Digitalis In Patients Research Articles

A New Method to Estimate Inhibition Percentage of Endogenous Digitalis in Patients with Pre-eclampsia.

Pre-eclampsia is an idiopathic pregnancy disorder characterized by appearance proteinuria and hypertension, with poorly understood etiology. It has been linked to a variety of system abnormalities, including ion transport disorders in neonatal, maternal, and placental cell lines. A new method was described to evaluate the inhibition percentage of endogenous digitalis in plasma of pre-eclampsia patients compared with normal pregnancies, with the estimation of sensitivity and specificity of the proposed test. This was a case-control study consisting of 130 cases that were divided into three groups, 55 normal pregnancies (positive control), 30 non-pregnant women (negative control), and 45 pre-eclampsia (patients). The new method included the estimation of the percentage inhibition of endogenous digitalis by measuring specific enzyme activity of Na-K ATPase for the patient and positive control. The results were analyzed using the statistical package for social sciences (SPSS®) software version 26.0. A p-value of≤ 0.05 was considered significant. In the pre-eclampsia patient, the specific activity of Na-K ATPase was significantly lower with mean= 0.239 mg/g±0.043 compared to the control group which was 0.397 mg/g±0.021, p< 0.001. While the result of inhibition percentage of endogenous digitalis showed significantly higher in the pre-eclampsia patient (mean= 35.852 mg/g %±2.692%) compared to the control group (mean= 17.964%±1.784), with a p< 0.001. Pre-eclampsia is linked with lower erythrocyte sodium pump activity significantly in pre-eclampsia patients than in normal pregnancies. Also, results show the inhibited percentage of endogenous digitalis elevation in patients with pre-eclampsia compared with normal pregnancy.

A Review on: Digitalis Purpurea

Digitalis contain cardiac glycosides and used in the treatment of congestive heart failure. Digitalis drug obtain from Digitalis Purpurea L. belongs to family scrophulariaceae. 200 years ago William Withering discover the use of digitalis in CHF treatment in 1785.In 18th century a controversy has existed about the benefits and risks of digitalis in patients with heart problems. Active component of digitalis classified as cardiac glycosides and cardiotonic steroids. The term "digitalis" or "cardiac glycosides" are used to refer to any of steroids or steroid glycosides compound which exert characteristic positively inotropic and electrophysiological effect on heart. In 20th century digitalis and its derivatives specially, digoxin is used in treatment of CHF. Cardiac glycosides are used in therapy of CHF since William Withering identify their uses. Digitalis purpurea is not only use in treatment of CHF also has wound healing, antioxidant and cytotoxic activity. In 1990 most prescribed drug is digoxin. It shows intermediate duration of action. Digoxin is use for its rate control in atrial fibrillation in the presence of marginal blood pressure. The introduction of diuretic provide an alternative more effective and safer for treatment of CHF.&#x0D; Keywords: CHF., Digitalis Purpurea L

Estimation of Na\K - ATPase Enzyme Activity and Endogenous Digitalis in Patients with Diabetic Neuropathy

Background: Among the most common complications of diabetes is diabetic neuropathy (DN). Diabetic neuropathy is a heterogeneous group of disorders, which involves a different part of somatic and autonomic nervous systems, with a gradual loss of neural conductivity. Some studies have shown that they reduce the activity of the Na/K ATPase, however, elevated levels of endogenous sodium pump inhibitor in diabetic individuals, including those with neuropathy. Changes in this transfer enzyme are believed to be due to several diabetes complications. Objective: The study had designed to evaluate the Na/K ATPase enzymatic activity in the erythrocyte-membrane among three groups. The first group had represented the patients with type 2 diabetes mellitus (DM2) and neuropathy. The second group is diabetics without neuropathy. The third group was a healthy subject. As well, the study had estimated the inhibitory activity of endogenous digitalis among patient groups. Furthermore, the aim of this research was to see whether there was a connection between red blood cell membrane Na-K ATPase activity and the medical facts of the analysis subjects. Design and Methods: One-hundred fifty subjects had enrolled in this case-control study; 80 patients complained of diabetic neuropathy of both sexes, the mean age 59.3 years with an age range of 40-81, 40 DM2 without neuropathy (53.9 years), (35 – 70), and 30 healthy controls (30 years, 25 to 45). Patients in the first group were selected carefully according to their clinical manifestations and the nerve conduction study results. The evaluations of both inhibitory activities of endogenous digitalis and Na/K ATPase had completed using a spectrophotometer. Enzyme activity had expressed in micrograms of phosphate concentration per grams of red cell ghost total protein concentration. Results: The mean enzyme activity of Na/K ATPase was significantly lower (p&lt;0.001) in patients with diabetic neuropathy (381±17.9) compared with the diabetic group without neuropathy (498±22.9) and the normal controls (837±61.43). There was a significant inhibitory activity of endogenous digitals (17.87±2.15) in patients with DNP, compared with the diabetics without neuropathy (8.78±0.89) and healthy control (5.3±1.33). There was a significant association of enzyme activity with the following parameters: duration of diabetes, age, level of glycated hemoglobin and endogenous digitalis with the respective p-values (0.000, 0.000, 0.000 and 0.021). Gender showed no significant relationship with enzyme activity (p 0.43). Conclusions: In DM2 with neuropathy, hyperglycemia can much reduce the activity of erythrocyte Na/K ATPase. In addition, it may enhance the inhibitory activity of endogenous digitals. The timedependent increase in diabetic complications can be due to a strong association between diabetes duration and erythrocyte Na/K-ATPase activities.

