Cardiac Physiology

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Chapter 3 Cardiac Physiology

Brian Johnson, MD, Maher Adi, MD, Michael G. Licina, MD, Zak Hillel, MD, Daniel Thys, MD, Roberta L. Hines, MD, Joel A. Kaplan, MD

A thorough knowledge of the principles of cardiovascular physiology is the foundation for the practice of cardiovascular anesthesia. It serves as the basis of understanding the pathophysiologic mechanisms of cardiac disease as well as the patient’s pharmacologic and surgical management.

To assess the physiologic basis for cardiac dysfunction, a systematic inspection of the elements that determine cardiac output (CO) is required. These intrinsic factors—heart rate (HR)/rhythm, preload, contractility, and afterload—are codependent such that abnormality in one often results in altered function in the others. This complex interaction is intrinsically designed to regulate beat-to-beat changes in the cardiovascular system, thereby adapting to changes in physiologic demands.

Heart rate, preload, afterload, and contractility determine CO, which, in turn, when combined with peripheral arterial resistance, determines arterial pressure for organ perfusion. Similarly, the arterial system contributes to ventricular afterload, and these interactions influence mechanoreceptors in the carotid artery and aortic arch, providing feedback signals to higher levels in the central nervous system (medullary and vasomotor center). These centers then modulate venous return, HR, contractility, and arterial resistance (Fig. 3-1).

Figure 3-1 Interactions controlling the intact circulation. Changes in one or more of the determinants of cardiovascular performance directly affect the integrity of the circulation. Such interdependence must be considered when analyzing or treating hemodynamic disturbances.

(Modified from Braunwald E: Regulation of the Circulation, NEJM 290 (20): 1124–1129, 1974.)

The heart’s primary function is to deliver sufficient oxygenated blood to meet the metabolic requirements of the peripheral tissues. Under normal circumstances, the heart acts as a servant by varying the CO in accordance with total tissue needs. Tissue needs may vary with exercise, heart disease, trauma, surgery, or administration of drugs. Although tissue needs regulate circulatory requirements, the heart can become a limiting factor, particularly in patients with cardiac disease. In this regard, it is important to differentiate circulatory function from cardiac and myocardial function.

The focus of this chapter is on the heart’s function as a pump. The various determinants of its pumping function are reviewed and, where applicable, newer clinical measurements of ventricular function are discussed.

CARDIAC CYCLE

The cardiac cycle of the left ventricle (LV) begins as excitation of the myocardium, which results in a sequence of mechanical events that lead to a pressure gradient being developed, ejection of the stroke volume (SV), and forward flow of blood through the body. These phases can be discussed based on the electrical activity, intracardiac pressures, intracardiac volumes, opening and closing of the cardiac valves, or the flow of blood into the peripheral circulation. Most practical of these is the relationship of pressure to volume over the course of the cycle. In this regard, systole represents the rapid increase in intracardiac pressure followed by the rapid decrease in volume. Diastole, on the other hand, represents first a rapid decrease in pressure followed by an increase in volume. An alternative to this approach is to exclude any temporal element and to study the relation of pressure to volume in the framework of a pressure-volume diagram (Fig. 3-2). In this diagram, the pressure is typically displayed on the vertical axis and the volume on the horizontal axis. This yields a pressure-volume loop of four distinct phases over the course of one contraction: isovolumic contraction, ventricular ejection (rapid and slow), isovolumic relaxation, and filling (rapid and diastasis).

Figure 3-2 Phases of the cardiac cycle displayed in a pressure-volume diagram.

Phases of the Cardiac Cycle

DIASTOLIC FUNCTION

Diastology, or the study of diastolic function, has become the most important focus of cardiac physiology in the past few years. Diastolic dysfunction has been seen in 40% to 50% of patients with congestive heart failure (CHF) despite normal systolic function.³ This led to a shift in thinking about cardiac function not only as the typical systolic factors of contractile force, ejection of SV, and generation of CO but also as diastolic factors. The use of transthoracic echocardiography (TTE) and TEE has greatly improved this knowledge of diastole by showing the actual real-time activities in the heart, as related to filling pressures, shape, and relaxation. It is now possible to relate diastolic dysfunction, which is increased impedance to ventricular filling, to structural and pathologic causes of CHF (Table 3-1).

