Biomedical subjects
K Nademanee
Publications and source records attributed to K Nademanee.
Hypothalamic-pituitary function during alcohol exposure and withdrawal and cocaine exposure.
This chapter examines the neuroendocrine effects of acute exposure to and withdrawal from alcohol and cocaine, with special emphasis on the hypothalamic-pituitary-adrenal (HPA) axis. We present the results from two preliminary controlled inpatient studies that document HPA dysfunction during acute exposure to alcohol and cocaine and during withdrawal from alcohol. We discuss the methodological approach of these studies in comparison to related attempts in the literature to use measures of thyroid and prolactin regulation to predict risk of relapse to alcohol and cocaine use, respectively. Our data and the results of related studies are presented in the context of a proposed index of HPA axis dysfunction that may provide a useful clinical measure of susceptibility to relapse during protracted abstinence from alcohol or cocaine.
Cardiovascular effects and toxicities of cocaine.
Cocaine exerts a myriad of adverse cardiovascular effects which are dependent on the dose, rate of administration, and duration of use. The drug has two primary pharmacologic actions: it is a powerful sympathomimetic agent and a local anesthetic. The drug blocks the presynaptic reuptake of catecholamines resulting in the marked hormonal increase at the postsynaptic receptor sites. These effects, in turn, lower the threshold for coronary vasoconstriction and vasospasm, myocardial ischemia and infarction. In addition, the drug's multiple pharmacologic and electrophysiologic cardiovascular actions can promote arrhythmias, myocarditis, cardiomyopathy, as well as unmasking subclinical diseases. Long-term cocaine use can cause autonomic disturbances and alter catecholamine homeostasis: chronic cocaine addicts face serious cardiovascular sequelae from the drug's multiple adverse effects. It is important to assess the prevalence of cocaine-related cardiovascular diseases, to understand how the drug affects the autonomic nervous system, and to determine its long-term effects on the cardiovascular system.
Identifying sites for catheter ablation of ventricular tachycardia.
The approach to localizing sites for catheter ablation of ventricular tachycardia foci depends on the type of tachycardia. In large reentry circuits such as those arising from infarct scars, areas of slow conduction in and around the scar should be targeted. During sinus rhythm, these can be suspected from the presence of fractionated electrograms and, at some sites, long stimulus to QRS delays during pacing. Slow conduction areas can be classified as: 1. central slow conduction zone sites, 2. exits from the slow conduction zone, 3. entrances to the slow conduction zone, and 4. bystander areas which are not involved in the tachycardia circuit. In the central slow conduction zone stimulation entrains or resets tachycardia with a long stimulus to QRS (S-QRS) delay (40 to greater than 300 ms) without altering the QRS morphology (entrainment with concealed fusion). At slow conduction zone exits, presystolic electrograms are recorded during VT, the pacemap matches the VT QRS morphology, and with pacing during VT the S-QRS interval is relatively short and VT may or may not be entrained. At entrances to the slow conduction zone electrogram timing is variable but early diastolic electrograms are expected and the pace-map QRS may differ from the VT QRS morphology. Relatively late stimuli or slow trains of stimuli entrain VT with concealed fusion with a relatively longer S-QRS interval than observed in the central slow conduction zone. Early stimuli may entrain VT while altering the QRS morphology due to propagation of the stimulated antidromic wavefront out of the scar from a site other than the tachycardia exit. At bystander sites electrogram timing, pace-mapping, and the effects of programmed stimulation are variable but may occasionally mimic reentry circuit sites. Relatively late stimuli are likely to capture the site without altering the VT. If discrete electrograms are present, analysis of these during pacing may provide further evidence that the site is not in the reentry circuit. Catheter ablation will probably be most effective at central slow conduction zone sites. When VT originates from a small focus surrounded by normal myocardium, such as is likely for idiopathic RV outflow tract and some idiopathic left ventricular tachycardias, presystolic electrical activity and pacemapping are likely to identify the tachycardia focus. For macroreentry involving the bundle branches, the right bundle branch can be easily targeted.
Refractory ventricular fibrillation in the electrophysiology laboratory: a nightmare from which we can awaken.
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Ventricular arrhythmias in ischemic heart disease.
Ventricular arrhythmias remain the leading cause of death from coronary artery disease. This review summarizes current thinking in several areas relating to the pathophysiology, prognosis, and therapy of ventricular arrhythmias associated with acute and chronic coronary artery disease syndromes. The experimental basis of arrhythmias in the setting of acute myocardial ischemia and chronic myocardial infarction is described, stressing the important pathophysiologic differences between these two conditions. The effects of the autonomic nervous system as a key modulator of ischemic arrhythmogenesis are discussed. Insights, derived from endocardial mapping studies, into the nature of ventricular tachycardia in humans with chronic myocardial infarction are described, including implications for risk stratification and therapy to prevent arrhythmia recurrence. Current therapeutic principles are discussed in the management of ventricular arrhythmias associated with coronary artery disease, including pharmacologic approaches, surgical and catheter ablation, and automatic implantable cardioverting and defibrillating devices.
