Rate-Related and Autonomic Effects on Atrioventricular Conduction Assessed Through Beat-to-Beat PR Interval and Cycle Length Variability

Atrioventricular Conduction Variability. Introduction: Atrioventricular AV) conduction time varies on a beat-by-beat basis in response to the influences of cardiac efferent autonomic activity and rate-dependent electrical recovery processes. The goals of this study were to distinguish these effects on AV conduction time and to compare the variability in sinoatrial and AV nodal function. Methods and Results: The PR interval on the surface ECG served as an index of AV conduction time in this study of 14 adult human subjects undergoing a random interval breathing protocol. P and R waves were located by a template-matching algorithm. Spectral analysis allowed frequency-domain comparisons between PR and RR interval variability. Spectra of PR and RR intervals had similar power distributions, although the power of the RR interval spectra was much greater. Autonomic blockade with atropine plus propranolol reduced the power of both spectra. Standing significantly decreased the spectral power from 0.15 to 0.5 Hz for PR and RR spectra, and introduced a peak near 0.1 Hz in the mean PR and RR spectra, although the latter finding was significant only for the RR interval spectra. Propranolol had no significant effects on the PR and RR interval spectra. Linear regression analysis allowed quantification of the autonomic and recovery effects on AV conduction and showed which effect predominated. Simple linear regression confirmed in adults a previous finding in children that conduction time may be either positively or negatively correlated with cycle length. By multiple regression and transfer function analysis, the inverse relation seen in some subjects was attributed to the effect of recovery from the preceding cycle. With the preceding recovery period accounted for, the conduction time and cycle length of the current beat were positively correlated, presumably due to the parallel autonomic effects on the sinoatrial and AV nodes. The magnitude of the recovery effect predicted by the regression analysis was similar to published values. Conclusion: A noninvasive evaluation of the surface ECG can be used to compare variability in AV conduction time and cycle length and characterize the effects of autonomic efferent activity and rate-related recovery on AV nodal function.     

Developmental Toxicology Studies of Vancomycin Hydrochloride Administered Intravenously to Rats and Rabbits

Pregnant CD rats were given vancomycin intravenously in dosesof 0, 40, 120, or 200 mg/kg on Gestation Days (GD) 6–15;pregnant New Zealand white rabbits were given 0, 40, 80, or120 mg/kg intravenously on GD 6–18. Cesarean sectionswere performed on rats and rabbits on GD 20 and 28, respectively.In rats, maternal toxicity was indicated in the 120- and 200-mg/kgtreatment groups by cortical tubular nephrosis. Maternal bodyweight gain and food consumption and fetal viability, weight,and morphology were not adversely affected by vancomycin. Maternaland developmental no observed adverse effect levels (NOAELs)in the rat were 40 and 200 mg/kg, respectively. In rabbits,maternal toxicity was indicated by cortical tubular nephrosisin the 80- and 120-mg/kg treatment groups; a single death anddepression of body weight gain and food consumption occurredin the 120-mg/kg treatment group. Developmental toxicity wasindicated by depression of fetal weight in the 120-mg/kg treatmentgroup; fetal viability and morphology were not adversely affectedby vancomycin. Maternal and developmental NOAELs in the rabbitwere 40 and 80 mg/kg, respectively. Based on these data, vancomycindid not exhibit selective toxicity toward the developing rator rabbit conceptus.     

Flecainide

Flecainide. Flecainide is a Class IC antiarrhythmic agent whose primary electrophysiologic effect is a slowing of conduction in a wide range of cardiac tissues. It is well absorbed and effective in suppressing isolated premature ventricular contractions (PVCs) or nonsustained ventricular arrhythmia but has only a modest efficacy when electrophysiologic testing is used as an endpoint. Us adverse effect on mortality in the CAST trial suggested a propensity to proarrhythmia-a phenomenon to which the Class IC agents appear particularly prone. Despite the applicability of the CAST study only to patients with a prior myocardial infarction, there has been a shift away from flecainide in ventricular arrhythmia, but the low noncardiac side effect profile of the agent allows for its continued use in a wide variety of supraventricular arrhythmias. ( J Cardiovasc Electrophysiol, Vol. 5, pp. 964–981. November 1994 )     

DISTANCE LEARNING: THE ROLE OF TELEMEDICINE

Growing awareness of the potential benefits of advanced medicine, emerging democracies, growing middle classes and an ageing population world-wide are significant forces shaping future demand for world-class health care. Coupled with an increased awareness of the potential benefits of advanced modern medical technologies, these factors will have a dramatic impact on medical education systems. Traditional academic institutions might not represent the optimal approach to education in the 21st century. They are expensive to build and run, typically reward academic excellence not exceptional health care delivery, teach matriculating students on site, and tend to perpetuate themselves. The expertise of centres of excellence needs to be disseminated more widely, to a 'student' or client base interacting with the institution only episodically. As relevant geographic distances increase, access to such centres becomes more difficult. To attack this problem on a global basis, we must be able to teach and interact at a distance. Telemedicine is likely to form an essential part of the solution.     

