The Treatment of Congestive Heart Failure

The Treatment of Congestive Heart Failure From the Department of Medicine, Tufts University School of Medicine, and the New England Center Hospital, Boston, Massachusetts

HERBERT J. LEVINE, M.D. Senior Instructor; Assistant Physician

THE MAJOH DI~FEC'l' in congestive heart failure is an inability of the myocardial fiber to shorten adequately. This defect, in turn, gives rise to a great number of secondary abnormalities in a complicated sequence which currently is only partly understood. The most obvious of theEe abnormalities are elevation of pulmonary and systemic venous pressures, a suboptimal cardiac output and the accumulation of excess sodium and water. In general all therapeutic efforts in the treatment of congestive failure seck to accomplish one or more of the following: 1. A decrease in pulmonary and/or systemic venous pressures. 2. An increase in the mechanical efficiency of the heart. a. An increase in stroke volume. b. A decrease in the energy requirements of the heart. 3. An increase in oxygen availability to the tissues. 4. Removal of accumulated sodium and water. The mechanical and pharmacologic agents employed by clinicians to achieve these ends are well known to all physicians. In some instances, however, conventional methods of treatment in a patient with congestive heart failure fail to produce a salutary effect and may actually further circulatory decompensation. Not infrequently this involves a worsening of one manifestation of congestive failure in order to achieve improvement in another. The present review seeks to examine the physiologic effects of therapeutic agents in congestive heart failure. Through knowledge of the pathophysiology of the above abnormalities in congestive failure, and the effect of chemical and physical agents upon each, one may then evolve a rational basis for treatment.

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FACTORS WHICH INFLUENCE PULMONARY VENOUS AND SYSTEMIC VENOUS PRESSURES

The physiological basis for cardiac dyspnea is an elevated pulmonary venous pressure, and all efforts which successfully lower this pressure can be expected to lessen respiratory distress. This is not to say that cardiac dyspnea is due wholly to pulmonary venous hypertension, but that the reduction of an elevated pulmonary venous pressure will not only reverse alveolar transudation directly, but interrupt a number of other processes which contribute to difficulty in breathing. Recent studies have emphasized that one of the important changes which occurs in acute pulmonary edema is a decrease in the compliance of the lung.ll This increase in the "stiffness" of the lung parenchyma implies that a greater distending pressure within the alveoli is necessary to attain a given inspiratory lung volume, and in such manner may contribute significantly to the respiratory distress of acute pulmonary congestion. Whether cardiac dyspnea is due primarily to alveolar transudation, secondary compliance changes in the lung or central nervous system reflex arcs, lowering of pulmonary venous pressure remains a focal objective in treatment. Posture, Tourniquets and Phlebotomy

In the treatment of the patient with acute cardiac dyspnea, the first and simplest maneuver to be employed is that of posture change. Not only is the central venous pressure reduced by changing from the recumbent to the upright position, but lung volume in the normal individual increases an average of 300 m!. and the vital capacity is improved by approximately 200 m!.37 In similar fashion, marked decreases in lung volume and vital capacity have been reported in orthopneic cardiac patients upon assuming the recumbent position. 2 , 9 The application of tourniquets above venous pressure in the extremities effectively sequesters blood in these areas, producing a lowering of central venous pressure and distal transudation of fluid from the vascular space. 3D . 38, 65 Although the total blood volume and red cell mass decreases only slightly during this procedure,5D vital capacity increases even in the normal individuaJ22 and it is likely that pulmonary blood volume is decreased significantly. Similarly, phlebotomy effects a lowering of venous pressure,38, 64 respiratory rate and total body oxygen consumption48 in patients with congestive failure. Changes in cardiac output following venesection have been unpredictable, but in the majority minute output has decreased.!· 3. 38 In some instances profound hypotension may be produced by blood-letting in subjects with severe congestive failure. For example, the removal of 300 to 500 m!. of whole blood from a severely hypoxic patient with cor pulmonale may well be catastrophic

