Depression of action potential characteristics and a decreased space constant are present in postischemic, reperfused myocardium.

Brief periods of ischemia and reperfusion may lead to arrhythmias and delayed epicardial activation. To determine the nature of the electrophysiologic substrate and to gain insight into potential mechanisms underlying the electrophysiologic and hemodynamic abnormalities that develop in this setting, standard microelectrode techniques were used to measure action potential characteristics, conduction velocity, and space constants in canine isolated epicardial preparations removed after a 15-min anterior descending artery occlusion and 20-min reflow period in vivo. Our results demonstrate a significant reduction in conduction velocity (0.78 +/- 0.38 vs. 0.31 +/- 0.12 m/s, P less than 0.001), space constant (1.05 +/- 0.42 vs. 0.45 +/- 0.12 mm, P = 0.004), resting membrane potential (81.3 +/- 2.5 vs. 61.7 +/- 7.8 mV, P less than 0.001), action potential amplitude (94.1 +/- 4.2 vs. 64.1 +/- 1.5 mV, P less than 0.001), and dV/dT (164.7 +/- 37.3 vs. 52.6 +/- 19.7 V/s, P less than 0.001) in postischemic reperfused myocardium. The space constant and dV/dT each correlated with conduction velocity; in addition, the space constant was an independent predictor of conduction velocity in these tissues. These electrophysiologic abnormalities may play a role in the arrhythmias and abnormalities of contraction present in postischemic, reperfused myocardium.

Evidence for structural dissociation of two biologic actions of growth hormone.

The effects of purified growth hormone and its CNBr fragments on somatomedin induction and on the stimulation of hepatic and renal ornithine decarboxylase (L-ornithine carboxylase, EC 4.1.1.17) activity in rats have been investigated. At the doses tested, none of the CNBr fragments induced somatomedin as evidenced by lack of an effect on sulfate, leucine, and thymidine incorporation into cartilage of hypophysectomized rats. However, the largest fragment, consisting of two peptides corresponding to Residues 6-124 and 150-179 linked by a disulfide bridge, stimulated both renal and hepatic ornithine decarboxylase activity in hypophysectomized rats and the activity of the hepatic enzyme in intact animals. A smaller CNBr fragment corresponding to Residues 125-149 slightly stimulated the activity of renal ornithine decarboxylase but failed to increase activity of the hepatic enzyme. A similar slight stimulation of the activity of the renal, but not the hepatic, enzyme was produced by a large carboxyl-terminal fragment (molecular weight 8000) prepared by proteolytic cleavage of partially purified ovine growth hormone. Circular dichroic spectra of the CNBr fragments demonstrated that the largest fragment retained much of the ordered secondary structure of intact growth hormone while two smaller CNBr fragments were devoid of ordered secondary structure. These observations indicate that different biological activities of growth hormone may be dissociated by fragmentation of the parent molecule.

Candidacidal activity prompted by N-terminus histatin-like domain of human salivary mucin (MUC7)1.

Histidine-rich peptides (histatins, Hsn) in saliva are thought to provide a non-immune defense against Candida albicans. Sequence homology search of the human salivary mucin, MUC7, against histatins revealed a domain at the N-terminus (R3-Q17) having 53% identity to Hsn-5. To determine its candidacidal activity, this 15 residue basic histidine-rich domain of MUC7 (I) was prepared by solid-phase Fmoc chemistry. Various N- and C-terminal protected derivatives of I were also synthesized to correlate the effect of peptide overall charge in exhibiting cidal potency. Candidacidal activity measurement of I and its variants showed considerable ED50 values (effective dosage required to kill 50% of candida cells), albeit greater than Hsn-5 (ED50 approximately 4-6 microM). Of the various analogs tested, N-terminal free acid (I, ED50 approximately 40 microM) and amide (V, ED50 approximately 16 microM) exhibited appreciable candidacidal activities suggesting the possible role of peptide net charge in cidal action. Blocking of N-terminus with a bulky octanoyl group showed only marginal effect on the cidal activity of I or V, indicating that hydrophobicity of these synthetic constructs may not be important for exerting such activities. Membrane-induced conformational transition from random coil to helical structures of all the test peptides implied their tendency to adapt order structures at the lipid-membrane interface similar to that of Hsn-5. However, comparison of propensity for helical structure formation vs. ED50 indicated that cidal potency of MUC7 Hsn-like peptides depends largely on electrostatic interactions irrespective of secondary structural elements. Delineation of solution structure of the most active peptide (V) by 2D-NMR revealed essentially a non-structured conformation in aqueous medium, which further supported the fact that the peptide helical structure may not be a prerequisite for posing candidacidal activity. The formation of smaller truncated peptides and/or Hsn-like fragments on proteolytic degradation of intact MUC7 in the presence of oral flora provided indirect evidence that mucin could serve as a backup candidacidal agent to salivary Hsn.

