Thioridazine lengthens repolarization of cardiac ventricular myocytes by blocking the delayed rectifier potassium current.
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Proarrhythmia has been observed with the antipsychotic agent thioridazine (THIO). The mechanisms underlying these effects are unknown. The objectives of this study were 1) to characterize the effects of THIO on cardiac repolarization and 2) to determine whether lengthening of the Q-T interval could be explained by blocking major K+-repolarizing currents. Isolated, buffer-perfused guinea pig hearts (n = 32) were stimulated at various pacing cycle lengths (150-250 ms) and exposed to THIO at concentrations ranging from 300 nM to 3 microM. THIO increased monophasic action potential duration at 90% repolarization (MAPD90) in a concentration-dependent manner from 14.9 +/- 1.8 at 300 nM to 37.1 +/- 3.2 ms at 3 microM. Increase in MAPD90 was also reverse frequency-dependent; THIO (300 nM) increased MAPD90 by 14.9 +/- 1.8 ms at a pacing cycle length of 250 ms, but by only 7.7 +/- 1.2 ms at a pacing cycle length of 150 ms. Patch-clamp experiments demonstrated that THIO decreases the time-dependent outward K+ current elicited by short depolarizations (250 ms; IK250) in a concentration-dependent manner. Estimated IC50 for IK250, which mostly underlies IKr, was 1.25 microM. Time-dependent outward K+ current elicited in tsA201 cells expressing high levels of HERG protein was also decreased approximately 50% by 1.25 microM THIO. On the other hand, THIO was less potent (IC50 of 14 microM) to decrease time-dependent K+ current elicited by long pulses (5000 ms; IK5000). Under the latter conditions, IK5000 corresponds mainly to IKs. Thus, these results demonstrate block of K+ currents and lengthening of cardiac repolarization by THIO in a concentration-dependent manner. This may provide an explanation of Q-T prolongation observed in some patients treated with THIO. (+info)
Inhibition of advanced glycation endproduct formation by acetaldehyde: role in the cardioprotective effect of ethanol.
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Epidemiological studies suggest that there is a beneficial effect of moderate ethanol consumption on the incidence of cardiovascular disease. Ethanol is metabolized to acetaldehyde, a two-carbon carbonyl compound that can react with nucleophiles to form covalent addition products. We have identified a biochemical modification produced by the reaction of acetaldehyde with protein-bound Amadori products. Amadori products typically arise from the nonenzymatic addition of reducing sugars (such as glucose) to protein amino groups and are the precursors to irreversibly bound, crosslinking moieties called advanced glycation endproducts, or AGEs. AGEs accumulate over time on plasma lipoproteins and vascular wall components and play an important role in the development of diabetes- and age-related cardiovascular disease. The attachment of acetaldehyde to a model Amadori product produces a chemically stabilized complex that cannot rearrange and progress to AGE formation. We tested the role of this reaction in preventing AGE formation in vivo by administering ethanol to diabetic rats, which normally exhibit increased AGE formation and high circulating levels of the hemoglobin Amadori product, HbA1c, and the hemoglobin AGE product, Hb-AGE. In this model study, diabetic rats fed an ethanol diet for 4 weeks showed a 52% decrease in Hb-AGE when compared with diabetic controls (P < 0.001). Circulating levels of HbA1c were unaffected by ethanol, pointing to the specificity of the acetaldehyde reaction for the post-Amadori, advanced glycation process. These data suggest a possible mechanism for the so-called "French paradox," (the cardioprotection conferred by moderate ethanol ingestion) and may offer new strategies for inhibiting advanced glycation. (+info)
Effects of MCI-154 on calcium sensitivity of contractile system and calcium release from sarcoplasmic reticulum in saponin-skinned rat myocardium.
