- Email: [email protected]
Recent advances in digitalis research
EDITORIALS
Recent Advances in Digitalis Research* DEAN T. MASON, MD, FACC NAJAM
A. .AWAN,
MD,
Davis and Sacramento,
FACC
California
In view of the exciting recent advances in digitialis research that have afforded physicians an improved understanding of the drug’s pharmacology and therapeutic nature, it is particularly relevant that four articles in this issue of the JoumaP4 focus attention on new knowledge germane to judicious application of the glycosides in the management of cardiac dysfunction in different clinical settings. Following the highly productive investigations of the 1960’s elucidating the mechanisms of the beneficial cardiocirculatory effects of digitalis on a physiologic basis,5 the present era of more fundamental understanding was initiated with Butler’s development6 of digitalis-specific antibodies and glycoside radioimmunoassay, which allowed for the first time an accurate and practical means for the clinical measurement of serum digitalis concentrations.7 Subsequently, considerable information has been gained8 about glycoside metabolism, cardiac receptor characteristics, pharmacokinetics,g intestinal absorption, dose-contractility response, lo digitalization, 11drug interactions,i2 toxicity13,14and specific arrhythmic antidotes’5 In addition, recent biochemical and electrophysiologic studie@-‘8 have provided valuable insight concerning the subcell mechanisms of the agent’s contractile and toxic actions. Digitalis in Sick Sinus Syndrome In this issue of the Journal, Reiffel, Bigger and Cramerl report on their investigation of the important clinical consideration of the influence of digitalis on sinus nodal function in patients with sick sinus syndrome. Their findings are in agreement with the previous observations by Vera et al.lg that digoxin does not exert negative chronotropic effects or cause further prolongation of sinus nodal recovery time. Because sinus
From the Section of Cardiovascular Medicine, Departments of Medicine and Physiology, University of California School of Medicine and Sacramento Medical Center, Davis and Sacramento, California. Manuscript received March 9, 1979, accepted March 12, 1979. Address for reprints: Dean T. Mason, MD, Section of Cardiovascular Medicine, Department of Medicine, University of California School of Medicine, Davis, California 95616.
nodal recovery testing lacks sensitivity,20 it is gratifying that our group ig also found in patients with the sick sinus syndrome that digoxin neither altered heart rate on ambulatory electrocardiographic monitoring nor affected maximal exercise heart rate. The new observation of Reiffel et al.’ of digoxin-induced slowing of heart rate and prolongation of sinus nodal recovery time in the sick sinus syndrome after administration of atropine indicates an effect similar to the effect of digitalis in the denervated human transplanted heart.21 Therefore, it appears to us that the post-atropine suppression of sinus nodal function is probably a direct effect of the glycoside rather than an antiadrenergic action,’ particularly when one also considers that masking rather than augmenting the antiadrenergic activity of digitalis would be expected after vagal blockade. In any event, the finding that digitalis adversely affects sinus nodal function in the absence of parasympathetic function1 appears to be limited to the special abnormal condition of sick sinus syndrome and to have limited clinical relevance. It is difficult to appreciate the recommendation1 that patients with particularly severe sinus node disease be given a trial of intravenous digoxin with electrophysiologic evaluation before long-term use of the glycoside is instituted, because no correlation has been notedl,lg between sinus nodal function and deleterious effects of the drug; indeeed those patients with marked sinus nodal depression demonstrated improved sinus nodal function after administration of digitalis.‘,l8 Nevertheless, we entirely agree with the principal clinically important conclusion that digoxin does not exert adverse effects on sinus nodal function in sick sinus syndrome, and that it can be used safely in patients with this syndrome when it is indicated for treatment of cardiac pump dysfunction or for control of tachyarrhythmias. Nitroprusside and Digoxin Combined Therapy in Myocardlal Infarction With Heart Failure Raabe2 in this issue has referred to the previously well documenteds2 salutary effects of intravenous nitroprusside on congestive heart failure complicating acute
’ Editorials published by the Journal reflect the views of the authors and do not necessarily represent the views of the Journal or of the American College of Cardiology.
