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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Torsades de pointes is a potentially lethal arrhythmia that occurs infrequently but may be drug-induced particularly in patients with pathological substrates. However drugs are usually evaluated for torsadogenicity in normal subjects, thus potentially limiting the sensitivity of studies to predict liability in man. Heart failure is a pathological substrate permissive to drug-induced torsades de pointes. Failing hearts may be produced with a high yield in rabbits with ligation of coronary arteries. Failing myocardium may be documented by reduced left ventricular ejection fraction and elevation of NTproBNP. QTc in failing hearts prolonged only slightly more in failing hearts than in normals in response to torsadogens, but incidence of torsades de pointes increased dramatically. Abnormal calcium cycling resulting in early afterdepolarizations appeared to develop more in hypertrophic myocardial cells located in the border between normal myocardium and infarct. In failing hearts, torsades de pointes appeared to develop more prevalently without greater lengthening of QT than in hearts from normal rabbits. Thus this model appears to be a facile and useful preparation for identifying torsadogenic potential of test articles, and it probably possesses anatomical and physiological substrates that mimic closely the torsadogenic substrates in the many millions of persons possessing failing hearts.
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PMID:Use of the rabbit with a failing heart to test for torsadogenicity. 1869 64

The present study aimed to investigate the causative medications and underlying risk factors that predispose to drug-induced QT interval prolongation. Twenty-one patients with drug-induced long QT (90% females, mean age 64.3 +/- 14.1 years) were included in the study. Transthoracic echocardiography as well as continuous or ambulatory 48-h electrocardiographic monitoring was carried out in all patients during their hospitalization. The mean corrected QT (QTc) interval was 542 +/- 56.8 ms. Known cardiac agents (mainly class III antiarrhythmics) were implicated in 13/21 (62%), antipsychotics in 8/21 (38%), and antibiotics in 5/21 patients (24%). Potential drug-interactions through inhibition of cytochrome P450 isoenzymes were considered responsible in 5/21 cases (24%). The underlying cardiovascular diseases included hypertension (57%) with left ventricular hypertrophy (29%), paroxysmal atrial tachyarrhytmias (48%), heart failure (14%), valvular heart disease (10%), and coronary artery disease (5%). Torsade de pointes (TdP) was recorded in 6/21 of patients, and cardiac arrest necessitating resuscitation occurred in five of them. A significant correlation was observed between administration of cardiac agents and TdP events (P < 0.05). TdP and cardiac arrest events were both associated with a QTc interval >510 ms (P < 0.05). Advanced age (>60 years), female gender, hypertension and paroxysmal atrial tachyarrhytmias were the most common identifiable pre-existing factors for drug-induced long QT in our patient cohort. Marked QTc interval prolongation should be considered of prognostic significance for TdP and cardiac arrest events.
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PMID:Clinical characteristics of patients with drug-induced QT interval prolongation and torsade de pointes: identification of risk factors. 1903 Oct 39

An 82-year-old woman was admitted to the hospital due to repeated episodes of syncope with incontinence. Electrocardiography showed torsades de pointes, complete atrioventricular (AV) block, T-wave inversions and a prolonged QTc interval. Urgent coronary angiography showed no significant coronary stenosis and left ventriculography demonstrated typical abnormal wall motion of takotusbo cardiomyopathy. Electrophysiology study suggested that the damaged structure might be the bundle of His. After temporary transvenous pacing and administration of intravenous lidocaine, no recurrence of torsade de pointes was found. Symptoms of worsening heart failure were not found. Although abnormal left ventricular wall motion improved, a complete AV block remained and the patient needed pacemaker implantation on Day 18 after admission. This case demonstrated that complete AV block associated with takotsubo cardiomyopathy may persist after improvement of left ventricular wall motion, and implantation of a pacemaker may be needed.
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PMID:Complete atrioventricular block associated with takotsubo cardiomyopathy. 1907 23

