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Contributions of Physiologic Research to Clinical Cardiology
Contributions of Physiologic Research to Clinical ~ardiology WILLIAM J. RASHKIND, M.D. *
IN attempting to assay the contributions of physiology to the understanding and management of clinical cardiovascular problems the development and trends in physiology must be delineated first. What have been the main directions and broad concepts in the field of cardiovascular physiology? To my mind there have been two main pathways: first, the concept of expanding the boundaries of the circulation to include the movement of fluids through all body tissues; and, second, the concept of the regulation of the circulation by humoral and neural control. It has sagely been stated by a late Oxford Professor of Medicine that "Oalen has often been blamed for 1300 years of progress that did not take place after him." By the same token William Harvey is equally culpable that his ingenious experiments directed cardiovascular physiologic researches for 300 years into the investigation of that narrowed segment of the circulation, the heart and the systemic blood vessels. The genius of Claude Bernard gave new direction to these researches. His thesis of Le Milieu Interier led to the development of knowledge of the totality of the circulation as exemplified by the experiments of Starling, Krogh and Lewis on the capillary circulation, and Gamble, Hevesy and many others on the circulation of all the body water and its solutes. Bernard's studies on the nervous control of vasomotion also preluded voluminous studies of the control of the circulation leading to the latter-day wedding of physiologic and electronic concepts in approaching the control of the circulation as a cybernetic, self-regulating servomechanism. In the ensuing discussion I shall try to show how these ideas and the experiments leading to their development also conFrom the Department of Physiology, University of Pennsylvania Graduate School of Medicine, and the Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia.
* Chief Resident in Pediatrics, University of Pennsylvania School of Medicine; Formerly Assistant Professor of Physiology, University of Pennsylvania Graduate School of Medicine, Philadelphia. 1565
1566
W illiam J. Rashkind
tributed to the better understanding of many clinical cardiovascular problems. In addition to these two main conceptual developments, the importance of technical developments cannot be minimized, since these have led to an even greater direct clinical application. Not discounting the importance of the string galvanometer, the oscillograph, the electromanometer, the automatically recording flowmeters of various designs, the spectrophotometer, the modern gas analyzer, the Geiger counter and many other significant instrumental advances, the single most significant technical advance must be credited to a hopelessly simple device, and a courageous investigator. Twenty-five years ago, Forssman performed, alone, and upon himself, the first human cardiac catheterization. This technique and the impetus given to its use by Cournand and his co-workers have led directly or indirectly to many of the specific advances to be discussed in the body of this essay. It is patently impossible within the scope of this discussion to be allinclusive. Similarly, even a partial bibliography would be overlong. Therefore, in this presentation, data and ideas will be stated without reference,* and only certain selected topics will be discussed, omitting many subjects equally important as those presented. Of the major topics omitted, including arrhythmias, the electrocardiogram, arteriosclerosis, hypertension, shock, and others, some are omitted by the author's whimsy and some because "When I considered the number of conflicting opinions touching a single matter that may be upheld by learned men, while there can be but one true, I reckoned as false all that was only probable" (Descartes). CONGENITAL HEART DISEASE
The most dramatic of all advances in the cardiovascular field has been the establishment of ameliorative and corrective surgery for congenital heart diseases of various types. The continued success of these procedures will depend on accurate anatomic and functional pathologicdiagnosis. The continued advance of the field will depend on increasing knowledge of the pathologic physiology of those conditions currently not amenable to surgery and the experimental evaluation of techniques designed to make them surgically approachable. At present the conditions most amenable to surgery are patent ductus arteriosus, tetrology of Fallot, coarctation of the aorta and valvular pulmonic stenosis; atrial septal defect, with or without anomalous pulmonary drainage, and aortic stenosis are rapidly joining that list. Although many of these diagnoses can be made entirely by clinical means, one of the most useful adjuncts to accurate diagnosis is cardiac catheterization. Proper * The author will gladly provide, by personal communication, specific references for any statements made.