Effect of streptozotocin-induced diabetes on renal ornithine decarboxylase activity.

The effects of streptozotocin(SZ)-induced diabetes on renal ornithine decarboxylase (ODC) activity, the rate-limiting enzyme in polyamine biosynthesis, were studied. Sixteen hours after the injection of SZ, renal ODC activity increased 50% above that of the vehicle-injected controls. The maximum increase in activity--600%--was observed from 24 to 72 h after SZ. Within a week, ODC activity fell below control levels and remained suppressed during a 3 wk follow-up period. Insulin treatment within 10 h of the SZ injection prevented the increase of ODC activity; however, insulin given after enzyme activity had increased did not restore ODC activity to control levels. The early increase of ODC activity occurred in the presence of mild hyperglycemia without ketosis or hyperglucagonemia, but the levels were much higher in severely diabetic animals. Adrenalectomy, performed before the initial increase in enzyme activity, prevented the subsequent increase in diabetic animals; however, when adrenalectomy was performed after the enzyme had increased, enzyme activity did not normalize.

Clinical interactions between pacemakers and automatic implantable cardioverter-defibrillators.

Concomitant use of a pacemaker and an automatic implantable cardioverter-defibrillator (AICD) is common. Seventeen percent of patients receiving an AICD at The Johns Hopkins Hospital also had a permanent pacemaker implanted before (16 patients), at the same time as (2 patients) or after (12 patients) AICD implantation. Four types of interactions were noted: 1) transient failure to sense or capture immediately after AICD discharge (seven patients); 2) oversensing of the pacemaker stimulus by the AICD, leading to double counting (one patient); 3) AICD failure to sense ventricular fibrillation resulting from pacemaker stimulus oversensing (three patients, one only at high asynchronous output); and 4) pacemaker reprogramming caused by AICD discharge (three patients). No clinical sequelae of these interactions were noted during follow-up study. Thus, potentially adverse clinical interactions are common and routine screening is recommended. With proper attention to lead placements and programming of the devices, clinical consequences of these interactions can be avoided.

Reversal of dysfunction in postischemic stunned myocardium by epinephrine and postextrasystolic potentiation.

After brief coronary occlusions, myocardium may become "stunned," exhibiting prolonged depression of function despite the absence of necrosis. Because of the accompanying decline in adenosine triphosphate and adenine nucleotide precursors, a deficiency of energy supply has been proposed as the basis for postischemic dysfunction. This study examined whether sufficient functional and metabolic reserve exists in stunned myocardium to sustain a prolonged, maximal inotropic response to epinephrine and postextrasystolic potentiation. In 11 open chest dogs, the left anterior descending coronary artery was occluded for 5 minutes, followed by 10 minutes of reflow, repeated 12 times, with a final 1 hour recovery period. Regional myocardial function was measured using pairs of ultrasonic dimension crystals implanted in ischemic and nonischemic zones. During repetitive reflows a progressive decrease in mean systolic segment shortening occurred: baseline 21.8%, 1st reflow 15.2%, 12th reflow 4.3%, 1 hour recovery 7.9%. Intravenous epinephrine, titrated to produce a maximal inotropic response, caused segment shortening to increase to 21.6% after 10 minutes and to 24.8% after 1 hour of infusion, despite a 20 mm Hg increase in systolic pressure. The same dose of epinephrine given before ischemia increased segment shortening to 30.5%. In six of the dogs, postextrasystolic potentiation before ischemia increased segment shortening from 21.8 to 31.1%, and after 1 hour of recovery from ischemia, from 7.9 to 24.8%. Lesser increases in segment shortening were also seen in nonischemic segments. The results indicate that stunned myocardium possesses considerable functional reserve. Deficient energy stores are therefore not likely to be the basis for depressed function seen at rest in stunned myocardium.

