impair relaxation. Blood vessels, except capillaries and small postcapillary venules, are composed of three layers: Capillaries and small postcapillary venules do not have media and adventitia.

The primary components are given for each layer. In larger vessels, a region of connective tissue also exists between the endothelial cells and the basal lamina. The media contains smooth muscle cells, imbedded in a matrix of collagen, elastin, and various glycoproteins. Depending on the size of the vessel, there may be several layers of smooth muscle cells, some arranged circumferentially and others arranged helically along the longitudinal axis of the vessel.

The smooth muscles cells are organized so that their contraction reduces the vessel diameter. The ratio of smooth muscle, collagen, and elastin, each of which has different elastic properties, determines the overall mechanical properties of the vessel. For example, the aorta has a large amount of elastin, which enables it to passively expand and contract as blood is pumped into it from the heart.

This mechanism enables the aorta to dampen the arterial pulse pressure see Chapter 5. In contrast, smaller arteries and arterioles have a relatively large amount of smooth muscle, which is required for these vessels to contract and thereby regulate arterial blood pressure and organ blood flow.

The outermost layer, or adventitia, is separated from the media by the external elastic lamina. The smallest vessels, capillaries, are composed of endothelial cells and a basal lamina; they are devoid of smooth muscle.

Numerous small invaginations caveolae found in the cell membrane significantly increase the surface area of the cell Fig. The sarcoplasmic reticulum is poorly developed compared with the sarcoplasmic reticulum found in cardiac myocytes. Contractile proteins actin and myosin are present; however, the actin and myosin in smooth muscle are not organized into distinct bands of repeating units as they are in cardiac and skeletal muscle. Instead, bands of actin filaments are joined together and anchored by dense bodies within the cell or dense bands on the inner surface of the sarcolemma, which function like Z-lines in cardiac myocytes.

N, nucleus. Similar to cardiac myocytes, vascular smooth muscle cells are electrically connected by gap junctions. These low-resistance intercellular connections allow propagated responses along the length of the blood vessels.

For example, electrical depolarization and contraction of a local site on an arteriole can result in depolarization at a distant site along the same vessel, indicating cell-to-cell propagation of the depolarizing currents.

Vascular smooth muscle tonic contractions are slow and sustained, whereas cardiac muscle contractions are rapid and relatively short a few hundred milliseconds. In blood vessels, the smooth muscle is normally in a partially contracted state, which determines the resting tone or diameter of the vessel. This tonic contraction is determined by stimulatory and inhibitory influences acting on the vessel.

Vascular smooth muscle contraction can be initiated by electrical, chemical, and mechanical stimuli. Electrical depolarization of the vascular smooth muscle cell membrane using electrical stimulation elicits contraction primarily by opening voltage-dependent calcium channels L-type calcium channels , which causes an increase in the intracellular concentration of calcium.

Membrane depolarization can also occur through changes in ion concentrations e. Many different chemical stimuli, such as norepinephrine, epinephrine, angiotensin II, vasopressin, endothelin-1, and thromboxane A2 can elicit contraction.

Each of these substances binds to specific receptors on the vascular smooth muscle cell. Different signal transduction pathways converge to increase intracellular calcium, thereby eliciting contraction. This probably results from stretch-induced activation of ionic channels that leads to calcium influx. Figure 3. An increase in free intracellular calcium can result from either increased entry of calcium into the cell through L-type calcium channels or release of calcium from internal stores e.

The free calcium binds to a special calciumbinding protein called calmodulin. The calcium—calmodulin complex activates myosin light chain kinase, an enzyme that phosphorylates myosin light chains in the presence of ATP. Myosin light chains are regulatory subunits found on the myosin heads. Myosin light chain phosphorylation leads to cross-bridge formation between the myosin heads and the actin filaments, thus leading to smooth muscle contraction. The concentration of intracellular calcium depends on the balance between the calcium that enters the cells, the calcium that is released by intracellular storage sites, and the movement of calcium either back into intracellular storage sites or out of the cell.

Calcium is removed from the cell to the external environment by either an ATP-dependent calcium pump or the sodium—calcium exchanger, as in cardiac muscle see Chapter 2. Several signal transduction mechanisms modulate intracellular calcium concentration and therefore the state of vascular tone. This section describes three different pathways: Dephosphorylation of myosin light chains by MLC phosphatase also produces relaxation.