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AIM: To explore the possible mechanisms underlying the positive inotropic effect of MCI-154. METHODS: Skinned fibers with disrupted or preserved sarcoplasmic reticulum (SR) were prepared by saponin 500 or 50 mg.L-1. The tension-pCa relationship and pCa50 of saponin (500 mg.L-1)-skinned fibers were taken as the indices of Ca2+ sensitivity of contractile proteins. The amplitude of caffeine-induced contracture was an index of Ca2+ release from SR in saponin (50 mg.L-1)-skinned fibers. RESULTS: 1) MCI-154 (0.1 mmol.L-1) showed a Ca2+ sensitizing effect on contractile proteins. The pCa50 was increased to 5.84 (5.54-6.14) compared with control value 5.54 (5.30-5.79) (P < 0.01, n = 8). Hill coefficient n was decreased by 0.29 (P < 0.01, n = 8); 2) No contracture was produced by MCI-154 in preparations with preserved SR. Caffeine-induced contracture before and after MCI-154 treatment were not changed (P > 0.05, n = 4). CONCLUSION: MCI-154 directly enhances the Ca2+ sensitivity of contractile protein but has little effect on Ca2+ release from SR in rat skinned cardiac fibers. (+info)
Study on propionyl-L-carnitine in chronic heart failure.
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AIMS: In patients with chronic heart failure, fatigue is independent of haemodynamic and neuroendocrine changes and possibly may be due to impaired muscle metabolism. Propionyl-L-carnitine, a carnitine derivative, was shown in previous studies to improve muscle metabolism. The objective of this study was to evaluate the effect of propionyl-L-carnitine on exercise capacity in mild moderate chronic heart failure patients, treated with ACE inhibitors and diuretics. METHODS AND RESULTS: This was a phase III, double-blind, randomized, parallel, multicentre study. The primary objective was the evaluation of the effect of propionyl-L-carnitine vs placebo on maximum exercise duration using a bicycle exercise test. The primary analysis performed in the intention-to-treat population (271 and 266 patients in propionyl-L-carnitine and placebo), showed no statistically significant difference between treatments. A difference of 15 s in favour of propionyl-L-carnitine was observed in the completer/complier population (P=0.092). An a priori specified subgroup analysis on patients stratified by baseline maximum exercise duration showed a trend of improvement in propionyl-L-carnitine patients with shorter maximum exercise duration. A non a priori specified analysis in patients stratified by ejection fraction (< or = 30% vs 30-40%), showed a statistically significant difference in maximum exercise duration in favour of propionyl-L-carnitine in those patients with a higher ejection fraction (40 s, P<0.01). There were no safety issues. CONCLUSION: The study fails to meet the primary objective, but confirms the good safety profile of propionyl-L-carnitine. An exploratory non-prespecified analysis suggests that propionyl-L-carnitine improves exercise capacity in patients with preserved cardiac function. This hypothesis needs to be confirmed by a specific tailored study. (+info)
Recovery of contractility of viable myocardium during inotropic stimulation is not dependent on an increase of myocardial blood flow in the absence of collateral filling.
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OBJECTIVES: The purpose of this study was to determine whether contractile recovery induced by dobutamine in dysfunctioning viable myocardium supplied by nearly occluded vessels is related to an increase in blood flow in the absence of collaterals. BACKGROUND: Dobutamine is used to improve contractility in ventricular dysfunction during acute myocardial infarction. However, it is unclear whether a significant increase in regional blood flow may be involved in dobutamine effect. METHODS: Twenty patients with 5- to 10-day old anterior infarction and > or =90% left anterior descending coronary artery stenosis underwent 99mTc-Sestamibi tomography (to assess myocardial perfusion) at rest and during low dose (5 to 10 microg/kg/min) dobutamine echocardiography. Rest echocardiography and scintigraphy were repeated >1 month after revascularization. Nine patients had collaterals to the infarcted territory (group A), and 11 did not (group B). RESULTS: Baseline wall motion score was similar in both groups (score 15.9+/-1.3 vs. 17.4+/-2.0, p = NS), whereas significant changes at dobutamine and postrevascularization studies were detected (F[2,30] = 409.79, p < 0.0001). Wall motion score improved significantly (p < 0.001) in group A both at dobutamine (-5.3+/-2.2) and at postrevascularization study (-5.5+/-1.9), as well as in group B (-3.9+/-2.8 and -4.5+/-2.4, respectively). Baseline 99mTc-Sestamibi uptake was similar in both groups (62.9+/-9.7% vs. 60.3+/-10.4%, p = NS), whereas at dobutamine and postrevascularization studies a significant change (F[2,30] = 65.17, p < 0.0001) and interaction between the two groups (F[2,30] = 33.14, p < 0.0001) were present. Tracer uptake increased significantly in group A both at dobutamine (+ 10.9+/-7.9%, p < 0.001) and at postrevascularization study (12.1+/-8.7%, p < 0.001). Conversely, group B patients showed no change in tracer uptake after dobutamine test (-0.4+/-5.8, p = NS), but only after revascularization (+8.8+/-7.2%, p < 0.001). CONCLUSIONS: The increase in contractility induced by low dose dobutamine infusion in dysfunctional viable myocardium supplied by nearly occluded vessels occurs even in the absence of a significant increase in blood flow. (+info)
Prognostic value of dobutamine stress echocardiography in predicting cardiac events in patients with known or suspected coronary artery disease.