The amiodarone--class I agent combination increases refractoriness, conduction, and the number of electrophysiologic studies. But does it increase survival rate?
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Prevalence of myocardial ischemia in cocaine addicts.
The finding that most young cocaine addict patients had a negative exercise treadmill test suggests that they did not have preexisting obstructive coronary artery disease. Noninvasive testing did show, however, that these patients frequently had a high incidence of ST elevation episodes during the first 2 weeks of withdrawal. The pathophysiological mechanism of cocaine-induced cardiovascular disease is not yet clearly understood, but it is probably more complex than the drug's acute direct effects on the cardiovascular system. It may be complicated by fluctuations in catecholamine homeostasis and further temporally complicated by cycles of cocaine use and withdrawal. Research on how cocaine use alters catecholamine homeostasis will increase the understanding of the pathophysiology of cocaine and assist in developing effective pharmacologic and prophylactic treatment for its abuse.
Effects of sotalol on ventricular tachycardia and fibrillation produced by programmed electrical stimulation: comparison with other antiarrhythmic agents.
Sotalol, a beta blocker, is now recognized as an important class III agent. The drug lengthens the action potential in most cardiac tissues without affecting conduction. Several studies have shown that sotalol is very effective in treating life-threatening arrhythmias. One hundred thirty-eight patients with inducible and clinically sustained tachycardia were retrospectively analyzed. With the use of the S1S2S3 stimulation protocol for ventricular tachycardia (VT) induction, sotalol prevented VT/ventricular fibrillation (VF) induction in 45% of the patients; other class I agents prevented VT/VF induction in only 15 to 22%. Data were also analyzed from a prospective multicenter study comparing sotalol with procainamide in suppressing sustained VT in 153 patients with symptomatic sustained VT/VF. With the use of the S1S2S3S4 stimulation protocol, sotalol prevented VT/VF induction in 35% of the patients, whereas procainamide prevented VT/VF induction in only 22% (difference not significant). When patients whose VT induced by the triple-stimuli protocol were excluded, sotalol prevented VT induction in 53%. These findings indicate that the antiarrhythmic effects of sotalol are comparable to those of class I agents in treating malignant arrhythmias. Although more data are needed on the comparative effects of sotalol, available data establish sotalol as an important addition to available antiarrhythmic agents.
Treatment of catecholamine-sensitive right ventricular tachycardia by endocardial catheter ablation.
Endocardial catheter ablation with direct current high voltage shocks was performed in a patient with recurrent syncope due to a catecholamine-sensitive ventricular tachycardia that was drug refractory and occurred in the absence of identifiable heart disease. Pace mapping and catheter activation mapping of the spontaneous and isoproterenol-induced ventricular tachycardia located the tachycardia origin in the right ventricular outflow tract. Ablation dramatically reduced spontaneous ventricular tachycardia and ectopic activity (from 50,000 to less than 100 ectopic beats/24 h). The patient has remained symptom free and without ventricular tachycardia recurrence for 3 years. These observations and review of previous studies suggest that catheter mapping can easily locate the arrhythmia focus in the right ventricular outflow tract and that catheter ablation can be performed at low risk. Catheter ablation is a viable option for the treatment of right ventricular catecholamine-sensitive tachycardias that are unresponsive to antiarrhythmic drugs.
Frequency-dependent effects of quinidine on the ventricular action potential and QRS duration in humans.
We studied the frequency-dependent effects of quinidine on the right ventricular action potential and QRS duration in 10 patients (nine men and one woman; mean age, 57 +/- 14 years) undergoing electrophysiologic studies for clinical indications. The right ventricular monophasic action potential, electrocardiographic, and conventional intracardiac electrical signals from various sites were recorded at different pacing cycle lengths from 30 seconds to 1 minute before and after a 10-mg/kg i.v. quinidine infusion. We used the extrastimulus technique to determine the effects of quinidine on ventricular refractory periods at different pacing cycle lengths and on the abrupt changes of the action potential duration. The action potential duration progressively decreased as the ventricular pacing rate increased at baseline and after quinidine infusion. Quinidine significantly increased the action potential duration from that of control by 25 msec (p less than 0.02) at the relatively slow pacing cycle lengths of 600, 500, and 400 msec. Quinidine's effect on the action potential duration was attenuated at the pacing cycle length of 350 msec and became negligible at 300 msec. In contrast, quinidine progressively lengthened the QRS duration as the pacing rate increased (20, 18, 37, 46, and 34 msec at pacing cycle lengths of 600, 500, 400, 350, and 300 msec, respectively; p less than 0.05). There were no rate-dependent changes in the QRS duration during the control period. The relation between the ventricular refractory periods and the action potential duration at different pacing cycle lengths was also determined before and after quinidine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
A tale of the spontaneous variability of premature ventricular contractions.
