Myocardial Na,K-ATPase: the molecular basis for the hemodynamic effect of digoxin therapy in congestive heart failure

Congestive heart failure may be deemed the epidemic of cardiology in the 21st century in the industrialized part of the world. Although new therapies improving morbidity and mortality from chronic heart failure have emerged it is likely that there is a growing role for digoxin. Thus, digoxin treatment is known to control symptoms of congestive heart failure when added to standard therapy. In this setting, we review the prevailing knowledge of the Na,K-ATPase, the cellular receptor for the inotropic action of digitalis glycosides, in relation to the hemodynamic effect of digoxin. It is concluded that if improvement of hemodynamics is needed in congestive heart failure, this knowledge should be taken into account and in many cases digoxin should be added to standard therapy. Digoxin is still the only safe inotropic drug for oral use that improves hemodynamics. Digoxin should be used to heart failure patients in sinus rhythm when they after institution of mortality reducing treatment still have heart failure symptoms, and to patients intolerant to heart failure mortality reducing drugs. Digoxin should probably in heart failure patients with sinus rhythm be given in the lowest possible dose that relieves symptoms sufficiently.     

Value of Digoxin in Heart Failure and Sinus Rhythm: New Features of an Old Drug?

Digoxin has been a controversial drug since its introduction >200 years ago. Although its efficacy in patients with heart failure and atrial fibrillation is clear, its value in patients with heart failure and sinus rhythm has often been questioned. In the 1980s, reports of some large-scale trials indicated that digoxin, with or without vasodilators or angiotensin-converting enzyme inhibitors, reduced signs and symptoms of congestive heart failure and improved exercise tolerance. This beneficial influence was mainly found in patients with more advanced heart failure and dilated ventricles, whereas the effect in those with mild disease appeared to be less pronounced. In the last few years, new data have shown that digoxin may also have clinical value in mild heart failure, either when used in combination with other drugs or when administered alone. As neurohumoral activation has increasingly been recognized to be a contributing factor in the disease progression of chronic heart failure, the modulating effects of digoxin on neurohumoral and autonomic status have received more attention. Also, there is evidence that relatively low doses of digoxin may be at least as effective as higher doses and have a lower incidence of side effects. Further, the recognition that the use of digoxin too early after myocardial infarction may be harmful and the development of other drugs, in particular angiotensin-converting enzyme inhibitors, have obviously changed the place of digoxin in the treatment of chronic heart failure. The large-scale survival trial by the Digitalis Investigators Group (DIG), whose preliminary results have recently been presented, has shown that although digoxin has a neutral effect on total mortality during long-term treatment, it reduces the number of hospital admissions and deaths due to worsening heart failure. The potentially new features of the old drug digoxin are discussed in this review.     

A perspective on re‐evaluating digoxin's role in the current management of patients with chronic systolic heart failure: targeting serum concentration to reduce hospitalization and improve safety profile

Digoxin improves exercise tolerance and reduces hospitalizations in patients with systolic heart failure, but its use has declined progressively for the past two decades. The Digitalis Investigation Group trial showed that digoxin reduced hospitalizations but had a neutral effect on total mortality. There was evidence that mortality caused by worsening heart failure was less, but there was also a signal suggesting an increase in other cardiac (presumed arrhythmic) death. Use of digoxin has declined substantially and recent guideline recommendations have significantly de‐emphasized the importance of this drug in the management of heart failure. Two developments suggest that re‐evaluation of the contemporary role of digoxin in the management of heart failure with reduced ejection fraction is warranted. First, heart failure remains progressive, characterized by chronic debility, exercise intolerance, and frequent and costly hospitalizations, despite evidence‐based drug and device therapies that prolong survival. Health economics have made reducing hospitalizations in patients with heart failure a major priority. Second, a strong association has emerged between serum concentration and the safety and efficacy of digoxin, which indicates a change in our approach to dosing this agent is needed. Experimental and clinical results suggest that optimizing therapeutic benefit and avoiding harm means dosing to achieve low serum digoxin concentrations (0.5–0.9 ng/mL). Digoxin is an inexpensive agent and the totality of evidence indicates that it reduces hospitalizations and improves symptoms safely when dosed to achieve low serum concentrations. These findings suggest digoxin should have a more prominent therapeutic role in patients with heart failure and reduced ejection fraction.     