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OBJECTIVES: The study sought to determine the utility of dobutamine stress echocardiography (DSE) in predicting cardiac events in the year after testing. BACKGROUND: Increasingly, DSE has been applied to risk stratification of patients. METHODS: Medical records of 1,183 consecutive patients who underwent DSE were reviewed. The cardiac events that occurred during the 12 months after DSE were tabulated: myocardial infarction (MI), cardiac death, percutaneous transluminal coronary angioplasty (PTCA), and coronary artery bypass surgery (CABG). Patient exclusions included organ transplant receipt or evaluation, recent PTCA, noncardiac death, and lack of follow-up. A positive stress echocardiogram (SE) was defined as new or worsened wall-motion abnormalities (WMAs) consistent with ischemia during DSE. Classification and regression tree (CART) analysis identified variables that best predicted future cardiac events. RESULTS: The average age was 68+/-12 years, with 338 women and 220 men. The overall cardiac event rate was 34% if SE was positive, and 10% if it was negative. The event rates for MI and death were 10% and 8%, respectively, if SE was positive, and 3% and 3%, respectively, if SE was negative. If an ischemic electrocardiogram (ECG) and a positive SE were present, the overall event rate was 42%, versus a 7% rate when ECG and SE were negative for ischemia. Rest WMA was the most useful variable in predicting future cardiac events using CART: 25% of patients with and 6% without a rest WMA had an event. Other important variables were a dobutamine EF <52.5%, a positive SE, an ischemic ECG response, history of hypertension and age. CONCLUSIONS: A positive SE provides useful prognostic information that is enhanced by also considering rest-wall motion, stress ECG response, and dobutamine EF. (+info)
Integrated evaluation of relation between coronary lesion features and stress echocardiography results: the importance of coronary lesion morphology.