1058
May 1979
The American Journal of CARDIDLOGY
Volume 43
EDITORIALS
myocardial infarction as shown by considerable alleviation of markedly elevated left ventricular filling pressure and elevation to normal values of decreased cardiac output. In his study,2 the addition of intravenous digoxin resulted in further elevation of the nitroprusside-induced normal cardiac output and further decrease of the nitroprusside-induced normal total systemic vascular resistance without decreasing the moderately increased, but optimal,23 left ventricular filling pressure. The addition of digitalis in these patients was unnecessary and potentially hazardous because the initially abnormal hemodynamic state had been corrected or optimized with use of nitroprusside alone. If the abnormal hemodynamic state was not satisfactorily improved with use of the vasodilator, the next approach would be to increase the infusion rate of nitroprusside to provide normal cardiac output and optimal left ventricular preload while maintaining normal systemic arterial pressure and ensuring that left ventricular filling pressure does not decline below the upper limit of normal. 24In the event a cardiotonic agent is required, intravenous dopamine or dobutamine should be utilized.25 That the moderately elevated left ventricular filling pressure was not diminished by digitalis while the cardiac output increased is highly unusual. Thus the increased left ventricular end-diastolic pressure should have decreased after digoxin for at least two reasons: (1) The greater stroke output afforded by the reduced impedance to left ventricular ejection and enhanced contractility decrease the chamber’s end-diastolic pressure,22 and (2) the sympathetic withdrawal that accompanies an increase in cardiac output in patients with heart failure results in systemic venodilation26 as well as the decrease in systemic vascular resistance that occured in the patients in this study. Parenthetically, we point out that when decreased cardiac output is not increased by digitalis, as may occur in a severely infarcted left ventricle unable to respond to the cardiotonic agent, the cardiac output may decrease further2? because the moderate direct systemic arteriolar constrictor action of digitalis is not overbalanced by greater indirect vasodilation due to sympathetic withdrawal,28 rather than because the drug’s direct effect of systemic arteriolar constriction precedes its direct effect of positive contractilityZ7; the direct vasoconstrictor action occurs simultaneously with the direct positive inotropic action of the glycoside.2g Digitalis is no longer considered an agent of first choice in the treatment of congestive heart failure due to myocardial infarction. 23 A diuretic drug or a longacting nitrate is used initially when left ventricular filling pressure is excessively elevated and cardiac output is norma12”; nitroprusside (with dopamine or dobutamine if necessary) is used initially when left ventricular end-diastolic pressure is excessively increased and cardiac output is substantially decreased.23 Furthermore, the beneficial effects of digitalis are inconsistent in heart failure due to myocardial infarction30; the ischemic myocardium is unresponsive to the drug at levels of hypoxia at which dopamine still fully exerts its direct positive inotropic action,31 and there
is probably increased arrhythmogenesis caused digitalis in the freshly necrotic myocardium.14
by
Digitalis Effects on Myocardial lschemia in Chronic Coronary Disease The crucial effect of digitalis on myocardial oxygen consumption in chronic coronary artery disease is examined in patients with stable angina pectoris by Loeb, Streitmatter, Braunstein, Jacobs, Croke and Gunnar3 in another article in this issue. Left ventricular oxygen demand is predominantly governed by interplay among three hemodynamic-related determinants: (1) intramyocardial tension (afterload [product of systolic blood pressure and chamber radius]), (2) contractile state, and (3) heart rate.8 However, Loeb et al. found that global energetics were unaltered by ouabain in hearts with a normal or a depressed ejection fraction. These findings are unexpected; one would anticipate that the glycoside would increase cardiac energetics in the normal functioning hearts and decrease cardiac energy demand in the abnormally performing hearts.32 In the normal heart the principal action of digitalis on the three determinants of cardiac oxygen requirements is to increase contractility; because the positive inotropic effect of the glycosides elevates myocardial oxygen needs in the normal heart (as is the case in one of the two groups studied by Loeb et al.:<), digitalis should have elevated myocardial energetics.8 In contrast, digitalis reduces overall myocardial oxygen consumption and increases cardiac efficiency in the dysfunctioning heart. Thus, in the enlarged heart with abnormal function, left ventricular wall tension is diminished by the decrease in heart size that accompanies the positive inotropic action of the glycoside. In terms of cardiac oxygen needs, this indirect reduction in wall tension together with the indirect decline in the relatively high heart rate due to sympathetic withdrawal is substantially greater than the direct increase in contractility produced by digita1is.s Therefore, in chronic ischemic heart disease with ventricular dysfunction (as in the other group studied by Loeb et al.:9, digitalis should have exerted an antianginal effect. This improvement by digitalis in myocardial energetics in the dysfunctioning heart is not a fundamental property of the agents; rather, in this condition, it overrides the increased need for oxygen normally associated with the direct positive inotropic action of the glycoside. The inability of Loeb et al.:< to demonstrate these anticipated results of the disparate effects of digitalis on cardiac aerobic metabolism in the two patient groups was probably due to insensitive methodology. Further, that concordant hemodynamic alterations produced by digitalis were not obtained adds to the difficulty in assessing these data concerning myocardial energetics. In addition, their study is lacking in the most critical aspect of myocardial energetics requiring examination in patients with coronary artery disease; their evaluation of only global ischemia fails to permit analysis of the metabolic and mechanical effects of digitalis on the
May 1979
The American Journal of CARDIOLOGY
Volume 43
1057
EDITORIALS
segmental regions of left ventricular teristic of this disease.