The place of cardiac glycosides in the treatment of chronic heart failure. Part II. Results of small studies

In a series of papers the authors analyze literature data on the use of cardiac glycosides for long term treatment of chronic heart failure. Part II is devoted to analysis of results of small controlled studies of pharmacological effects of low dose digoxin in patients with sinus rhythm. Low dose digoxin improves exercise tolerance and lowers risk of decompensation of heart failure but produces no substantial effect on contractility of left ventricular myocardium. Therefore its favorable action on clinical course and outcomes of chronic heart failure is most probably related to modulation of neuro-humoral systems. Retrospective analysis of some trials shows that digoxin is able to increase mortality of survivors of acute myocardial infarction. Hence great care is required when digoxin is used for long term treatment of chronic heart failure due to systolic left ventricular dysfunction after myocardial infarction.     

Digoxin prescribing for heart failure in elderly residents of long-term care facilities

BACKGROUND: Digoxin is often used in long-term care (LTC) residents with heart failure despite a high risk of toxicity associated with increased age, comorbidities and polypharmacy. This toxicity may occur at serum digoxin concentrations that are as low as 1.54 nmol/L. OBJECTIVES: To determine the prevalence of digoxin use, estimate the proportion at risk of toxicity and identify correlates of digoxin use in LTC residents with heart failure. METHODS: Cross-sectional survey in eight LTC facilities that lodge a total of 1223 residents. RESULTS: The prevalence of heart failure was 20%. Digoxin was prescribed for 32% of residents with heart failure and was associated with arrhythmia (primarily atrial fibrillation), anticoagulant and diuretic use, and higher serum thyroid-stimulating hormone. Digoxin doses higher than those that achieve the recommended therapeutic peak body stores of 6 microg/kg and 10 microg/kg were prescribed to 80% and 33% of residents with heart failure, respectively. Serum digoxin concentrations were greater than 1.5 nmol/L in 30% of patients. Comorbidities and concurrently prescribed medications that increase the risk of digoxin toxicity were prescribed to 26% of the patients. CONCLUSIONS: Approximately one-third of LTC residents with heart failure received digoxin. Atrial fibrillation was the most important determinant of use. At least 26% of these residents were exposed to an increased risk of digoxin toxicity. Studies are required to determine safe and effective digoxin dosing regimens for frail elderly heart failure patients. Clinicians should exercise caution when using digoxin in LTC residents.     

The role of digitalis in the treatment of heart failure.

Over the past 200 years, digoxin has been commonly used to treat patients with congestive heart failure. Clinical trials have demonstrated the benefits of the use of digoxin on exercise tolerance, ejection fraction, and neurohormone production. The Digoxin Investigators Group trial has recently provided strong evidence for the long-term benefits of digoxin on morbidity for patients with heart failure. This article will review the evidence of the benefits of digoxin and its current role in the treatment of patients with congestive heart failure.     

The place of cardiac glycosides in the treatment of chronic heart failure

In a series of papers the authors analyze literature data on the use of cardiac glycosides for long term treatment of chronic heart failure. Part 1 is devoted to clinical pharmacology of glycosides with special emphasis on digoxin. In low doses digoxin produces no substantial effect on contractility of left ventricular myocardium but can cause worsening of its diastolic function. Favorable action of digoxin on clinical course and outcomes of chronic heart failure is most probably related to modulation of neuro-humoral systems. Data on factors influencing sensitivity to glycosides in various categories of patients with heart failure, their interaction with other drugs, and contraindications for digoxin are also presented.     

Digoxin use and digoxin toxicity in the post-DIG trial era

BackgroundThe advent of medical therapies for congestive heart failure that have proven survival benefits, specifically angiotensin-converting enzyme (ACE) inhibitors, β-adrenergic antagonists, and the aldosterone antagonists, have called into question the use of digoxin for patients with normal sinus rhythm, left ventricular dysfunction, and symptomatic heart failure. This issue appears to have been heightened after the publication of the results of the Digitalis Investigation Group (DIG) Trial in 1997 that did not demonstrate a statistically significant impact of digoxin on mortality.Methods and ResultsWe used data from a large heart failure registry to examine digoxin use at the time of hospital admission for heart failure, a surveillance system for recording toxic drug exposures to describe patterns in digoxin toxicity and industry estimates for the use of digoxin antibody. Digoxin use has decreased significantly from 31.4% in late 2001 to 23.5% in late 2004 (P < .00001) independent of patient age, gender, or baseline creatinine. Conversely, the number of toxic or potentially toxic exposures to digoxin requiring hospitalization has not decreased.ConclusionDigoxin use is decreasing but there has not been a similar decline in cases of toxicity. Further analyses are required to delineate the reasons underlying these trends and the appropriateness of prescribing practices for both digoxin and its antidote.     