Levosimendan increases the sensitivity of the cardiac fibrils to calcium, favorably affects hemodynamics in patients with heart failure. It is a positive inotrope and a peripheral vasodilator. The elimination half-life of the compound is about 1 hour. The drug decreases pulmonary capillary wedge pressure, increases cardiac output with the improvement in left ventricular ejection fraction leading to symptomatic improvement which includes decreased dyspnea and fatigue. Levosimendan can be used safely with diuretics, nitrates, beta-blockers, digoxin, and angiotensin-converting enzyme inhibitors. The most common adverse effects of levosimendan are headache and hypotension. Prolongation of the QTc interval does not appear to increase the incidence of arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Levosimendan is a novel agent in the treatment of decompensated heart failure, representing a newer class of medications aimed at increasing calcium sensitivity. Its properties holds promise for the treatment of heart failure but further large-scale studies will be needed to determine its precise efficacy, safety, as well as the compound's long-term impact on mortality.
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PMID:Levosimendan and calcium sensitization of the contractile proteins in cardiac muscle: impact on heart failure. 1908 50

This is the first of two reports that describes the compilation of a database of drug-related cardiac adverse effects (AEs) that was used to construct quantitative structure-activity relationship (QSAR) models to predict these AEs, to identify properties of pharmaceuticals correlated with the AEs, and to identify plausible mechanisms of action (MOAs) causing the AEs. This database of 396,985 cardiac AE reports was linked to 1632 approved drugs and their chemical structures, 1851 clinical indications (CIs), 997 therapeutic targets (TTs), 432 pharmacological MOAs, and 21,180 affinity coefficients (ACs) for the MOA receptors. AEs were obtained from the Food and Drug Administration's (FDA's) Spontaneous Reporting System (SRS) and Adverse Event Reporting System (AERS) and publicly available medical literature. Drug TTs were obtained from Integrity; drug MOAs and ACs were predicted by BioEpisteme. Significant cardiac AEs and patient exposures were estimated based on the proportional reporting ratios (PRRs) for each drug and each AE endpoint as a percentage of the total AEs. Cardiac AE endpoints were bundled based on toxicological mechanism and concordance of drug-related findings. Results revealed that significant cardiac AEs formed 9 clusters affecting Purkinje nerve fibers (arrhythmia, bradycardia, conduction disorder, electrocardiogram, palpitations, QT prolongation, rate rhythm composite, tachycardia, and Torsades de pointes), and 5 clusters affecting the heart muscle (coronary artery disorders, heart failure, myocardial disorders, myocardial infarction, and valve disorders). Based on the observation that each drug had one TT and up to 9 off-target MOAs, cardiac AEs were highly correlated with drugs affecting cardiovascular and cardioneurological functions and certain MOAs (e.g., alpha- and beta-adeno, dopamine, and hydroxytryptomine receptors).
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PMID:Prediction of drug-related cardiac adverse effects in humans--A: creation of a database of effects and identification of factors affecting their occurrence. 1993 26

This article reports the case of a puerperal patient admitted with diagnosis of urinary tract infection and heart failure. This condition evolved with torsades de pointes ventricular arrhythmias, then, hypokalemia, and use of Ciprofloxacin. Ventricular arrhythmias did not present any improvement after potassium and magnesium replacement, but after implantation of temporary pacemaker, this condition showed signs of improvement. The patient was discharged with QTc at 490 ms, taking Propranolol.
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PMID:Postpartum torsades de pointes and long QT syndrome. 1993 43

This report describes the use of three quantitative structure-activity relationship (QSAR) programs to predict drug-related cardiac adverse effects (AEs), BioEpisteme, MC4PC, and Leadscope Predictive Data Miner. QSAR models were constructed for 9 cardiac AE clusters affecting Purkinje nerve fibers (arrhythmia, bradycardia, conduction disorder, electrocardiogram, palpitations, QT prolongation, rate rhythm composite, tachycardia, and Torsades de pointes) and 5 clusters affecting the heart muscle (coronary artery disorders, heart failure, myocardial disorders, myocardial infarction, and valve disorders). The models were based on a database of post-marketing AEs linked to 1632 chemical structures, and identical training data sets were configured for three QSAR programs. Model performance was optimized and shown to be affected by the ratio of the number of active to inactive drugs. Results revealed that the three programs were complementary and predictive performances using any single positive, consensus two positives, or consensus three positives were as follows, respectively: 70.7%, 91.7%, and 98.0% specificity; 74.7%, 47.2%, and 21.0% sensitivity; and 138.2, 206.3, and 144.2 chi(2). In addition, a prospective study using AE data from the U.S. Food and Drug Administration's (FDA's) MedWatch Program showed 82.4% specificity and 94.3% sensitivity. Furthermore, an external validation study of 18 drugs with serious cardiotoxicity not considered in the models had 88.9% sensitivity.
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PMID:Prediction of drug-related cardiac adverse effects in humans--B: use of QSAR programs for early detection of drug-induced cardiac toxicities. 1994 24