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if no prior effort is made to improve oxygenation. In this instance, the reduction in cardiac output and oxygen-carrying capacity may be greater than the benefit derived in lowering pulmonary pressures, heart volume and blood viscosity, and phlebotomy will best be deferred until hypoxia and hypercapnea have been improved. Nonetheless, phlebotomy can produce dramatic improvement in many patients with acute pulmonary edema. In chronic congestive heart failure the results are even more gratifying, and in this form of heart failure venesection has become one of the most neglected forms of treatment. Morphine

Certainly the most useful drug in the treatment of acute pulmonary edema is morphine. It depresses the respiratory center, producing a lowering of respiratory minute volume and rate 14 • 63 and a mild decrease in the metabolic rate. 63 However, these actions are not sufficient to explain the dramatic effect of this drug in the relief of acute cardiac dyspnea. The mechanism by which morphine promptly reverses acute pulmonary edema is not known, but may be related to the interruption of reflex arcs set up by the rising venous pressure. The role played by central nervous system pathways in the genesis of acute pulmonary edema has been emphasized by Luisada. 35 Morphine should be used with a great deal of caution in persons with myxedema, bronchospasm or severe cor pulmonale, where respiratory depression may result in fatal apnea. Mitral Stenosis

In the management of mitral stenosis, the importance of lowering pulmonary venous pressure becomes pre-eminent. In this instance the hydraulic events which determine the height of the pulmonary venous pressure may be examined more easily and thus provide a rational basis for effective treatment. In pure mitral stenosis, the pulmonary venous pressure may be derived from the following formula: 21 (00)2 (DFP X MVA X 0)2

PVP where:

PVP 00 DFP MVA

o

LVdm

= = = = = =

+ LVdm

pulmonary venous pressure, mm.Hg cardiac output, ml./min. diastolic filling period, seconds/min. mitral valve area, cm. 2 constant left ventricular diastolic mean pressure, mm.Hg

From this relationship it is apparent that any increase in cardiae output or any decrease in the duration of diastole will result in a rise in pulmonary venous pressure and attendant dyspnea. Thus, the correction

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of anemia, the control of tachycardia, the lysis of fever or the treatment of any hypermetabolic state will necessarily reduce pulmonary venous pressure and relieve dyspnea. The critically ill patient with mitral stenosis, influenza and sinus tachycardia will profit far more from vigorous attempts to control fever than from the random use of digitalis glycosides. These hydraulic rules apply equally well to the patient with left ventricular failure in whom the obstruction to blood flow is the result of a decreased myocardial compliance rather than a stenotic valve orifice. Except in the cases of extreme hyrervolemia, such as occurs in patients with acute glomerular nephritis15 or in iatrogenic volume loading, reduction in ventricular filling pressures (central venous pressures) alone is usually not sufficient to reverse the many physiological defects in congestive heart failure. In chronic congestive failure, although pulmonary congestion may be relieved by such maneuvers, one is left with a further reduction in cardiac output and a persistent stimulus to sodium and water retention. Thus, other measures must be employed if one is to restore a more competent circulation. FACTORS WHICH INFLUENCE THE MECHANICAL EFFICIENCY OF THE HEART

The mechanical efficiency of the heart is an expression of the energy cost of pressure-volume work performed by the heart. * In chronic congestive heart failure the mechanical efficiency of the heart pump has been shown to be subnormal,20, 34 due to a decrease in effective pressure-volume work, an absolute increase in the energy requirements of the heart, or more often both. Ideally, therapeutic efforts which simultaneously increase the stroke volume of the failing heart and decrease the oxygen demands of this organ would be most beneficial to both cardiac and total body economy in chronic congestive failure. Energy Requirements of the Heart

It was shown many years ago that increases in pressure within the heart were costly in terms of oxygen utilization, while increases in flow (stroke volume) were notYMore recently, Sarnoff et a1. 61 have shown that in acute experiments the oxygen consumed by the heart closely paralleled the total pressure generated by the heart (the area under the systolic pressure curve). While this observation served to explain acute changes in cardiac energetics, it was not sufficient to account for the work performed d' In the case of the left ventricle, the energy consume work performed is equal to the cardiac output in L./min. times the mean leftventricular systolic pressure in mm.Hg times 13.6 X 10- 3 and is expressed as kg.-m./min. The energy consumed is equal to the oxygen consumption of the left ventricle ml./min. times 2.06 (the energy equivalentofl m!. of oxygen),