Table 3-1 Conditions Involving Diastolic Heart Failure^*

Conditions	Mechanisms of Diastolic Dysfunction
Mitral or tricuspid stenosis	Increased resistance to atrial emptying
Constrictive pericarditis	Increased resistance to ventricular inflow, with decreased ventricular diastolic capacity
Restrictive cardiomyopathies (amyloidosis, hemochromatosis, diffuse fibrosis)	Increased resistance to ventricular inflow
Obliterative cardiomyopathy (endocardial fibroelastosis, Loeffler’s syndrome)	Increased resistance to ventricular inflow
Ischemic heart disease	Postinfarction scarring and hypertrophy (remodeling)
Flash pulmonary edema, dyspnea during angina	Diastolic calcium overload
Impaired myocardial relaxation	Increased resistance to ventricular inflow
Hypertrophic heart disease (hypertrophic cardiomyopathy, chronic hypertension, aortic stenosis)	Impaired myocardial relaxation Diastolic calcium overload Increased resistance to ventricular inflow due to thick chamber walls, altered collagen matrix Activation of renin-angiotensin system

Volume overload (aortic or mitral regurgitation, arteriovenous fistula)

Increased diastolic volume relative to ventricular capacity

Myocardial hypertrophy, fibrosis

Dilated cardiomyopathy

Impaired myocardial relaxation

Diastolic calcium overload

Myocardial fibrosis or scar

* Diastolic heart failure is increased resistance to filling of one or both cardiac ventricles.

From Grossmvan W: Diastolic dysfunction in congestive heart failure. N Engl J Med 325:1557, 1991.

Determinants of Diastolic Function

Myocardial Relaxation

Relaxation of the myocardium is the first step in the physiologic process of diastole. It begins during the end of the previous systolic contraction and is intimately related to systolic forces. It is also key in the determination of the length and amount of earlypassive ventricular filling. Relaxation relies heavily on the use of energy and adenosine triphosphate (ATP) to drive the calcium from the cell into the sarcoplasmic reticulum. This energy-dependent process is controlled by myriad regulatory proteins and by numerous clinical factors. Failure of relaxation leads to rapid Ca²⁺ overload, particularly at increased levels of stimulating frequency.

passive ventricular filling

The first phase of filling starts with the opening of the mitral valve and the flow of blood down the newly generated pressure gradient from the LA into the LV. The rate of flow has both a rapid rate and slow rate as the pressure gradient approaches equilibration. Diastasis is the period of no flow across the mitral valve after the conclusion of passive filling and immediately before atrial systole. The main determinants of transmitral flow are the LV compliance (stiffness) and the rate of rise of the transmitral gradient. Many disease states can contribute to increasing stiffness of the ventricle and thus affect the amount of passive filling that can occur during the early phase of diastole. In aging, angina, coronary artery disease, and hypertrophic obstructive cardiomyopathy, myocardial stiffness is greatly increased, thus impairing inflow into the ventricle.⁴ Numerous drugs and cardiac revascularization can all improve dysfunction or reduce exercise-induced stiffness.

atrial or active filling

Atrial contraction, or “atrial kick,” occurs at the end of diastole just before the closing of the mitral valve and after passive flow has reached the diastasis. Normally, greater than 75% of flow occurs during the passive portion of diastole. In the presence of severe diastolic dysfunction, this normal relationship cannot take place and the atrial kick becomes essential to maintain SV and cardiac output. The atrial kick continues to compensate for decreased LV compliance (increase in LVEDP), and LV filling is initially maintained. Eventually, the increased pressures overcome the capacity of the LA to contribute to the total LV volume, and the atrium assumes a very passive role and becomes dilated. If normal sinus rhythm is not maintained, the atrial kick cannot function in its supportive role, and further CHF occurs rapidly. Reestablishment of normal sinus rhythm by cardioversion or sequential pacing can reverse the CHF symptoms.

Relating Echocardiography to Diastolic Function

The relationship between the stages of diastolic function and findings on both TEE and TTE has greatly enhanced the study and importance of diastolic function (Box 3-1). Using TTE and TEE in combination with Doppler techniques has made it possible via indirect means to obtain LV filling patterns.⁵ The most commonly accepted means of analyzing the flow patterns are via the Doppler transmitral flow and the pulmonary vein flow. Newer modes of measurement using tissue Doppler and color M-mode are leading to further insights into diastolic function.