Differential effects of procainamide, lidocaine and acetylstrophanthidin on body surface potentials and epicardial conduction in dogs with chronic myocardial infarction.

Twenty-eight anesthetized mongrel dogs were studied 2 to 74 months after experimental myocardial infarction in order to examine the effects of procainamide, lidocaine and acetylstrophanthidin on conduction within the infarcted region and the way such effects relate to changes in body surface potentials and antiarrhythmic efficacy. In each animal, 100 to 200 QRS complexes in the X, Y, Z leads were signal averaged, vector summed and high pass filtered at 50 Hz. Susceptibility to ventricular arrhythmia was evaluated using routine programmed ventricular extrastimulation in the anesthetized open chest animal. Epicardial electrograms were sequentially recorded at 45 standard sites within the infarcted region and referenced to the beginning of the QRS complex. Of the three agents, only procainamide exhibited antiarrhythmic action whereas lidocaine and acetylstrophanthidin produced inconsistent effects. Procainamide prolonged the time at which activity in the epicardial electrographic recordings ended relative to the beginning of the body surface QRS complex. This effect was significantly greater in electrograms that ended late in the QRS complex in the control state than for those that ended earlier. Such preferential effect on more abnormal sites was reflected on the body surface as a greater effect of procainamide in prolonging the lower energy terminal portion of the signal-averaged QRS complex than the earlier high energy portion. In contrast, lidocaine significantly prolonged the time at which electrograms ended only for those relatively normal electrograms that ended early in the QRS complex in the control state. In the signal-averaged body surface QRS complex, lidocaine produced a small but significant prolongation of the early high energy portion of the QRS complex but no change in the late portion. Acetylstrophanthidin produced a significant prolongation in early-ending electrograms and, surprisingly, significantly shortened the end time of electrograms that ended late in the QRS complex in the control state. Such effects were not reflected, however, on the body surface because acetylstrophanthidin had no significant effect on either the early or the late portion of the QRS complex. It is concluded that procainamide's differential effect between early- and late-ending electrograms is detected on the body surface by a greater prolongation in the terminal portion of the QRS complex. The signal-averaged body surface QRS complex is less sensitive in detecting the more subtle effects on conduction caused by lidocaine and acetylstrophanthidin.(ABSTRACT TRUNCATED AT 400 WORDS)

Double sequential external shocks for refractory ventricular fibrillation.

OBJECTIVES: A technique for terminating refractory ventricular fibrillation is described. BACKGROUND: Refractory ventricular fibrillation can occur in up to 0.1% of electrophysiologic studies. Animal studies have shown that rapid sequential shocks may reduce ventricular fibrillation threshold. METHODS: Five patients of 2,990 consecutive patients in a 3-year period experienced refractory ventricular fibrillation during 5,450 routine electrophysiologic studies. Multiple shocks were delivered by means of a single defibrillator. Double sequential shocks were delivered externally 0.5 to 4.5 s apart by means of two defibrillators with separate pairs of electrodes. RESULTS: In all patients, standard defibrillation was unsuccessful, but all were successfully resuscitated using the double sequential shocks. CONCLUSIONS: This report stresses the importance of an additional defibrillator being readily available during electrophysiologic testing. This technique of rapid, double sequential external shocks may have general applicability, providing a simple and potentially lifesaving approach to refractory ventricular fibrillation.

Intravenous amiodarone for recurrent sustained hypotensive ventricular tachyarrhythmias. Intravenous Amiodarone Multicenter Trial Group.

