John H. Lawrence

Sudden cardiac death in heart failure. The role of abnormal repolarization.

Congestive heart failure is a common, highly lethal cardiovascular disorder claiming over 200,000 lives a year in the United States alone. Some 50% of the deaths in heart failure patients are sudden, and most of these are probably the result of ventricular tachyarrhythmias. Methods designed to identify patients at risk have been remarkably unrewarding, as have attempts to intervene and prevent sudden death in these patients. The failure to impact favorably on the incidence of sudden death in heart failure patients stems largely from a lack of understanding of the underlying mechanisms of arrhythmogenesis. This article explores the role of abnormalities of ventricular repolarization in heart failure patients. We will examine evidence for the hypothesis that alteration of repolarizing K+ channel expression in failing myocardium predisposes to abnormalities in repolarization that are arrhythmogenic. The possible utility of novel electrophysiological and ECG measures of altered ventricular repolarization will be explored. Understanding the mechanism of sudden death in heart failure may lead to effective therapy and more accurate identification of patients at greatest risk.

Acceleration of widespread adenoviral gene transfer to intact rabbit hearts by coronary perfusion with low calcium and serotonin.

Previous attempts at adenoviral gene transfer to the intact heart have been limited by the requirement for prolonged exposure to high virus concentrations. In an ex vivo coronary perfusion model of intact adult rabbit hearts, we previously reported gene transfer to 96% of cardiac myocytes after a 60 min exposure to 1.6 × 109 p.f.u./ml Adβgal, a recombinant adenovirus encoding β-galactosidase. Here we sought to decrease the virus exposure time by enhancing microvascular permeability to increase the efficiency of adenoviral gene transfer. Baseline perfusion with 1.0 × 108 p.f.u./ml Adβgal in normal Krebs solution (1 mM calcium) caused infection of 22% of myocytes at 30 min and 40% at 60 and 120 min. Increasing the virus concentration, decreasing perfusate calcium concentration, or pretreating with serotonin or bradykinin in Krebs solution or L-NAME in heparinized rabbit blood significantly decreased the necessary exposure time. Under optimal conditions of serotonin pretreatment, 50 μmol/l perfusate calcium, and a virus concentration of 1.6 × 109 p.f.u./ml, 2 min of coronary perfusion sufficed to produce near-total infection. This profound enhancement of infection parameters has important implications for in vivo myocardial gene transfer, where a similar strategy could facilitate gene therapy for common myocardial disorders.

Local anesthetics as effectors of allosteric gating. Lidocaine effects on inactivation-deficient rat skeletal muscle Na channels.

Time- and voltage-dependent local anesthetic effects on sodium (Na) currents are generally interpreted using modulated receptor models that require formation of drug-associated nonconducting states with high affinity for the inactivated channel. The availability of inactivation-deficient Na channels has enabled us to test this traditional view of the drug-channel interaction. Rat skeletal muscle Na channels were mutated in the III-IV linker to disable fast inactivation (F1304Q: FQ). Lidocaine accelerated the decay of whole-cell FQ currents in Xenopus oocytes, reestablishing the wild-type phenotype; peak inward current at -20 mV was blocked with an IC50 of 513 microM, while plateau current was blocked with an IC50 of only 74 microM (P < 0.005 vs. peak). In single-channel experiments, mean open time was unaltered and unitary current was only reduced at higher drug concentrations, suggesting that open-channel block does not explain the effect of lidocaine on FQ plateau current. We considered a simple model in which lidocaine reduced the free energy for inactivation, causing altered coupling between activation and inactivation. This model readily simulated macroscopic Na current kinetics over a range of lidocaine concentrations. Traditional modulated receptor models which did not modify coupling between gating processes could not reproduce the effects of lidocaine with rate constants constrained by single-channel data. Our results support a reinterpretation of local anesthetic action whereby lidocaine functions as an allosteric effector to enhance Na channel inactivation.

Prospective randomized comparison of the safety and effectiveness of placement of endocardial pacemaker and defibrillator leads using the extrathoracic subclavian vein guided by contrast venography versus the cephalic approach

CALKINS, H., et al.: Prospective Randomized Comparison of the Safety and Effectiveness of Placement of Endocardial Pacemaker and Defibrillator Leads Using the Extrathoracic Subclavian Vein Guided by Contrast Venography Versus the Cephalic Approach. The purpose of this prospective randomized study was to compare the safety and efficacy of the cephalic approach versus a contrast‐guided extrathoracic approach for placement of endocardial leads. Despite an increased incidence of lead fracture, the intrathoracic subclavian approach remains the dominant approach for placement of pacemaker and implantable defibrillator leads. Although this complication can be prevented by lead placement in the cephalic vein or by lead placement in the extrathoracic subclavian or axillary vein, these approaches have not gained acceptance. A total of 200 patients were randomized to undergo placement of pacemaker or implantable defibrillator leads via the contrast‐guided extrathoracic subclavian vein approach or the cephalic approach. Lead placement was accomplished in 99 of the 100 patients randomized to the extrathoracic subclavian vein approach as compared to 64 of 100 patients using the cephalic approach. In addition to a higher initial success rate, the extrathoracic subclavian vein medial approach was determined to be preferable as evidenced by a shorter procedure time and less blood loss. There was no difference in the incidence of complications. In conclusion, these results demonstrate that lead placement in the extrathoracic subclavian vein guided by contrast venography is effective and safe. It was also associated with no increased risk of complications as compared with the cephalic approach. These findings suggest that the contrast‐guided approach to the extrathoracic portion of the subclavian vein should be considered as an alternative to the cephalic approach.

