Regulation of Cardiac Output

Arteriovenous Oxygen Difference

Maintenance of adequate tissue oxygenation depends on the integrated function of the heart, the central and peripheral vasculature, lungs, blood, and metabolism. According to the Fick principle, the oxygen extracted from the circulation and consumed by the body is equal to the product of the CO and the A-V o ₂ difference. Under normal circumstances at rest, oxygen delivery exceeds consumption, so that adequate tissue oxygenation is provided with an A-V o ₂ difference of 40 ± 10 mL/L. If CO decreases, tissues extract a greater fraction of oxygen from the arterial blood, and mixed venous oxygen saturation decreases. If arterial oxygen tension and serum hemoglobin are normal, a mixed venous oxygen saturation of 70% or more is observed, indicating that oxygen delivery is sufficient to meet the physiologic need.

A wide A-V o ₂ difference and reduced mixed venous oxygen saturation may result from reduced CO, a defect in blood oxygen-carrying capacity, or pulmonary disease (impairment of gas exchange). Once tissue is no longer able to increase its extraction of oxygen, tissue hypoxia results. Under these conditions, anaerobic metabolism manifests by a precipitous increase in venous lactate levels.

During exercise, oxygen consumption can increase 18-fold. This demand for increased oxygen delivery is met by a sixfold increase in CO (from 3 to 18 L/min per m ² ), and a concomitant threefold increase in the A-V o ₂ difference (from 40 to 120 mL/L), resulting in a mixed venous oxygen saturation decrease from 75% to 25%. Since CO = SV (stroke volume) × HR (heart rate), the six-fold increase in CO is not accompanied by a sixfold increase in HR, indicating that SV must increase as HR increases in response to increased demand.

The resting myocardium nearly maximally desaturates oxygenated (99% saturated) blood. Hence, coronary sinus oxygen saturation is low (<40%), and therefore an increase in oxygen extraction as a compensatory mechanism for inadequate coronary nutritive flow cannot be utilized by the myocardium.

Reflex Control of Cardiac Output

Under normal conditions, the heart has a large functional reserve; it is usually not the limiting factor in determining CO. The arterial (perfusion) pressure and CO adjust to meet the needs of the body as they vary with posture and activity. The regulatory mechanisms involve sensory and effector components. The sensory components include peripheral receptors that react to changes in blood pressure (e.g., baroreceptors in aortic arch and carotid sinuses), blood volume (e.g., stretch receptors in the atria, Bainbridge reflex), and ventilation (e.g., carotid chemoreceptors). In addition, there are loci in the cortex, hypothalamus, and diencephalon of the brain that react to emotions, anxiety, anticipation, exercise, hypoxia, and temperature. CO (as described by Ohm's law) is modulated through changes in HR, SV, and vasomotor tone (peripheral resistance) that are mediated by direct parasympathetic and sympathetic neural pathways and by circulating catecholamines. Other humoral factors—such as adrenocortical steroids, thyroid hormones, insulin, and glucagons—have been shown to have an effect on cardiac function, requiring longer time scales; the importance of these hormones for regulation of CO is unclear. It should be noted that the heart is also an endocrine organ—by virtue of the fact that the atria function as volumetric strain gauges in response to being distended (increased volume), by generating atrial natriuretic peptide (ANP), and by increasing sodium and water excretion to achieve volume control by targeting the kidney.

Direct sympathetic neural stimulation and circulating catecholamines exert a powerful stimulatory effect, increasing HR and contractile state, whereas vagal stimulation decreases HR and contractile state. The sympathetic and parasympathetic systems interact with each other in a complex fashion to influence cardiovascular performance. In general, two types of interactions exist: accentuated antagonism and reciprocal excitation. Accentuated antagonism refers to the finding that the negative inotropic and chronotropic effects of vagal stimulation are more pronounced when vagal stimulation occurs in the presence of an increased adrenergic tone. Reciprocal excitation refers to the paradoxical effects of stimulation by one division on the autonomic nervous system, which results in effects normally expected from stimulation by the opposite autonomic division. The most common example of this is the production of positive inotropic effects by vagal stimulation or acetylcholine administration under experimental conditions.