Hypomagnesemia is common in hospitalized patients, especially in the elderly with coronary artery disease (CAD) and/or those with chronic heart failure. Hypomagnesemia is associated with an increased incidence of diabetes mellitus, metabolic syndrome, mortality rate from CAD and all causes. Magnesium supplementation improves myocardial metabolism, inhibits calcium accumulation and myocardial cell death; it improves vascular tone, peripheral vascular resistance, afterload and cardiac output, reduces cardiac arrhythmias and improves lipid metabolism. Magnesium also reduces vulnerability to oxygen-derived free radicals, improves human endothelial function and inhibits platelet function, including platelet aggregation and adhesion, which potentially gives magnesium physiologic and natural effects similar to adenosine-diphosphate inhibitors such as clopidogrel. The data regarding its use in patients with acute myocardial infarction (AMI) is conflicting. Although some previous, relatively small randomized clinical trials demonstrated a remarkable reduction in mortality when administered to relatively high risk AMI patients, two recently published large-scale randomized clinical trials (the Fourth International Study of Infarct Survival and Magnesium in Coronaries) failed to show any advantage of intravenous magnesium over placebo. Nevertheless, there are theoretical potential benefits of magnesium supplementation as a cardioprotective agent in CAD patients, as well as promising results from previous work in animal and humans. These studies are cost effective, easy to handle and are relatively free of adverse effects, which gives magnesium a role in treating CAD patients, especially high-risk groups such as CAD patients with heart failure, the elderly and hospitalized patients with hypomagnesemia. Furthermore, magnesium therapy is indicated in life-threatening ventricular arrhythmias such as Torsades de Pointes and intractable ventricular tachycardia.
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PMID:Magnesium and cardiovascular system. 2035 3

QT prolongation may increase the risk of torsades de pointes (TdP). Early afterdepolarizations (EADs) and transmural dispersion of repolarization have been known to serve as physiological substrates and predictors for TdP. Abnormal Ca(2+) cycling is the proximate cause of EADs, and Ca(2+) cycling is abnormal in heart failure (HF). However, the mechanisms for drug-induced TdP in HF are poorly understood. The purpose of this study was to search for torsadogenic-modifying effects of verapamil, ryanodine, KB-R7943, W-7, KN-93, and H-8 on ventricular premature depolarizations (VPD) and TdP in rabbits with HF. Rabbits with HF were pretreated with propranolol followed by test articles before continuous infusion of dofetilide to induce TdP. In the control hearts, VPD and TdP were induced in all rabbits and the onsets of VPD and TdP were 3.6 +/- 1.3 minutes and 10.3 +/- 1.4 minutes, respectively. Dofetilide lengthened RR, QT and QTc. Verapamil, ryanodine and H-8 significantly delayed onset of VPD (P < 0.05) and suppressed TdP (P < 0.01). KB-R7943, W-7, and KN-93 accelerated onset of TdP. Blockades of L-type Ca(2+) channel, ryanodine channel, and protein kinase A prevent dofetilide-induced TdP, suggesting roles for intracellular Ca(2+) overload and Ca(2+) signaling pathways in drug-induced TdP.
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PMID:Effects of sarcolemmal Ca(2+) entry, ryanodine function, and kinase inhibitors on a rabbit model of heart failure. 2071 47

Early afterdepolarizations (EADs) are an important cause of lethal ventricular arrhythmias in long QT syndromes and heart failure, but the mechanisms by which EADs at the cellular scale cause arrhythmias such as polymorphic ventricular tachycardia (PVT) and torsades de pointes (TdP) at the tissue scale are not well understood. Here we summarize recent progress in this area, discussing (1) the ionic basis of EADs, (2) evidence that deterministic chaos underlies the irregular behavior of EADs, (3) mechanisms by which chaotic EADs synchronize in large numbers of coupled cells in tissue to overcome source-sink mismatches, (4) how this synchronization process allows EADs to initiate triggers and generate mixed focal reentrant ventricular arrhythmias underlying PVT and TdP, and (5) therapeutic implications.
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PMID:Early afterdepolarizations and cardiac arrhythmias. 2086 74


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