* Mechanical Efficiency

=

in

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Fig. 1. In these two pumps, movement of the piston is governed by the tension generated by the operator and the angle subtended by the piston and direction of pull. When this angle and the area to which pressure is applied is ~t----------.=!...---­ large (A), the tension (T,) necessary to generate a given pressure and flow within the pump must be great. With a decrease in this angle and the surface area of the pump (B), the tensile force (T 2 ) need be less to generate the same pressure and flow (see text).

large energy requirements of dilated, hypertrophied hearts generating a normal arterial pressure. To resolve this apparent contradiction, the well known observations of Starling and his colleagues,43.57 relating myocardial oxygen utilization to diastolic fiber length, have been incorporated with the findings of Sarnoff through application of the geometric law of Laplace. According to the law of Laplace, the tension developed in the wall of a hollow chamber, i.e., sphere, cone, cylinder, is a function of the pressure within the chamber and the radius or radii of that chamber. Thus, it is generally believed today that the energy requirements of the heart are governed by the tension developed in the myocardial wall during systole. 32 ',51 This tension, in turn, is a function of the pressure generated by the heart and the mean radius of the cardiac chamber. From the foregoing it is apparent that the total tension in the myocardial wall necessary to generate a certain pressure, stroke volume and heart rate will be greater when the heart is large than when it is small. Since the energy expended by the heart muscle is determined primarily by this tensile force, the oxygen requirement of the heart will be less when the heart is smaller, although the pressure-volume work performed may be the same. In this fashion the efficiency of the heart pump is increased. The importance of decreasing the mean radius of the failing heart can be illustrated in another fashion. When the heart is large, much of the contractile effort of the myocardial sarcomeres is expended in tension development. As illustrated in Figure 1, A, in order to generate a given pressure within this pump, a great deal of tension is needed when the radius is large and little movement of the piston will be achieved. With a decrease in chamber radius (Fig. 1, B) myocardial tension development need oe less to maintain the same pressure and thus some of the contrac-

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50

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BEFORE OUABAIN AFTER OUABAIN

Fig. 2. The action of digitalis glycosides (ouabain) on the ventricular function curve of the nonfailing dog heart. (From Cotten and Stopp'2 by courtesy of the American Journal of Physiology.)

( 0.05 mg.lkg.,

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LEFT ATRIAL MEAN PRESSURE

cm. H20

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tile effort may now be diverted to fiber shortening (movement of the piston). This phenomenon has been well described in skeletal muscle contraction as the force-velocity relationship.28 These concepts find their application in the treatment of congestive heart failure. Digitalis glycosides enable both the normal dog heart12 , 18 and the failing human heart 6 to produce more work at any given ventricular filling pressure of chamber volume. Recently, Braunwald et al. 7 have demonstrated that digitalis augments the contractile force of the nonfailing human heart as well. In Figure 2, taken from Cotten and Stopp,12 this drug action is demonstrated by a shift in the ventricular function curve to the left. Interestingly enough, a similar shift in the ventricular function curve has been observed in the nonfailing heart following stimulation of the stellate ganglion or upon administration of norepinephrine. 62 In congestive heart failure the effects of this shift in the ventricular function curve to the left are many. In addition to a decrease in central venous pressures, cardiac output to skeletal muscle is increased, thereby reducing anaerobiasis and the production of lactic acid. 27 Renal blood flow in particular is augmented and aids in the excretion of sodium and water. Skin blood flow may return to normal, reinstituting an efficient mechanism for the dissipation of heat, often compromised in the patient with congestive failure. 8 , 10 Body temperature may then return to normal, further reducing the total body metabolic rate and in such fashion lessen the demands on the heart. Additional decreases in total body oxygen consumption may be

