Digoxin is used for rate control in atrial fibrillation (AF), but evidence for its efficacy and safety after myocardial infarction (MI) is scarce and mixed. We studied post-MI digoxin use effects on AF patient outcomes in a nationwide registry follow-up study in Finland. Digoxin was used by 18.6% of AF patients after MI, with a decreasing usage trend during 2004-2014. Baseline differences in digoxin users (n = 881) and controls (n = 3898) were balanced with inverse probability of treatment weight adjustment. The median follow-up was 7.4 years. Patients using digoxin after MI had a higher cumulative all-cause mortality (77.4% vs. 72.3%; hazard ratio [HR]: 1.19; confidence interval [CI]: 1.07-1.32; p = 0.001) during a 10-year follow-up. Mortality differences were detected in a subgroup analysis of patients without baseline heart failure (HF) (HR: 1.23; p = 0.019) but not in patients with baseline HF (HR: 1.05; p = 0.413). Cumulative incidences of HF hospitalizations, stroke and new MI were similar between digoxin group and controls. In conclusion, digoxin use after MI is associated with increased mortality but not with HF hospitalizations, new MI or stroke in AF patients. Increased mortality was detected in patients without baseline HF. Results suggest caution with digoxin after MI in AF patients, especially in the absence of HF.

Severe mitral annular calcification causing degenerative mitral stenosis (DMS) is increasingly encountered in patients undergoing mitral and aortic valve interventions. However, its clinical profile and natural history and the factors affecting survival remain poorly characterized. The goal of this study was to characterize the factors affecting survival in patients with DMS.

An institutional echocardiographic database was searched for patients with DMS, defined as severe mitral annular calcification without commissural fusion and a mean transmitral diastolic gradient of ≥2 mm Hg. This resulted in a cohort of 1,004 patients. Survival was analyzed as a function of clinical, pharmacologic, and echocardiographic variables.

The patient characteristics were as follows: mean age, 73 ± 14 years; 73% women; coronary artery disease in 49%; and diabetes mellitus in 50%. The 1- and 5-year survival rates were 78% and 47%, respectively, and were slightly worse with higher DMS grades (P = .02). Risk factors for higher mortality included greater age (P < .0001), atrial fibrillation (P = .0009), renal insufficiency (P = .004), mitral regurgitation (P < .0001), tricuspid regurgitation (P < .0001), elevated right atrial pressure (P < .0001), concomitant aortic stenosis (P = .02), and low serum albumin level (P < .0001). Adjusted for propensity scores, use of renin-angiotensin system blockers (P = .02) or statins (P = .04) was associated with better survival, and use of digoxin was associated with higher mortality (P = .007).

Prognosis in patients with DMS is poor, being worse in the aged and those with renal insufficiency, atrial fibrillation, and other concomitant valvular lesions. Renin-angiotensin system blockers and statins may confer a survival benefit, and digoxin use may be associated with higher mortality in these patients.

To review digoxin use in systolic congestive heart failure, atrial fibrillation, and after myocardial infarction.

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.

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.

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.

To clarify the impact of digoxin on death and clinical outcomes across all observational and randomised controlled trials, accounting for study designs and methods.

Comprehensive literature search of Medline, Embase, the Cochrane Library, reference lists, and ongoing studies according to a prospectively registered design (

CRD42014010783), including all studies published from 1960 to July 2014 that examined treatment with digoxin compared with control (placebo or no treatment).

Unadjusted and adjusted data pooled according to study design, analysis method, and risk of bias.

Primary outcome (all cause mortality) and secondary outcomes (including admission to hospital) were meta-analysed with random effects modelling.

52 studies were systematically reviewed, comprising 621,845 patients. Digoxin users were 2.4 years older than control (weighted difference 95% confidence interval 1.3 to 3.6), with lower ejection fraction (33% v 42%), more diabetes, and greater use of diuretics and anti-arrhythmic drugs. Meta-analysis included 75 study analyses, with a combined total of 4,006,210 patient years of follow-up. Compared with control, the pooled risk ratio for death with digoxin was 1.76 in unadjusted analyses (1.57 to 1.97), 1.61 in adjusted analyses (1.31 to 1.97), 1.18 in propensity matched studies (1.09 to 1.26), and 0.99 in randomised controlled trials (0.93 to 1.05). Meta-regression confirmed that baseline differences between treatment groups had a significant impact on mortality associated with digoxin, including markers of heart failure severity such as use of diuretics (P=0.004). Studies with better methods and lower risk of bias were more likely to report a neutral association of digoxin with mortality (P<0.001). Across all study types, digoxin led to a small but significant reduction in all cause hospital admission (risk ratio 0.92, 0.89 to 0.95; P<0.001; n=29,525).

Digoxin is associated with a neutral effect on mortality in randomised trials and a lower rate of admissions to hospital across all study types. Regardless of statistical analysis, prescription biases limit the value of observational data.