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Myocardial ischemia during cocaine withdrawal.
STUDY OBJECTIVE: To determine the prevalence of myocardial ischemia in patients with cocaine addiction. DESIGN: Myocardial ischemia in chronic cocaine users was detected by serial 24-hour electrocardiographic ambulatory (Holter) monitoring and exercise treadmill testing in chronic cocaine users. The Holter tapes were coded, scanned in a blinded manner, and mixed with the tapes of 42 normal volunteers and 119 patients with either stable or unstable angina. SETTING: A 28-day inpatient, substance abuse treatment program followed by an outpatient treatment program. PATIENTS: Twenty-one consecutive male chronic cocaine users. MAIN RESULTS: Eight of the 21 patients with cocaine addiction had frequent episodes of ST elevation during Holter monitoring; these episodes occurred almost exclusively during the first 2 weeks of withdrawal. None of the volunteers and patients with stable angina and only 4% of the patients with unstable angina had episodes of ST elevation during Holter monitoring (cocaine users compared with volunteers, P = 0.0004). Of the 20 cocaine patients who had exercise treadmill testing, only 1 had a positive test for ischemia. CONCLUSIONS: Cocaine users frequently develop silent myocardial ischemia manifesting as episodes of ST elevation during the first weeks of withdrawal. The underlying mechanisms for these changes remain unknown, but our observations support the hypothesis that coronary vasospasm plays an important role in cocaine-related ischemic syndromes.
Variability of indexes for myocardial ischemia: a comparison of exercise treadmill test, ambulatory electrocardiographic monitoring and symptoms of myocardial ischemia.
Fifty-four patients with chronic stable angina were studied to determine and compare weekly variability of indexes for the detection of myocardial ischemia. All patients underwent three single-blind placebo periods, each lasting 1 week. An exercise treadmill test, 24 h ambulatory electrocardiographic (Holter) monitoring (analyzed blindly) and an accurate diary of anginal attacks and nitroglycerin use were obtained at the end of each placebo period. An unbalanced, completely random component of variance analysis was used to calculate a component for within subject variability and a component for among subject variability. The coefficient of variation and percent variation (within subjects) of onset of chest pain during exercise were 19% and 30%, respectively; the corresponding values were 28% and 33% for onset of 1 mm ST depression, 15% and 15% for exercise duration, 44% and 27% for number of ischemic episodes/24 h, 56% and 43% for anginal frequency and 55% and 27% for nitroglycerin consumption, respectively. With use of this statistical method and variation within subjects, the change in the value of each variable necessary to exceed those attributable to spontaneous variation was determined. The trade-off between repeated measurements and number of subjects, the sample size estimated for planning studies and the minimal sample size for using various designs were also determined. Although the data indicate that all indexes for myocardial ischemia, both during exercise and during daily activity, vary considerably, but the exercise variables have less variability and are more reproducible.(ABSTRACT TRUNCATED AT 250 WORDS)
Oral N-acetylprocainamide compared to quinidine plus digoxin in the chronic suppression of atrial flutter in humans.
Antiarrhythmic therapy for the suppression of atrial flutter has conventionally entailed the use of a class Ia agent such as quinidine or procainamide. However, atrial flutter often recurs despite the use of these conventional antiarrhythmic regimens. Experimental and clinical evidence suggests that the pharmacologic suppression of atrial flutter may depend on the prolongation of the atrial action potential duration and consequently the voltage-dependent refractoriness. Therefore, the efficacy and tolerance of the class III antiarrhythmic agent N-acetylprocainamide was compared to that of the conventional regimen of the class Ia agent quinidine combined with digoxin (to control ventricular response) in patients with a history of symptomatic sustained atrial flutter. The study was randomized but nonblinded, with a crossover to the alternate regimen if the first failed. Eighteen patients entered the study and were followed for up to 18 months. Of the 12 receiving N-acetylprocainamide (eight randomized and four crossovers), one (8%) failed therapy due to side effects, but none had atrial flutter. Of the 11 receiving quinidine and digoxin (10 randomized and one crossover), three (28%) had a recurrence of atrial flutter, two of whom also had intolerable side effects, and two more (18%) had side effects alone requiring withdrawal of therapy (total 46% failed). The probability of therapeutic success over time was greater (p less than 0.04) for N-acetylprocainamide than for quinidine and digoxin. The data suggest that N-acetylprocainamide may be more effective and better tolerated than the conventional regimen of quinidine plus digoxin. Therefore, large-scale blinded studies of the efficacy of N-acetylprocainamide in the suppression of atrial flutter may be warranted.