Pharmacoclinical audit on the use of digitalis in patients aged over 75 years hospitalized in an acute geriatric unit.

A retrospective, unicentric study carried out within the unit of Internal medicine and geriatrics, Reims University Hospital Center, between January and June 2014. Collection of all patients hospitalized, after 75 years, receiving treatment with digitalis, either as soon as they enter (present on the usual prescription of the patient), during their hospitalization and on their exit. 20 patients were included. The median age was 89 years (range: 78-94). Digitalis was only used in slowing down the ventricular rate during atrial fibrillation; 7 patients (35%) had a high serum digoxin concentration, of which 4 had renal failure. Three patients presented a digital cup on the electrocardiogram. In our series, in digoxin overdosage, 3 patients with electrical signs of digoxin overdosage have all 3 digoxin-beta-blockers. We are in the limit of the significance, for the connection between digoxinemia and the appearance of electrical signs of overdose in digitalis (p=0.06). Digoxin therefore remains a drug that is difficult to manage, mainly in the elderly, as there are many clinical, biological drug and therapeutic constraints. Failure to comply with the rules for the use and monitoring of digoxin may prove fatal in the elderly.

Association of digitalis treatment with outcomes following myocardial infarction in patients with heart failure or evidence of left ventricular dysfunction: an analysis from the High-Risk Myocardial Infarction Database Initiative

Contradictory findings have been reported regarding the safety and efficacy of digitalis in patients recovering from acute myocardial infarction (MI). We studied the association of digitalis use with long-term and short-term prognosis in patients presenting with an acute MI complicated with heart failure (HF), left ventricular dysfunction, or both. Using the High-Risk MI Database Initiative combining data from 4 major clinical trials, totaling 27,673 patients, we investigated the association between digitalis use at baseline (3093 patients with digitalis and 24,580 without) with the rate of all-cause death, sudden cardiac death, cardiovascular death, HF hospitalization and the combination of the latter two, over a mean follow-up time of 2.7years. Patients with and without atrial fibrillation (AF) were studied separately. After a propensity score-based analysis, among patients without AF, those receiving digitalis experienced a higher rate of all-cause [hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.42-1.67] and sudden cardiac death (HR 1.65, 95% CI 1.44-1.89), compared to those not receiving digitalis; similar results were found for the other 3 endpoints (all HR around 1.6). In contrast, in AF patients, digitalis had a milder effect on all outcomes (all HR≤1.12), with significant association only for the composite endpoint (HR 1.10, 95% CI 1.00-1.21, p=0.049); comparable results were obtained at 30days. Finally, the detrimental effect associated with digitalis use appeared to be more pronounced in patients with ejection fraction ≥ 40%. In MI survivors with HF and/or systolic dysfunction, digitalis was associated with a significant increased risk of death in patients without AF with mild to neutral associations for patients with AF. These findings raise concerns regarding the safety of digitalis in MI survivors with HF, especially for those without AF.

Digitalis for treatment of heart failure in patients in sinus rhythm.