ischemia charac-
Digitalis Effects on Abnormal Segmental Mechanics in Coronary Artery Disease The final paper on digitalis in this issue, by Kleiman, Alderman, Goldman, Ingels, Daughters and Stinson,4 explores the effects of intravenous digoxin on regional dyssynergy and left ventricular function in patients with chronic coronary heart disease. Segmental movement and global function were derived by dynamic fluoroscopic analysis of seven mid-wall metallic markers placed at intervals in an attempt to outline the left ventricular silhouette and to establish transverse chamber axes, As judged by this difficult technique, the investigators were unable to demonstrate major beneficial effects of digitalis on regional wall shortening in these patients with minimally abnormal left ventricular performance. In contrast, patients with stable coronary heart disease evaluated at our institution33 with complete left heart catheterization and ventriculography performed before and approximately 1 hour after intravenous administration of ouabain demonstrated considerable enhancement of left ventricular function and improvement in segmental dyssynergy. In additional studies34 on the effects of digitalis on segmental contraction abnormalities, we determined the extent of contractile response in infarcted, ischemic and normal areas in the intact canine heart. Intravenous ouabain, given 15 minutes after a stable state had been achieved after coronary occlusion, produced positive responses in all areas, expressed as percent increases in tension in each of these zones as measured with strain gauge arches (infarcted area 13 percent, ischemic area 25 percent, normal area 27 percent). Thus, the acutely ischemic myocardium responds to digitalis, and the positive inotropic action of the agent decreases with increasing degrees of ischemia. Also relevant in this regard are studies in experimental animals35 showing that raising
myocardial oxygen requirements in the normal heart by stimulating contractility with digitalis increases the extent of left ventricular ischemia and necrosis that follows subsequent coronary occlusion. In contrast, in the presence of ventricular dysfunction and cardiomegaly, treatment with the glycoside before coronary arterial obstruction reduces the size of myocardial ischemia and infarction. Conclusions The fundamental therapeutic action of digitalis is stimulation of ventricular contractile state. The expression of this increased contractility is dependent on the integrity of cardiocirculatory status when the glycoside is administered. Thus, by interplay between direct and indirect cardiac and vascular effects, variable and even opposite changes in cardiac output, peripheral circulatory dynamics and myocardial oxygen consumption can occur. At the subcell level, the positive inotropic property of digitalis appears to result from glycoside-induced enhanced intracell influx of calcium produced by the drug’s action on the cardiac cell membrane. In contrast, transmembrane fluxes of sodium and potassium underlie the electrical properties of the glycosides. Future research should clarify the nature of the digitalis receptor and further define the subcell contractile and toxic mechanisms of the agent, as well as elucidate more completely the modified actions of the glycosides in specific types of cardiac diseases as exemplified by the four studies reported in this issue of the Journal. Lastly, it is of considerable importance to formulate the most judicious medical management for heart failure refractory to conventional therapy with digitalis and diuretic drugs,3e particularly in view of the current interest in systemic vasodilators and innovative new cardiotonics. Acknowledgment We gratefully acknowledge the technical assistance of Raya Drahun.
References 1. Relffel JA, Bigger JT Jr, Cramer M: The effects of digoxin on sinus node function before and after vagai blockade in patients with sinus node dysfunction: a clue to the mechanisms of digitalis-action on the sinus node. Am J Cardiol 43:963-989, 1979 2. Raabe DS Jr: Combined therapy with digoxin and nitroprusside in heart failure complicating acute myccardiil infarction. Am J Cardioi 43:990-994,1979 3. Loeb HS, Streftmatter N, Braunsteln D, Jacobs WR, Creke RP, Gunnar RM: Lack of ouabain effect on oacinc in&M mvocardial ischemia in patients with coronary artery disease. Am 2 Cardioi 43:995-1000, 1979 4. Kleiman JH, Alderman EL, Goldman RH, Ingels NB, Daughters GT II, Stlneen EB: Effects of digitalis on normal and abnormal left ventricular segmental dynamics. Am J Cardiol 43:1001-1008, 1979 5. Mason DT, *arut JF Jr, Zells R: New developments in the understanding of the actions of digitalis giycosides. Prog Cardiovasc Dis 11~443-478, 1969 6. Butler VP Jr: Digoxin: immunologic approaches to measurement and reversal of toxicity. N Engl J Med 263: 1150-l 156, 1970 7. Smlth TW, Haber E: Progress in digitalis. N Engl J Med 269:
1058
May lS79
The Atnerkan
Journal of CARDlDLDGY
1063-1072, 1973 6. Masen DT: Digitalis pharmacology and therapeutics: recent advances. Ann Intern Med 80520-530, 1974 9. Deherty JE, de Soyza N, Kane JJ, Blseett JK, Murphy ML: Clinical pharmacokinetics of digitalis giycosides. Prog Cardiovasc Dis 21:141-158, 1978 10. Lee 0, Zella R, Mason Df: Linear dose-response and quantitative attentuation by potassium on the inotropic action of acetylstrophanthidin. Clin Pharm Ther 22:34-41, 1977 11. Marcus FI, Burkhalter L, Cuccia C, Pavlovlch J, Kapadla 00: Administration of tritiited digoxin with and wfthout a loading dose. Circulation 34:865-874, 1966 12. Leahey EB Jr, Refffel JA, Drualn RE, Helesenhuhel RH, Lovejoy WP, Bigger .D Jr: interact&n between quinidfneand diixin. JAMA 240533-534, 1978 13. Glllls RA: Cardiac sympathetic nerve activity: changes induced by ouabain and propranoiol. Science 166:506-510, 1969 14. Smtth lW. Haher E: Dixin intoxication. The relationship of clinical presentation to serum digoxin concentration. J Clin Invest 49: 2377-2378, 1970 15. Smith TW. Haher E, Yeatman L, Butler VP Jr: Reversal of ad-
Velurne 43
EDITORIALS
18.
