Guyton’s contributions were of great importance, although the works of his associates and others in the field surely were also significant. Several key advances of Guyton and those with whom he worked led the way forward. One of their first critical developments was a technique using extracorporal shunts and pumps to repeatedly measure mean systemic pressure in animals. He combined this with the method he developed for continuous measurement of cardiac output using the Fick principle with oxygen saturation in the arterial and venous blood as the indicator. He developed the equipment for cardiac output measurement more than 50 years ago, long before electromagnetic and Doppler flow meters that have been used routinely in research for the last several decades. His methods made possible determination of complete venous return curves during manipulation of the variables that affect the system. He was able to analyze exactly how changes in blood volume affect the system, the significance of resistance to venous return, the importance of the differences in capacitance in the arterial and venous beds, and the pivotal role of the pressure gradient for venous return in determining the rate of flow to the heart. The knowledge he gained from analyzing venous return led to understanding of other significant cardiovascular concepts, possibly the most far reaching being the dominant long-term role of whole-body tissue oxygen demand in determining cardiac output, and the mechanisms by which tissue regulation of blood flow to meet local metabolic demand for oxygen could affect systemic resistance to venous return for the entire body.
During the same period in the 1950s and 1960s, he perfected preparations that enabled control of atrial pressure over a wide range while cardiac output was measured continuously, yielding complete cardiac output function curves obtained over a period of a few minutes, before excessive demand on the myocardium damaged and degraded function. His subsequent realization that cardiac function and venous return curves intersect at only one point at any given moment, at the equilibrium point, led to decades of fruitful analyses of the operation of the integrated cardiovascular system that remains the basis for understanding the regulation of cardiac output.
In the latter half of the 1960s, Guyton and Coleman began developing mathematical models of the cardiovascular system. Initially, the models were small and limited in scope, but even the first efforts produced new insights into the control of the system. As they expanded the limits of the models, they were able to begin considering the dynamics of the system, moving beyond the single point in time analyses considered using graphical techniques. Once time was included as a variable in the dynamic models, a new level of complexity was introduced into the understanding of cardiovascular control.
The importance of inclusion of time as a variable is intuitively obvious; however, many of the implications were not apparent until the models were developed. In the mid-1960s, Coleman and Guyton were working together with an early version of the digital cardiovascular model running simulations, and they observed a result, a surprising one at the time: regardless of how the cardiovascular variables were manipulated, steady-state arterial blood pressure could not be changed from its initial value. Changes in strength of cardiac contraction (within the range that did not cause heart failure), resistance to venous return, arterial resistance, capacitance of various segments, blood volume, and mean systemic pressure could not affect the level of arterial pressure for longer than a few days.
The explanation they soon discovered was the function relating the value of arterial pressure perfusing the kidneys to the rate of renal excretion of sodium and water. As long as this function is unchanged and intake of sodium and water are constant, changes in other components of the cardiovascular system could not alter the steady-state value of arterial pressure. If an initial change is introduced in a function that increased arterial pressure, for example, a decrease in vascular compliance resulting in an elevation of mean systemic pressure, pressure gradient for venous return, right atrial pressure, and cardiac output, the resulting elevation of renal perfusion pressure would raise the rate of renal excretion of extracellular fluid to a value exceeding the rate of intake. Consequently, extracellular fluid would decrease by a few milliliters with each iteration of the model. With the simulated passage of time, extracellular fluid volume would decrease progressively, reducing blood volume, mean systemic pressure, and the subsequent dependent variables, including arterial blood pressure. Extracellular fluid balance would continue to be negative as long as renal perfusion pressure was above the initial control level. Even if the perfusion level were only slightly greater than normal, the model simulations indicated that the renal excretory–body fluid volume–arterial pressure negative feedback system had the capacity to correct completely an initial error in arterial blood pressure leaving no residual error. This was the case for correcting errors that caused either initial positive or negative arterial blood pressure errors. However, in many situations, the model predicted that several days would be required for the negative feedback system to return the level of arterial pressure to the initial value. The potency of the renal excretory rate–body fluid volume–arterial pressure negative feedback system in blood pressure regulation predicted by the cardiovascular model led to decades of experiments concerning hypertension. Ultimately, a hypothesis concerning the causes and treatment of the disease was developed that was based on changes in the relationship between renal perfusion pressure and excretion of sodium being the cause of all forms of hypertension. Long-term blood pressure regulation and hypertension are the subject of a forthcoming volume in this series by J. P. Granger.