Digitalis glycosides have been in clinical use for the treatment of heart failure (HF) for longer than 200 years. In recent years, several trials have been conducted to address concerns about their efficacy and toxicity. To examine the effectiveness of digitalis glycosides in treating HF in patients with normal sinus rhythm. To examine the effects of digitalis in patients taking diuretics and angiotensin-converting enzyme inhibitors; in patients with varying severity and duration of disease; in patients with prior exposure to digitalis versus no prior exposure; and in patients with "HF due to systolic dysfunction" versus "HF with preserved ejection fraction." Searches on the following databases were updated in May 2013: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Dissertation Abstracts. Annual meeting abstracts of the American Heart Association, the American College of Cardiology, and the European Society of Cardiology were searched from 1996 to March 2013. In addition, reference lists provided by the pharmaceutical industry (GlaxoSmithKline and Covis Pharma) were searched. Included were randomized placebo-controlled trials of 20 or more adult participants of either sex with symptomatic HF who were studied for seven weeks or longer. Excluded were trials in which the prevalence of atrial fibrillation was 2% or greater, or in which any arrhythmia that might compromise cardiac function or any potentially reversible cause of HF such as acute ischemic heart disease or myocarditis was present. Articles selected from the searches described above were evaluated in a joint effort of the review authors. The staff of the Cochrane Heart Group ran searches on the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE. No new studies were identified in the updated searches. Thirteen studies (7896 participants) are included, and major endpoints of mortality, hospitalization, and clinical status, based respectively on 8, 4, and 12 of these selected studies, were recorded and analyzed. The data show no evidence of a difference in mortality between treatment and control groups, whereas digitalis therapy is associated with lower rates of both hospitalization and clinical deterioration. The largest study, in which most participants were taking angiotensin-converting enzyme inhibitors, showed a significant rise in "other cardiac" deaths, possibly due to arrhythmias. However collectively, these findings were based on studies done before beta-blockers, as well as angiotensin receptor blockers and aldosterone antagonists, became widely used to treat HF. The literature indicates that digitalis may have a useful role in the treatment of patients with HF who are in normal sinus rhythm. New trials are needed to elucidate the importance of the dosage of digitalis and its usefulness in the era of beta-blockers and other agents shown to be effective in treating HF.

Role of Digitalis in the Contemporary Management of Systolic Heart Failure in African Americans

Introduction: The effects of digitalis in patients with systolic heart failure (SHF) have not been evaluated in the era of contemporary medical therapy including the use of beta blockers. In the African-American Heart Failure Trial (A-HeFT), the fixed-dose combination of isosorbide dinitrate/hydralazine (FDC I/H) decreased mortality and morbidity and improved patient reported functional status in self-identified black patients with SHF stabilized on contemporary heart failure (HF) therapy. Objective: We investigated the effect of digitalis in A-HeFT. Methods: A pre-specified Kaplan-Meier survival analysis was performed to determine the effect of FDC I/H compared to placebo with or without the use of digitalis (n = 1050). Analogous retrospective analyses within the FDC I/H and placebo groups were performed. Results: In A-HeFT, 62% of patients received digitalis at baseline. Patients receiving digitalis had lower systolic BP (125 vs. 128 mmHg), diastolic BP (76 vs. 78 mmHg), and qualifying LV ejection fraction (23.3 vs. 25.6%). Concomitant medications were comparable for either ACEI or ARB (93%) and beta blockers (87%). Digitalis users had significantly higher use of diuretics (94 vs. 89%) and spironolactone (45 vs. 29%). Compared to placebo, FDC I/H was associated with 53% improvement in survival (p < 0.01), and a 32% decrease in death or first HF hospitalization (p < 0.01) in patients treated with digitalis. There was a trend for an increase in all-cause mortality in patients receiving digitalis (Table) that was noted in the placebo group (HR = 1.65; 95% CI 0.91-2.76; p = 0.102) and not the FDC I/H group (HR = 1.02; 95% CI 0.50-2.10; p = 0.96). Digitalis use was associated with a significant increase in the risk of mortality or first heart failure hospitalization. Conclusions: FDC I/H improved outcomes in patients with HF independent of the use of digitalis. Within the limitations of sub-group analysis, our data indicate that the use of digitalis was not associated with beneficial effects on morbidity and mortality in black patients with SHF receiving contemporary therapy.Tabled 1Effect of Digitalis on Outcomes in All A-HeFT PatientsOutcomeHazard Ratio95% CIRisk Increasep ValueDeath1.380.88-2.1138%0.166Death or 1st HF Hospitalization1.381.06-1.7438%0.015 Open table in a new tab

Amodarone loading therapy, beta-blockers and digitalis in patients with atrial fibrillation and structural heart disease: Is there danger of early proarrhythmic effects?