PhysioZogic Research and Clinical Cardiology
1567
evaluation of the pressure measurements and oxygen saturations presupposes a knowledge of elementary physiologic principles and normal values. The use of these principles makes it possible to identify both the direction and magnitude of abnormal shunts, and the localization of valvular changes, either stenosis or insufficiency. The normal values for oxygen saturation and for pressure established in the experimental animal have been verified in man. The pressure values in millimeters of mercury are as follows: right atrium, 5/0; right ventricle, 25/0; pulmonary artery, 25/10; left ventricle, 120/0; and peripheral artery, 115/70. The percentages of oxygen saturations are as follows: left atrium, ventricle, and systemic arteries, 98 per cent; pulmonary artery and right ventricle, about 75 to 80 per cent; and right atrium, almost any value from 30 to 90 per cent, depending on the completeness of mixing. At present circulation time de terminations are used in only a few centers. This technique involves the injection of some foreign detectable material (isotope, dye, electrolyte, and the like) into the blood stream at one point and determining its concentration serially at another point. In the original investigations by physiologists concentrated salt solutions were used, but the blue dye T-1824, or Evans' blue, has replaced salt as the test material. Rapid serial arterial sampling has been replaced by modified oximetric techniques to allow continuous recording of the arterial dye concentration. It has been shown both on animals and man that proper analysis of the data obtained in these studies will yield a reasonable estimate of the circulation time and of the volume of flow between the point of injection and the point of sampling, and of the volume flow, i.e., cardiac output. This technique is bound to come into fuller use as an aid in the evaluation of congenital heart disease because it adds these advantages to the present methods: (1) it can be used as a screening test on infants in heart failure to differentiate abnormal shunts from such conditions as glycogen storage disease and fibroelastosis; (2) it can aid considerably in making the important, but often confusing, differentiation between tetrology of Fallot and pulmonic stenosis with atrial septal defect; (3) it is useful in evaluating anomalous pulmonary vein drainage into the right atrium; and (4) it will be of considerable help in evaluating septal defects, particularly in differentiating high ventricular septal defect from patent ductus with pulmonic insufficiency, and in differentiating true atrial septal defect from "probe patent" foramen ovale. Physiologists and clinical investigators alike are rivaling the searches of Diogenes for an honest heart-lung machine. Although progress has been considerable, the prosperity of this device is still "just around the corner." It is inevitable, however, that an adequate machine will be available in a matter of a few years. The main problems remaining at the time of this writing are hemolysis and the release of a potent vaso-
1568
William J. Rashkind
depressor substance. Perfection of this device is mandatory before adequate surgical trial can be made to attempt to correct ventricular septal defects or other currently inoperable lesions. Vein-switching experiments have reached the stage of application in attempting to correct complete transposition of the pulmonary veins. The established physiologic principle of decreased oxygen utilization with hypothermia is being applied in human cardiac surgery with impressive results. Techniques worked out on dogs to defibrillate the heart in ventricular fibrillation have also been used in the operating room. Further laboratory remedies for ventricular fibrillation such as drug control and artificial electronic pacemakers will probably be applied to man. Current physiologic investigations of the dynamic circulatory changes produced by artificial heart valves and development of techniques for microanalysis of blood gases and of continuous blood gas analysis are but a few of the present investigations which doubtless will be directed into further clinical progress in this exciting field. CONGESTIVE HEART FAILURE
This fascinating and important clinical problem has seen the rise and fall of many theories pertaining to its genesis. Clinicians and physiologists alike have girded to do battle on either side of the numerous opposed concepts: forward failure versus backward failure, high output versus low output, mechanical cardiac failure versus fluid retention overload, cardiac versus renal versus adrenal versus antidiuretic hormone versus neural versus venous hypertension. The battle currently in the ascendancy is high blood volume versus low or normal blood volume. The physiologic investigations leading to this multiplicity of ideas are of considerable interest. It has been demonstrated that nearly total destruction, or even bypassing the right ventricle, does not produce the syndrome. That increase in weight, owing to accumulation of edema fluid, precedes venous hypertension has been demonstrated in resting man, while the opposite sequence has been shown for the exercising dog. Since the first experiments demonstrating retention of sodium and water were published, hosts of investigators have "proved" the mechanism of this phenomenon, an admittedly important aspect of the syndrome. Increased production of antidiuretic hormone, decreased hepatic destruction of antidiuretic hormone due to anoxic centrolobular necrosis, anoxic alterations in cellular metabolism, variations in flow distribution to the kidney by neural and/or hormonal pathways, administration of ACTH, DOCA or cortisone, increased gastrointestinal absorption, changes in intrathoracic pressure, increased renal vein pressure, and engorgement of any sizable peripheral venous bed have all been shown to produce or be associated with the congestive syndrome. In the introduction to this discussion it was pointed out that one of