OBJECTIVES: We sought to determine the response rate and safety of intravenous amiodarone in patients with ventricular tachyarrhythmias refractory to standard therapies. BACKGROUND: Numerous small retrospective reports suggest a response of refractory ventricular tachyarrhythmias to intravenous amiodarone, yet no controlled prospective trials exist. METHODS: Two hundred seventy-three patients with recurrent hypotensive ventricular tachyarrhythmias refractory to lidocaine, procainamide and bretylium were randomized to receive one of three doses of intravenous amiodarone: 525, 1,050 or 2,100 mg/24 h (mean [+/- SE] dose 743.7 +/- 418.7, 1,175.2 +/- 483.7, 1,921.2 +/- 688.8 mg, respectively) by continuous infusion over 24 h. RESULTS: Of the 273 patients, 110 (40.3% response rate) survived 24 h without another hypotensive ventricular tachyarrhythmic event while being treated with intravenous amiodarone as a single agent (primary end point). A significant difference in the time to first recurrence of ventricular tachyarrhythmia (post hoc analysis) over the first 12 h was observed when the combined 1,050- and 2,100-mg dose groups were compared with the 525-mg dose group (p = 0.046). The number of supplemental (150 mg) infusions of intravenous amiodarone (given for breakthrough destabilizing tachyarrhythmias) during hours 0 to 6 (prespecified secondary end point) was significantly greater in the 525-mg dose group than in the 2,100-mg dose group (1.09 +/- 1.57 vs. 0.51 +/- 0.97, p = 0.0043). However, there was no clear dose-response relation observed in this trial with respect to success rates (primary end point), time to first recurrence of tachyarrhythmia (post hoc analysis) or mortality (secondary end point) over 24 h. CONCLUSIONS: Intravenous amiodarone is a relatively safe therapy for ventricular tachyarrhythmias refractory to other medications.

The genetics of levamisole resistance in the nematode Caenorhabditis elegans.

We have characterized a small group of genes (13 loci) in the nematode Caenorhabditis elegans that, when mutated, confer resistance to the potent anthelmintic levamisole. Mutants at the 7 loci conferring the most extreme resistance generally possess almost identical visible and pharmacological phenotypes: uncoordinated motor behavior, most severe in early larval life, extreme resistance to cholinergic agonists and sensitivity to hypo-osmotic shock. Mutants with exceptional phenotypes suggest possible functions for several of the resistance loci. The most extreme mutants can readily be selected by their drug resistance (211 mutants, as many as 74 alleles of one gene). The more common resistance loci are likely to be unessential genes, while loci identified by only a few alleles may be essential genes or genes conferring resistance only when mutated in a special way. We propose that these mutants represent a favorable system for understanding how a small group of related genes function in a simple animal. The extreme drug resistance of these mutants makes them useful tools for the genetic manipulation of C. elegans. And, as the most resistant class of mutants might lack pharmacologically functional acetyl-choline receptors (LEWIS et al. 1980), these mutants may also be of some neurobiological significance.

Electrophysiological effect of varied rate and extent of acute in vivo left ventricular load increase.

STUDY OBJECTIVE: The aim was to determine whether the rate, the magnitude, or both, of increased left ventricular wall stress in vivo has consistent and prominent effects on repolarisation, afterdepolarisations, or arrhythmogenicity. DESIGN: Ten anaesthetised dogs underwent transient proximal aortic occlusion. Wall stress was estimated from pressure-volume data obtained by volume catheter, normalised to preocclusion values, and correlated with simultaneously determined changes in monophasic action potential duration (MAPd). Data were obtained during both fast (greater than 50% rise in wall stress within two beats) and slow occlusions, as well as during innervated and denervated conditions. EXPERIMENTAL MATERIAL: Adult mongrel dogs (20-25 kg) were used. MEASUREMENTS AND MAIN RESULTS: Two- to threefold increases in wall stress resulted in less than 5 ms shortening in MAPd and there was little correlation between wall stress and MAPd shortening. The strongest relation between normalised wall stress (EWSnorm) and MAPd was observed under denervated conditions during rapid aortic occlusion (delta MAPd = -2.5 x EWSnorm +2.1, r2 = 0.44, p less than 0.001). Afterdepolarisations were observed in fewer than 10% of occlusions and were not related to the magnitude or rate of loading change. Ventricular ectopy occurred more frequently during rapid than slow occlusions (87% v 56%, p = 0.01), but was unrelated to the level of wall stress increase or the presence of afterdepolarisations. CONCLUSIONS: Marked acute increases in left ventricular loading in vivo minimally alter repolarisation, and rarely lead to afterdepolarisations. The speed rather than magnitude of load change appears more important in the development of ventricular ectopy. These findings suggest that load induced ventricular ectopy is due to stretch induced automaticity rather than triggered activity or re-entry.