Background: Amiodarone (Amio) is considered the most efficient and safe antiarrhythmic drug in the treatment of atrial fibrillation (AF). Though proarrhythmic effects under Amio are rare, the aim of the present study was to identify clinical constellations which may lead to Amio associated proarrhythmia. Methods: 63 consecutive patients (pts) with persistent or paroxysmal AF [14 female and 49 male, 64 10.3 years; 35 with coronary (CAD) and 11 with congestive (CHD) heart disease] were included in this retrospective analysis. All received an oral (92.1%) or i.v. (7.9%) loading dose of Amio in hospital. Cardiac diseases, concomitant treatment and proarrhythmic effects were analyzed. Results: 11 pts (17.5%) were concomitantly treated with a beta-blocker, 19 pts (30.2%) with digitalis. In 12 pts (19.0%) Amio was used in combination with both beta-blockers and digitalis. 3 pts (4.8%) developed a clinical relevant Torsade de pointes tachycardia (TdP), 3-48h after initiation of Amio loading (2 pts i.v., 1 pt oral). In all pts with proarrhythmia, Amio was initiated with concomitant beta-blocker-/digitalis-therapy. 25% with this ‘triple’ therapy developed TdP. The mean QTc was prolonged (483.7ms 61.8ms), mean heart was decreased (61.0 7.5bpm vs. 74.5 24.1bpm; p 0.05). CAD was present in all of these pts, in 2 pts left ventricular ejection fraction (EF) was severely reduced (30%). EF in pts treated for heart failure with triple therapy (40.8 10.8%) was not signifcantly different as compared to pts with beta-blocker (42.7 11.9%) or digitalis (48.9 11.9%) alone. Conclusion: Out of 63 consecutive pts with initiation of Amio therapy, in 3 pts TdP were observed. These were characterized by CAD and a combination-therapy of Amio with beta-blockers and digitalis. As a result of the changes in the treatment of heart failure, use of beta-blockers with digitalis is more widespread. The present study implicates that additional Amio therapy in such pts with AF may increase the risk of Amio-associated proarrhythmia and predispose to the development of TdP. P6-112 UNUSUAL MANIFESTATIONS OF ENDLESS LOOP TACHYCARDIA IN A CARDIAC RESYNCHRONIZATION DEFIBRILLATOR *Sergio L. Pinski, MD and Marcelo E. Helguera, MD. Cleveland Clinic Florida, Weston, FL.

Digitalis for treatment of congestive heart failure in patients in sinus rhythm.

Digitalis glycosides have been in clinical use in the treatment of congestive heart failure (CHF) for more than 200 years. In recent years several trials have been conducted to address concerns about efficacy and toxicity. Although a systematic review of the literature was published in 1990, an update is required to include more current trials. To examine the effectiveness of digitalis glycosides in treating CHF in patients with normal sinus rhythm. To examine the effect of digitalis in patients taking diuretics, angiotensin converting enzyme inhibitors, and beta-blockers; patients with varying severity and duration of disease; patients with prior exposure to digitalis vs. no prior exposure; and patients with "CHF due to systolic dysfunction" vs. "CHF with preserved systolic function." The Cochrane Central Register of Controlled Trials (CENTRAL) 2003 Issue 4, MEDLINE (1966 to December 2003) and EMBASE (1990 to December 2003) were searched. Dissertation Abstracts and annual meeting abstracts of the American Heart Association, American College of Cardiology, and European Society of Cardiology were also searched from 1996-2003. In addition, reference lists provided by the pharmaceutical industry (Glaxo Wellcome Inc.) were searched. Included were randomized placebo-controlled trials of 20 or more adult patients of either sex with symptomatic CHF who were studied for seven weeks or more. Excluded were trials in which the prevalence of atrial fibrillation was 2% or greater, or in which any arrhythmia that might compromise cardiac function or any potentially reversible cause of CHF such as acute ischemic heart disease or myocarditis was present. Articles selected from the searches described above were evaluated as a joint effort of the coauthors. The staff of the Cochrane Heart Group ran searches on the Cochrane Central Register of Controlled Trials. Thirteen articles meeting the defined criteria were identified, and major endpoints of mortality, hospitalization, and clinical status, based respectively upon 8, 4, and 12 of these selected studies, were recorded and analyzed. The data show that there is no evidence of a difference in mortality between treatment and control groups, whereas digitalis therapy is associated with a lower rate of hospitalization and of clinical deterioration. The literature indicates that digitalis has a useful role in the treatment of patients with CHF who are in normal sinus rhythm.

Role of intracardiac renin-angiotensin-aldosterone system in extracellular matrix remodeling.