A Subset of Patients With Recurrent Spontaneous Abortion Is Deficient in Transforming Growth Factor β-2-Producing “Suppressor Cells” in Uterine Tissue Near the Placental Attachment Site

PROBLEM : To determine if patients with unexplained recurrent miscarriage have a deficiency of decidual immunosuppressor cells that produce transforming growth factor β type 2, as has been found in mice with abortion due to rejection and/or trophoblast failure. METHODS : Decidual biopsy specimens were taken as near to the placental attachment site as possible under ultrasound guidance from first trimester legal termination (control) patients with recurrent miscarriage and non-viable pregnancy, and from patients with sporadic missed abortion. The tissue was tested for TGFβ-2⁺ suppressor cells by in situ hybridization, immunohistochemistry, and analysis of supernatants. RESULTS : TGFβ-2-related suppressor molecules similar but not identical to those identified in pregnant mice were released by decidual lymphoid cells. Fifty percent of 14 recurrent miscarriage patients showed a lack of suppressor cells and 59% were subnormal in comparison to 20 controls and 5 sporadic miscarriage patients, where 80–85% of the patients had detectable suppressor cells. CONCLUSIONS : Suppressor cell deficiency is compatible with a role for rejection and/or trophoblast failure in some patients with recurrent miscarriage. Presence of suppressor cells in most patients with missed abortion (4/5) is compatible with an alternative cause of fetal death, similar to findings reported in genetic fetal death mice.     

The Inhalation Toxicology, Genetic Toxicology, and Metabolism of Difluoromethane in the Rat

Difluoromethane (HFC32) is under development as a replacementfor chlorofluorocarbons (CFCs) in some refrigeration applications.It has been evaluated by standard studies of toxicity, developmentaltoxicity, and genotoxicity. In addition, the metabolism anddisposition of HFC32 was investigated and a physiologicallybased pharmacokinetic (PB-PK) model constructed. Inhalationof HFC32 (up to 50,000 ppm) caused no organ-specific effects,but resulted in slight maternal toxicity to the pregnant ratand rabbit and some fetotoxicity to the rat. HFC32 did not sensitizethe heart to adrenaline. The pharmacokinetics of [¹⁴C]difluoromethane(10,000 to 50,000 ppm/6 hr) revealed that about 2.1% of theinhaled HFC32 was absorbed and that steady state blood levelswere achieved within 2 hr and were proportional to dose. Carbondioxide was the major metabolite of HFC32 at all exposure levels.Carbon monoxide was not detected. The in vivo data were usedto validate a PB-PK model to describe the uptake and metabolismof HFC32. Absorption and distribution are adequately describedusing rat blood:air and tissue:air partition coefficients. Metabolism,which was linear across the dose range, was described by a firstorder rate constant (K_f=8.98 hr^–1). Of the absorbed HFC32,about 63% was metabolized at all doses; however, when metabolismwas expressed as a percentage of the inhaled dose it was muchlower, being about 1.4% of the HFC32 entering the airways. Overall,the results indicate that HFC32 is of very low toxicity andshould be an acceptable alternative to CFCs.     

Is There Space for Surgery in the Treatment of Tachyarrhythmias?

Curative treatment of both supraventricular and ventricular tachyarrhythmias started with the introduction of surgical therapy. Surgical treatment modalities were often very successful and associated with low mortality and morbidity, especially in patients with various supraventricular tachyarrhythmias. However, results were acceptable in patients with ventricular tachyarrhythmias, with often a very complex and extended arrhythmogenic area associated with structural heart disease. Because of the development and proven effectiveness of catheter ablation and defibrillator implantation, the role of surgical therapy became limited. In the treatment of supraventricular arrhythmias, surgical therapy is an option after failure of catheter ablation. Since His-bundle catheter ablation is only a palliative treatment for atrial fibrillation, the potentially curative Maze operation may be an acceptable alternative. However, its potential against formation of intracavitary thrombi has not yet been proven. In the treatment of ventricular tachyarrhythmias, ischemia related polymorphic ventricular tachycardia and ventricular fibrillation can be treated very effectively by revascularization. Map-guided surgery is an appropriate treatment modality for patients with monomorphic ventricular tachycardia and an extended arrhythmogenic area. However, patients with very poor left ventricular function may have an unacceptable perioperative risk. In patients with congenital long QT syndrome who are refractory to beta blocking agents, left-sided sympathectomy is the most appropriate choice.