Effect of streptozotocin-induced diabetes on hepatic ornithine decarboxylase activity in the rat.

The effect of diabetes on rat hepatic ornithine decarboxylase (ODC) activity was studied in male rats 4 h to 8 days after the ip or iv administration of streptozotocin. Hepatic ODC activity increased 4-fold above control on the fourth day of diabetes. Increased ODC activity was observed with a dose of streptozotocin (70 mg/kg iv) which increased plasma ketones and glucagon and reduced plasma insulin. No change was seen with doses causing only mild hyperglycemia without change in plasma ketones, glucagon, or insulin. Insulin therapy prevented the increase in hepatic ODC activity in diabetic rats. Adrenalectomy or hypophysectomy also prevented the diabetes-associated increase of ODC activity. The studies suggest that insulin deficiency may result in increased hepatic polyamine synthesis.

The mechanism of ACTH stimulation of adrenal ornithine decarboxylase activity.

The mechanism of action of adrenocorticotrophin (ACTH) stimulation of rat adrenal orticotrophin (ACTH) stimulation of rat adrenal ornithine decarboxylase activity was investigated. ACTH induction or ornithine decarboxylase activity was not prevented by administration of drugs that inhibit adrenal steroid biosynthesis. A dose of ACTH that produced maximal levels of adrenal cyclic AMP did not induce ornthine decarboxylase activity. Ovine growth hormone, which caused no increase in adrenal cyclic AMP, stimulated adrenal ornithine decarboxyase activity. These observations suggest that the increase in adrenal ornithine decarboxylase activity stimulated by ACTH is not dependent upon steroidogenesis, nor is it dependent on the early peak of cyclic AMP, although it may be influenced by the sustained levels of tissue cyclic AMP that follow the administration of large doses of ACTH. Furthermore, it appears there may be a pathway of ornithine decarboxylase activation in the adrenal which is entirely independent of cyclic AMP mediation. The effects of hypophysectomy on adrenal ornithine decarboxylase response to ACTH were examined. In rats given ACTH 16 h after hypophysectomy, the increase in ornithine decarboxylase activity was delayed when compared with the response in animals given ACTH 1 h after hypophysectomy. Actinomycin D given during the first 3 h after ACTH in the 16 h hypophysectomized rat abolished the expected increase in ornithine decarboxylase activity. Thereafter, a progressive increase in ornithine decarboxylase activity was observed as the interval between ACTH and Actinomycin D administration was further increased. In contrast, Actinomycin D administered 15 min before ACTH in the 1 h hypophysectomized rat had no effect on the subsequent increase in ornithine decarboxylase activity, and actually progressively enhanced the response the longer its administration after ACTH was delayed. Cycloheximide abolished the response to ACTH in both the 1 h and the 16 h hypophysectomized rat. Thus, it appears that ACTH stimulates a post-transcriptional mechanism regulating ornithine decarboxylase activity in the acutely hypophysectomized animal, whereas, in the chronically hypophysectomized rat, ACTH must first stimulate transcription of new messenger RNA which is involved in regulation of adrenal ornithine decarboxylase synthesis.

Hormonal regulation of renal ornithine decarboxylase activity in the rat.

The regulation of the activity of the renal enzyme ornithine decarboxylase (L-ornithine carboxy-lyase, EC 4.1.1.17) was examined in the rat. In the intact animal adapted to a light/dark cycle of 14 hours and 10 hours, respectively, the level of renal ornithine decarboxylase activity was rhythmical and paralleled the diurnal rhythm in plasma corticosteroid concentration. Renal ornithine decarboxylase activity and plasma corticosterone were highest during the early hours of darkness and lowest during the hours of light. Following hypophysectomy, the level of renal ornithine decarboxylase activity declined rapidly and remained low and without a demonstrable diurnal rhythm. When pituitary hormone levels were temporarily restored in the hypophysectomized rat by the injection of pituitary extract, renal ornithine decarboxylase activity increased rapidly, reached a peak within 8 hours, and returned toward pre-injection levels by 12 hours. Exogenous growth hormone, ACTH and cortisol each increased renal ornithine decarboxylase activity in the hypophysectomized rat, with the highest levels of activity being achieved with growth hormone. Other pituitary hormones (FSH, LH, TSH and prolactin) were ineffective. After bilateral adrenalectomy, renal ornithine decarboxylase activity retained a rhythmical pattern similar to that observed in the intact rat, but the levels were increased. Growth hormone and cortisol increased renal ornitine decarboxylase activity in the adrenalectomized-hypophysectomized animal to the same extent as in the hypophysectomized animal, but ACTH was almost totally ineffective. These data suggest that the pituitary plays a major role in the regulation of renal ornithine decarboxylase activity in the rat, primarily through the rhythmical secretion of growth hormone and ACTH.