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achieved which benefit the individual in congestive failure. The respiratory effort of dyspnea imposes added energy demands upon the heart and may be sufficient to induce a true hypermetabolic state in dyspneic cardiac subjects. 44 ,48 This contribution to the resting metabolic rate assumes even greater magnitude in pulmonary emphysema and cor pulmonale, as resistance breathing has been shown to be much more costly (per foot-pound of work performed) than flow breathing (low resistance hyperventilation).36 Even in the individual without dyspnea, the increased oxygen consumption accounted for by hypertrophy and dilatation of the heart may contribute greatly to the metabolic rate. 3l , 32 Irrespective of the etiology, a reduction in these excess energy needs will decrease the flow requirements of body tissues and thus achieve a further reduction in pulmonary venous pressure (vide supra) and dyspnea. Valvular Insufficiency

The discussion of the mechanical efficiency of the heart becomes more complicated when one considers the problem of valvular insufficiency or abnormal shunting of blood. In the patient with mitral insufficiency, for example, the ratio of work done by the heart to energy consumed will be considerably higher if one includes the mitral regurgitant work. However, this latter moiety is not useful work, and alterations in hemodynamics which serve to divert this regurgitant flow to effective flow obviously will be beneficial. Therefore, in mitral insufficiency and hypertension, an added dividend may be gained in reducing systemic vascular resistance by virtue of a decreased systolic gradient across the mitral valve. Similarly, in patients with relative mitral insufliciency, in whom the mitral leak is the result of dilatation of the mitral annulus, a decrease in chamber volume will lessen the quantity of regurgitant flow by a reduction in the functional regurgitant valve area. Mitral regurgitation is a particularly devastating complication in aortic stenosis, for in this circumstance the intraventricular hypertension imposes a high systolic gradient across the mitral valve and a large degree of regurgitation is produced even when the size of the regurgitant defect is small. Unless a prompt decrease in ventricular volume is achieved or surgical correction of the aortic stenosis is performed, a rapid downhill course is usually observed. In aortic insufficiency a decrease in heart rate will reduce myocardial oxygen requirements. However, the associated prolongation of diastole will allow more time for regurgitation and thereby reduce the effective mechanical efficiency of the heart. In applying these considerations to an individual patient with congestive failure and valvular insufficiency, one must be governed by those factors which assume priority in a particular instance. For example, if coronary insufficiency and ischemic pain are more important in a patient with aortic regurgitation than left ventricular failure, bradycrotic agents may produce a beneficial effect.

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OXYGEN AVAILABILITY

The flow restrictions imposed by the failing myocardium produce tissue hypoxia and force muscle and viscera to function at a lower p02 than normal. In the treatment of congestive failure, this deficiency may be dealt with directly. Increasing the oxygen content of arterial blood serves not only to lessen the flow demands upon the burdened heart, but to improve myocardial function in other ways. Even the dyspneic cardiac patient whose arterial oxygen saturation is normal will profit from breathing a mixture of 95 to 100 per cent oxygen, as this will furnish an average of 2 volumes per eent of added oxygen partly as dissolved gas in the plasma. When arterial unsaturation exists, which is not due to right to left shunting at the pulmonary or cardiac level, the benefit derived obviously will be considerably greater. Hypoxia and Anemia