Physiologic Research and Clinical Cardiology
1569
the significant conceptual advances in modern cardiovascular physiology is the integration of the movement of all body fluids into an overall picture of the circulation. It is reasonable to presume that there are alterations in the circulation in this broadest sense in congestive heart failure. In line with this concept of the circulation the author postulates that initial stimuli, probably secondary to anoxia, directly alter cellular metabolism, and reflexly trigger a host of reactions including renal, hormonal, hepatic, cardiac, venous, arteriolar, capillary and other responses, the summation of which results in this complex clinical syndrome. REGIONAL CIRCULATIONS
Although one of the main motifs of this essay has been emphasis on the broad view of the boundaries of the circulation, there have been important investigations of narrow segments of the circulatory tree which are so significant clinically as to warrant a digression. Extensive increases in knowledge of the coronary, pulmonary, cerebral, renal, hepatic, skin, muscle and other regional flows have been made. Most of the techniques used for the measurement of flow in any of these beds are modifications of the Fick principle, which may be stated as follows: flow through an organ or organ unit can be calculated by dividing the quantity of a substance, either taken up or given off by that organ unit, by the difference in concentration of that substance between the inflowing and outflowing blood of that organ. For example, if the amount of oxygen taken up by the lung per minute is 250 cc., and if the differ~ ence in oxygen concentration between pulmonary artery blood and pulmonary vein blood is 50 cc. per liter, then the lung blood flow is 5 liters. These techniques were, for many years, routine procedures on experimental animals. Human catheterization techniques allow sampling from any systemic artery, the pulmonary artery, the renal vein, the coronary sinus, the jugular bulb, the hepatic veins and, under special circumstances, from the pulmonary veins and any of the heart chambers, so that the animal studies have now been extended to man. Only the coronary, pulmonary and cerebral circulations will be considered here. One interesting generalization can be made about many, if not all, of these regional circulatory beds. Various ingenious techniques have revealed the presence of arteriovenous communications of significant caliber. These demonstrations have led to rather a hubbub in some instances, but I must admit that the clinical applicability of this knowledge by and large escapes me. Coronary Flow and Cardiac MetaholisIll
Basic physiologic studies on the coronary circulation in man have yielded considerable information regarding the amount, character and
1570
W illiam J. Rashkind
control of flow. These studies have been made possible by exploiting an accidental entry of a catheter into the coronary sinus during cardiac catheterization. The technique was worked out on dogs and then applied purposefully to man. Measurements of flow obtained by this technique indicate coronary flow to be 5 to 10 per cent of the total cardiac output. It has been demonstrated, too, that the blood in the coronary sinus has a lower oxygen saturation than blood anywhere else in the body. There is also relatively little vasomotor, chemical or hormonal alteration of coronary flow, although decreased oxygen partial pressure (p02) in coronary blood seems to be the most potent stimulus for increased coronary flow. The prime mechanisms whereby cardiac muscle obtains additional oxygen are by a high extraction ratio and by raising the coefficient of oxygen utilization by heart muscle. This is true for failing as well as normal cardiac muscle; in fact, the failing heart can increase its coefficient of oxygen from a normal figure of about 60 to 90 per cent, a very efficient mechanism, indeed. Moreover, metabolic studies on cardiac metabolism, also made possible by the availability of human coronary venous blood, show that the normal and the failing heart have the same high glucose, pyruvate and lactate extraction. Where, then, is the defect in the failing heart, in which coronary flow is normal and in which the extraction ratio for oxygen and combustible materials is high? The block apparently involves conversion of extracted energy into useful work. Experimental studies are now in progress to evaluate cardiac enzyme systems in the normal and failing heart. Some clinics are using high glucose intake in the management of heart failure. Future advances in the knowledge of the enzymatic factors in conversion of extracted energy into useful work will certainly lead to more efficient management of myocardial insufficiency. Pulmonary Circulation
Clinical interest in the physiology of the pulmonary circulation has been considerable. A reasonable approximation of the pulmonary capillary pressure in man is obtainable by wedging a catheter into a small pulmonary artery. With this technique, it has been shown in patients with cardiopulmonary disease that the pulmonary capillary pressure bears no necessary relationship to the pulmonary artery pressure. This is important in evaluating the pathogenesis of pulmonary hypertension in several clinical conditions. In mitral stenosis, for example, the standard explanation of pulmonary arterial hypertension as a back pressure phenomenon, retrograde from the stenosed valve, is no longer tenable. It has been demonstrated frequently that the pulmonary capillary pressure may not be elevated even when marked pulmonary arterial hypertension exists. Since this indicates the existence of increased pulmonary
Physiologic Research and Clinical Cardiology
o
1571