Functional angiotensin II receptors have been documented in cardiac fibroblasts as well as an intracardiac aldosterone system that responds to short- and long-term physiological stimuli. In vitro, angiotensin II increased cardiac fibroblast-mediated collagen synthesis and mRNA levels of collagen type I, type III, pro-alpha1 (I) collagen, pro-alpha1 (III) collagen and fibronectin, and inhibited matrix metalloproteinase I activity. The angiotensin II-stimulated secretion and expression of collagen was completely abolished by AT1 receptor antagonism, but not affected by AT2 receptor antagonism. In vivo, chronic infusion of angiotensin II increased the collagen volume fraction in the ventricles. Angiotensin-converting enzyme (ACE) inhibition and AT1 receptor antagonism, but not AT2 receptor antagonism, reduced collagen deposition in the myocardium in spontaneously hypertensive rats and in rat myocardium following myocardial infarction. During chronic aldosterone infusion in uninephrectomized rats on a high-salt diet, a marked accumulation of interstitial and to a lesser extent perivascular collagen occurs in the heart in both ventricles. The cardiac fibrosis in this aldosterone model is prevented by spironolactone. During the continuous infusion of aldosterone in the rat, the appearance of fibrosis was delayed and started 4 weeks after the beginning of the infusion, which argues against a direct effect of aldosterone. The mechanism of aldosterone-salt-induced cardiac fibrosis possibly involves angiotensin II acting through upregulated AT1 receptors and the cardiac AT1 receptor is the target for aldosterone. An accumulation of collagen in the heart has also been found in patients with adrenal adenomas and during chronic activation of the renin-angiotensin-aldosterone system such as in surgically-induced unilateral renal ischemia, unilateral renal artery banding or renovascular hypertension. Spironolactone prevents aortic collagen accumulation in spontaneously hypertensive rats. In patients with stable chronic heart failure, spironolactone treatment in addition to diuretics and ACE inhibition reduced circulating levels of procollagen type III N-terminal aminopeptide. Also, in the Randomized Aldactone Evaluation Study, spironolactone coadministered with conventional therapy of ACE inhibitors, loop diuretics and digitalis in patients with symptomatic heart failure defined as NYHA classes III-IV, reduced total mortality by 30%.

Digitalis for treatment of congestive heart failure in patients in sinus rhythm.

Digitalis glycosides have been in clinical use in the treatment of congestive heart failure for more than 200 years. In recent years several trials have been conducted to address concerns about efficacy and toxicity. Although a systematic review of the literature was recently published, an update is required to include more current trials. To examine the effectiveness of digitalis glycosides in treating congestive heart failure in patients with normal sinus rhythm. To examine the effect of digitalis in patients taking diuretics, angiotensin converting enzyme (ACE) inhibitors, and beta blockers; patients with varying severity and duration of disease; patients with prior exposure to digitalis vs. no prior exposure; and patients with diastolic vs. systolic dysfunction. Electronic databases were searched between 1966 and 2000. Dissertation Abstracts and annual meeting abstracts of the American Heart Association, American College of Cardiology, and European Society of Cardiology were searched from 1996-2000. In addition, reference lists provided by the pharmaceutical industry (Glaxo Wellcome Inc.) were searched. Included were randomized placebo-controlled trials of 20 or more adult patients of either sex with symptomatic congestive heart failure who were studied for seven weeks or more. Excluded were trials in which the prevalence of atrial fibrillation was 2% or greater, or in which any arrhythmia that might compromise cardiac function or any potentially reversible cause of heart failure such as acute ischemic heart disease or myocarditis was present. Articles selected from the searches described above were reviewed by one of the coauthors, and validated by staff from the central office of the Heart Collaborative Review Group in Bristol, UK. Eleven articles meeting the defined criteria were identified, and major endpoints of mortality, hospitalization, and clinical status, based respectively upon 8, 4, and 10 of these selected studies, were recorded and analyzed. The data show that there is no difference in mortality between treatment and control groups, whereas digitalis therapy is associated with a lower rate of hospitalization and of clinical deterioration. The literature indicates that digitalis has a useful role in the treatment of patients with congestive heart failure who are in normal sinus rhythm.