Digoxin: A systematic review in atrial fibrillation,congestive heart failure and post myocardial infarction

AIM: To review digoxin use in systolic congestive heart failure, atrial fibrillation, and after myocardial infarction.METHODS: A comprehensive PubMed search was performed using the key words “digoxin and congestive heart failure”, “digoxin and atrial fibrillation”, “digoxin, atrial fibrillation and systolic congestive heart failure”, and “digoxin and myocardial infarction”. Only articles written in English were included in this study. We retained studies originating from randomized controlled trials, registries and included at least 500 patients. The studies included patients with atrial fibrillation or heart failure or myocardial infarction and had a significant proportion of patients (at least 5%) on digoxin. A table reviewing the different hazard ratios was developed based on the articles selected. Our primary endpoint was the overall mortality in the patients on digoxin vs those without digoxin, among patients with atrial fibrillation and also among patients with atrial fibrillation and systolic heart failure. We reviewed the most recent international guidelines to discuss current recommendations.RESULTS: A total of 18 studies were found that evaluated digoxin and overall mortality in different clinical settings including systolic congestive heart failure and normal sinus rhythm (n = 5), atrial fibrillation with and without systolic congestive heart failure (n = 9), and myocardial infarction (n = 4). Overall, patients with systolic congestive heart failure with normal sinus rhythm, digoxin appears to have a neutral effect on mortality especially if close digoxin level monitoring is employed. However, most of the observational studies evaluating digoxin use in atrial fibrillation without systolic congestive heart failure showed an increase in overall mortality when taking digoxin. In the studies evaluated in this systematic review, the data among patients with atrial fibrillation and systolic congestive heart failure, as well as post myocardial infarction were more controversial. The extent to which discrepancies among studies are based on statistical methods is currently unclear, as these studies’ findings are generated by retrospective analyses that employed different techniques to address confounding.CONCLUSION: Based on the potential risks and benefits, as well as the presence of alternative drugs, there is a limited role for digoxin in the management of patients with normal sinus rhythm and congestive heart failure. Based on the retrospective studies reviewed there is a growing volume of data showing increased mortality in those with only atrial fibrillation. The proper role of digoxin is, however, less certain in other subgroups of patients, such as those with both atrial fibrillation and systolic congestive heart failure or after a myocardial infarction. Further studies may provide helpful information for such subgroups of patients.     

Is There Still a Role for Digoxin in the Management of Atrial Fibrillation?

Purpose of Review

A number of recent observational analyses have assessed clinical outcomes associated with digoxin use in patients with atrial fibrillation. In this review, we review these data and provide suggestions on the contemporary use of digoxin in patients with atrial fibrillation as supported by the recent evidence.

Recent Findings

Observational data from clinical trials and registries have provided variable results on the safety and efficacy of chronic digoxin use in patients with atrial fibrillation. In general, results have been consistent with an associated increase in adverse clinical outcomes with digoxin use in atrial fibrillation patients without heart failure. In atrial fibrillation patients with heart failure, while the weight of evidence suggested an associated risk with digoxin therapy, the results are inconsistent.

Summary

In patients with atrial fibrillation without heart failure, digoxin should generally be avoided. In atrial fibrillation patients with heart failure, digoxin should generally be reserved for patients that do not achieve adequate rate control or are not tolerant of other rate control therapies.

     

Treatment of the african-american patient with congestive heart failure

Opinion statement African Americans have a higher burden of cardiovascular disease than white Americans, including a higher prevalence of heart failure. In addition, heart failure in African Americans conforms to a more malignant natural history. Hypertension is most often cited as the sole etiology of heart failure in African Americans. Most of the major trials of pharmacotherapy for the management of chronic heart failure have failed to include significant numbers of African-American patients. Based on the available evidence, there is no reason to withhold standard evidence-based medical therapy for heart failure. Even though there is much controversy as to the efficacy of angiotensin-converting enzyme (ACE) inhibitors and β blockers in African Americans, in the absence of definitive data they should be used. Recently, the combination of isosorbide dinitrate and hydralazine has been demonstrated to improve survival in African Americans with New York Heart Association class III and IV heart failure, and represents an adjunctive treatment option when added to standard medical therapy consisting of ACE inhibitors, β blockers, digoxin, diuretics, and aldosterone antagonists. Emerging evidence suggests that this therapy may be targeting a novel mechanism of heart failure progression (ie, nitric oxide bioavailability) found in African Americans.     