vascular resistance, and since this is often reversible, it suggests that vasoconstriction has occurred; this is probably reflex in origin. The puhnonary circulation is now almost as well studied as the systemic circulation, and many papers have dealt with the alterations in the puhnonary circulation in emphysema, acute and chronic cor pulmonale and pulmonary embolism. Of these, the latter two will be discussed. pulmonary Edema. Physiologic experiments on human beings have indicated that acute pulmonary edema is accompanied by a lowered output of both right and left ventricles. Animal experiments have been performed demonstrating that acute pulmonary edema can be produced by stimulation of the central nervous system by methods as divergent as direct electrical stimulation and thrombin injections into the cerebral ventricles. This type of finding has led to consideration of possibilities other than acute left ventricular failure as the initiating mechanism in acute pulmonary edema. One such possibility is a neural control over pulmonary capillary permeability. In every instance, however, systemic vasoconstriction, marked elevation of systemic arterial and left ventricular blood pressure, and increased pulmonary capillary pressure have been found. In patients with pulmonary edema the circulation time is just as prolonged whether they are in failure or not. In addition, lowered vital capacity has been observed with pulmonary edema. This is sometimes related to the horizontal position, i.e., orthopnea, and has been presumed to be due to pulmonary congestion secondary to an increase in blood volume when reclining. In many instances, however, a whee7ing, nonedematous type of cardiac asthma occurs in these patients, presumably indicating a bronchospastic phenomenon with or without actual edema. It is possible that alteration of the oxygenation and nutrition of nervous tissue (probably in the brain stem) may result in systemic and pulmonary cardiovascular reflexes as well as in bronchial reflexes, all of which contribute to the symptom complex of acute pulmonary edema. Acute Cor Pulmonale. The problem of acute cor pulmonale remains an area of considerable speculation and interest. It has long been substantiated experimentally that 50 per cent or more of the cross-sectional areas of the pulmonary arterial tree must be occluded before there are significant mechanical circulatory changes. An entire main pulmonary artery may be suddenly and permanently occluded during pneumonectomy with only transient changes in cardiovascular dynamics. Yet in fatal pulmonary embolization only a few small vessels may be involved. Experimental attacks on this problem have suggested reflex phenomena initiated in the lungs and ending with coronary arteriospasm. In the experimental animal fatal outcome from acute pulmonary embolization can be prevented by surgical or pharmacologic vagotomy. Although this approach has been tried only sporadically in man, atropinization in large dosage may yet prove its clinical worth.
1572
William J. Rashkind
More recently the question of chemically induced reflexes has been raised. Serum from clotted blood has been shown to contain a vasodepressor material. * Preliminary experiments in cats suggest that the release of this material at the site of pulmonary embolism may stimulate chemosensitive receptors in the lung leading to harmful and perhaps fatal systemic cardiovascular alterations; however, man may react quite differently to the same substance. Further investigations along this line may well clarify some of the unanswered questions pertaining to the pathogenesis of acute cor pulmonale and may also lead to improved therapy of this frequently fatal condition. Cerebral Circulation
Studies on this circulatory bed have been extensive recently as a result of the availability of a technique for the measurement of cerebral blood flow, Much of the early data obtained on experimental animals has been checked in man. It must still be stated that, as is also true of coronary and pulmonary arteries, the control of the caliber of the cerebral vessels is poorly understood. Nonetheless, even if the essential questions about cerebral arteriomotion remain unanswered, flow studies on man have led to several useful clinical applications. The one agent most certain to result in cerebral artery dilation is carbon dioxide. For practical purposes this is most useful in preventing postpneumoencephalogram complications and in preventing or relieving postlumbar puncture headache. It has been shown that epinephrine increases cerebral metabolism more than it increases cerebral blood flow, whereas norepinephrine results in decreased flow with no increase in metabolism. Norepinephrine is rapidly becoming the vasopressor drug of choice in virtually all hypotensive states; possibly one must be cautious in its use in patients with restricted cerebral circulation initially. Studies on cerebral blood flow in psychiatric conditions are widespread. This aspect of the subject is out of the realm of this discussion, but is an interesting attempt at application of physiologic techniques even to ethereal problems. CONCLUSIONS
It has been evident throughout this essay that there is a healthy overlap between physiologic and clinical research in both pure and applied forms. Researches that have led to the establishment of certain broad principles in cardiovascular physiology have led to important clinical advances. Progress in experimental techniques and instrumentation has played an important role in both fields. It is interesting to note • Usually called serotonin, and probably 5-0H-tryptamine chemically.
Physiologic Research and Clinical Cardiology
1573
that in the chapter on the heart in the Annual Reviews of Physiology for 1953 the authors state that it is "impossible to review the large number of clinical papers on this subject which contain physiologic measurements." For it is certainly true that the alert cardiovascular clinician uses continuously the advances and techniques developed by physiologists. Indeed, though both may resent the designation, the cardiologist is a physiologist and has as much to contribute to the basic knowledge of cardiovascular physiology as the physiologist has to contribute to clinical progress. 3400 Spruce Street Philadelphia 4, Pa.