BOX 3-1 Diastolic Function Can Be Measured Clinically by Use of

• Transmitral pulsed-wave Doppler flow patterns

• Pulmonary vein two-dimensional Doppler flow patterns

• Color M-mode Doppler echocardiography

• Tissue Doppler echocardiography

Transmitral flow patterns are the first method, which is performed by placing a pulsed-wave Doppler signal in the area between the leaflet tips of the mitral valve. Two waves are obtained: first the E wave, which represents the early passive flow across the mitral valve; and second, the A wave, which represents atrial systole (Fig. 3-3). The small area of no flow between the E and A waves represents the diastasis.By comparing the ratios of these two waves it is possible to form a view of diastolic function. The ratios change with disease and age to yield several patterns, which represent different stages of failure. In early diastolic failure, the E/A wave ratio becomes less than 1, and the waves reverse with the E wave being shorter than the A wave; this is known as the delayed relaxation pattern. As failure progresses, the waves become pseudonormalized; that is, the E/A ratio reverts to the normal pattern of greater than 1. The final stage of failure as seen via the mitral valve shows a high, rapidly decelerating E wave with a small A wave; this pattern is known as the restrictive pattern. The use of these patterns on Doppler imaging allows for the staging of diastolic failure from a mild form to a more severe form.^6,⁷

Figure 3-3 Transmitral flow-velocity profile and diagrammatic representation of its quantification.

SYSTOLIC FUNCTION

Systolic function is the period existing between closure of the mitral valve and the start of contraction to the end of ejection of blood from the heart. The primary purpose of systole is the ejection of blood into the circulation via the generation of a pressure gradient. Systolic function has been used to determine outcome and therapeutic effectiveness for years.

Cardiac Output

Cardiac output is the amount of blood flowing into the circulation per minute. It reflects not only the condition of the heart but also the entire vascular system and is subject to the autoregulatory systems of the vasculature and tissues. The equation for CO is listed below and involves HR and SV.

The primary determinants for CO are the HR and the SV. It is also dependent on many other secondary factors, including venous return, systemic vascular resistance, peripheral oxygen use, total blood volume, respiration, and body position. Normal range of CO is between 5 and 6 L/min in a 70-kg man, with an SV of 60 to 90 mL per beat and an HR of 80 beats per minute. CO is highly variable in the normal healthy individual, being able to increase up to 25 to 30 L/min during situations of high metabolic demand.

The cardiac index (CI) is used to compare different sizes of individuals and is now part of routine clinical practice. This is done by correcting the standard CO equation for body surface area (BSA).

Normal values are 2.5 to 3.5 L/min/m² for the normal 70-kg man. By correcting for BSA, it is then possible to compare patients at a common level of function, despite differences in body habitus.

Stroke Volume

The SV is the amount of blood ejected by the ventricle with each single contraction. The determinants of SV are preload, afterload, and contractility. Although these variables have a very clear meaning in reference to isolated muscles, their exact significance is much more ambiguous in the intact heart.

Preload

definition

Preload is equal to the ventricular wall stress at end-diastole. It is determined by ventricular EDV, end-diastolic pressure (EDP), and wall thickness. To apply the preload principle to clinical practice, the following adjustments can be made:

1. Substituting ventricular volumes for preload stress. In clinical practice, ventricular volumes appear to most closely approximate muscle fiber length. In normal humans, a straight-line relationship has been demonstrated between EDV and SV.

2. Substituting ventricular pressures for ventricular volumes. Ventricular pressures are often substituted for ventricular volumes when assessing the filling conditions of the ventricle. Clinically, left atrial pressure (LAP), pulmonary artery occlusion or capillary wedge pressure (PAOP or PCWP), pulmonary artery diastolic pressure (PADP), right atrial pressure (RAP), and central venous pressure (CVP) are often used as substitutes for LVEDP and LVEDV. Their accuracy in predicting LV preload is determined by the distensibility properties of the ventricle, the integrity of the mitral valve, the presence of normal pulmonary conditions, the integrity of the pulmonic and tricuspid valves, and RV function.

The assumption that ventricular distensibility is normal is not a valid assumption in many patients with cardiac disease. With coronary artery disease or aortic disease, diastolic function is often altered so that small increases in ventricular volume can produce large changes in ventricular pressure.

determinants

Factors affecting the preload of the heart include the total blood volume, body position, intrathoracic pressure, intrapericardial pressure, venous tone, pumping action of skeletal muscles, and the atrial contribution to ventricular filling.

measurement

The LVEDV is difficult to measure clinically, and measurements have only recently become possible with techniques such as echocardiography. TEE has been extensively used to measure LV areas as an approximation of LV volumes. Some studies have found a good correlation between areas and volumes and have also shown that in surgical patients EDV derived from a single plane is a significant determinant of SV.⁸