Superiority of “triple” drug therapy in heart failure: insights from the PROVED and RADIANCE trials

Objectives. We sought to study the efficacy of “triple” therapy with digoxin, diuretic and angiotensin-converting enzyme inhibitor (ACEI) compared to other combinations of these drugs in patients with symptomatic left ventricular systolic dysfunction.Background. Controversy continues concerning the role of combining digoxin with diuretic and ACEI in the initial management of patients with heart failure.Methods. The study utilized data from two studies of digoxin efficacy: Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED) and Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE). Worsening heart failure defined as augmentation of heart failure therapy or an emergency room visit or hospitalization for increased heart failure was the main outcome measure.Results. A total of 266 patients comprising the four treatment groups of the combined PROVED (diuretic alone or digoxin and diuretic) and RADIANCE (ACEI and diuretic, or digoxin, diuretic and ACEI) trials were analyzed. Worsening heart failure occurred in only 4 of the 85 patients who continued digoxin, diuretic and ACEI therapy (4.7%) compared to 18 of the 42 patients (19%) on digoxin and diuretic therapy (p = 0.009), to 23 of the 93 patients (25%) on ACEI and diuretic therapy (p = 0.001) and to 18 of the 46 patients (39%) on diuretic alone (p < 0.001). Life table and multivariate analysis also demonstrated that worsening heart failure was least likely in patients treated with triple therapy (p < 0.01 vs. all other groups).Conclusion. Pending definitive, prospective clinical trials, our results argue for triple therapy as the initial management of patients with symptomatic heart failure due to systolic dysfunction.     

Digoxin Therapy in Chronic Heart Failure

Digitalis has been used for more than 250 years, but its role in the treatment of chronic heart failure has been intensively investigated only during the past two decades. Digoxin increases cardiac output both at rest and during exercise, alone or in combination with ACE inhibitors, and these hemodynamic effects are sustained during chronic therapy. A daily dose of digoxin that achieves a serum concentration of approximately 1.2 ng/ml is associated with a significant improvement in central hemodynamics, particularly in patients with impaired cardiac function despite pretreatment with diuretics and ACE inhibitors. Acute administration of digoxin in patients with chronic heart failure has an immediate sympathoinhibitory effect, and chronic therapy is associated with a sustained decrease in serum norepinephrine concentration. Discontinuation of digoxin in patients with chronic heart failure resulted in hemodynamic deterioration, which was reversed when the drug was readministered. Randomized withdrawal of digoxin in patients receiving only diuretics (PROVED study), or its withdrawal in patients receiving diuretics and ACE inhibitors (RADIANCE study), was associated with worsening of the clinical evidence of heart failure and a decrease in left ventricular systolic function in both studies. In the only large-scale, placebo-controlled mortality study reported thus for (DIG Trial), 7788 patients received standard drug treatment for chronic heart failure in addition to either digoxin or placebo. Digoxin had no impact on survival over the 37 months of follow-up, but the incidence of hospitalizations due to worsening heart failure was significantly reduced in patients receiving the drug compared with those receiving placebo.     

Angiotensin type-1 receptor blockers in heart failure

Chronic heart failure is a common condition with a poor prognosis, usually associated with poor exercise tolerance and debilitating symptoms despite optimal modern therapy. Standard therapy includes diuretics, digoxin, angiotensin-converting enzyme inhibitors (ACEIs) and beta-blockers. Despite this, many patients remain symptomatic, and interest is high as to whether the angiotensin receptor blockers (ARBs) would offer further advantage to a patient already receiving quadruple therapy. In addition, some patients are intolerant of ACEIs, and for this group the ARBs seem a logical choice. This article reviews the evidence for the use of ARBs as a class in heart failure concentrating on clinical recommendations and clinical needs and evidence rather than purely on statistical issues of significance in trials. The trials to date have demonstrated clearly similar hemodynamic effects to those seen with ACEIs and variety of ancillary benefits such as improvements in endothelial function, anti-thrombotic effects, and effects on neurohormonal inhibition. There is consistent evidence of a preservation of exercise tolerance when patients with heart failure are crossed over from stable ACEI therapy, and when added to ACEIs exercise tolerance appears to increase with ARBs. In terms of major outcomes, the two largest trials, Elite-II and Val-Heft, demonstrate that angiotensin receptor blockers probably have a clinical role in improving mortality and morbidity as an alternative to ACEIs in those patients unable to tolerate these agents, which remain, however, the first choice in unselected patients with heart failure. There is a worrying suggestion of a negative interaction when ARBs are added to beta-blockers, which is a reason for caution in using the ARBs, not a reason not to use beta-blockers.     