Induction of Cardiac Fibrosis by Aldosterone

P. Lijnen and V. Petrov. Induction of Cardiac Fibrosis by Aldosterone. Journal of Molecular and Cellular Cardiology (2000) 32, 865–879. An intracardiac aldosterone system which responds to short- and long-term physiological stimuli has been described. This cardiac generated aldosterone has possibly autocrine or paracrine actions. Normal cardiac tissue contains mineralocorticoid receptors (MR) and cardiac high affinity MR are localized in cardiac myocytes and endothelial cells. Data concerning the presence of MR in cardiac fibroblasts are, however, controversial. MR are not specific for aldosterone but they also bind glucocorticoids. Cardiac fibroblasts however contain the enzyme 11 β -hydroxy-steroid dehydrogenase II which converts these glucocorticoids to inactive metabolites. Discordant findings on the in vitro effect of aldosterone on the collagen synthesis in cardiac fibroblasts are reported and can at least partly attributed to the presence of various fibroblasts phenotypes. During chronic aldosterone infusion in uninephrectomized rats on a high-salt diet, a marked accumulation of interstitial and to a lesser extent perivascular collagen occurs in the heart in both ventricles. This cardiac fibrosis in this aldosteronism model is prevented by spironolactone. This effect of aldosterone is crucially dependent on the salt status of the rat. Indeed, rats on a restricted salt intake infused with aldosterone had no cardiac fibrosis above control levels. During the continuous infusion of aldosterone in the rat the appearance of fibrosis was delayed and starts 4 weeks after the beginning of the infusion which argues against a direct effect of aldosterone. The mechanism of aldosterone-salt induced cardiac fibrosis possibly involves angiotensin II acting through upregulated AT1receptors and the cardiac AT1receptor is the target for aldosterone. An accumulation of collagen in the heart has also been found in patients with adrenal adenomas and during chronic activation of the renin–angiotensin–aldosterone system such as in surgically induced unilateral renal ischemia, unilateral renal artery banding or renovascular hypertension. Spironolactone prevents aortic collagen accumulation in spontaneously hypertensive rats. In patients with stable chronic heart failure spironolactone treatment in addition to diuretics and angiotensin-converting enzyme (ACE) inhibition reduced circulating levels of procollagen type III N-terminal aminopeptide. Also, in the Randomized Aldactone Evaluation Study spironolactone coadministered with conventional therapy of ACE inhibitors, loop diuretics and digitalis in patients with symptomatic heart failure defined as NYHA classes III–IV reduces total mortality by 30%.

Digitalis therapy--relevance of heart rate reduction.

Although digitalis is of limited antiarrhythmic value in patients with atrial fibrillation, it does control ventricular heart rate in the majority of patients at rest. It may be necessary, to add a beta-blocking agent or a calcium antagonist to control ventricular heart rate during exercise. This therapeutic approach should be controlled by exercise testing. In heart failure patients with sinus rhythm digitalis decreases heart rate, has antiadrenergic effects, and restores baroreceptor and parasympathetic activity. These actions are seen only in patients with severe heart failure due to left ventricular enlargement and low ejection fraction. In mild heart failure as well as in diastolic heart failure or cor pumonale, digitalis does not seem to be of clinical value. Thus, the use of digitalis in patients with sinus rhythm should be restricted to those with severe heart failure.

Diastolic effects of chronic digitalization in systolic heart failure

Background The efficacy of short-term digitalization on exercise tolerance may, in part, reflect enhanced diastolic performance. However, cardiac glycosides can impair ventricular relaxation from cytosolic Ca++ overload. To detect any time-dependent adverse effect, we assessed the diastolic function after long-term use of digitalis in patients with mild to moderate systolic left ventricular failure. Methods and Results From a cohort of 80 patients who received long-term, randomized, double-blind treatment with digitalis versus placebo at the WJB Dorn Veterans Affairs Medical Center, 38 survivors were evaluated at the end of follow-up (mean 48.4 months) with evaluators blinded to treatment used. Each survivor underwent equilibrium scintigraphic and echocardiographic assessment of diastolic function. Peak and mean filling rates normalized with filling volume (FV), diastolic phase durations normalized with duration of diastole, and filling fractions were measured from the time-activity curve. The isovolumic relaxation period and ventricular dimensions were computed echocardiographically. By actual-treatment-received analysis, treated versus untreated patients manifested a trend toward longer isovolumic relaxation (80.76 ms vs 61.54 ms, P = .06) but a markedly lower peak rapid filling rate (6.39 FV/sec vs 10.56 FV/sec, P = .02) despite comparable loading conditions. In addition, treated patients exhibited a lower mean rate of rapid filling (2.75 FV/sec vs 3.78 FV/sec, P = .05) in the absence of a longer rapid filling duration. However, the end-diastolic ventricular dimension did not differ between the 2 groups. Similar results were obtained by intention-to-treat analysis. Importantly, the mortality rate from worsening heart failure in the inception cohort was lower in the digitalis group versus the placebo group ( P = .05) with no difference in total cardiac or all-cause mortality. Conclusions After long-term digitalization for systolic left ventricular failure, cross-sectional comparison with a control group from the same inception cohort shows a decrease in the rate and degree of ventricular relaxation. This effect did not interfere with the overall ventricular filling or with a favorable impact on outcome from worsening heart failure. (Am Heart J 1998;136:688-95.)