In obstructive emphysema with severe cor pulmonale, an improvement in alveolar ventilation is the most important factor governing successful treatment of the congestive failure. The two physiological sequelae of a decreased alveolar ventilation in emphysema, hypoxia and retention of carbon dioxide, both contribute independently to the syndrome of pulmonary hypertension and right ventricular failure. Hypoxia, as a powerful peripheral vasodilator, produces an increase in cardiac output. Fowler has reviewed the literature on the effects of hypoxia on pulmonary hemodynamics and has concluded that, irrespective of changes in cardiac output, pulmonary pressures are further increased by hypoxia through active pulmonary vasoconstriction. 19 The effects of hypercapnea on the pulmonary circulation, on the other hand, are less clear, but it has been demonstrated that hypercapnea and/or attendant acidosis decreases myocardial contractility,40 thus furthering the development of ventricular failure in chronic cor pulmonale. A significant improvement in alveolar ventilation, therefore, not only improves congestive failure directly, but gives the anoxic heart a greater margin of safety with regards to digitalis therapy, phlebotomy or diuretics. The role played by anemia in congestive heart failure is, in most respects, similar to that of hypoxia. Of particular importance are the observed abnormalities in renal hemodynamics. A reduction in renal blood flow was found by Bradley and Bradley to be a prominent feature of chronic anemia,6 and Strauss and Fox noted that when anemic subjects were loaded with salt and water, the degree of water retention varied inversely with the hemoglobin level:\9 Whitaker studied patients with anemia and congestive failure before and after treatment and found that the absolute renal blood flow was low despite an elevated cardiac

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output, and that the former rose and the latter fell with correction of anemia. 66 As the author suggests, the normal p02 of the kidney is quite high and disturbances in renal excretion of sodium and water in anemia may be a result of renal ischemia. Davies and his colleagues have demonstrated that the kidney is the site of production of an aldosteronestimulating hormone. I3 Whether this mechanism is responsible for the sodium and water retention observed in anemia remains to be shown. FACTORS INFLUENCING THE REMOVAL OF ACCUMULATED SALT AND WATER

Every physician has observed the patient in congestive failure who has failed to respond to a vigorous diuretic program on an ambulatory basis, but in whom diuresis promptly takes place when he is hospitalized despite no apparent change in therapy. The explanation for this is not always clear, but doubtless multiple factors are at play. The emotional state of the patient has been shown to exert a very real influence on the excretion of salt and water. A number of studies have demonstrated that feelings of tension or discouragement are associated with a decrease in renal excretion of water and particularly sodium, when compared to relaxed, tranquil periods. 4 • 53 Interestingly enough, in these same subjects, excitement, apprehension and anger appeared to increase sodium excretion. This latter observation has also been reported by others.39 It would appear, therefore, that reassurance on the part of the physician, nurse and social worker may achieve an unexpected salutary effect in the treatment of patients with congestive heart failure. Recumbency, too, favors diuresis in patients with heart failure 60 and in hydropenie subjects. 28 According to Hulet and Smith, this is an osmotic diuresis due primarily to natriuresis. 28 Other mechanical procedures are also helpful. With the advent of potent oral diuretics, thoracentesis and paracentesis have become neglected in the treatment of heart failure. Each not only effects prompt symptomatic improvement, but may reinstitute responsiveness in a previously refractory case of anasarca. The development of dilutional hyponatremia may be prevented by abdominal binding and water restriction following abdominal paracentesis. Although almost a forgotten procedure, Sou they tubes are capable, in some instances, of removing tremendous quantities of edema fluid. In one patient this technique removed 52 pounds of edema fluid in a period of 48 hours, and in a second ease 40 poulHls were removed in three days.3a In the latter instance responsiveness to conventional diuretics was reinstituted following the procedure and the patient is alive and ambulatory eight years later.