Digoxin use and heart failure outcomes: results from the Valsartan Heart Failure Trial (Val-HeFT)

Several retrospective studies have raised concerns regarding digoxin therapy in select subgroups of heart failure patients. To assess the impact of digoxin therapy on outcomes in the current era of heart failure therapy, the authors analyzed data representing 5010 patients enrolled in the Valsartan Heart Failure Trial (Val-HeFT) to examine the relationship of baseline digoxin use and all-cause mortality, first morbid event, and heart failure hospitalizations. At baseline, 3374 patients (67%) were receiving digoxin therapy and 1636 (33%) were not. Patients receiving digoxin had features of worse heart failure with higher New York Heart Association class and lower blood pressure, ejection fraction, and β-blocker use (32.1% vs 40.8%). Digoxin use was associated with worse mortality (21.1 vs 15.0%, P<.001), first morbid event (34.6 vs 21.7, P<.001), and HF hospitalization rate (19.1 vs 10.1%, P<.001). After adjustment for baseline group differences including medical therapy and baseline rhythm, patients receiving digoxin remained at a higher risk for all-cause mortality (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.05-1.57), first morbid event (HR, 1.35; 95% CI, 1.15-1.59), and heart failure hospitalization (HR, 1.41; 95% CI, 1.12-1.78). These results remained materially unchanged with propensity matched analysis. No benefit with digoxin use was observed in this study, underscoring the need to reassess the role of digoxin in the contemporary management of heart failure.     

Inappropriate use of digoxin in older hospitalized heart failure patients

BACKGROUND: Older adults are more likely to suffer from the adverse effects of digoxin. Studies have described the inappropriate use of digoxin in various populations. The objective of this study was to determine the correlates of inappropriate digoxin use in older heart failure patients. METHODS: We studied older hospitalized heart failure patients with documented left ventricular (LV) function evaluation and electrocardiography. Digoxin use was considered inappropriate if patients had preserved LV systolic function (ejection fraction greater > or =40%) or if they had no atrial fibrillation (AF). We compared baseline patient characteristics by indication for digoxin and tested statistical significance using Pearson's chi-square analysis and Student's t tests. Using logistic regression, we determined the correlates of inappropriate use and initiation of digoxin. RESULTS: Subjects (N = 603) had a mean age of 79 (+/-7) years; 59% were women, and 18% were African American. A total of 376 patients (62%) were discharged on digoxin, and 223 (37%) had no indication for its use. Half of the patients without an indication for digoxin received the drug. Of 132 patients without an indication and not already on digoxin, 38 (29%) were initiated on it. After adjustment for various patient and care characteristics, prior digoxin use (adjusted odds ratio [OR] 11.47, 95% confidence interval [CI] 5.72-23.02) and pulse > or =100/min (adjusted OR 2.33, 95% CI 1.10-4.94) were associated with inappropriate digoxin use. Pulse > or =100/min was also associated with inappropriate initiation of the drug (adjusted OR 2.95, 95% CI 1.28-6.78). CONCLUSIONS: Inappropriate use of digoxin was common and was associated with prior use. Tachycardia was associated with inappropriate use and initiation. Electrocardiography and echocardiography should be performed in all older heart failure patients. Digoxin therapy should not be initiated or continued in patients without any evidence of LV systolic dysfunction or chronic AF.     

Does digoxin have a place in the treatment of the child with congenital heart disease?