Membrane potential (V(M))-dependent inhibitors of the Na(+),K(+)-ATPase are a new class of compounds that may have inherent advantages over currently available drugs targeting this enzyme. However, two questions remain unanswered regarding these inhibitors: (1) what is the mechanism of V(M)-dependent Na(+),K(+)-ATPase inhibition, and (2) is their binding affinity high enough to consider them as possible lead compounds? To address these questions, we investigated how a recently synthesized V(M)-dependent Na(+),K(+)-ATPase inhibitor, para-nitrobenzyltriethylamine (pNBTEA), binds to the enzyme by measuring the extracellular pNBTEA concentration and V(M) dependence of ouabain-sensitive transient charge movements in whole-cell patch-clamped rat cardiac ventricular myocytes. By analyzing the kinetics of charge movements and the steady-state distribution of charge, we show that the V(M)-dependent properties of pNBTEA binding differ from those for extracellular Na(+) and K(+) binding, even though inhibitor binding is competitive with extracellular K(+). The data were also fit to specific models for pNBTEA binding to show that pNBTEA binding is a rate-limiting V(M)-dependent reaction that, in light of homology models for the Na(+),K(+)-ATPase, we interpret as a transfer reaction of pNBTEA from a peripheral binding site in the enzyme to a site near the known K(+) coordination sites buried within the transmembrane helices of the enzyme. These models also suggest that binding occurs with an apparent affinity of 7 μM. This apparent binding affinity suggests that high-affinity V(M)-dependent Na(+),K(+)-ATPase inhibitors should be feasible to design and test as specific enzyme inhibitors.

Acute Myocardial Infarction (AMI) is one of the main causes of mortality and disability in Colombia. The factors associated to a new event in surviving subjects to a first AMI in our population have not yet been fully identified.

Two hundred and ninety five surviving subjects to a first AMI (58.8±12.6 years) were included in a prospective cohort study between 2000 and 2006. Lipid profile, glycemia and plasma insulin levels were measured. Deaths of cardiovascular origin, a new AMI, unstable angina, heart failure, stroke, new myocardial revascularization or angioplasty were considered new cardiovascular events.

The study included 61 (20.6%) women and 234 (79.4%) men. The mean follow up time was 50±30 months with a 38.9% incidence of new events. Fifty five patients (18.6%) were diabetic. Bi-varied analysis identified as risk factors for a new cardiovascular event the presence of: hypertension, anterior descending coronary artery stenosis, intrahospital cardiac failure, age over 55, low income, lack of education, Killip III-IV, heart rate over 76 bpm, pulse pressure over 80 mmHg, total cholesterol over 200 mg/dl and insulin over 10 IU/ml. After logistic regression analysis, the log values of insulin remained as the only significant predictor for new cardiovascular events.

Hyperinsulinism was the most important factor associated to the occurrence of new cardiovascular events in Colombian patients with AMI, which emphasizes the pivotal role of insulin resistance in the physiopathologic mechanisms of atherosclerosis, especially in undeveloped countries.

To investigate characteristics, management and outcome of patients with acute myocardial infarction (AMI) and chronic renal insufficiency (CRI).

Patients with AMI and CRI are considered to be at high risk of complications and death. Physicians may be reluctant to prescribe life-saving medications to patients with concomitant CRI.

We compared clinical characteristics, management and outcome of 1,683 consecutive AMI patients in three categories of renal function: (1) normal renal function (<1.5 mg/dl) (n = 1,559), (2) mild to moderate CRI (1.5-3.5 mg/dl) (n = 77), and (3) severe CRI (>3.5 mg/dl) (n = 47).

CRI patients were older and were more likely to have other co-morbidities such as hypertension, diabetes mellitus, prior AMI, stroke, angina and heart failure. Compared with patients with normal renal function, standard therapy for AMI including thrombolysis, aspirin, angiotensin-converting-enzyme inhibitors, beta-blockers and lipid lowering agents was underutilized in CRI patients and these patients were more likely to have in-hospital complications such as heart failure, atrial or ventricular fibrillation, cardiogenic shock, sepsis, worsening of renal function and death within 30 days [odds ratio (OR) = 3.3; 95% confidence interval (CI) = 2.0-4.8]. After adjustment for age and co-morbidities, the association between mild to moderate CRI and 30-days mortality declined, whereas severe CRI remained an independent determinant of mortality (OR = 4.8; 95% CI = 2.0-11.4). Adjustment for aspirin, angiotensin-converting-enzyme inhibitors and beta-blocker therapy weakened the association between CRI and death within 30 days after AMI.

CRI patients are more likely to experience serious complications and death early after AMI. Underutilization of standard care, particularly beta-blocker therapy, contributes to increased mortality risk in these patients.

After 200 years of use, digitalis still appears to have a place in our armamentarium for heart failure and atrial fibrillation despite the proven survival benefits with ACE inhibitors and beta-blockers. Digoxin therapy is inexpensive and well tolerated and may result in considerable savings. Digoxin is the only oral inotrope that does not increase mortality in heart failure patients, particularly if low doses are being used. Digoxin therapy should be used in patients with systolic heart failure who continue to have signs and symptoms despite therapeutic doses of ACE inhibitors or diuretics or in patients with atrial fibrillation with or without heart failure for rate control.