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Diuretics

The organic mercurials are probably the most effective diuretic agents available today. Following the intramuscular injection of these compounds, maximum increases in urine flow occur within six hours. While the mechanism of action is not entirely clear, it is thought to be related to the binding of -SH groups of proteins in the terminal portions of the proximal renal tubules. 24 . 62 It is of interest that the administration of dimercaprol (BAL) produces suppression of mercurial-induced diuresis within 10 to 20 minutes of injection. 23 Mercurials produce a greater excretion of sodium and chloride than of water,25 and when given frequently to patients with moderate or advanced congestive failure on rigid salt restriction may produce hypochloremic alkalosis, hypokalemia and mercury unresponsiveness. Hypochloremic alkalosis may be treated or prevented by the administration of acid salts. Ammonium chloride, hydrochloric acid or calcium chloride if given by mouth not only corrects the alkalosis but re-establishes responsiveness to the diuretic. Whether the absolute chloride concentration in the serum or the tissue pH is the important factor governing mercury responsiveness is not known. However, the fact that some patients may be refractory at a chloride level of 105 mEq./L. but responsive at 112 mEq./L. suggests that a "normal" chloride level is not the important factor. The work of Mudge and Hardin would indicate that it is tissue acidosis and not extracellular chloride concentration which establishes responsiveness to mercurial diuretics. 42 Aminophylline has proved to increase the effectiveness of mercurial diuretics, although like the other xanthines it is a relatively weak diuretic when used alone. Its diuretic effect is the result of both an inhibition of tubular reabsorption of sodium 41 and an increase in cardiac output58 and renal blood flow. 46 To obtain optimal effect from aminophylline, it is best given as an intravenous drip of 500 mg. in 200 cc. of dextrose and water, one to one and one-half.hours after the parenteral administration of the mercurial. An alternate procedure is to administer a 500 mg. of aminophylline suppository shortly after the mercurial injection. Acetazolamide (Diamox) is a relatively weak diuretic, having approximately one-third the effect of 2 ml. of intramuscular meralluride (Mercuhydrin).25 It is a particularly useful drug, however, in two clinical situations. As an inhibitor of carbonic anhydrase, acetazolamide interferes with the production of H+ ions derived from the hydration of carbon dioxide in the renal tubule, and sodium is excreted preferentially with bicarbonate ion. In this manner a hyperchloremic acidosis is produced and provides a useful mechanism for the "priming" of mercurial diuretics. When used for this purpose acetazolamide should not be given concurrently but alternately between courses of the mercurial. The drug also may be an effective diuretic in compensated respiratory acidosis,

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i.e., pulmonary emphysema and cor pulmonale, where the glomerular filtered load of bicarbonate is high. Schwartz et a1. 54 have demonstrated that the diuretic response to carbonic anhydrase inhibition is proportional to the quantity of bicarbonate presented to the renal tubule. When acidosis is present, whether due to respiratory or metabolic disease, carbonic anhydrase inhibitors are to be studiously avoided as a further fall in pH, occasionally with acute hyperkalemia, may result. The chlorothiazide compounds are extremely potent oral diuretics which act promptly after ingestion. The maximum diuretic effect is observed two to four hours after administration and slowly wanes in 12 to 18 hours. IS Chlorothiazide does not produce acidosis or alkalosis and, therefore, may be given daily for long periods, although there is a conspicuous renal loss of potassium when dietary sodium is restricted. With higher doses of the drug the electrolyte excretion pattern approaches that of acetazolamide, with an increasing excretion of bicarbonate. 25 As with the mercurials and acetazolamide, potassium supplementation is indicated with chlorothiazide therapy, and may be supplied as potassium salts or dietary items high in potassium, i.e., citrus fruits and juices and bananas. Chlorothiazide and acetazoleamide should be administered cautiously to patients with severe liver disease as acute hepatic insufficiency and coma may follow. There is some evidence to suggest that this is due to potassium depletion and alkalosis, and that if potassium losses are prevented a gratifying diuresis may be achieved safely in these patientsY The most recent of the potent diuretics are the spirolactones, introduced by Kagawa and his colleagues. 29 These compounds have no effect on glomerular filtration rate or renal plasma flow, but produce a sodium and water diuresis with retention of potassium 67 by direct antagonism of the action of aldosterone on the renal tubule. Even the normal subject on salt restriction is unable to conserve sodium when given spirolactones,49 and these drugs have been shown to produce a good diuresis of sodium and water in patientH with nephrosis and cirrhosis and in some individuals with congestive heart failure. 56, 61 Spirolactones may be of particular value when used in conjunction with other diuretic agents,"5 or in the treatment of fluid retention associated with severe hepatic insufficieney or digitalis intoxication, where potassium depletion must be avoided. For more detailed information on the mode of action and clinical use of diuretics, a number of excellent reviews are available. 25 , 45, 46 SUMMARY