Summary The place of digoxin in the pediatric cardiologist's armamentarium remains uncertain. As an antiarrhythmic, its use in the Wolff-Parkinson-White syndrome is obsolete, but it remains useful in the treatment of the chronic atrial fibrillation seen in some patients postoperatively and in children with dilated cardiomyopathy. The efficacy of digoxin in heart failure is unproven. There is some evidence of improvement in non invasive left ventricular contractile indices in neonates and infants, but it is unclear whether this is associated with sustained clinical improvement. There is even less evidence of its effectiveness in the older child. Whilst the measurement of any effect will undoubtedly be difficult, the time has come for double-blind, placebo-controlled trials in selected groups of patients. These should be designed not only to test the notion that digoxin does not improve ventricular function, but also to embrace the possibility that its administration may result in clinical improvement over and above that following diuretics alone. An absence of proof of efficacy must be distinguished from no efficacy—more data are needed.JSC is supported by the Hyman Marks Pediatric Research Fund.     

Digitalis: is it useful in congestive heart failure in patients in normal sinus rhythm?

The value of digoxin in the patient in normal sinus rhythm with chronic congestive heart failure continues to be controversial. Although many patients taking digoxin have no clinical deterioration after its discontinuance, there is a subgroup of patients (up to 30% of the total group) who demonstrate clinical deterioration on digoxin withdrawal. Patients with an S3 gallop and an enlarged left ventricle are especially likely to benefit from digoxin therapy. Furthermore, there is good evidence in patients with congestive heart failure that there is a persistent, chronic, positive inotropic effect with digoxin. Since digitalis is the only presently available, chronic, oral positive inotropic drug capable of increasing stroke volume at any given filling pressure, it should be used in patients with congestive heart failure.     

Atrial fibrillation in patients with heart failure: pharmacologic options

Atrial fibrillation is a common arrhythmia in patients with heart failure. The presence of atrial fibrillation deteriorates cardiac function and increases the risk of thromboembolic events. The management of patients with atrial fibrillation in association with heart failure should consist of ventricular rate control, prevention of thromboembolic events, and conversion to normal sinus rhythm. Traditionally, digoxin has been widely used in patients with heart failure and atrial fibrillation; however, it does very little to restore sinus rhythm and requires the addition of another rate-limiting agent to control ventricular rate. The likelihood of successful cardioversion is dependent on the duration of heart failure and the degree of neurohormonal activation. The initiation of antiarrhythmic drug therapy in patients with heart failure should be guided by safety issues as well as consideration of potential benefits vs. risks associated with therapy. Amiodarone has been evaluated in numerous clinical trials and appears to be safe and effective when used in low dosage. Treatment with dofetilide is another option. Comparative studies with oral dofetilide vs. amiodarone are needed to evaluate their efficacy in restoration and maintenance of sinus rhythm in patients with heart failure. Such trials will clearly define the role of dofetilide in the treatment of atrial fibrillation. Routine prophylactic use of antiarrhythmic drug therapy for chronic atrial fibrillation in the setting of heart failure is not recommended due to a low efficacy rate and high proarrhythmic risk. Anticoagulation with warfarin and rate control remain the standard therapy. (c)2001 by CHF, Inc.     

Effect of digoxin on contractility and symptoms in infants with a large ventricular septal defect

The effect of digoxin on contractility and symptoms in infants with a large ventricular septal defect (VSD) is controversial. Nineteen infants with symptoms of congestive heart failure due to a VSD were studied with load-independent indexes during 4 study periods: (1) before any medication; (2) while on chronic diuretics; (3) while on both diuretics and digoxin; and (4) while on diuretics alone, to determine if digoxin: (a) increases "contractility" when added to diuretic therapy; and (b) improves symptoms. Symptoms, signs (heart and respiratory rates, and weight gain), shortening fraction, preload (left ventricular end-diastolic dimension), afterload (left ventricular end-systolic wall stress) and contractility were measured at each period. The difference between the measured and predicted velocities of circumferential fiber shortening for the measured left ventricular end-systolic wall stress served as an index of contractility. Eighteen infants also underwent catheterization. Mean pulmonary-to-systemic blood flow ratio was 3:1. When digoxin was added to diuretics, contractility index was significantly greater than in control subjects (0.13 +/- 0.15 vs 0.0 +/- 0.12 circ/s, p = 0.04). When patients were again on diuretics alone (after discontinuation of digoxin), contractility index was no longer different. Symptoms and signs were not significantly improved by either diuretics or digoxin. It is concluded that in infants with a large left-to-right VSD shunt and receiving digoxin and diuretics, contractility index was significantly greater than in control subjects. However, neither diuretics alone nor in combination with digoxin improved symptoms significantly.