The LVEDP can be measured with placement of a catheter into the LA. The LA catheter is commonly inserted surgically through one of the pulmonary veins. The LAP provides a good approximation of LVEDP, provided the mitral valve is normal (Fig. 3-4). The most common technique for the estimation of LVEDP during cardiac surgery is the placement of a pulmonary artery (PA) catheter. The PCWP usually provides a good approximation of LVEDP. Marked alterations in airway pressure, such as occur during the use of high levels of positive end-expiratory pressure (PEEP), may disturb the relationship between the PCWP and LAP. Depending on the compliance of the pulmonary parenchyma, either part or all of the airway pressure may be transmitted to the PA catheter. This must be considered when evaluating LV filling pressure with the PA catheter in patients receiving mechanical ventilation and PEEP. When the catheter cannot be advanced into the wedge position, the PADP may be used to estimate the LVEDP. It is usually quite accurate unless the pulmonary vascular resistance (PVR) is markedly elevated. The CVP provides the poorest estimateof LVEDP, although it is frequently used in patients with good function of the RV and LV. When cardiac disease is characterized by disparate RV and LV functions, the CVP may be misleading as an indicator of LVEDP.

Figure 3-4 The Frank-Starling relation of chamber diastolic length (represented as left ventricular end-diastolic pressure [LVEDP], pulmonary capillary wedge pressure [PCWP], or left atrial pressure [LAP]) and ventricular performance (cardiac output [CO], stroke volume [SV], cardiac index [CI], left ventricular [LV] stroke work). With increasing diastolic muscle fiber length, that is, preload, both left and right ventricular performance can increase steadily. However, once the limit of preload reserve is reached, myocardial performance cannot be enhanced further by augmenting SV.

Afterload

definition

Afterload is the second major determinant of the mechanical properties of cardiac muscle fibers and performance of the intact heart (Box 3-2). Afterload can be considered either as the stress imposed on the ventricular wall during systole or as the arterial impedance to the ejection of SV.

BOX 3-2 Measurements of Afterload

• Wall stress

• Impedance

• Effective arterial elastance

• Systolic intraventricular pressure

• Systemic vascular resistance

• Pulmonary vascular resistance

wall stress

Afterload defined as systolic ventricular wall stress is the burden that the RV or LV wall has to shoulder for ejecting its SV. This stress can be expressed and quantified by the Laplace equation:

where σ is the stress (dynes·cm⁻²), P is the pressure generated by the LV throughout systole, and r and h are the corresponding radius and thickness of the RV or LV wall.

impedance

Afterload can also be considered as the external or extracardiac forces (impedance) present in the systemic circulation that oppose ventricular ejection and pulsatile flow. Because the LV is coupled to the systemic circulation through the open aortic valve, the pulsatile flow (SV) and pressure generated by the LV will be hindered by the compliance and resistance of the arterial system. These are determined by the physical properties of the aorta and its side branches (viscoelastic properties and diameter) and by the properties of their content (blood).

The SVR clinically obtained as the ratio of the pressure differential between mean arterial pressure (MAP) and RAP or CVP and CO is an oversimplified version of the resistance. It is based on the circulatory analog of Ohm’s law:

which determines that the pressure (P) generated during the ejection of a given flow (Q) is proportional to that flow and to the resistance (R) encountered by that flow. This resistance is mainly determined by arteriolar resistance (SVR) so that

Contractility

definition

The third determinant of SV is contractility. Contractility is an intrinsic property of the cardiac cell that defines the amount of work that the heart can perform at a given load. It is primarily determined by the availability of intracellular Ca²⁺. With depolarization of the cardiac cell, a small amount of Ca²⁺ enters the cell and triggers the release of additional Ca²⁺ from intracellular storage sites (sarcoplasmic reticulum). The Ca²⁺ binds to troponin, tropomyosin is displaced from the active binding site on actin, and actin-myosin crossbridges are formed. All agents with positive inotropic properties, such as the catecholamines, have in common that they increase intracellular Ca²⁺, whereas negative inotropes have the opposite effect (Table 3-2).⁹

Table 3-2 Factors Affecting Contractility

Factors Increasing Contractility

• Sympathetic stimulation—direct increases of the force of contraction, as well as indirect increases due to increased heart rate (rate treppe effect or Bowditch phenomenon)

• Parasympathetic inhibition producing increased heart rate

• Administration of positive inotropic drugs such as digitalis

Factors Decreasing Contractility

• Parasympathetic stimulation—decreased rate effect

• Sympathetic inhibition via withdrawal of catecholamines or blockade of adrenergic receptors

• Administration of β-adrenergic–blocking drugs, slow calcium channel blockers, or other myocardial depressants

• Myocardial ischemia and infarction

• Intrinsic myocardial diseases such as cardiomyopathies

• Hypoxia and acidosis

determinants

The large number of methods developed to measure contractility in the intact heart suggests that it is difficult to measure. Indices of contractility can be classified according to the phase of the cardiac cycle during which they are obtained.