Slow conduction in the infarct scar: relevance to the occurrence, detection, and ablation of ventricular reentry circuits resulting from myocardial infarction.
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Fractionated endocardial electrograms are associated with slow conduction in humans: evidence from pace-mapping.
Fractionated ventricular electrograms recorded during catheter mapping may arise from areas of asynchronous depolarization associated with slow conduction, the substrate for reentrant ventricular tachycardia, but can also be a nonspecific abnormality or even artifact. To determine whether fractionated sinus rhythm electrograms are associated with slow conduction in humans, the results of endocardial catheter mapping and pacing at 133 endocardial sites in 13 patients were analyzed. Eleven patients had sustained monomorphic ventricular tachycardia and two patients had old myocardial infarction without ventricular tachycardia. Functional evidence of slow conduction at the recording site was assessed by pacing at that site and measuring the interval between the stimulus artifact (S) and the onset of the QRS complex in the 12 lead electrocardiogram (ECG). During pacing at 89 of 90 sites without fractionated sinus rhythm electrograms, the S-QRS interval was less than 40 ms, a value consistent with rapid propagation of the stimulated wave front away from the pacing site. During pacing at 21 (49%) of 43 sites with fractionated sinus rhythm electrograms, the S-QRS interval was greater than 40 ms (range 40 to 140), consistent with slow conduction at the pacing site (p less than 0.001 versus nonfractionated sites). In 9 of the 11 patients with ventricular tachycardia analysis of the paced QRS configuration, electrograms during induced ventricular tachycardia or programmed stimulation during tachycardia suggested that a site with a long S-QRS interval during pacing was located at or near a ventricular tachycardia circuit. Therefore, fractionated sinus rhythm electrograms are often associated with slow conduction, which may be the substrate for reentrant ventricular tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)
Programmed electrical stimulation at potential ventricular reentry circuit sites. Comparison of observations in humans with predictions from computer simulations.
The purpose of this study was to define specific types of resetting responses to programmed electrical stimulation during human ventricular tachycardia and to use computer simulations of reentry circuits to assess the possible mechanisms and pacing site location relative to the reentry circuit for each type of response. The effects of scanning single stimuli at 35 left ventricular endocardial sites during sustained monomorphic ventricular tachycardia in 12 patients were studied. In considering alterations in QRS configuration and the delay between the stimulus and the advanced QRS, we identified three types of resetting responses to scanning stimuli consistent with stimulation at sites in or near the reentry circuit at 12 abnormal endocardial sites in eight patients. Type 1: all capturing stimuli were followed after a delay by early QRS complexes that had the same configuration as the tachycardia complexes. Type 2: late stimuli reset tachycardia as in type 1 but early stimuli reset the tachycardia after altering the QRS configuration. Type 3: late stimuli reset tachycardia as in type 1, but early stimuli advanced tachycardia with a short stimulus to QRS delay without altering the QRS configuration. In the simulations, premature depolarization of sites in the circuit produced orthodromic and antidromic wavefronts. The orthodromic wavefront propagated through the circuit and exited the circuit at the same site as did the previous tachycardia wavefronts and advanced the tachycardia without altering the configuration of the advanced QRS. The antidromic wavefront of relatively late stimuli was confined within or near the circuit by collision with the orthodromic wavefront of the preceding tachycardia beat and failed to alter ventricular activation distant from the circuit. Therefore, the QRS configuration after the stimulus was unchanged. A type 1 response occurred when all capturing stimuli produced this effect. However, with increasing stimulus prematurity, the antidromic wavefront propagated farther before colliding with an orthodromic wavefront, and under some conditions, it exited the circuit from a site other than the original circuit "exit," and altered the ventricular activation sequence distant from the circuit and, therefore, the QRS configuration, producing a type 2 pattern. The type 3 pattern occurred when the antidromic wavefront of early premature beats captured the original circuit exit. The effect of a stimulus was dependent on the stimulus prematurity, the relative conduction times from the stimulation site to the potential sites of "exit" from the circuit, and the timing of the excitable gap at the stimulation site.(ABSTRACT TRUNCATED AT 400 WORDS)