Effects of Increasing Maintenance Dose of Digoxin on Left Ventricular Function and Neurohormones in Patients With Chronic Heart Failure Treated With Diuretics and Angiotensin-Converting Enzyme Inhibitors

Despite almost three centuries of use, the appropriate dosage of digitalis in patients with chronic heart failure and normal sinus rhythm has not been well studied. We studied 22 patients with heart failure who were receiving constant daily doses of digoxin, diuretics, and angiotensin-converting enzyme (ACE) inhibitors. In 18 patients, the oral daily dose of digoxin was increased from a mean of 0.20 +/- 0.07 to 0.39 +/- 0.11 mg/day corresponding to an increase in the serum digoxin concentration from 0.67 +/- 0.22 to 1.22 +/- 0.35 ng/mL. Radionuclide and echocardiographic left ventricular ejection fraction; maximal treadmill time; heart failure score; serum concentrations of norepinephrine, aldosterone, atrial natriuretic factor, and antidiuretic hormone; and plasma renin activity were obtained before and after the increase in digoxin dose. Subsequently, 9 patients were randomized to receive digoxin and 9 to receive placebo and radionuclide ejection fraction measured after 12 weeks. With the higher dose of digoxin compared with the lower dose, there was a significant increase in radionuclide ejection fraction from 23.7 +/- 9.6% to 27.1 +/- 11.8% (P = .007). No significant changes were noted in heart failure score; exercise tolerance; serum concentrations of norepinephrine, atrial natriuretic factor, and antidiuretic hormone; and plasma renin activity. There was, however, an increase in serum aldosterone concentration. Twelve weeks after the patients were randomized to receive digoxin or placebo, there was a significant decrease in ejection fraction (from 29.4 +/- 10.4% to 23.7 +/- 8.9%) in the placebo group but not in patients who continued to receive digoxin (P = .002). The increase in maintenance digoxin dose, while maintaining serum concentrations within therapeutic range, resulted in a significant increase in left ventricular ejection fraction that was not associated with significant changes in heart failure score, exercise tolerance, and neurohumoral profile.

Comparison of lisinopril versus digoxin for congestive heart failure during maintenance diuretic therapy

Lisinopril 5–20 mg once daily was compared with digoxin 0.125–0.375 mg once daily in a double-blind, randomized, parallel-group study involving 217 patients with mild-to-moderate heart failure (New York Heart Association [NYHA] grades II–III) who were maintained on optimized diuretic therapy. After 6 weeks of treatment, digoxin and lisinopril had increased exercise duration by 18 seconds (p = 0.015) and 32 seconds (p = 0.0007), respectively, versus the baseline run-in period. The difference between treatments was not statistically significant (p = 0.1343). After 12 weeks, digoxin and lisinopril had increased exercise duration by 29 seconds and 51 seconds, respectively. The effect of digoxin compared with the baseline value was not significant but that for lisinopril was (p = 0.0027). The difference between treatments approached statistical significance (p = 0.0813). There was no difference between lisinopril and digoxin with regard to their effects on the frequency of ventricular ectopic counts, couplets, or nonsustained ventricular tachycardia. Blood pressures were not significantly different between treatments, although both systolic and diastolic blood pressure were consistently lower in the lisinopril group throughout randomized treatment. The proportions of patients demonstrating an improvement in NYHA grading were similar for both lisinopril and digoxin. Both treatments had similar effects on the symptoms of heart failure. Both drugs appeared to be equally well tolerated with a similar frequency of adverse events reported for both drugs (30% for lisinopril vs 29% for digoxin). Withdrawals from treatment were of a similar frequency for both treatments. It is concluded that lisinopril may be a useful alternative to digitalis in patients with heart failure who remain symptomatic on diuretic therapy.

