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.:
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.:
