Biomedical subjects
K Nademanee
Publications and source records attributed to K Nademanee.
Characterization of silent ischemia in patients with unstable angina: prognostic and therapeutic implications.
The occurrence of silent ischemia in various ischemic myocardial syndromes has attracted increasing attention. In unstable angina hemodynamic monitoring has suggested that the symptomatic and silent episodes of ischemia do not differ significantly. In two discrete studies we determined the characteristics and prognostic significance of silent ischemic episodes in unstable angina. In one study with 41 patients, there were 781 episodes of ischemia in Holter recordings: 392 (50%) with ST-segment depression, 242 (31%) with ST-elevation, 45 (6%) with ST-elevation and depression in different leads, 70 (9%) with pseudonormalization of T waves and 32 (4%) with T wave augmentation. Ventricular arrhythmias were associated with 18% of the episodes. The mean duration of ischemia was 14 minutes (range 30 seconds to almost twelve hours), the majority being less than five minutes. Only 154 (20%) of the 781 episodes of ischemia were associated with pain. Conversely, 77 episodes of chest pain were not associated with electrocardiographic changes. Analysis of the temporal sequence of heart rate during the development of ischemia (analysed in 415 episodes) showed that in only 43 (10%) the heart rate at the beginning of ischemia was significantly (exceeding 6 beats/minute) greater than that at five minutes (baseline) preceding the onset of ischemia. At the peak of ischemia, the mean heart rate increase was 10% and returned to baseline at the end of the ischemic episode. The data indicate that 80% of ischemic episodes in unstable angina are silent and over 90% are not triggered by increases in heart rate indicating that increased oxygen demand is an uncommon cause of ischemia in unstable angina.(ABSTRACT TRUNCATED AT 250 WORDS)
Prevalence and prognostic significance of silent myocardial ischemia in patients with unstable angina.
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Amiodarone, thyroid hormone indexes, and altered thyroid function: long-term serial effects in patients with cardiac arrhythmias.
Amiodarone, a drug that has electrophysiologic actions resembling those of hypothyroidism, increases serum levels of T4 and reverse T3 (rT3) and decreases T3. The drug's long-term effects on thyroid function are poorly defined. Serial thyroid hormone indexes in 76 patients given amiodarone for 6 to 32 months (mean +/- standard deviation 16 +/- 7) for arrhythmias were determined serially. Over this period, 68 patients (89%) remained euthyroid; hypothyroidism developed in 6 (8%) and hyperthyroidism developed in 2 (3%). In patients who remained euthyroid, thyroid hormone alterations attained steady-state values at 3 months: T4 increased 42% (p less than 0.01), rT3 increased 172% (p less than 0.01) and T3 decreased 16% (p less than 0.05), without significant effect on thyroid stimulating hormone. For the euthyroid patients, the 90% tolerance limits (95% confidence) over the follow-up period for T4 was 5 to 19 micrograms/dl (normal 4 to 12), for T3 36 to 163 ng/dl (normal 60 to 160), for rT3 22 to 131 ng/dl (normal 15 to 50) and for thyroid stimulating hormone 0 to 14 microU/ml (normal 1 to 6). The changes in hormone indexes in hyperthyroid or hypothyroid patients were unrelated to the cumulative dose or duration of drug therapy. The most reliable diagnostic indexes for amiodarone-induced altered thyroid state were: thyroid stimulating hormone level over 20 microU for hypothyroidism and T4 over 20 ng/dl or high T3 over 200 ng/dl for hyperthyroidism. All levels were within the 90% tolerance limits derived for these hormones from patients remaining euthyroid on amiodarone long-term.(ABSTRACT TRUNCATED AT 250 WORDS)
Hemodynamic and electrocardiographic correlates of symptomatic and silent myocardial ischemia: pathophysiologic and therapeutic implications.
Numerous hemodynamic, electrocardiographic, metabolic and radionuclide measurements in various subsets of patients with coronary artery disease (CAD) reveal that ischemia does not always occur on the basis of increases in myocardial oxygen consumption. Continuous hemodynamic monitoring indicates that most episodes of myocardial ischemia are not preceded by increases in such major determinants of oxygen consumption as heart rate or blood pressure, but that these usually increase in response to the development of ischemia. The development of pain during ischemia is a late feature and most episodes are silent. There are no significant differences in the hemodynamic characteristics of symptomatic versus asymptomatic episodes of myocardial ischemia in patients with angina at rest or between those associated with ST-segment depression and those with ST-segment elevation. Continuous Holter recordings analyzed by compact analog technique in hospitalized and ambulatory patients with ischemic heart disease indicate that in both unstable and chronic stable angina, over two-thirds of myocardial ischemic episodes are clinically silent. Symptomatic and silent episodes do not differ significantly with respect to duration. Most symptomatic and asymptomatic episodes are not triggered by increases in the determinants of oxygen demand. Such episodes may arise on the basis of a critical reduction in the lumen of the diseased coronary artery leading to a primary reduction in blood flow. Intermittent obstruction due to changes in coronary vasomobility or possibly formation of thrombi may be a common mechanism for the pathogenesis of myocardial ischemia in patients with a varying spectrum of coronary artery lesions. At present, the precise clinical and prognostic significance of silent ischemia in CAD is not completely defined.(ABSTRACT TRUNCATED AT 250 WORDS)
Characteristics and clinical significance of silent myocardial ischemia in unstable angina.
The frequency and duration of transient myocardial ischemia on Holter recordings, analyzed by the compact analog technique, were determined in 41 patients (all men, mean age 54) with unstable angina (33 with angiographic evidence). There were 781 episodes of ischemia: 392 (50%) with ST-segment depression, 242 (31%) with ST elevation, 45 (6%) with ST elevation and depression in different leads, 70 (9%) with pseudonormalization of T waves and 32 (4%) with T-wave augmentation. Ventricular arrhythmias were associated with 18% of the episodes. The mean duration of ischemic episodes was 14 minutes (range 30 seconds to almost 12 hours); most were less than 5 minutes. Only 154 (20%) of the 781 episodes of ischemia were associated with pain. Conversely, 77 episodes of chest pain were not associated with electrocardiographic changes. Analysis of the temporal sequence of heart rate during the development of ischemia (analyzed in 415 episodes) showed that in only 43 (10%) the heart rate at the beginning of ischemia was significantly (greater than 6 beats/min) higher than that at 5 minutes (baseline) before the onset of ischemia. At the peak of the ischemic abnormality, the mean heart rate increase was 10% and returned to baseline at the end of the ischemic episode. The data indicate that 80% of ischemic episodes in unstable angina are silent and over 90% are not triggered by increases in heart rate; apparently increased oxygen demand is an uncommon cause of ischemia in unstable angina. Although most of the episodes were short-lived, some were extremely protracted without the development of myocardial infarction. The findings are of therapeutic significance.
Beta-adrenergic blockade in unstable angina pectoris.
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Calcium antagonists and beta blockers in the control of mild to moderate systemic hypertension, with particular reference to verapamil and propranolol.
The antianginal and antiarrhythmic role of calcium antagonists is well established. Recent preliminary studies have indicated that, like beta blockers, calcium antagonists may produce short- and long-term hypotensive effects in patients with mild to moderate essential hypertension. The pharmacologic properties of calcium antagonists provide a clear rationale for their use in the control of essential hypertension. The comparative hypotensive effects of verapamil (80 to 160 mg 3 times a day) and propranolol (40 to 120 mg 3 times a day) were evaluated over 4 weeks, preceded by a 4-week placebo phase, in a double-blind protocol in 17 patients with mild to moderate hypertension. Verapamil (n = 10) reduced the mean sitting systolic blood pressure by 10.7% (p less than 0.01) and standing by 7.6% (p less than 0.04). The corresponding data for propranolol (n = 7) were 4.8% (not significant) and 5% (p = 0.04). Verapamil reduced the sitting diastolic blood pressure by 10.8% (p less than 0.01), propranolol by 7.5% (p = 0.01); the standing diastolic blood pressure was reduced by 10.7% with verapamil (p less than 0.01) and by 8.6% (p = 0.01) with propranolol. With verapamil the mean heart rate fell from 77.60 +/- 8.42 to 70.20 +/- 4.85 beats/min (p = 0.03); with propranolol it fell from 76.85 +/- 6.91 to 66.29 +/- 4.54 beats/min (p less than 0.01). Although a trend towards a slightly greater hypotensive effect was apparent with verapamil compared with propranolol, the difference was not statistically significant. It is concluded that verapamil and propranolol exert comparable hypotensive potency in patients with mild to moderate hypertension.
Atrioventricular block complicating amiodarone-induced hypothyroidism in a patient with pre-excitation and rate-dependent bilateral bundle branch block.
As a clinical entity atrioventricular (AV) block due to hypothyroidism is rare. Such a case induced by hypothyroidism complicating long-term therapy with amiodarone in a 45 year old woman with pre-excitation is presented. Electrophysiologic data obtained before and during thyroxine replacement therapy showed that hypothyroidism lengthens the effective refractory period of the atria, AV node, bypass tract and His-Purkinje system (that in the ventricle not being measured); this lengthening resembles the effects of long-term administration of amiodarone. These observations suggest that depressed thyroid function may be protective against arrhythmias but a patient with preexisting conduction system disease may develop AV block. The tendency to develop AV block in a patient who is euthyroid was reduced by bypass tract conduction. These findings are significant not only in monitoring amiodarone effects during chronic prophylactic drug therapy but also in providing further insight into the complex interrelation between the action of the drug and the thyroid hormones on cardiac muscle.
Thyroxine and triiodothyronine kinetics in cardiac patients taking amiodarone.
Cardiac patients taking amiodarone, a potent anti-arrhythmic drug, often have supranormal serum thyroxine (T4) levels and normal or mildly reduced serum triiodothyronine (T3) levels. We studied T4 and T3 kinetics and conversion of T4 to T3 in 5 men with recurrent paroxysmal tachycardia before and after 5-6 weeks of therapy with amiodarone (dose 200-800 mg/day). The patients were also receiving various medicines for cardiac disease. Each was injected with tracer doses of labelled T4 and T3; serum samples were processed by TCA precipitation and ethanol extraction. The data were analyzed with the aid of six-compartment model for T4 and T3 kinetics. Mean total body T3 production rate, total body T3 pool size, and conversion of T4 to T3 were all reduced in patients taking amiodarone.
Newer concepts in the pathogenesis of myocardial ischaemia. Implications for the evaluation of antianginal therapy.
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Arrhythmia control by selective lengthening of cardiac repolarization: role of N-acetylprocainamide, active metabolite of procainamide.
In recent years, data has become available to support the concept that a selective lengthening of the cardiac action potential (a Class III antiarrhythmic action) by whatever mechanism with an attendant increase in the effective refractory period constitutes a distinct antiarrhythmic mechanism. Such an action is exemplified clinically by hypocalemia and hypothyroidism and pharmacologically by amiodarone, sotalol and bretylium, all of which have other associated features. The N-acetylation of procainamide leads to the pharmacologically active compound, N-acetylprocainamide (NAPA). The loss of propensity to block depolarization with the preservation of the effect on repolarization in the case of NAPA makes the compound a class III antiarrhythmic agent. The process of N-acetylation has also led to longer elimination half-life and predominantly renal excretion with linear kinetics but with the preservation of the antiarrhythmic properties of the parent compound. The electrophysiologic data are consistent with the results of studies which have demonstrated that NAPA has the potential to suppress premature ventricular contractions and prevent spontaneously occurring as well inducible ventricular tachycardia in patients with heart disease. The effects on atria indicate that the drug has the potential to electively reverse atrial flutter and fibrillation to normal rhythm and maintain stability of sinus rhythm. The overall experimental and clinical data warrant further evaluation of NAPA as an antiarrhythmic agent.
Comparative electrophysiologic profiles of calcium antagonists with particular reference to bepridil.
The calcium antagonist bepridil hydrochloride differs pharmacologically from the conventional agents that block the myocardial slow channel. Its clinical electrophysiologic effects are poorly defined. The effects of 2 mg/kg + 1 mg/kg of intravenously administered bepridil in 10 patients were compared with those of 3 mg/kg + 1 mg/kg in 9 patients undergoing electrophysiologic evaluation of clinical symptoms. The overall effects of the 2 regimens did not differ significantly. The drug reduced the heart rate slightly; it had no effect on the PR interval but significantly lengthened the AH interval by 2 to 10%, HV by 2 to 12% and QTc by 5 to 8%. The most striking effect was the prolongation of the functional (up to 17%, p less than 0.001) and the effective (up to 13%, p less than 0.001) refractory periods of the atrioventricular node with a lengthening of the Wenckebach cycle (up to 17%, p less than 0.001). In contrast to the action of verapamil, bepridil significantly prolonged the ventricular (4 to 7%, p less than 0.01 to p less than 0.001) and the atrial (12 to 19%, p less than 0.05 to p less than 0.001) effective refractory periods. The data indicate that bepridil hydrochloride has a wide spectrum of electrophysiologic activity in man consistent with inhibitory actions on myocardial slow and fast channels and a significant lengthening of cardiac repolarization. These overall effects suggest that the antiarrhythmic profile of the drug is likely to be wider than those of conventional calcium antagonists.
Second-generation calcium antagonists: search for greater selectivity and versatility.
Calcium antagonists have a variable specificity for cardiac and peripheral activity. Based on such activity, these compounds, new and old, can be classified into 4 categories. Type 1 agents, typified by verapamil, its congeners (tiapamil and gallopamil) and diltiazem, prolong atrioventricular nodal conduction and refractoriness with little effect on ventricular or atrial refractoriness. These actions, to a large extent, account for the antiarrhythmic properties of this type of calcium antagonists. Type 2 agents include nifedipine and other dihydropyridines. In vivo, these agents are devoid of electrophysiologic effects in usual doses and concentrations. They are potent peripheral vasodilators with some selectivity of action for different vascular beds; their overall hemodynamic effects are dominated by this peripheral vasodilatation and reflex augmentation of sympathetic reflexes. Type 3 agents are flunarizine and cinnarizine (piperazine derivatives); in vitro and vivo, they are potent dilators of peripheral vessels, with no corresponding calcium-blocking actions in the heart. Type 4 agents (perhexiline, lidoflazine and bepridil) have a broader pharmacologic profile; they block calcium fluxes in the heart, in the peripheral vessels or in both. They may inhibit the fast channel in the heart and have other electrophysiologic actions. A clear understanding of the varied pharmacologic properties of the different classes of calcium antagonists is likely to provide a rational basis for the use of the newer agents in clinical therapeutics.(ABSTRACT TRUNCATED AT 250 WORDS)
Mexiletine: double-blind comparison with procainamide in PVC suppression and open-label sequential comparison with amiodarone in life-threatening ventricular arrhythmias.
The antiarrhythmic effects of mexiletine (n = 14) were compared to procainamide (n = 16) by a double-blind parallel protocol in 30 patients (group I) with frequent premature ventricular contractions (PVCs) (greater than 20/hr), and to amiodarone by an open-label sequential approach in 25 patients (mean left ventricular ejection fraction of 32.6 +/- 13.4%) with life-threatening ventricular arrhythmias (group II) resistant to two or more conventional agents. The predetermined end point of therapy in group I patients was met in 6 of 14 (43%) given mexiletine, with 7 (50%) requiring drug discontinuation for severe gastrointestinal or central nervous system side effects and only 3 of 16 patients (19%) given procainamide, with 5 (31%) developing limiting side effects. Increases in dose led to a higher efficacy rate for PVC suppression with a corresponding increase in side effects with mexiletine; with procainamide, the higher dose was not associated with greater PVC suppression. In group II patients, mexiletine was effective in 4 (16%), with one patient discontinuing the drug during long-term therapy; mexiletine was ineffective in 16 (64%) and early side effects developed in 5 (20%). Patients not responding to or not tolerating mexiletine were given amiodarone; 20 of 21 (95%) responded with arrhythmia control after the loading dose. During a mean follow-up period of 2 years, sudden death occurred in two patients, death from heart failure in two, and death from subarachnoid hemorrhage in one patient; 15 (75%) patients are alive and free of arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)
Control of cardiac arrhythmias by selective lengthening of repolarization: theoretic considerations and clinical observations.
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Electrophysiologic and antiarrhythmic effects of sotalol in patients with life-threatening ventricular tachyarrhythmias.
Sotalol is a unique beta-blocker that lengthens cardiac repolarization and effective refractory period (ERP). Its efficacy after intravenous (1.5 mg/kg) and oral (160 to 480 mg bid) administration was therefore evaluated in 37 patients with refractory recurrent ventricular tachycardia/fibrillation (VT/VF). Thirty-five patients, 33 with inducible VT/VF, underwent electrophysiologic testing. Intravenous sotalol lengthened the ERP in the atrium (+24.6%, p less than .01), atrioventricular node (+24.9%, p less than .01), and ventricle (+14.9%, p less than .01). It also significantly lengthened sinus node recovery time, corrected QT interval (QTc), and the AH interval, but not the HV interval. Sotalol prevented reinduction of VT/VF in 15 patients (45.5%). Twenty-five of the 33 patients (15 with positive results of electrophysiologic tests; 10 with negative results) were given oral sotalol. The drug was ineffective in seven (26.9%) and aggravated arrhythmia in one (3.8%). In four patients sotalol was withdrawn because of side effects; arrhythmias recurred late in two (7.7%). Eleven patients (42.3%) have continued on oral sotalol over a mean follow-up period of 9.2 +/- 8.6 months. Sotalol reduced (n = 21) total premature ventricular complex (PVC) count on the Holter electrocardiogram by 73% (p less than .01), paired PVCs by 89% (p less than .01), and beats of ventricular tachycardia by 95% (p less than .01). In 52% (n = 11), total reduction in PVCs was at least 85%, and incidence of paired and tachycardiac beats was reduced at least 90% (group A). In the remainder (n = 10), PVC suppression was not significant (group B). Group A included nine patients with nonreinducible VT/VF and two in whom it was reinducible; in group B, eight of 10 patients had reinducible VT/VF. The difference between the two groups (Fisher exact test) was significant (p less than .01). The prevention of reinduction of VT/VF by intravenous sotalol and suppression of spontaneously occurring arrhythmias by the oral drug were both predictive of long-term drug efficacy. Sotalol is a significant advance in the short- and long-term management of life-threatening ventricular tachyarrhythmias.
Electrophysiologic effects of amiodarone: experimental and clinical observation relative to serum and tissue drug concentrations.
Oral amiodarone is a potent antiarrhythmic agent with a slow onset of action. Its electrophysiologic properties following chronic administration are well known, but its acute electrophysiologic actions are poorly defined. The objectives of the present study were to correlate the electrophysiologic actions of intravenous amiodarone in humans with the acute and chronic effects of the drug relative to plasma and tissue concentrations of the drug. In humans (n = 10), 5 mg/kg intravenous amiodarone (serum concentration 6.50 +/- 3.34 micrograms/ml at 10 minutes; 2.13 +/- 0.71 micrograms/ml at 20 minutes, n = 7) increased the AH interval by 16.4% (p less than 0.005), the antegrade effective refractory period (ERP) of the atrioventricular (AV) node by 14.4% (p less than 0.025), and the functional refractory period (FRP) of the AV node by 15.5% (p less than 0.005). The ERP or FRP of the atrium of the right ventricle was not significantly changed; there was no effect on the HV interval or the QT and R-R intervals of the ECG. In rabbits (n = 11) given 10 mg/kg intravenous amiodarone (mean +/- SD serum concentration 0.49 +/- 0.17 micrograms/ml; mean myocardial concentration 7.0 +/- 1.9 micrograms/gm, n = 3), there were no significant effects on the ECG intervals. In isolated rabbit sinoatrial (SA) node, atria, and AV node (three preparations) superfused with 5 X 10(-6)M amiodarone (3.41 micrograms/ml), there was no effect on the action potential duration (APD) or other parameters of the transmembrane potential.(ABSTRACT TRUNCATED AT 250 WORDS)