ATP, adenosine triphosphate; Pi, phosphate group. The IP3 pathway in vascular smooth muscle is similar to that found in the heart. IP3 then directly stimulates the sarcoplasmic reticulum to release calcium. The formation of diacylglycerol from PIP2 activates protein kinase C, which can modulate vascular smooth muscle contraction as well via protein phosphorylation. Receptors coupled to the Gs-protein stimulate adenylyl cyclase, which catalyzes the formation of cAMP.

The mechanism for this process is cAMP inhibition of myosin light chain kinase see Fig. Adenosine and prostacyclin PGI2 also activate Gs-protein through their receptors, leading to an increase in cAMP and smooth muscle relaxation.

Many endothelial-dependent vasodilator substances e. This activates the IP3 pathway and stimulates calcium release by the sarcoplasmic reticulum, which leads to increased smooth muscle contraction. If the endothelium is intact, stimulation of the NO—cGMP pathway dominates over the actions of the IP3 pathway; therefore, acetylcholine normally causes vasodilation. Ultrastructure of the heart.

Handbook of Physiology, vol 1. American Physiological Society, ; 3— Regulation of cardiac contraction by calcium. American Physiological Society, ; — Physiology from Cell to Circulation. Rhodin JAG. Architecture of the vessel wall. Handbook of Physiology, vol 2. American Physiological Society, ; 1— Sanders KM. Invited review: J Appl Physiol ; Somlyo AV: Ultrastructure of vascular smooth muscle. American Physiological Society, ; 33— The right atrium is a highly distensible chamber that can easily expand to accommodate the venous return at a low pressure 0 to 4 mm Hg.

Blood flows from the right atrium, across the tricuspid valve right atrioventricular [AV] valve , and into the right ventricle. The free wall of the right ventricle wraps around part of the larger and thicker left ventricle. The outflow tract of the right ventricle is the pulmonary artery, which is separated from the ventricle by the semilunar pulmonic valve. Blood returns to the heart from the lungs via four pulmonary veins that enter the left atrium.

Blood flows from the left atrium, across the mitral valve left AV valve , and into the left ventricle. The left ventricle has a thick muscular wall that allows it to generate high pressures during contraction. The left ventricle ejects blood across the aortic valve and into the aorta. The papillary muscles contract when the ventricles contract. This generates tension on the valve leaflets via the chordae tendineae, preventing the valves from bulging back and leaking blood into the atria i.

The semilunar valves pulmonic and aortic do not have analogous attachments. Autonomic Innervation Autonomic innervation of the heart plays an important role in regulating cardiac function. The heart is innervated by parasympathetic vagal and sympathetic efferent fibers see Chapter 6 for details on the origin of these autonomic nerves. Atrial muscle is also innervated by vagal efferents; the ventricular myocardium is only sparsely innervated by vagal efferents. Sympathetic efferent nerves are present throughout the atria especially in the SA node and ventricles, and in the conduction system of the heart.

Vagal activation of the heart decreases heart rate negative chronotropy , decreases conduction velocity negative dromotropy , and decreases contractility negative inotropy of the heart.

Vagal-mediated inotropic influences are moderate in the atria and relatively weak in the ventricles. Activation of the sympathetic nerves to the heart increases heart rate, conduction velocity, and inotropy.

Sympathetic influences are pronounced in both the atria and ventricles. As Chapter 6 describes in more detail, the heart also contains vagal and sympathetic afferent nerve fibers that relay information from stretch and pain receptors. The stretch receptors are involved in feedback regulation of blood volume and arterial pressure, whereas the pain receptors produce chest pain when activated during myocardial ischemia. The cardiac cycle diagram in Figure 4.

Furthermore, the timing of mechanical events in the right side of the heart is very similar to that of the left side. The main difference is that the pressures in the right side of the heart are much lower than those found in the left side.

For example, the right ventricular pressure typically changes from about 0 to 4 mm Hg during filling to a maximum of 25 to 30 mm Hg during contraction.