17. 18. 19.
20. 21.
22.
23.
24.
25.
26.
vanced digoxin intoxication with fab fragments of digoxin-specific antibodies. N Engl J Med 294:797-800, 1978 Schwartz A, Allen JC, Harlgaya S: Possible involvement of cardiac Na+,K+-adenosine triphosphatase in the mechanism of action of cardiac glycosides. J Pharmacol Exp Ther 168:31-41, 1969 Langer GA: Effects of digitalis on myocardial ionic exchange. Circulation 46180-187, 1972 SmHh TW: Digitalis: Ions, inotropy and toxicity. N Engl J Med 299545546, 1978 Vera 2, Miller RR, YcYlllin 0. Mason OT: Effects of digitalis on sinus nodal function in patients with sick sinus syndrome. Am J Cardiol 41:318-323. 1978 Narula OS, Samet P, Javler RP: Significance of the sinus node recovery time. Circulation 45140-158, 1972 Goodman OJ, Rossen RM, lngham R, Rider AK, Harrlson DC: Sinus node function in the denervated human heart: effects of digitalis. Br Heart J 37:612-618, 1975 Mason OT: Afterload reduction and cardiac performance: physiologic basis of systemic vasodilators as a new approach in treatment of congestive heart failure. Am J Med 65:106-125. 1978 Mason 01, Amsterdam EA, Miller RR, OeMarla AN, Lee G, Foerster JM, Awan NA, Berman OS: Congestive heart failure and cardiogenic shock due to acute myocardial infarction. In. Cardiac Emergencies (Mason DT, ed). Baltimore, Willlams & Wilkins, 1978, p 95-172 Mason OT: Ventricular afterload reduction therapy in management of congestive heart failure. A rational new concept that has rapidly come of age by systemic vasodilator drugs. Clin Cardiol 1:55-59, 1978 Amsterdam EA, Awan NA, DeMaria AN, Mason OT: Va’sodilators in myocardial infarction: rationale and current status. Drugs 16: 506-521, 1978 Mason 01, Braunwald E: Studies on digitalis. X. Effects of ouabain on forearm vascular resistance and venous tone in normal subjects and in patients with heart failure. J Clin Invest 43532-543, 1964
27. Cohn JN, Trlatani FE, Khatrl IM: Cardiac and peripheral vascular effects of digitalis in clinical cardiogenic shock. Am Heart J 78: 318-325, 1969 28. Mason 01, Zells R, Amsterdam EA: Unified concept of the mechanism of action of digitalis: influence of ventricular function and cardiac disease on hemodynamic response to fundamental contractile effect. In, Basic and Clinical Pharmacology of Digitalis (Marks BH, Weissler AM, ed). Springfield, IL, Charles C Thomas, 1972, p 206-229 29. Mason OT, Ross J Jr, Braunwald E: Digitalis and extracardiac effects. In, Digitalis (Fisch C. Surawicz B, ed). New York, Grune & Stratton, 1969, p 78-90 30. Mason OT, Amsterdam EA, Lee G: The digitalis glycosides: clinical pharmacology and therapeutics. In, Congestive Heart Failure (Mason DT, ed). New York, Yorke Medical Books, 1976, p 321342 3 1. Amsterdam EA. Choquet Y, OeMaria A, Vismara L, Massuml R, Zelis R, Mason OT: Digitalis and acute myocardial infarction: effects in isolated hypoxic cardiac muscle and in patients. Proc Fifth Asian-Pacific Congress of Cardiology, Singapore, 1972. p 251254, 1974 32. Covell JW, Braunwald E, Ross J Jr: Studies on digitalis. XVI. Effects on myocardial oxygen consumption. J Clin Invest 45: 1535-1542. 1966 33. Amsterdam EA, OeMarla AN, Miller RR, Awan NA, Mason OT: Enhancement of left ventricular function in chronic ischemic heart disease by digitalis (abstr). Circulation 54: Suppl ll:ll-212. 1976 34. Amsterdam EA, Kamlyama T, Rendig S, Mason OT: Differential regional contractile actions of digitalis in experimental myocardial infarction (abstr). Clin Res 22:256A, 1974 35. Maroko PR, Kjekshus JK, Sobef BE, Watanabe 1, Cove9 JW, Ross J, Braunwald E: Factors influencing infarct size following experimental coronary artery occlusion, Circulation 43:67-82, 1971 36. Mason DT: Symposium perspective on vasodilator and inotropic therapy of heart failure. Am J Med 65:101-125, 1978
May 1973
The American Journal of CARMOLOGY
Volume 43
1059
Recent Advances in Digitalis Research* DEAN T. MASON, MD, FACC NAJAM
A. .AWAN,
MD,
Davis and Sacramento,
FACC
California