Decreased high density lipoprotein cholesterol in hypopituitarism.

Serum triglyceride, cholesterol, and high density lipoprotein cholesterol (HDL-C) levels were measured in 10 men and 3 women with hypopituitarism. The mean total cholesterol and triglyceride levels were significantly increased but were within the range of controls. The mean HDL-C concentration and the HDL-C to total cholesterol ratio were significantly decreased. Similar findings were present in a patient with isolated GH deficiency. Two men with Kallman's syndrome and 3 patients with active acromegaly had values that were either within or just below the normal range. Replacement therapy with thyroid hormone and prednisone resulted in a normalization of HDL-C concentrations in four of the five patients studied. This improvement suggests a role for thyroid hormone and/or glucocorticoids in the maintenance of normal HDL-C concentrations. These observations also suggest that the distribution of plasma lipoprotein fractions is dependent in part, either directly or indirectly, on pituitary hormones.

Relation between growth hormone levels and Von Willebrand factor activity.

The relationship between growth hormone and von Willebrand factor activity was studied in fasting plasma samples, nocturnal samples, and after intramuscular injection of growth hormone. A significant correlation was seen between the two levels in fasting samples. During sleep, peaks of growth hormone were associated with peaks of von Willebrand factor activity. A subject with isolated growth hormone deficiency had no peaks of either. Intramuscular injection of growth hormone produced a rise of von Willebrand factor activity in all subjects studied. These results indicate that there is a relationship between growth hormone and von Willebrand factor activity.

Urinary kallikrein excretion in insulin-dependent diabetes mellitus and its relationship to glycemic control.

The renal kallikrein-kinin system is thought to be involved in vasoregulatory and epithelial ion-transporting processes. Renal kallikrein has not been studied in patients with diabetes mellitus, a disease in which abnormalities of renal hemodynamics and electrolyte handling occur. The urinary excretion of this kallikrein was measured in 20 type I diabetic patients and 10 normal subjects. On a 120-meq Na diet, daily kallikrein excretion, determined by both esterase activity and direct RIA, in 12 poorly controlled diabetic patients [hemoglobin A1c (HbA1c) = 14.2 +/- 0.5% (mean +/- SEM)] was significantly greater (P less than 0.05) than excretion in 8 diabetic patients in good to moderately good control (HbA1c = 9.4 +/- 0.5%) or in 10 normal subjects. In these groups, urinary esterase activities were 9.4 +/- 1.0, 6.1 +/- 1.4, and 6.7 +/- 0.5 esterase units/24 h, respectively. Corresponding excretion values of immunoreactive kallikrein were 171 +/- 14, 118 +/- 26, and 123 +/- 11 micrograms/24 h. Creatinine clearances were similar in the three groups. Urinary kallikrein was also measured in 8 diabetic and 8 normal subjects during 7 subsequent days of 10 meq Na intake. It increased less in diabetic patients than in normal subjects during Na depletion (P less than 0.02). The increase in urinary kallikrein in the diabetic patients was inversely related to their HbA1c levels (r = 0.88; P less than 0.01). The effect of glycemic control on urinary kallikrein excretion was determined in nine diabetic patients. Initial glycemic control was achieved using an artificial endocrine pancreas (Biostator) and was maintained by continuous sc insulin infusion with a portable pump. Before glycemic control, urinary kallikrein was 190 +/- 30 micrograms/24 h (by RIA). After 8-12 days of glycemic control, excretion fell to 144 +/- 23 micrograms/24 h (P less than 0.02). The abnormalities in kallikrein excretion in diabetic patients were not correlated with differences in water, electrolyte, protein, glucose, or aldosterone excretion in any of the studies. These results show that kallikrein excretion was increased in patients with poorly controlled insulin-dependent diabetes, and excretion rose less in diabetic subjects with low Na intake than in normal subjects. Strict glycemic control decreased urinary kallikrein excretion. These findings suggest that the renal kallikrein-kinin system is functioning abnormally in diabetes mellitus.