The digitalis drugs are plant-derived cardenolide compounds used medicinally for several hundred years. These drugs elicit inotropic and chronotropic effects on the heart, but they also affect many other tissues. The mechanism of action involves inhibition of the ion-transport activity of a membrane-associated protein called Na, K-ATPase (sodium pump). Present theory holds that the sodium pump is the principal molecular receptor for the digitalis drugs. Recent evidence indicates the presence of naturally occurring digitalis-like compounds in mammals. It is believed these compounds, collectively known as either digitalis-like (DLF) or ouabain-like (OLF) factors, may be endogenous hormones regulating the biological activity of the sodium pump and its isoforms. The presence of deglycosylated and other congeners of one specific DLF, the digoxin-like immunoreactive factor (DLIF), has very recently been described in humans. Digoxin as a drug is the most widely prescribed digitalis in the U.S., and its measurement in serum has established a model for present-day therapeutic drug monitoring (TDM). Historically, the accurate measurement of digoxin in blood has been difficult. This article focuses on the present understanding of the clinical use of digoxin, factors that affect the accuracy of measuring digoxin, the principle of measuring metabolically active species of digoxin, and the effects of DLIF and other interfering substances in digoxin immunoassay.

Previous reports have yielded contradictory conclusions regarding the safety of digoxin therapy in patients with acute myocardial infarction. The purpose of our study was to determine whether digoxin therapy is associated with increased mortality in patients with chronic coronary artery disease. We analyzed data from 8173 patients who were screened for participation in the Bezafibrate Infarction Prevention (BIP) trial and who survived an acute myocardial infarction at least 6 months prior to the study. Three-year overall mortality of the 451 (15.5%) patients receiving digoxin (according to the judgement of their treating physician) at the time of screening for BIP participation, was 22.4% compared to 8.3% in the patients who did not receive digoxin. Cardiac mortality was 16.2% in the digoxin-treated group, compared to 4.9% in the non-treated patients. The increased risk associated with digoxin remained statistically significant when patients were stratified according to sex, age groups, functional capacity and the presence of hypertension, diabetes or angina. The administration of digoxin to survivors of an acute myocardial infarction in the chronic phase of their disease, is statistically associated with a 30-50% increase in the risk of overall and cardiac mortality during long-term follow-up. A propensity of increased risk of arrhythmias in ischemic coronary patients may explain this finding.

Despite the documented efficacy of cardiac glycosides in improving symptoms in patients with heart failure caused by systolic ventricular dysfunction, considerable debate continues as to whether the use of this class of drugs should continue into the next millennium. In this review, the authors briefly examine the basic pharmacology of these drugs relevant to the treatment of heart failure, emphasizing their role in reducing sympathetic nervous system activity in patients with advanced heart failure. Next, withdrawal trials and the Digoxin Investigation Group dataset are reviewed in some detail. Despite these important additional data on the safety and efficacy of digitalis use in heart failure that became available in the 1990s, considerable controversy remains. Perhaps most importantly, if the mechanism by which these drugs improve symptoms in patients with heart failure is principally mediated by sympatholytic activity, do they remain relevant as beta-adrenergic antagonists become standard therapy for this disease?

Although supported by more than 200 years of experience and anecdotal clinical evidence, the efficacy of digitalis in the management of heart failure has been questioned until the past decade. The idea to improve contractility of the diseased myocardium with an inotropic agent is fundamental in the management of left ventricular dysfunction. The majority of clinical trials published since 1980, most of which examined patients with mild to moderate heart failure, indicate that digitalis alone or in combination with vasodilators may improve the clinical outcome particular in those patients with more advanced symptoms and poorer left ventricular function. Aside from its action as an inotropic drug the pharmacology and the mechanisms by which digitalis influence the diseased myocardium and peripheral circulation in heart failure has gained more complexity within the last years, raising the idea of other mechanisms that might be involved in its action. Particular for ACE inhibition multiple clinical trials have conclusively demonstrated its impact on survival and morbidity in congestive heart failure. Improvement of clinical outcome as measured in terms of fewer hospitalizations and improvement of symptoms in patients receiving digitalis seems to be comparable to patients receiving beta-blockers additional to diuretics and ACE inhibitors, an entirely different approach to the treatment of heart failure. Despite initial improvement of hemodynamics it now appears that there is no survival benefit found for digitalis in the management of heart failure.

A 71 year old man with hypertensive heart disease and chronic renal failure was wearing a Holter monitor when he had a cardiac arrest. He had ventricular fibrillation (VF) and died despite prompt resuscitation. In the 15 minutes preceding the VF there was a sudden increase in heart rate, followed by a brief period of atrial fibrillation leading to ventricular tachycardia, which in turn rapidly degenerated into VF. The QT interval and heart rate variability were studied half hourly over the seven hours preceding the cardiac arrest, using a computerised Holter system. A further detailed analysis was performed over the final hour before the cardiac arrest. An abrupt increase in the steepness of the QT/RR slope, a prolonged QTc, and a reduction in the heart rate variability were observed in the interval that immediately preceded the onset of the terminal rhythm disturbance.