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OBJECTIVES: The aim of this study was to analyze, in the same group of patients, the relationship between multiple variables of coronary lesion and results of exercise, dobutamine and dipyridamole stress echocardiography tests. BACKGROUND: Integrated evaluation of the relation between stress echocardiography results and angiographic variables should include not only the assessment of stenosis severity but also evaluation of other quantitative and qualitative features of coronary stenosis. METHODS: Study population consisted of 168 (138 male, 30 female, mean age 51+/-9 years) patients, on whom exercise (Bruce treadmill protocol), dobutamine (up to 40 mcg/kg/min) and dipyridamole (0.84 mg/kg over 10 min) stress echocardiography tests were performed. Stress echocardiography test was considered positive for myocardial ischemia when a new wall motion abnormality was observed. One-vessel coronary stenosis ranging from mild stenosis to complete obstruction of the vessel was present in 153 patients, and 15 patients had normal coronary arteries. The observed angiographic variables included particular coronary vessel, stenosis location, the presence of collaterals, plaque morphology according to Ambrose classification, percent diameter stenosis and obstruction diameter as assessed by quantitative coronary arteriography. RESULTS: Covariates significantly associated with the results of physical and pharmacological stress tests included for all three stress modalities presence of collateral circulation, percent diameter stenosis and obstruction diameter, as well as lesion morphology (p < 0.05 for all, except collaterals for dobutamine stress test, p = 0.06). By stepwise multiple logistic regression analysis, the strongest predictor of the outcome of exercise echocardiography test was only percent diameter stenosis (p = 0.0002). However, both dobutamine and particularly dipyridamole stress echocardiography results were associated not only with stenosis severity - percent diameter stenosis (dobutamine, p = 0.04; dipyridamole, p = 0.003) - but also, and even more strongly, with lesion morphology (dobutamine, p = 0.006; dipyridamole, p = 0.0009). As all of stress echocardiography results were significantly associated with percent diameter stenosis, the best angiographic cutoff in relation to the results of stress echocardiography test was: exercise, 54%; dobutamine, 58% and dipyridamole, 60% (p < 0.05 vs. exercise). CONCLUSIONS: Integrated evaluation of angiographic variables have shown that the results of dobutamine and dipyridamole stress echocardiography are not only influenced by stenosis severity but also, and even more importantly, by plaque morphology. The results of exercise stress echocardiography, although separately influenced by plaque morphology, are predominantly influenced by stenosis severity, due to a stronger exercise capacity in provoking myocardial ischemia in milder forms of coronary stenosis. (+info)
Functional status and quality of life in patients with heart failure undergoing coronary bypass surgery after assessment of myocardial viability.
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OBJECTIVES: The aim of this study was to evaluate whether preoperative clinical and test data could be used to predict the effects of myocardial revascularization on functional status and quality of life in patients with heart failure and ischemic LV dysfunction. BACKGROUND: Revascularization of viable myocardial segments has been shown to improve regional and global LV function. The effects of revascularization on exercise capacity and quality of life (QOL) are not well defined. METHODS: Sixty three patients (51 men, age 66+/-9 years) with moderate or worse LV dysfunction (LVEF 0.28+/-0.07) and symptomatic heart failure were studied before and after coronary artery bypass surgery. All patients underwent preoperative positron emission tomography (PET) using FDG and Rb-82 before and after dipyridamole stress; the extent of viable myocardium by PET was defined by the number of segments with metabolism-perfusion mismatch or ischemia. Dobutamine echocardiography (DbE) was performed in 47 patients; viability was defined by augmentation at low dose or the development of new or worsening wall motion abnormalities. Functional class, exercise testing and a QOL score (Nottingham Health Profile) were obtained at baseline and follow-up. RESULTS: Patients had wall motion abnormalities in 83+/-18% of LV segments. A mismatch pattern was identified in 12+/-15% of LV segments, and PET evidence of viability was detected in 30+/-21% of the LV. Viability was reported in 43+/-18% of the LV by DbE. The difference between pre- and postoperative exercise capacity ranged from a reduction of 2.8 to an augmentation of 5.2 METS. The degree of improvement of exercise capacity correlated with the extent of viability by PET (r = 0.54, p = 0.0001) but not the extent of viable myocardium by DbE (r = 0.02, p = 0.92). The area under the ROC curve for PET (0.76) exceeded that for DbE (0.66). In a multiple linear regression, the extent of viability by PET and nitrate use were the only independent predictors of improvement of exercise capacity (model r = 0.63, p = 0.0001). Change in Functional Class correlated weakly with the change in exercise capacity (r = 0.25), extent of viable myocardium by PET (r = 0.23) and extent of viability by DbE (r = 0.31). Four components of the quality of life score (energy, pain, emotion and mobility status) significantly improved over follow-up, but no correlations could be identified between quality of life scores and the results of preoperative testing or changes in exercise capacity. CONCLUSIONS: In patients with LV dysfunction, improvement of exercise capacity correlates with the extent of viable myocardium. Quality of life improves in most patients undergoing revascularization. However, its measurement by this index does not correlate with changes in other parameters nor is it readily predictable. (+info)