Cardiovascular Physiology Concepts

A catheter can be placed in the ascending aorta and left ventricle to obtain the pressure and volume information shown in the cardiac cycle diagram and to measure simultaneous changes in aortic and intraventricular pressure as the heart beats.

This catheter can also be used to inject a radiopaque contrast agent into the left ventricular chamber. This permits fluoroscopic imaging contrast ventriculography of the ventricular chamber, from which estimates of ventricular volume can be obtained; however, real-time echocardiography and nuclear imaging of the heart are more commonly used to obtain clinical assessment of volume and function.

In the following discussion, a complete cardiac cycle is defined as the cardiac events initiated by the P wave in the electrocardiogram ECG and continuing until the next P wave. The cardiac cycle is divided into two general categories: Systole refers to events associated with ventricular contraction and ejection.

Diastole refers to the rest of the cardiac cycle, including ventricular relaxation and filling. The cardiac cycle is further divided into seven phases, beginning when the P wave appears. These phases are atrial systole, isovolumetric contraction, rapid ejection, reduced ejection, isovolumetric relaxation, rapid filling, and reduced filling.

The events associated with each of these phases are described below.

Bestselling Series

Phase 1. Atrial Systole: This can be observed when a person is recumbent and the jugular vein in the neck expands with blood, which permits pulsations to be visualized. Therefore, ventricular filling is mostly passive and depends on the venous return. However, at high heart rates e. In addition, atrial contribution to ventricular filling is enhanced by an increase in the force of atrial contraction caused by sympathetic nerve activation. This leads to inadequate ventricular filling, particularly when ventricular rates increase during physical activity.

After atrial contraction is complete, the atrial pressure begins to fall, which causes a slight pressure gradient reversal across the AV valves. At the end of this phase, which represents the end of diastole, the ventricles are filled to their end-diastolic volume EDV.

The left ventricular EDV typically about mL is associated with end-diastolic pressures of about 8 mm Hg. The right ventricular end-diastolic pressure is typically about 4 mm Hg.

A heart sound is sometimes heard during atrial contraction Fourth Heart Sound, S4. The sound is caused by vibration of the ventricular wall as blood rapidly enters the ventricle during atrial contraction.

This sound generally is noted when the ventricle compliance is reduced i. The sound is commonly present in older individuals because of changes in ventricular compliance. Isovolumetric Contraction: All Valves Closed This phase of the cardiac cycle, which is the beginning of systole, is initiated by the QRS complex of the ECG, which represents ventricular depolarization. As the ventricles depolarize, myocyte contraction leads to a rapid increase in intraventricular pressure.

The abrupt rise in pressure causes the AV valves to close as the intraventricular pressure exceeds atrial pressure. Contraction of the papillary muscles with their attached chordae tendineae prevents the AV valve leaflets from bulging back or prolapsing into the atria and becoming incompetent i. This heart sound is generated when sudden closure of the AV valves results in oscillation of the blood, which causes vibrations i.

During the time between the closure of the AV valves and the opening of the aortic and pulmonic semilunar valves, ventricular pressures rise rapidly without a change in ventricular volumes i. During this phase, some individual fibers shorten when they contract, whereas others generate force without shortening or can be mechanically stretched as they are contracting because of nearby contracting cells. Ventricular chamber geometry changes considerably as the heart becomes more spheroid in shape, although the volume does not change.

Early in this phase, the rate of pressure development becomes maximal. Phase 3. Rapid Ejection: Aortic and Pulmonic Valves Open; AV Valves Remain Closed When the intraventricular pressures exceed the pressures within the aorta and pulmonary artery, the aortic and pulmonic valves open and blood is ejected out of the ventricles. Ejection occurs because the total energy of the blood within the ventricle exceeds the total energy of blood within the aorta. The total energy of the blood is the sum of the pressure energy and the kinetic energy; the latter is related to the square of the velocity of the blood flow.

In other words, ejection occurs because an energy gradient is present mostly owing to pressure energy that propels blood into the aorta and pulmonary artery.

During this phase, ventricular pressure normally exceeds outflow tract pressure by only a few millimeters of mercury mm Hg. Although blood flow across the valves is high, the relatively large valve opening i. Maximal outflow velocity is reached early in the ejection phase, and maximal systolic aortic and pulmonary artery pressures are achieved, which are typically about and 25 mm Hg in the aorta and pulmonary artery, respectively.