IN attempting to assay the contributions of physiology to the understanding and management of clinical cardiovascular problems the development and trends in physiology must be delineated first. What have been the main directions and broad concepts in the field of cardiovascular physiology? To my mind there have been two main pathways: first, the concept of expanding the boundaries of the circulation to include the movement of fluids through all body tissues; and, second, the concept of the regulation of the circulation by humoral and neural control. It has sagely been stated by a late Oxford Professor of Medicine that "Oalen has often been blamed for 1300 years of progress that did not take place after him." By the same token William Harvey is equally culpable that his ingenious experiments directed cardiovascular physiologic researches for 300 years into the investigation of that narrowed segment of the circulation, the heart and the systemic blood vessels. The genius of Claude Bernard gave new direction to these researches. His thesis of Le Milieu Interier led to the development of knowledge of the totality of the circulation as exemplified by the experiments of Starling, Krogh and Lewis on the capillary circulation, and Gamble, Hevesy and many others on the circulation of all the body water and its solutes. Bernard's studies on the nervous control of vasomotion also preluded voluminous studies of the control of the circulation leading to the latter-day wedding of physiologic and electronic concepts in approaching the control of the circulation as a cybernetic, self-regulating servomechanism. In the ensuing discussion I shall try to show how these ideas and the experiments leading to their development also conFrom the Department of Physiology, University of Pennsylvania Graduate School of Medicine, and the Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia.
* Chief Resident in Pediatrics, University of Pennsylvania School of Medicine; Formerly Assistant Professor of Physiology, University of Pennsylvania Graduate School of Medicine, Philadelphia. 1565
1566
W illiam J. Rashkind
tributed to the better understanding of many clinical cardiovascular problems. In addition to these two main conceptual developments, the importance of technical developments cannot be minimized, since these have led to an even greater direct clinical application. Not discounting the importance of the string galvanometer, the oscillograph, the electromanometer, the automatically recording flowmeters of various designs, the spectrophotometer, the modern gas analyzer, the Geiger counter and many other significant instrumental advances, the single most significant technical advance must be credited to a hopelessly simple device, and a courageous investigator. Twenty-five years ago, Forssman performed, alone, and upon himself, the first human cardiac catheterization. This technique and the impetus given to its use by Cournand and his co-workers have led directly or indirectly to many of the specific advances to be discussed in the body of this essay. It is patently impossible within the scope of this discussion to be allinclusive. Similarly, even a partial bibliography would be overlong. Therefore, in this presentation, data and ideas will be stated without reference,* and only certain selected topics will be discussed, omitting many subjects equally important as those presented. Of the major topics omitted, including arrhythmias, the electrocardiogram, arteriosclerosis, hypertension, shock, and others, some are omitted by the author's whimsy and some because "When I considered the number of conflicting opinions touching a single matter that may be upheld by learned men, while there can be but one true, I reckoned as false all that was only probable" (Descartes). CONGENITAL HEART DISEASE
The most dramatic of all advances in the cardiovascular field has been the establishment of ameliorative and corrective surgery for congenital heart diseases of various types. The continued success of these procedures will depend on accurate anatomic and functional pathologicdiagnosis. The continued advance of the field will depend on increasing knowledge of the pathologic physiology of those conditions currently not amenable to surgery and the experimental evaluation of techniques designed to make them surgically approachable. At present the conditions most amenable to surgery are patent ductus arteriosus, tetrology of Fallot, coarctation of the aorta and valvular pulmonic stenosis; atrial septal defect, with or without anomalous pulmonary drainage, and aortic stenosis are rapidly joining that list. Although many of these diagnoses can be made entirely by clinical means, one of the most useful adjuncts to accurate diagnosis is cardiac catheterization. Proper * The author will gladly provide, by personal communication, specific references for any statements made.