In the four or five decades since they completed their first series of cardiovascular analyses, Guyton and colleagues and many others have moved forward from the basis they established. However, none of the thousands of later studies disproved or even raised doubts about the validity of the initial work; rather, subsequent investigations have reaffirmed the importance of the logic derived from those studies carried out in Jackson beginning in the 1950s and 1960s. Its tenets can be summarized briefly and generally as follows:
- Cardiac output is always equal to venous return to the heart, except for brief, transient periods.
- The heart’s output is determined by the rate of venous return from the peripheral tissues. Within physiological limits, the heart will increase output over a wide range in response to small elevations in the right atrial pressure resulting from increases in venous return. For a normal heart operating in the physiological range, increases in strength of contraction alone will not result in significant, sustained increases in output, unless venous return also increases. In addition, reduction in strength of the heart by disease may not affect the normal resting level of cardiac output if the plateau value of the weakened heart’s function curve is greater than the body’s demand for flow under normal conditions.
- Venous return is a function of resistance to venous return and the pressure gradient for venous return. Resistance to venous return is the total resistance from the root of the aorta to the right atrium. The pressure gradient for venous return is the difference between mean systemic pressure and right atrial pressure.
- Resistance to venous return is affected by factors that cause changes in smooth muscle tone of resistance vessels or changes in pressure in the tissue surrounding thin-walled venous structures. One of the most powerful factors affecting resistance to venous resistance is autoregulation of blood flow to meet local tissue demand throughout the body for oxygen and other metabolic requirements. Consequently, whole-body oxygen demand and metabolic rate are primary long-term determinants of cardiac output.
- The pressure gradient for venous return is the difference between mean systemic pressure and right atrial pressure. Mean systemic pressure is affected by the capacitance of the circulatory system, its unstressed volume, and the volume of blood circulating within it. Right atrial pressure is a function of the rate of flow into it from the veins and the pumping ability of the ventricles. In conditions of health, the normal heart can increase or decrease output over the range normally required with only a few millimeters of mercury variation in atrial pressure. Conversely, mean systemic pressure commonly may increase as much as 100% from the resting level in response to physiological demands.
- Cardiac and circulatory system functions both respond to cardiovascular challenges. The sympathetic and parasympathetic nervous systems alter cardiac function by affecting heart rate and strength of contraction, shifting the cardiac function curve either upward and to the left (sympathetic) or downward and to right (parasympathetic). The sympathetic nervous system affects many of the determinants of venous return, including mean systemic pressure and resistance to venous return. Circulation hormones, including angiotensin II, vasopressin, epinephrine, and locally acting hormones, including prostaglandins, endothelins, and numerous cytokines, affect vascular resistance and hence resistance to venous return. Long-term effects of the sympathetic nervous system and the endocrine system can lead to decreased rates of renal sodium excretion, increasing blood volume, mean systemic pressure, and the pressure gradient for venous return.
- The renal sodium excretion–body fluid volume–arterial pressure negative feedback system regulates steady-state arterial blood pressure, although several days may be required for arterial pressure to return to the initial level following a perturbation. Although alterations in many cardiovascular functions can initially change cardiac output and arterial pressure, only those that affect the basic renal sodium excretion–body fluid volume–arterial pressure negative feedback system can produce sustained changes in arterial blood pressure.
That logic remains the fundamental basis of understanding of cardiac output control.