Digitoxin-associated mortality in acute myocardial infarction

The use of digitalis in patients who have sustained an acute myocardial infarction has been controversial. A number of reports have suggested that the use of the glucoside actually can increase mortality. In all previous reports, digoxin has been the glucoside in use. In 620 patients admitted to Hamar Hospital from January 1, 1982 to December 31, 1984 with an acute myocardial infarction, 159 were using digitoxin at entry. Their survival until January 1, 1985 was compared with the rest of the population, not using digitoxin. The patients on digitoxin had a significantly higher mortality than those who were not, with a relative risk ratio of 2.33. However, major differences in baseline risk factors existed, and a multivariate Cox regression analysis was employed to adjust for the inequalities in baseline covariates. Only variables available at the entry of the index infarction were used for adjustment. Serum sodium, serum creatinine, age and no smoking were identified in a backward selection procedure as independently influencing mortality. By adjusting for these variables the relative risk ratio was reduced to 1.41, but digitoxin still exerted a significant influence on mortality. It is concluded that the results obtained with the use of digitoxin during a myocardial infarction is similar to previous reports with digoxin. Most of the excess mortality in the digitoxin group can be accounted for by inequalities in baseline characteristics. However, the possibility that a small excess in mortality is due to the digitalis glucoside cannot be excluded.

Digitalis

Use of digitalis declined in the 1970s, especially among younger physicians, but several recent studies have conclusively documented the hemodynamic and symptomatic benefits of digitalis in patients with class III and IV heart failure resulting from left ventricular systolic dysfunction. The S3 gallop is a useful marker for a subset with a highly favorable response. Symptomatic benefit cannot be shown in most patients with class I and II heart disease (e.g., most myocardial infarction patients). When patients are monitored carefully for evidence of toxicity with serum digitalis assays and for factors that may affect drug bioavailability or clearance, digitalis is well tolerated.

Ibopamine as a substitute for digitalis in patients with congestive heart failure on chronic digoxin therapy

The substitution of digoxin with ibopamine, a new inotropic and vasodilating agent, was evaluated in a multicenter study in 58 patients with mild-to-moderate congestive heart failure, stabilized on diuretics, and digoxin therapy. The study was a parallel, double-blind, randomized trial of four weeks duration in which half of the group continued the pre-study medication (diuretics and digoxin) and half of the group was treated with diuretics and ibopamine (100 mg, three times a day). At baseline evaluation, the two groups were similar for age, sex, underlying cardiac disease, duration of congestive heart failure, symptom score, cardiothoracic ratio, echocardiographic parameters of left ventricular function and exercise tolerance as measured by bicycle ergometry. After four weeks, no clinical deterioration was found in the patients treated with ibopamine in any measured parameter. There were two deaths during the study: a sudden death and one following an acute myocardial infarction. Both patients were on digoxin. This study suggests that in patients with mild-to-moderate congestive heart failure, ibopamine therapy may effectively and safely substitute digoxin therapy for up to four weeks, representing an option for patients requiring inotropic support but are at risk for potential digoxin toxicity.

Studies on ergometer exercise testing. II. Effect of previous myocardial infarction, digoxin, and beta-blockade on exercise electrocardiography.

The results of exercise electrocardiography were studied in a random sample of 317 subjects with clinical suspicion of coronary artery disease. In 278 patients with coronary artery disease the rate of false negative tests was 18% with and 12% without previous myocardial infarction. If ST elevation was considered a negative response, the corresponding values were 25% and 13%, respectively, p less than 0.01. The greatest prevalence of negative tests was seen after anterior myocardial infarction: 27% or 42% when ST elevation was not included into positive responses. The sensitivity of exercise-induced ST depression for the presence of multivessel disease was lower after anterior infarction (67%) than in other patients with previous infarction (86%), p less than 0.01. The corresponding specificities were 71% and 22%, respectively, p less than 0.005. If ST elevation was included into positive responses these differences were abolished. In subjects without myocardial infarction the sensitivity was 89% and specificity 43%. Digitalized patients had somewhat higher sensitivity in the exercise electrocardiogram than those without digoxin, 90% vs. 81% (p less than 0.05), but the difference was not seen with exclusion of ST elevation. The specificity was not influenced by digitalis. beta-blockade had no effect on the sensitivity or specificity, but the prevalence of postexercise ST evolution was lower with (11%) than without (30%) beta-blockade. The prevalence of slowly ascending ST depression was reduced by three factors: the presence of digitalis in patients without previous myocardial infarction, infarction itself, and the extent of coronary artery disease. We conclude that exercise electrocardiography has only a limited value in prediction of multivessel disease.(ABSTRACT TRUNCATED AT 250 WORDS)