While blood is being ejected and ventricular volumes decrease, the atria continue to fill with blood from their respective venous inflow tracts. Although atrial volumes are increasing, atrial pressures initially decrease x' descent as the base of the atria is pulled downward, expanding the atrial chambers.

No heart sounds are ordinarily heard during ejection. The opening of healthy valves is silent. The presence of a sound during ejection i. Reduced Ejection: This causes ventricular active tension to decrease i.

Ventricular pressure falls slightly below outflow tract pressure; however, outward flow still occurs owing to kinetic or inertial energy of the blood that helps to propel the blood into the aorta and pulmonary artery. Atrial pressures gradually rise during this phase owing to continued venous return into the atrial chambers. The end of this phase concludes systole. Phase 5. Isovolumetric Relaxation: All Valves Closed As the ventricles continue to relax and intraventricular pressures fall, a point is reached at which the total energy of blood within the ventricles is less than the energy of blood in the outflow tracts.

When this total energy gradient reversal occurs, the aortic and pulmonic valves to abruptly close. At this point, systole ends and diastole begins. Valve closure causes the Second Heart Sound S2 , which is physiologically and audibly split because the aortic valve closes before the pulmonic valve. Normally, little or no blood flows backward into the ventricles as these valves close. Valve closure is associated with a characteristic notch incisura in the aortic and pulmonary artery pressure tracings.

Unlike in the ventricles, where pressure rapidly falls, the decline in aortic and pulmonary artery pressures is not abrupt because of potential energy stored in their elastic walls and because systemic and pulmonic vascular resistances impede the flow of blood into distributing arteries of the systemic and pulmonary circulations. Ventricular volumes remain constant isovolumetric during this phase because all valves are closed. The residual volume of blood that remains in a ventricle after ejection is called the end-systolic volume ESV.

For the left ventricle, this is approximately 50 mL of blood. Although ventricular volume does not change during isovolumetric relaxation, atrial volumes and pressures continue to increase owing to venous return.

Phase 6. Rapid Filling: Initially, the ventricles are still relaxing, which causes intraventricular pressures to continue to fall by several mm Hg despite ongoing ventricular filling. The rate of initial filling is enhanced by the fact that atrial volumes are maximal just prior to AV valve opening. Once the valves open, the elevated atrial pressures coupled with declining ventricular pressures ventricular diastolic suction and the low resistance of the opened AV valves results in rapid, passive filling of the ventricles.

Once the ventricles are fully relaxed, their pressure begins to rise as they fill. The opening of the AV valves causes a rapid fall in atrial pressures. The v wave and y descent are transmitted into the proximal venous vessels such as the jugular vein on the right side of the heart and pulmonary veins on the left side.

Clinically, changes in atrial pressures and jugular pulses are useful in the diagnosis of altered cardiac function see Chapter 9. If the AV valves are functioning normally, no prominent sounds will be heard during filling.

When a Third Heart Sound S3 is audible during ventricular filling, it may represent tensing of chordae tendineae and the AV ring, which is the connective tissue support for the valve leaflets.

This S3 heart sound is normal in children, but it is considered pathologic in adults because it is often associated with ventricular dilation. Reduced Filling: The reduced filling phase is the period during diastole when passive ventricular filling is nearing completion.

This is sometimes referred to as the period of ventricular diastasis. As the ventricles continue to fill with blood and expand, they become less compliant i. This causes the intraventricular pressures to rise, as described later in this chapter.

Increased intraventricular pressure reduces the pressure gradient across the AV valve the pressure gradient is the difference between the atrial and ventricular pressure so that the rate of filling declines, even though atrial pressures continue to increase slightly as venous blood continues to flow into the atria. Aortic pressure and pulmonary arterial pressure continue to fall during this period as blood flows into the systemic and pulmonary circulations. It is important to note that Figure 4.

At low heart rates, the length of time allotted to diastole is relatively long, which lengthens the time of the reduced filling phase. High heart rates reduce the overall cycle length and are associated with reductions in the duration of both systole and diastole, although diastole shortens much more than systole. Without compensatory mechanisms, this cycle length reduction would lead to less ventricular filling i.