The treatment of congestive heart failure is based not only on an accurate structural and etiologic cardiac diagnosis, but an appreciation of certain hydraulic principles and a precise awareness of other systemic

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abnormalities and associated diseases. The failing heart is burdened with an increase in total body and myocardial oxygen requirements by virtue of: (1) an increase in the work of breathing, (2) an increase in myocardial energy needs due to dilatation and hypertrophy, and (;{) an inefficient mechanism for the dissipation of body heat. This demand upon a restricted cardiac output may be furthered by the presence of hypoxia, anemia or any superimposed hypermetabolic state, and forms a basis for effective treatment. All efforts directed towards the control of fever, an increase in the oxygen-carrying capacity of the blood, a prolongation of cardiac diastole, or a reduction in central venous pressure and cardiac output, will relieve dyspnea and the demands upon the failing heart. A reduction in the mean radius of the dilated, failing heart reduces myocardial energy requirements and permits a more efficient conversion of energy consumed to useful work performed by the heart. While this advantage may result from a number of maneuvers which cause a decrease in central venous pressures, digitalis glycosides enable the failing myocardium to achieve greater contractility at any given filling pressure or chamber volume. A decrease in excess energy requirements and an increase in flow capabilities by the heart then serves to restore normal blood flow to kidneys, musele and skin. The use of diuretic agents, either singly or in combination, further aids in the restoration of a more normal circulation. REFERENCES 1. Altschule, M. D.: Physiology in Diseases of the Heart and Lungs. Cambridge,

Mass., Harvard University Press, 1949, p. 228. 2. Altschule, M. D., Zamecheck, N. and Iglauer, A.: The Lung Volume and Its Subdivisions in the Upright and Recumbent Positions in Patients with Congestive Failure. Pulmonary Factors in the Genesis of Orthopnea. J. Clin. Invest. 22: 805, 1943. a. Barcroft, H., Edholm, O. G., McMichael, .T. and Sharpey-Schafer, E. P.: Posthemorrhagie Failure. Study by Cardiac Output and Forearm Flow. Lancet 1: 489,1944. 4. Bames, R. and Schottstaedt, W. W.: Relation of Emotional State to Renal Excretion of Water and Electrolytes in Patients with Congestive Heart Failure. Am. J. Med. 29: 217,1960. 5. Bloomfield, R. A., Rapoport, E., Milnor, J. P., Long, W. K., Mebane, J. G. and Ellis, L. B.: Effects of Cardiac Glycosides upon Dynamics of Circulation in Congestive Heart Failurc; Ouabain. J. Clin. Invest. 27: 588, 1948. 6. Eradley, S. E. and Eradlcy, G. P.: Renal Function During Chronic Anemia in Man. Blood 2: 192, 1947. 7. Eraunwald, E., Bloodwell, R. D., Goldberg, L. 1. and Morrow, A. G.: Studies on Digitalis. IV. Observations in Man of the Effects of Digitalis Preparations on the Contractility of the Non-failing Heart and on Total Vascular Resistance. J. Clin. Invest. 40: 52, 1961. 8. Burch, G. E.: Rate of Water and Heat Loss from the Respiratory Tract of Patients with Congestive Heart Failure Who Were from a Subtropical Climate and Resting in a Comfortable Atmosphere. Am. Heart J. 32: 88, 1946.