In view of the exciting recent advances in digitialis research that have afforded physicians an improved understanding of the drug’s pharmacology and therapeutic nature, it is particularly relevant that four articles in this issue of the JoumaP4 focus attention on new knowledge germane to judicious application of the glycosides in the management of cardiac dysfunction in different clinical settings. Following the highly productive investigations of the 1960’s elucidating the mechanisms of the beneficial cardiocirculatory effects of digitalis on a physiologic basis,5 the present era of more fundamental understanding was initiated with Butler’s development6 of digitalis-specific antibodies and glycoside radioimmunoassay, which allowed for the first time an accurate and practical means for the clinical measurement of serum digitalis concentrations.7 Subsequently, considerable information has been gained8 about glycoside metabolism, cardiac receptor characteristics, pharmacokinetics,g intestinal absorption, dose-contractility response, lo digitalization, 11drug interactions,i2 toxicity13,14and specific arrhythmic antidotes’5 In addition, recent biochemical and electrophysiologic studie@-‘8 have provided valuable insight concerning the subcell mechanisms of the agent’s contractile and toxic actions. Digitalis in Sick Sinus Syndrome In this issue of the Journal, Reiffel, Bigger and Cramerl report on their investigation of the important clinical consideration of the influence of digitalis on sinus nodal function in patients with sick sinus syndrome. Their findings are in agreement with the previous observations by Vera et al.lg that digoxin does not exert negative chronotropic effects or cause further prolongation of sinus nodal recovery time. Because sinus
From the Section of Cardiovascular Medicine, Departments of Medicine and Physiology, University of California School of Medicine and Sacramento Medical Center, Davis and Sacramento, California. Manuscript received March 9, 1979, accepted March 12, 1979. Address for reprints: Dean T. Mason, MD, Section of Cardiovascular Medicine, Department of Medicine, University of California School of Medicine, Davis, California 95616.
nodal recovery testing lacks sensitivity,20 it is gratifying that our group ig also found in patients with the sick sinus syndrome that digoxin neither altered heart rate on ambulatory electrocardiographic monitoring nor affected maximal exercise heart rate. The new observation of Reiffel et al.’ of digoxin-induced slowing of heart rate and prolongation of sinus nodal recovery time in the sick sinus syndrome after administration of atropine indicates an effect similar to the effect of digitalis in the denervated human transplanted heart.21 Therefore, it appears to us that the post-atropine suppression of sinus nodal function is probably a direct effect of the glycoside rather than an antiadrenergic action,’ particularly when one also considers that masking rather than augmenting the antiadrenergic activity of digitalis would be expected after vagal blockade. In any event, the finding that digitalis adversely affects sinus nodal function in the absence of parasympathetic function1 appears to be limited to the special abnormal condition of sick sinus syndrome and to have limited clinical relevance. It is difficult to appreciate the recommendation1 that patients with particularly severe sinus node disease be given a trial of intravenous digoxin with electrophysiologic evaluation before long-term use of the glycoside is instituted, because no correlation has been notedl,lg between sinus nodal function and deleterious effects of the drug; indeeed those patients with marked sinus nodal depression demonstrated improved sinus nodal function after administration of digitalis.‘,l8 Nevertheless, we entirely agree with the principal clinically important conclusion that digoxin does not exert adverse effects on sinus nodal function in sick sinus syndrome, and that it can be used safely in patients with this syndrome when it is indicated for treatment of cardiac pump dysfunction or for control of tachyarrhythmias. Nitroprusside and Digoxin Combined Therapy in Myocardlal Infarction With Heart Failure Raabe2 in this issue has referred to the previously well documenteds2 salutary effects of intravenous nitroprusside on congestive heart failure complicating acute
’ Editorials published by the Journal reflect the views of the authors and do not necessarily represent the views of the Journal or of the American College of Cardiology.