Compensatory mechanisms are important for maintaining adequate ventricular filling during exercise see Chapter 9. Summary of Intracardiac Pressures It is important to know normal values of intracardiac pressures, as well as the pressures within the veins and arteries entering and leaving the heart, because abnormal pressures can be used to diagnose certain types of cardiac disease and dysfunction.

Figure 4. The higher of the two pressure values expressed in mm Hg in the right ventricle RV , left ventricle LV , pulmonary artery PA , and aorta Ao represent the normal peak pressures during ejection systolic pressure , whereas the lower pressure values represent normal end of diastole pressure ventricles or the lowest pressure diastolic pressure found in the PA and Ao.

Pressures in the right atrium RA and left atrium LA represent average values during the cardiac cycle. Note that the pressures on the right side of the heart are considerably lower than those on the left side of the heart, and that the pulmonary circulation has low pressures compared to the systemic arterial system. The pressures shown for the right and left atria indicate an average atrial pressure during the cardiac cycle—atrial pressures change by several mm Hg as they fill and contract.

Ventricular Pressure—Volume Relationship Although measurements of pressures and volumes over time can provide important insights into ventricular function, pressure— volume loops provide another powerful tool for analyzing the cardiac cycle, particularly ventricular function.

Pressure—volume loops Fig. In Figure 4. The area within the pressure—volume loop is the ventricular stroke work. The filling phase moves along the end-diastolic pressure—volume relationship EDPVR , or passive filling curve for the ventricle.

The slope of the EDPVR at any point along the curve is the reciprocal of ventricular compliance, as described later in this chapter. The maximal pressure that can be developed by the ventricle at any given left ventricular volume is described by the end-systolic pressure—volume relationship ESPVR. The pressure—volume loop, therefore, cannot cross over the ESPVR, because the ESPVR defines the maximal pressure that can be generated at any given volume under a given inotropic state, as described later in this chapter.

The changes in pressures and volumes described in the cardiac cycle diagram and by the pressure—volume loop are for normal adult hearts at resting heart rates. Pressure— volume loops appear very differently in the presence of valve disease and heart failure as described in Chapter 9. The heart achieves this by contracting its muscular walls around a closed chamber to generate sufficient pressure to propel blood from the left ventricle, through the aortic valve, and into the aorta. Each time the left ventricle contracts, a volume of blood is ejected into the aorta.

Obviously, this approach cannot be used in humans; therefore, indirect techniques are used. The most commonly used is the thermodilution technique, which uses a special multilumen, thermistor-tipped catheter Swan-Ganz that is inserted into the pulmonary artery from a peripheral vein.

A cold saline solution of known temperature and volume is injected into the right atrium from a proximal port on the catheter. The cold injectate mixes into the blood and cools the blood, which then passes through the right ventricle and into the pulmonary artery.

The thermistor at the catheter tip measures the blood temperature, and a cardiac output computer is used to calculate flow cardiac output. Doppler echocardiography can be used to estimate real-time changes in flow within the heart, pulmonary artery, or ascending aorta. Echocardiography and various radionuclide techniques can also be used to measure changes in ventricular dimensions during the cardiac cycle in order to calculate SV, which, when multiplied by heart rate, gives cardiac output.

This method is based on the following relationship Fick Principle: Sarcomere length cannot be determined in the intact heart, so indirect indices of preload, such as ventricular EDV or pressure, must be used.

These measures of preload are not ideal because they may not always reflect sarcomere length because of changes in the structure and mechanical properties of the heart. Despite these limitations, acute changes in end-diastolic pressure and volume are useful indices for examining the effects of acute preload changes on SV.

Normally, compliance curves are plotted with volume on the Y-axis and pressure on the X-axis, so that the compliance is the slope of the line at any given pressure i. For the ventricle, however, it is common to plot pressure versus volume Fig. Plotted in this manner, the slope of the tangent at a given point on the curve is the reciprocal of the compliance. Therefore, the steeper the slope of the pressure—volume relationship, the lower the compliance.