PhysioZogic Research and Clinical Cardiology
1567
evaluation of the pressure measurements and oxygen saturations presupposes a knowledge of elementary physiologic principles and normal values. The use of these principles makes it possible to identify both the direction and magnitude of abnormal shunts, and the localization of valvular changes, either stenosis or insufficiency. The normal values for oxygen saturation and for pressure established in the experimental animal have been verified in man. The pressure values in millimeters of mercury are as follows: right atrium, 5/0; right ventricle, 25/0; pulmonary artery, 25/10; left ventricle, 120/0; and peripheral artery, 115/70. The percentages of oxygen saturations are as follows: left atrium, ventricle, and systemic arteries, 98 per cent; pulmonary artery and right ventricle, about 75 to 80 per cent; and right atrium, almost any value from 30 to 90 per cent, depending on the completeness of mixing. At present circulation time de terminations are used in only a few centers. This technique involves the injection of some foreign detectable material (isotope, dye, electrolyte, and the like) into the blood stream at one point and determining its concentration serially at another point. In the original investigations by physiologists concentrated salt solutions were used, but the blue dye T-1824, or Evans' blue, has replaced salt as the test material. Rapid serial arterial sampling has been replaced by modified oximetric techniques to allow continuous recording of the arterial dye concentration. It has been shown both on animals and man that proper analysis of the data obtained in these studies will yield a reasonable estimate of the circulation time and of the volume of flow between the point of injection and the point of sampling, and of the volume flow, i.e., cardiac output. This technique is bound to come into fuller use as an aid in the evaluation of congenital heart disease because it adds these advantages to the present methods: (1) it can be used as a screening test on infants in heart failure to differentiate abnormal shunts from such conditions as glycogen storage disease and fibroelastosis; (2) it can aid considerably in making the important, but often confusing, differentiation between tetrology of Fallot and pulmonic stenosis with atrial septal defect; (3) it is useful in evaluating anomalous pulmonary vein drainage into the right atrium; and (4) it will be of considerable help in evaluating septal defects, particularly in differentiating high ventricular septal defect from patent ductus with pulmonic insufficiency, and in differentiating true atrial septal defect from "probe patent" foramen ovale. Physiologists and clinical investigators alike are rivaling the searches of Diogenes for an honest heart-lung machine. Although progress has been considerable, the prosperity of this device is still "just around the corner." It is inevitable, however, that an adequate machine will be available in a matter of a few years. The main problems remaining at the time of this writing are hemolysis and the release of a potent vaso-
1568
William J. Rashkind
depressor substance. Perfection of this device is mandatory before adequate surgical trial can be made to attempt to correct ventricular septal defects or other currently inoperable lesions. Vein-switching experiments have reached the stage of application in attempting to correct complete transposition of the pulmonary veins. The established physiologic principle of decreased oxygen utilization with hypothermia is being applied in human cardiac surgery with impressive results. Techniques worked out on dogs to defibrillate the heart in ventricular fibrillation have also been used in the operating room. Further laboratory remedies for ventricular fibrillation such as drug control and artificial electronic pacemakers will probably be applied to man. Current physiologic investigations of the dynamic circulatory changes produced by artificial heart valves and development of techniques for microanalysis of blood gases and of continuous blood gas analysis are but a few of the present investigations which doubtless will be directed into further clinical progress in this exciting field. CONGESTIVE HEART FAILURE
This fascinating and important clinical problem has seen the rise and fall of many theories pertaining to its genesis. Clinicians and physiologists alike have girded to do battle on either side of the numerous opposed concepts: forward failure versus backward failure, high output versus low output, mechanical cardiac failure versus fluid retention overload, cardiac versus renal versus adrenal versus antidiuretic hormone versus neural versus venous hypertension. The battle currently in the ascendancy is high blood volume versus low or normal blood volume. The physiologic investigations leading to this multiplicity of ideas are of considerable interest. It has been demonstrated that nearly total destruction, or even bypassing the right ventricle, does not produce the syndrome. That increase in weight, owing to accumulation of edema fluid, precedes venous hypertension has been demonstrated in resting man, while the opposite sequence has been shown for the exercising dog. Since the first experiments demonstrating retention of sodium and water were published, hosts of investigators have "proved" the mechanism of this phenomenon, an admittedly important aspect of the syndrome. Increased production of antidiuretic hormone, decreased hepatic destruction of antidiuretic hormone due to anoxic centrolobular necrosis, anoxic alterations in cellular metabolism, variations in flow distribution to the kidney by neural and/or hormonal pathways, administration of ACTH, DOCA or cortisone, increased gastrointestinal absorption, changes in intrathoracic pressure, increased renal vein pressure, and engorgement of any sizable peripheral venous bed have all been shown to produce or be associated with the congestive syndrome. In the introduction to this discussion it was pointed out that one of