1058
May 1979
The American Journal of CARDIDLOGY
Volume 43
EDITORIALS
myocardial infarction as shown by considerable alleviation of markedly elevated left ventricular filling pressure and elevation to normal values of decreased cardiac output. In his study,2 the addition of intravenous digoxin resulted in further elevation of the nitroprusside-induced normal cardiac output and further decrease of the nitroprusside-induced normal total systemic vascular resistance without decreasing the moderately increased, but optimal,23 left ventricular filling pressure. The addition of digitalis in these patients was unnecessary and potentially hazardous because the initially abnormal hemodynamic state had been corrected or optimized with use of nitroprusside alone. If the abnormal hemodynamic state was not satisfactorily improved with use of the vasodilator, the next approach would be to increase the infusion rate of nitroprusside to provide normal cardiac output and optimal left ventricular preload while maintaining normal systemic arterial pressure and ensuring that left ventricular filling pressure does not decline below the upper limit of normal. 24In the event a cardiotonic agent is required, intravenous dopamine or dobutamine should be utilized.25 That the moderately elevated left ventricular filling pressure was not diminished by digitalis while the cardiac output increased is highly unusual. Thus the increased left ventricular end-diastolic pressure should have decreased after digoxin for at least two reasons: (1) The greater stroke output afforded by the reduced impedance to left ventricular ejection and enhanced contractility decrease the chamber’s end-diastolic pressure,22 and (2) the sympathetic withdrawal that accompanies an increase in cardiac output in patients with heart failure results in systemic venodilation26 as well as the decrease in systemic vascular resistance that occured in the patients in this study. Parenthetically, we point out that when decreased cardiac output is not increased by digitalis, as may occur in a severely infarcted left ventricle unable to respond to the cardiotonic agent, the cardiac output may decrease further2? because the moderate direct systemic arteriolar constrictor action of digitalis is not overbalanced by greater indirect vasodilation due to sympathetic withdrawal,28 rather than because the drug’s direct effect of systemic arteriolar constriction precedes its direct effect of positive contractilityZ7; the direct vasoconstrictor action occurs simultaneously with the direct positive inotropic action of the glycoside.2g Digitalis is no longer considered an agent of first choice in the treatment of congestive heart failure due to myocardial infarction. 23 A diuretic drug or a longacting nitrate is used initially when left ventricular filling pressure is excessively elevated and cardiac output is norma12”; nitroprusside (with dopamine or dobutamine if necessary) is used initially when left ventricular end-diastolic pressure is excessively increased and cardiac output is substantially decreased.23 Furthermore, the beneficial effects of digitalis are inconsistent in heart failure due to myocardial infarction30; the ischemic myocardium is unresponsive to the drug at levels of hypoxia at which dopamine still fully exerts its direct positive inotropic action,31 and there
is probably increased arrhythmogenesis caused digitalis in the freshly necrotic myocardium.14
by
Digitalis Effects on Myocardial lschemia in Chronic Coronary Disease The crucial effect of digitalis on myocardial oxygen consumption in chronic coronary artery disease is examined in patients with stable angina pectoris by Loeb, Streitmatter, Braunstein, Jacobs, Croke and Gunnar3 in another article in this issue. Left ventricular oxygen demand is predominantly governed by interplay among three hemodynamic-related determinants: (1) intramyocardial tension (afterload [product of systolic blood pressure and chamber radius]), (2) contractile state, and (3) heart rate.8 However, Loeb et al. found that global energetics were unaltered by ouabain in hearts with a normal or a depressed ejection fraction. These findings are unexpected; one would anticipate that the glycoside would increase cardiac energetics in the normal functioning hearts and decrease cardiac energy demand in the abnormally performing hearts.32 In the normal heart the principal action of digitalis on the three determinants of cardiac oxygen requirements is to increase contractility; because the positive inotropic effect of the glycosides elevates myocardial oxygen needs in the normal heart (as is the case in one of the two groups studied by Loeb et al.:<), digitalis should have elevated myocardial energetics.8 In contrast, digitalis reduces overall myocardial oxygen consumption and increases cardiac efficiency in the dysfunctioning heart. Thus, in the enlarged heart with abnormal function, left ventricular wall tension is diminished by the decrease in heart size that accompanies the positive inotropic action of the glycoside. In terms of cardiac oxygen needs, this indirect reduction in wall tension together with the indirect decline in the relatively high heart rate due to sympathetic withdrawal is substantially greater than the direct increase in contractility produced by digita1is.s Therefore, in chronic ischemic heart disease with ventricular dysfunction (as in the other group studied by Loeb et al.:9, digitalis should have exerted an antianginal effect. This improvement by digitalis in myocardial energetics in the dysfunctioning heart is not a fundamental property of the agents; rather, in this condition, it overrides the increased need for oxygen normally associated with the direct positive inotropic action of the glycoside. The inability of Loeb et al.:< to demonstrate these anticipated results of the disparate effects of digitalis on cardiac aerobic metabolism in the two patient groups was probably due to insensitive methodology. Further, that concordant hemodynamic alterations produced by digitalis were not obtained adds to the difficulty in assessing these data concerning myocardial energetics. In addition, their study is lacking in the most critical aspect of myocardial energetics requiring examination in patients with coronary artery disease; their evaluation of only global ischemia fails to permit analysis of the metabolic and mechanical effects of digitalis on the
May 1979
The American Journal of CARDIOLOGY
Volume 43
1057
EDITORIALS
segmental regions of left ventricular teristic of this disease.