The Treatment of Congestive Heart Fa1:lure 9. Calholln, J. A., Cullen, G. E., Harrison, T. R, Wilkins, W. L. and Tims, M. M.: Studies in Congestive Heart Failure. XIV. Orthopnea: Its Relation to Ventilation, Vital Capacity, Oxygen Saturation and Acid-Base Condition of Arterial and Jugular Blood. J. Clin. Invest. 10: 8:33, 1931. 10. Cohn, A. E. and Steele, J. M.: Unexplained Fever in Heart Failure. J. Clin. Invest. 13: 85:3, 1934. 11. Cook, C. D., Mead, J., Sehreiner, G. L., Frank, N. R. and Craig, J. M.: Pulmonary Mechanics During Induced Pulmonary Edema in Anesthetized Dogs. J. Appl. Physiol. 14: 177, 1957. 12. Cotten, M. deV. and Stopp, P. E.: Action of Digitalis on the Non-failing Heart of the Dog. Am. J. Physiol. 192: 114, 1958. 13. lJavis, J. 0., Carpenter, C. C. J., Ayers, C. R., Holman, J. E. and Bahn, R. C.: Evidence for Secretion of an Aldosterone-Stimulating Hormone by the Kiduey. J. Clin. Invest. 40: 684, 1961. 14. lJripps, IL D. and Comroe, J. H. Jr.: Clinical Studies on Morphine. I. Immediate Effect of Morphine Administered Intravenously and Intramuscularly upon the Respiration of Normal Man. Anesthesiology 6: 462, 1945. 15. Eisenberg, S.: Blood Volume in Patients with Acute Glomerulonephritis as Determined by Radioactive Chromium Tagged Red Cells. Am. J. Med. 27: 241, 1959. 16. Etsten, B. E.: Personal communication. 17. Evans, C. A. L. and Matsuoka, Y.: Effect of Various Mechanical Conditions Oil the Gaseous Metabolism and Efficiency of the Mammalian Heart. J. PhysioI. 49: 378, 1915. 18. Ford, R. V., Moyer, J. H. and Spurr, C.: Clinical and Laboratory Observations on Chlorothiazide (Diuril), an Orally Effective Non-mercurial Diuretic. Arch. Int. Med. 100: 582, 1957. HI. Fowler, N. 0.: Effects of Pharmacologic Agents on the Pulmonary Circulation. Am. J. Med. 28: 927, 1960. 20. Gorlin, R: Measurement of Coronary Flow in Health and Disease. In Modern Trends in Cardiology (A. MOI'gau Jones, Ed.). London, Butterworth & Co., 1960, pp. HH-213. 21. Gorlin, Rand Gorlin, S. G.: Hydraulic Formula for Calculation of the Area of the Stenotic Mitral Valve, Other Cardiac Valves, and Central Circulatory Shunts. Am. Heart.f. 41: 1, 1951. 22. Hamilton, W. E. and Morgan, A. B.: Mechanism of Postural Reduction on Capacity in Relation to Orthopnea and Storage of Blood in the Lungs. Am. J. PhysioI. 99: 526, 19a2. 2:{. Handley, C. A. and LaForge, M.: Effects of Thiols on Mercurial Diuresis. Proc. Soc. Expel'. BioI. & Med. 65: 74, 1947. 24. Handley, C. A. and Lavik, P. S.: Inhibition of the Kidney Succinic Dehydrogenase Systpm by Mercurial Diuretics. J. PharmacoI. & Expel'. Therap. 100: 115,1950. 25. Handley, C. A. and Moyer, J. H.: Pharmacology and Clinical Use of Diuretics. Springfield, Ill., Charles C Thomas, 1959. 26. Hill, A. V.: The Heat of Shortening and the Dynamic Constants of Muscle. Proc. Roy. Soc. London, S.B. 126: 136, 1938. 27. Huckabee, W. K and Judson, W. E.: Role of Anaerobic Metabolism in the Performance of Mild Muscular Work. I. Relationship to Oxygen Consumption and Cardiac Output, and the Effect of Congestive Heart Failure. J. Clin. Invest. 37: 1577, 1958. 28. Hulet, W. H. and Smith, H. W.: Postural Natriuresis and Urine Osmotic COllcentration in Hydroppnic Subjects. Am. J. Med. 30: 8, 1961. 2\1. Kagawa, C. M., Cella, .1. A. and Van Arman, C. G.: Action of New Steroids ill Blocking Effpets of Aldosterone and Deoxycorticosterone OIl Salt. Science 126: 1015, 1957. 30. Kountz, W. B., Smith, J. R. and Wright, S. T.: Observations on the Effect of Tourniquets on Acute Cardiac Crises, Normal Subjects and Chronic Heart Failure. Am. Heart J. 23: 621, 1942.

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