Physiologic Research and Clinical Cardiology
1569
the significant conceptual advances in modern cardiovascular physiology is the integration of the movement of all body fluids into an overall picture of the circulation. It is reasonable to presume that there are alterations in the circulation in this broadest sense in congestive heart failure. In line with this concept of the circulation the author postulates that initial stimuli, probably secondary to anoxia, directly alter cellular metabolism, and reflexly trigger a host of reactions including renal, hormonal, hepatic, cardiac, venous, arteriolar, capillary and other responses, the summation of which results in this complex clinical syndrome. REGIONAL CIRCULATIONS
Although one of the main motifs of this essay has been emphasis on the broad view of the boundaries of the circulation, there have been important investigations of narrow segments of the circulatory tree which are so significant clinically as to warrant a digression. Extensive increases in knowledge of the coronary, pulmonary, cerebral, renal, hepatic, skin, muscle and other regional flows have been made. Most of the techniques used for the measurement of flow in any of these beds are modifications of the Fick principle, which may be stated as follows: flow through an organ or organ unit can be calculated by dividing the quantity of a substance, either taken up or given off by that organ unit, by the difference in concentration of that substance between the inflowing and outflowing blood of that organ. For example, if the amount of oxygen taken up by the lung per minute is 250 cc., and if the differ~ ence in oxygen concentration between pulmonary artery blood and pulmonary vein blood is 50 cc. per liter, then the lung blood flow is 5 liters. These techniques were, for many years, routine procedures on experimental animals. Human catheterization techniques allow sampling from any systemic artery, the pulmonary artery, the renal vein, the coronary sinus, the jugular bulb, the hepatic veins and, under special circumstances, from the pulmonary veins and any of the heart chambers, so that the animal studies have now been extended to man. Only the coronary, pulmonary and cerebral circulations will be considered here. One interesting generalization can be made about many, if not all, of these regional circulatory beds. Various ingenious techniques have revealed the presence of arteriovenous communications of significant caliber. These demonstrations have led to rather a hubbub in some instances, but I must admit that the clinical applicability of this knowledge by and large escapes me. Coronary Flow and Cardiac MetaholisIll
Basic physiologic studies on the coronary circulation in man have yielded considerable information regarding the amount, character and
1570
W illiam J. Rashkind
control of flow. These studies have been made possible by exploiting an accidental entry of a catheter into the coronary sinus during cardiac catheterization. The technique was worked out on dogs and then applied purposefully to man. Measurements of flow obtained by this technique indicate coronary flow to be 5 to 10 per cent of the total cardiac output. It has been demonstrated, too, that the blood in the coronary sinus has a lower oxygen saturation than blood anywhere else in the body. There is also relatively little vasomotor, chemical or hormonal alteration of coronary flow, although decreased oxygen partial pressure (p02) in coronary blood seems to be the most potent stimulus for increased coronary flow. The prime mechanisms whereby cardiac muscle obtains additional oxygen are by a high extraction ratio and by raising the coefficient of oxygen utilization by heart muscle. This is true for failing as well as normal cardiac muscle; in fact, the failing heart can increase its coefficient of oxygen from a normal figure of about 60 to 90 per cent, a very efficient mechanism, indeed. Moreover, metabolic studies on cardiac metabolism, also made possible by the availability of human coronary venous blood, show that the normal and the failing heart have the same high glucose, pyruvate and lactate extraction. Where, then, is the defect in the failing heart, in which coronary flow is normal and in which the extraction ratio for oxygen and combustible materials is high? The block apparently involves conversion of extracted energy into useful work. Experimental studies are now in progress to evaluate cardiac enzyme systems in the normal and failing heart. Some clinics are using high glucose intake in the management of heart failure. Future advances in the knowledge of the enzymatic factors in conversion of extracted energy into useful work will certainly lead to more efficient management of myocardial insufficiency. Pulmonary Circulation
Clinical interest in the physiology of the pulmonary circulation has been considerable. A reasonable approximation of the pulmonary capillary pressure in man is obtainable by wedging a catheter into a small pulmonary artery. With this technique, it has been shown in patients with cardiopulmonary disease that the pulmonary capillary pressure bears no necessary relationship to the pulmonary artery pressure. This is important in evaluating the pathogenesis of pulmonary hypertension in several clinical conditions. In mitral stenosis, for example, the standard explanation of pulmonary arterial hypertension as a back pressure phenomenon, retrograde from the stenosed valve, is no longer tenable. It has been demonstrated frequently that the pulmonary capillary pressure may not be elevated even when marked pulmonary arterial hypertension exists. Since this indicates the existence of increased pulmonary
Physiologic Research and Clinical Cardiology
o
1571