ischemia charac-
Digitalis Effects on Abnormal Segmental Mechanics in Coronary Artery Disease The final paper on digitalis in this issue, by Kleiman, Alderman, Goldman, Ingels, Daughters and Stinson,4 explores the effects of intravenous digoxin on regional dyssynergy and left ventricular function in patients with chronic coronary heart disease. Segmental movement and global function were derived by dynamic fluoroscopic analysis of seven mid-wall metallic markers placed at intervals in an attempt to outline the left ventricular silhouette and to establish transverse chamber axes, As judged by this difficult technique, the investigators were unable to demonstrate major beneficial effects of digitalis on regional wall shortening in these patients with minimally abnormal left ventricular performance. In contrast, patients with stable coronary heart disease evaluated at our institution33 with complete left heart catheterization and ventriculography performed before and approximately 1 hour after intravenous administration of ouabain demonstrated considerable enhancement of left ventricular function and improvement in segmental dyssynergy. In additional studies34 on the effects of digitalis on segmental contraction abnormalities, we determined the extent of contractile response in infarcted, ischemic and normal areas in the intact canine heart. Intravenous ouabain, given 15 minutes after a stable state had been achieved after coronary occlusion, produced positive responses in all areas, expressed as percent increases in tension in each of these zones as measured with strain gauge arches (infarcted area 13 percent, ischemic area 25 percent, normal area 27 percent). Thus, the acutely ischemic myocardium responds to digitalis, and the positive inotropic action of the agent decreases with increasing degrees of ischemia. Also relevant in this regard are studies in experimental animals35 showing that raising
myocardial oxygen requirements in the normal heart by stimulating contractility with digitalis increases the extent of left ventricular ischemia and necrosis that follows subsequent coronary occlusion. In contrast, in the presence of ventricular dysfunction and cardiomegaly, treatment with the glycoside before coronary arterial obstruction reduces the size of myocardial ischemia and infarction. Conclusions The fundamental therapeutic action of digitalis is stimulation of ventricular contractile state. The expression of this increased contractility is dependent on the integrity of cardiocirculatory status when the glycoside is administered. Thus, by interplay between direct and indirect cardiac and vascular effects, variable and even opposite changes in cardiac output, peripheral circulatory dynamics and myocardial oxygen consumption can occur. At the subcell level, the positive inotropic property of digitalis appears to result from glycoside-induced enhanced intracell influx of calcium produced by the drug’s action on the cardiac cell membrane. In contrast, transmembrane fluxes of sodium and potassium underlie the electrical properties of the glycosides. Future research should clarify the nature of the digitalis receptor and further define the subcell contractile and toxic mechanisms of the agent, as well as elucidate more completely the modified actions of the glycosides in specific types of cardiac diseases as exemplified by the four studies reported in this issue of the Journal. Lastly, it is of considerable importance to formulate the most judicious medical management for heart failure refractory to conventional therapy with digitalis and diuretic drugs,3e particularly in view of the current interest in systemic vasodilators and innovative new cardiotonics. Acknowledgment We gratefully acknowledge the technical assistance of Raya Drahun.