Serial lung function testing in patients treated with amiodarone: a prospective study.

PURPOSE: Amiodarone has proven to be effective in many cases of cardiac arrhythmias, refractory ventricular tachycardia, and ventricular fibrillation. Pulmonary toxicity is a possible side effect of the drug, with a reported incidence of 2 to 15 percent per year. To determine the effect of amiodarone on lung function, we prospectively studied serial lung function tests in a cohort of 91 patients with refractory cardiac arrhythmias treated with this agent. PATIENTS AND METHODS: Spirometry and carbon monoxide diffusing capacity (DLCO) were measured at zero, three, six, 12, 18, and 24 months, with a mean follow-up of 351 days. RESULTS: For the whole population taking a mean dose of amiodarone of 367 mg daily (range: 136 to 512 mg), there was no accelerated rate of decline in spirometric indices or DLCO. Analysis of lung function changes by multivariate analysis demonstrated that an accelerated decline in DLCO values occurred in elderly patients (p less than 0.05) but not in patients with pre-existing lung disease or cigarette smokers. In four patients (4.5 percent), clinical evidence of amiodarone pulmonary toxicity developed that was associated with a fall in DLCO of greater than 20 percent. All four patients recovered after the drug was stopped. Another 15 patients, without clinical evidence of pulmonary toxicity, had a sustained decline in DLCO of greater than 20 percent. These 15 patients remained asymptomatic over the next 11 months without interruption of therapy. A greater than 20 percent fall in DLCO was a sensitive test for clinically evident amiodarone pulmonary toxicity, but had a positive predictive value of only 21 percent. CONCLUSION: An isolated fall in DLCO, in the absence of clinical evidence of toxicity, does not necessitate stopping amiodarone. An unchanged DLCO value appears to be a reliable negative predictor of pulmonary toxicity.

Failure to visualize adrenal glands in a patient with bilateral adrenal hyperplasia.

A patient with clinical and biochemical evidence of Cushing's disease and severe hyperlipidemia underwent an adrenal imaging procedure with NP-59 (6 beta-[131I]iodomethyl-19-norcholesterol), without visualization of either gland. Correction of the hyperlipidemia followed by repeated adrenal imaging resulted in bilateral visualization. A pituitary tumor was removed at surgery, confirming the diagnosis of Cushing's disease.

Compatibility of a nonthoracotomy lead system with a biphasic implantable cardioverter-defibrillator. Cadence-Endotak 60-Series IDE investigators.

This prospective multicenter study was conducted under the Food and Drug Administration Investigational Device Exemption to evaluate the safety and efficacy of the combination of the Cadence implantable defibrillator (Ventritex, Inc.) and 60-series Endotak C leads (Cardiac Pacemakers, Inc.). Implantation was attempted in 148 patients with hemodynamically compromising ventricular tachycardia or fibrillation (VF), or with pace-terminable ventricular tachycardia. The system was successfully implanted in 97% of patients, with 96% of implants in a transvenous-lead-alone configuration. At implantation, the defibrillation threshold was 455 +/- 94 V (14 +/- 6 J) for lead-alone patients and 532 +/- 40 V (19 +/- 3 J) for those requiring a subcutaneous patch. VF conversion efficacy was reconfirmed in patients who underwent a 3-month chronic induction study. The system successfully detected all 763 induced arrhythmias and terminated 99.5% of them; after system modification, successful conversion was demonstrated in the 2 patients who initially had induced episodes requiring external defibrillation (1 lead revision; 1 reprogramming). All spontaneous episodes were terminated with an implantable-cardioverter defibrillator. Postshock VF redetection times were significantly shorter than initial detection times (4.5 +/- 1.8 seconds detection, 2.1 +/- 0.7 seconds redetection; p<0.0001). During an 8-month mean follow-up (range 1 to 31 months), 2 unwitnessed deaths were classified as sudden cardiac deaths, and 11 patients experienced a total of 12 complications, none of which was associated with the Cadence-Endotak combination.