The relationship between pressure and volume is nonlinear in the ventricle as in most biological tissues ; therefore, compliance decreases with increasing pressure or volume. When pressure and volume are plotted as in Figure 4. Ventricular compliance is determined by the physical properties of the tissues making up the ventricular wall and the state of ventricular relaxation.

For example, in ventricular hypertrophy, the increased muscle thickness decreases the ventricular compliance; therefore, ventricular end-diastolic pressure is higher for any given EDV. This is shown in Figure , in which the filling curve of the hypertrophied ventricle shifts upward and to the left. From a different perspective, for a given end-diastolic pressure, a less compliant ventricle will have a smaller EDV i. If ventricular relaxation lusitropy is impaired, as occurs in some forms of diastolic ventricular failure see Chapter 9 , the functional ventricular compliance will be reduced.

This will impair ventricular filling and increase enddiastolic pressure. If the ventricle becomes chronically dilated, as occurs in other forms of heart failure, the filling curve shifts downward and to the right. This enables a dilated heart to have a greater EDV without causing a large increase in end-diastolic pressure.

The length of a sarcomere prior to contraction, which represents its preload, depends on Decreased Compliance e. The slope of the tangent of the passive pressure—volume curve at a given volume represents the reciprocal of the ventricular compliance. The slope of the normal compliance curve is increased by a decrease in ventricular compliance e. LV, left ventricle. This, in turn, depends on the ventricular end-diastolic pressure and compliance.

Although end-diastolic pressure and EDV are sometimes used as indices of preload, care must be taken when interpreting the significance of these values in terms of how they relate to the preload of individual sarcomeres.

An elevated end-diastolic pressure may be associated with sarcomere lengths that are increased, decreased, or unchanged, depending on the ventricular volume and compliance at that volume. For example, a stiff, hypertrophied ventricle may have an elevated end-diastolic pressure with a reduced EDV owing to the reduced compliance. Because the EDV is reduced, the sarcomere length will be reduced despite the increase in end-diastolic pressure.

As another example, a larger than normal EDV may not be associated with an increase in sarcomere length if the ventricle is chronically dilated and structurally remodeled such that new sarcomeres have been added in series, thus maintaining normal individual sarcomere lengths. Effects of Preload on Tension Development Length—Tension Relationship We have seen how ventricular EDV, which is determined by ventricular end-diastolic Muscle L pressure and ventricular compliance, can alter the preload on sarcomeres in cardiac muscle cells.

This change in preload will alter the ability of the myocyte to generate force when it contracts. The length—tension relationship examines how changes in the initial length of a muscle i. To illustrate this relationship, a piece of cardiac muscle e. One end of the muscle is attached to a force transducer to measure tension, and the other end is attached to an immovable support rod Fig.

The end that is attached to the force transducer is movable so that the initial length preload of the muscle can be fixed at a desired length.

The muscle is then electrically stimulated to contract; however, the length is not permitted to change and therefore the contraction is isometric. By stretching the muscle to a longer initial length, the passive tension will be increased prior to stimulation. The left side shows how muscle length and tension are measured in vitro.

The right side shows how increased preload initial length increases both passive and active developed tension.

The greater the preload, the greater the active tension generated by the muscle. When the muscle is stimulated at the increased preload, there will be a larger increase in active tension curve b than had occurred at the lower preload.

If the preload is again increased, there will be a further increase in active tension curve c. Therefore, increases in preload lead to an increase in active tension. Not only is the magnitude of active tension increased, but also the rate of active tension development i.The Heart: The opposite occurs in depo- the membrane. The thermistor at the catheter tip measures the blood temperature, and a cardiac output computer is used to calculate flow cardiac output.

The concentration of intracellular calcium depends on the balance between the calcium that enters the cells, the calcium that is released by intracellular storage sites, and the movement of calcium either back into intracellular storage sites or out of the cell.

Heart rate, however, can vary zation as shown in the following equation: To illustrate this, the pulmonary artery pressure represents the a papillary muscle is placed in an in vitro bath, major afterload component. The cardiac myocyte is composed of bundles of myofibrils that contain myofilaments Fig. An increase in after- sion relationship requires that as the preload load rotates the Frank-Starling curve down is increased, there is an increase in active ten- and to the right.

Physiology of the Heart.

VIVIAN from Downey
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