References 1. Relffel JA, Bigger JT Jr, Cramer M: The effects of digoxin on sinus node function before and after vagai blockade in patients with sinus node dysfunction: a clue to the mechanisms of digitalis-action on the sinus node. Am J Cardiol 43:963-989, 1979 2. Raabe DS Jr: Combined therapy with digoxin and nitroprusside in heart failure complicating acute myccardiil infarction. Am J Cardioi 43:990-994,1979 3. Loeb HS, Streftmatter N, Braunsteln D, Jacobs WR, Creke RP, Gunnar RM: Lack of ouabain effect on oacinc in&M mvocardial ischemia in patients with coronary artery disease. Am 2 Cardioi 43:995-1000, 1979 4. Kleiman JH, Alderman EL, Goldman RH, Ingels NB, Daughters GT II, Stlneen EB: Effects of digitalis on normal and abnormal left ventricular segmental dynamics. Am J Cardiol 43:1001-1008, 1979 5. Mason DT, *arut JF Jr, Zells R: New developments in the understanding of the actions of digitalis giycosides. Prog Cardiovasc Dis 11~443-478, 1969 6. Butler VP Jr: Digoxin: immunologic approaches to measurement and reversal of toxicity. N Engl J Med 263: 1150-l 156, 1970 7. Smlth TW, Haber E: Progress in digitalis. N Engl J Med 269:
1058
May lS79
The Atnerkan
Journal of CARDlDLDGY
1063-1072, 1973 6. Masen DT: Digitalis pharmacology and therapeutics: recent advances. Ann Intern Med 80520-530, 1974 9. Deherty JE, de Soyza N, Kane JJ, Blseett JK, Murphy ML: Clinical pharmacokinetics of digitalis giycosides. Prog Cardiovasc Dis 21:141-158, 1978 10. Lee 0, Zella R, Mason Df: Linear dose-response and quantitative attentuation by potassium on the inotropic action of acetylstrophanthidin. Clin Pharm Ther 22:34-41, 1977 11. Marcus FI, Burkhalter L, Cuccia C, Pavlovlch J, Kapadla 00: Administration of tritiited digoxin with and wfthout a loading dose. Circulation 34:865-874, 1966 12. Leahey EB Jr, Refffel JA, Drualn RE, Helesenhuhel RH, Lovejoy WP, Bigger .D Jr: interact&n between quinidfneand diixin. JAMA 240533-534, 1978 13. Glllls RA: Cardiac sympathetic nerve activity: changes induced by ouabain and propranoiol. Science 166:506-510, 1969 14. Smtth lW. Haher E: Dixin intoxication. The relationship of clinical presentation to serum digoxin concentration. J Clin Invest 49: 2377-2378, 1970 15. Smith TW. Haher E, Yeatman L, Butler VP Jr: Reversal of ad-
Velurne 43
EDITORIALS
18.
17. 18. 19.
20. 21.
22.
23.
24.
25.
26.
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27. Cohn JN, Trlatani FE, Khatrl IM: Cardiac and peripheral vascular effects of digitalis in clinical cardiogenic shock. Am Heart J 78: 318-325, 1969 28. Mason 01, Zells R, Amsterdam EA: Unified concept of the mechanism of action of digitalis: influence of ventricular function and cardiac disease on hemodynamic response to fundamental contractile effect. In, Basic and Clinical Pharmacology of Digitalis (Marks BH, Weissler AM, ed). Springfield, IL, Charles C Thomas, 1972, p 206-229 29. Mason OT, Ross J Jr, Braunwald E: Digitalis and extracardiac effects. In, Digitalis (Fisch C. Surawicz B, ed). New York, Grune & Stratton, 1969, p 78-90 30. Mason OT, Amsterdam EA, Lee G: The digitalis glycosides: clinical pharmacology and therapeutics. In, Congestive Heart Failure (Mason DT, ed). New York, Yorke Medical Books, 1976, p 321342 3 1. Amsterdam EA. Choquet Y, OeMaria A, Vismara L, Massuml R, Zelis R, Mason OT: Digitalis and acute myocardial infarction: effects in isolated hypoxic cardiac muscle and in patients. Proc Fifth Asian-Pacific Congress of Cardiology, Singapore, 1972. p 251254, 1974 32. Covell JW, Braunwald E, Ross J Jr: Studies on digitalis. XVI. Effects on myocardial oxygen consumption. J Clin Invest 45: 1535-1542. 1966 33. Amsterdam EA, OeMarla AN, Miller RR, Awan NA, Mason OT: Enhancement of left ventricular function in chronic ischemic heart disease by digitalis (abstr). Circulation 54: Suppl ll:ll-212. 1976 34. Amsterdam EA, Kamlyama T, Rendig S, Mason OT: Differential regional contractile actions of digitalis in experimental myocardial infarction (abstr). Clin Res 22:256A, 1974 35. Maroko PR, Kjekshus JK, Sobef BE, Watanabe 1, Cove9 JW, Ross J, Braunwald E: Factors influencing infarct size following experimental coronary artery occlusion, Circulation 43:67-82, 1971 36. Mason DT: Symposium perspective on vasodilator and inotropic therapy of heart failure. Am J Med 65:101-125, 1978
May 1973
The American Journal of CARMOLOGY
Volume 43
1059