Isovolumic Contraction Phase Indices.

Isovolumic phase indices are obtained during the isovolumic phase of the contraction before the opening of the aortic valve. The prototype of such indices is dP/dt. It is obtained by placing a catheter with a micromanometer at its tip into the LV. The LV pressure is continuously sampled while an electronic differentiator calculates the first derivative of pressures, or dP/dt (mm Hg/s). The highest value of dP/dt, or peak dP/dt, is considered proportional to contractility. Because the heart’s developed tension, or pressure, is dependent on the initial length of the cardiac muscle, it is predictable that dP/dt will be preload dependent.

Ejection Phase Indices.

The standard ejection phase index of contractility is the EF:

With the increasing availability of noninvasive cardiac imaging techniques, ejection phase indices are widely used in clinical practice. One of the reasons for their widespread use is that a clear association between EF and prognosis has been found.

Load-Independent Indices.

Because traditional indices of contractility are load dependent, different approaches to the quantification of the contractile properties of the heart have been explored. In one such approach, Suga and colleagues ^10,¹¹ studied instantaneous pressure and volume in the canine heart. The ratio of ventricular pressure over volume is the ventricular elastance, which varies throughout the cardiac cycle. For each cardiac cycle, these researchers defined the maximal value of this ratio as the end-systolic elastance (E_ES) and the point at which it was reached as the end-systolic point. They further noted that with rapid decreases in preload all consecutive end-systolic points were positioned on a single straight line, known as the end-systolic pressure-volume relation (ESPVR) (Fig. 3-5). The slope of this line (E_ES) is proportional to contractility; it is steeper at higher contractility and flatter at lower contractility.

Figure 3-5 The end-systolic pressure-volume relationship (ESPVR) is obtained by connecting all the end-systolic points measured during a rapid decrease in preload.

Heart Rate

The second major determinate of CO is HR. It is one of the most variable determinants of overall cardiac function. It also has great importance to all portions of the cardiac cycle. The HR is controlled by multiple systems, such as the cardiac conduction system, central nervous system, and autonomic nervous system, which respond via complex pathways to changes in the internal and external conditions. Besides the neural and hormonal factors, many pharmacologic controls are available as well.

An interesting relationship is the fact that HR itself can increase the contractility of the heart. This is known as the treppe or step (Bowditch) phenomenon, which shows that at increased HRs, the slope of the ESPVR increases in a stepwise fashion related to the increased rate. This increase is thought to be due to increases in the level of intracellular calcium.

RIGHT VENTRICULAR FUNCTION

The contractile pattern, as well as the afterload presented to each ventricle (i.e., RV vs. LV), results in marked physiologic differences between the ventricles (Box 3-3). In contrast to the LV, which has a relatively simple and unified mechanism of contraction (by coaxial shortening), RV contraction occurs in three distinct phases. Initially, the spiral muscles contract, resulting in a downward movement of the tricuspid valve and shortening of the longitudinal axis of the RV chamber. This is followed by movement of the RV free wall inward toward the intraventricular septum. Because the RV free wall has limited muscular power, alterations in or failure of the intraventricular septum to contract normally will disturb the systolic function of the RV to a much greater degree than does a loss of RV free wall contractility. Finally, the third phase of RV contraction occurs when LV contraction imposes a “wringer” action, further augmenting overall RV contraction.

BOX 3-3 In Comparison to the Left Ventricle, the Right Ventricle Is

• More complex with phases of contraction

• Better suited to eject large volumes of blood

• More sensitive to afterload

• Less sensitive to preload

Global RV function is exquisitely sensitive to the impedance offered by the pulmonary vasculature.¹² In comparison with the LV, which maintains a constant output over a relatively wide range of afterloads, the RV output abruptly decreases with even small increases in afterload (Fig. 3-6). Under normal conditions of RV function, any increase in afterload is accompanied by a substantial decrease in RVEF. However, normal RV contractile function is usually maintained until the mean PAP is 40 mm Hg or greater. Conversely, the RV appears to be less preload dependent than the LV (i.e., for a given preload, a smaller increase in SV is seen in the RV).

Figure 3-6 Varying effects of afterload and preload seen in ventricular function curves from the right and left ventricles. The RV output is more afterload dependent and less preload dependent than the LV output.

(From McFadden ER, Braunwald E: Cor pulmonale and pulmonary thromboembolism. In Braunwald E [ed]: Textbook of Cardiovascular Medicine. Philadelphia, WB Saunders, 1980, pp 1643−1680.)