vascular resistance, and since this is often reversible, it suggests that vasoconstriction has occurred; this is probably reflex in origin. The puhnonary circulation is now almost as well studied as the systemic circulation, and many papers have dealt with the alterations in the puhnonary circulation in emphysema, acute and chronic cor pulmonale and pulmonary embolism. Of these, the latter two will be discussed. pulmonary Edema. Physiologic experiments on human beings have indicated that acute pulmonary edema is accompanied by a lowered output of both right and left ventricles. Animal experiments have been performed demonstrating that acute pulmonary edema can be produced by stimulation of the central nervous system by methods as divergent as direct electrical stimulation and thrombin injections into the cerebral ventricles. This type of finding has led to consideration of possibilities other than acute left ventricular failure as the initiating mechanism in acute pulmonary edema. One such possibility is a neural control over pulmonary capillary permeability. In every instance, however, systemic vasoconstriction, marked elevation of systemic arterial and left ventricular blood pressure, and increased pulmonary capillary pressure have been found. In patients with pulmonary edema the circulation time is just as prolonged whether they are in failure or not. In addition, lowered vital capacity has been observed with pulmonary edema. This is sometimes related to the horizontal position, i.e., orthopnea, and has been presumed to be due to pulmonary congestion secondary to an increase in blood volume when reclining. In many instances, however, a whee7ing, nonedematous type of cardiac asthma occurs in these patients, presumably indicating a bronchospastic phenomenon with or without actual edema. It is possible that alteration of the oxygenation and nutrition of nervous tissue (probably in the brain stem) may result in systemic and pulmonary cardiovascular reflexes as well as in bronchial reflexes, all of which contribute to the symptom complex of acute pulmonary edema. Acute Cor Pulmonale. The problem of acute cor pulmonale remains an area of considerable speculation and interest. It has long been substantiated experimentally that 50 per cent or more of the cross-sectional areas of the pulmonary arterial tree must be occluded before there are significant mechanical circulatory changes. An entire main pulmonary artery may be suddenly and permanently occluded during pneumonectomy with only transient changes in cardiovascular dynamics. Yet in fatal pulmonary embolization only a few small vessels may be involved. Experimental attacks on this problem have suggested reflex phenomena initiated in the lungs and ending with coronary arteriospasm. In the experimental animal fatal outcome from acute pulmonary embolization can be prevented by surgical or pharmacologic vagotomy. Although this approach has been tried only sporadically in man, atropinization in large dosage may yet prove its clinical worth.
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William J. Rashkind
More recently the question of chemically induced reflexes has been raised. Serum from clotted blood has been shown to contain a vasodepressor material. * Preliminary experiments in cats suggest that the release of this material at the site of pulmonary embolism may stimulate chemosensitive receptors in the lung leading to harmful and perhaps fatal systemic cardiovascular alterations; however, man may react quite differently to the same substance. Further investigations along this line may well clarify some of the unanswered questions pertaining to the pathogenesis of acute cor pulmonale and may also lead to improved therapy of this frequently fatal condition. Cerebral Circulation
Studies on this circulatory bed have been extensive recently as a result of the availability of a technique for the measurement of cerebral blood flow, Much of the early data obtained on experimental animals has been checked in man. It must still be stated that, as is also true of coronary and pulmonary arteries, the control of the caliber of the cerebral vessels is poorly understood. Nonetheless, even if the essential questions about cerebral arteriomotion remain unanswered, flow studies on man have led to several useful clinical applications. The one agent most certain to result in cerebral artery dilation is carbon dioxide. For practical purposes this is most useful in preventing postpneumoencephalogram complications and in preventing or relieving postlumbar puncture headache. It has been shown that epinephrine increases cerebral metabolism more than it increases cerebral blood flow, whereas norepinephrine results in decreased flow with no increase in metabolism. Norepinephrine is rapidly becoming the vasopressor drug of choice in virtually all hypotensive states; possibly one must be cautious in its use in patients with restricted cerebral circulation initially. Studies on cerebral blood flow in psychiatric conditions are widespread. This aspect of the subject is out of the realm of this discussion, but is an interesting attempt at application of physiologic techniques even to ethereal problems. CONCLUSIONS
It has been evident throughout this essay that there is a healthy overlap between physiologic and clinical research in both pure and applied forms. Researches that have led to the establishment of certain broad principles in cardiovascular physiology have led to important clinical advances. Progress in experimental techniques and instrumentation has played an important role in both fields. It is interesting to note • Usually called serotonin, and probably 5-0H-tryptamine chemically.
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that in the chapter on the heart in the Annual Reviews of Physiology for 1953 the authors state that it is "impossible to review the large number of clinical papers on this subject which contain physiologic measurements." For it is certainly true that the alert cardiovascular clinician uses continuously the advances and techniques developed by physiologists. Indeed, though both may resent the designation, the cardiologist is a physiologist and has as much to contribute to the basic knowledge of cardiovascular physiology as the physiologist has to contribute to clinical progress. 3400 Spruce Street Philadelphia 4, Pa.