The factors that influence CO are summarized in Table 5.1 . The CO regulatory system can become dysfunctional and result in syncope as a result of enhanced atrial and peripheral baroreceptor sensitivity, autonomic dysfunction, or complete heart block. In a critically ill cardiac patient, the normal regulatory/compensatory mechanisms are usually saturated by maximal sympathetic and catecholamine stimulation. Under these conditions, the major CO determinants are no longer the normal neurohormonal regulatory pathways but rather the interaction between pump function and load, that is, peripheral vasculature. The determinants of ventricular pump function are of paramount importance.

Left Ventricular Performance

Pressure-Volume Loop

Although the integrity of left ventricular (LV) and right ventricular (RV) function and pulmonary and peripheral circulations is important, most cardiovascular dysfunction in adults is the result of impaired LV function. The performance of the LV can be understood by examining the relationship between LV pressure and volume during a single cardiac cycle in the pressure-volume plane ( Fig. 5.1 ). Instantaneous intraventricular pressure is plotted on the y axis and simultaneous ventricular volume is plotted on the x axis. At end diastole (point a ), ventricular pressure is relatively low and ventricular volume is relatively high. The segment ab is due to isovolumic contraction (typically <90 ms), with an increase in intraventricular pressure but no ejection. Point b represents the start of ejection, coincident with the opening of the aortic valve when ventricular pressure exceeds aortic pressure (AoP). Note that after peak AoP is reached and AoP begins to decline—the aortic valve (AoV) is still open and LV volume is decreasing. At end systole (point c ), the AoV closes, and isovolumic relaxation (typically <90 ms) commences (segment cd ). The mitral valve opens at point d, when ventricular pressure decreases to less than atrial pressure, and ventricular filling commences. By definition, the slope (dP/dV) of the end-diastolic pressure volume relationship (EDPVR) at a given end-diastolic volume is the chamber stiffness. Note that left ventricular pressure (LVP) continues to decrease until minimum LVP is reached after mitral valve opening, In other words, as LV volume increases, LV pressure continues to drop (dP/dV<0) until minimum LV pressure is reached.

The difference between the end-diastolic and end-systolic volumes (aortic SV) or end-systolic and end-diastolic volumes (diastolic filling volume) defines the SV. The ratio of SV to end-diastolic volume (EDV) is the LV ejection fraction (LVEF). The LVEF is a clinically useful index of systolic and diastolic function. LVEF = SV/LVEDV is interpreted as a systolic function index. Its role as a diastolic function index is easily appreciated when rewritten as LVEF = [E-wave volume + A-wave volume]/[LV diastatic volume + A-wave volume]. In atrial fibrillation, this reveals that LVEF = [E-wave volume]/[LV volume at diastasis], underscoring the physiologic importance of LV volume at diastasis as the equilibrium volume of the LV. In the absence of aortic stenosis, the LV pressure at end systole is the same as the pressure in the proximal aorta and approximates systolic blood pressure (actually the pressure at the dicrotic notch in the aortic pressure-time course). The pressure-volume (PV) loop provides a useful way to analyze the effects of contractile state, preload, and afterload on CO. The area of the PV loop is the external work of the ventricle.

Effect of Alterations in Preload on the Pressure-Volume Loop

Preload (in sinus rhythm) is defined as the stretch of the myocardium by atrial systole before activation and is readily indexed by end-diastolic volume. Within physiologic ranges, the greater the stretch on the myocardium, the stronger the ensuing contraction; this is known as the Frank-Starling relationship. This prestretch is absent in atrial fibrillation. From studies in isolated heart preparations in which preload, afterload, and contractile state were controlled, it has been shown that an increase in preload, produced by an increase in end-diastolic volume, results in an increase in the end-systolic pressure and SV of the ensuing beat.

Three PV loops under three different preload conditions are shown in Fig. 5.2 . For clarity, it is assumed that HR, contractile state, and afterload remain constant. Baseline conditions are represented by the shaded loop. A decrease in preload as a result of loss of blood volume, if not associated with any other change in afterload or contractile state, results in a smaller EDV and a smaller PV loop that is shifted to the left. Conversely, a volume load results in a larger PV loop that is shifted to the right. An isolated increase in preload without any change in afterload or contractile state results in increases in SV and end-systolic pressure if HR, afterload, and contractile state are unchanged. These idealized conditions do not apply precisely in vivo. Isolated changes in preload, afterload, contractile state, or HR occur rarely because these changes are usually a response to, or in themselves result in, compensatory neurohormonal reflexes, which simultaneously influence all of these variables in a complex fashion. It may be useful, however, for an understanding of cardiovascular dynamics to analyze these factors separately.