ACUTE RADIATION DERMATITIS FOLLOWING RADIOFREQUENCY CATHETER ABLATION OF ATRIOVENTRICULAR NODAL REENTRANT TACHYCARDIA

Radiation exposure during fluoroscopic imaging poses potential risks to patients and physicians, especially during protracted cardiovascular or radiological interventional procedures. We describe a woman with refractory paroxysmal supraventricular tachycardia who underwent radiofrequency catheter ablation of the slow pathway involved in atrioventricular nodal reentrant tachycardia. The patient subsequently returned 4 weeks later with acute radiation dermatitis that was retrospectively attributed to a malfunction in the fluoroscopy unit that lacked a maximum current output cut‐off switch. Using dose reconstruction studies and her estimated biological response, we determined that she received between 15 and 20 Gy (1 Gy = 100 rods) to the skin on her back during the procedure. The exposure will result in an increase in her lifelong risk of skin and lung cancer. This article underscores the potential for radiation‐induced injury during lengthy therapeutic procedures using x‐ray equipment.

Barriers to employment among working-aged patients with major burn injury

The purpose of this study was to examine the prevalence of preexisting and burn-related impairments and to describe their association with preburn employment status. Data gathered during the acute hospitalization were analyzed on a consecutive series of burn patients aged 16 to 64 years (N = 770) enrolled in a prospective, longitudinal, multicenter study. Patients who were unemployed before the injury were more likely than those who were employed to report being alcohol-dependent (36 vs 18%), abusing other drugs (22 vs 10%), having received psychiatric treatment in the past year (21 vs 6%), and having preexisting physical disability (23 vs 3%); all were significant at P < .001). Of the unemployed patients who received toxicologic screening at admission, 49% tested positive for alcohol and 39% positive for other drugs, percentages that were significantly higher than 26 and 31%, respectively, for the employed. With adjustment for age, sex, race, and education, variables that were most predictive of preinjury unemployment status were preexisting physical disability (odds ratio, 51.0; 95% confidence interval, 7.7-336.9) and being alcohol-positive at admission (odds ratio, 2.8; 95% confidence interval, 1.2-6.8). Unemployed and employed patients also differed significantly in injury patterns and clinical outcomes, with inhalation injury and psychiatric distress being more prevalent among the unemployed and both hand burns and hand surgery among the employed. The greater prevalence of preexisting impairments among survivors who were unemployed before the injury helps explain why preburn employment status is such a powerful determinant of postburn work outcomes, and suggests the need to include psychosocial services in a program of comprehensive rehabilitation.

Coupling between fast and slow inactivation revealed by analysis of a point mutation (F1304Q) in mu 1 rat skeletal muscle sodium channels.

1. We sought to elucidate the mechanism of the defective inactivation that characterizes sodium channels containing mutations in the cytoplasmic loop between the third and fourth domains (the III‐IV linker). Specifically, we measured whole‐cell and single‐channel currents through wild‐type and F1304Q mutant mu 1 rat skeletal muscle Na+ channels expressed in Xenopus laevis oocytes. 2. In wild‐type channels, inactivation is complete and the faster of two decay components predominates. In F1304Q, inactivation is incomplete; the slow decay component is larger in amplitude and slower than in wild‐type. The fraction of non‐inactivating current is substantial (37 +/‐ 2% of peak current at ‐20 mV) in F1304Q. 3. Cell‐attached patch recordings confirmed the profound kinetic differences and indicated that permeation was not altered by the F1304Q mutation. The F1304Q phenotype must be conferred entirely by changes in gating properties and is not remedied by coexpression with the beta 1‐subunit. 4. Recovery from inactivation of F1304Q channels is faster than for wild‐type channels and three exponentials are required to describe recovery adequately following long (5 s) depolarizations. Thus, there are three inactivated states even in ‘inactivation‐deficient’ F1304Q channels. 5. The steady‐state voltage dependence of F1304Q inactivation is right‐shifted by 26 +/‐ 2 mV. 6. A gating model incorporating three inactivated states, all directly accessible from multiple closed states or the open state, was constrained to fit wild‐type and F1304Q inactivation (h infinitive) data and repriming data simultaneously. While it was necessary to alter the rate constants entering and exiting all three inactivated states, the model accounted for the F1304Q‐induced rightward shift in steady‐state inactivation without imposing voltage dependence on the inactivation rate constants. 7. We conclude that the F1304Q mutation in mu 1 sodium channels modifies several inactivation processes simultaneously. The fact that a single amino acid substitution profoundly alters both fast and slow inactivation indicates that these processes share physical determinants in Na+ channels.

THE UPTAKE AND ELIMINATION OF KRYPTON AND OTHER INERT GASES BY THE HUMAN BODY

Chemically inert gases, such as nitrogen, helium, neon, argon, krypton and xenon, apparently do not participate at normal pressures in biochemical reactions of the human body. These gases are present in physical solution, chiefly in the body water and fat. In recent years much interest has been focused on the exchange of these gases between body fluids and external air, through the lungs, skin and intestinal wall. A number of important physiological processes may be studied by means of inert gas exchange measurements. During rapid decompression from several atmospheres to one atmosphere or from one atmosphere to a fraction of an atmosphere the dissolved inert gases originally in equilibrium may become relatively supersaturated so that under certain conditions gas bubbles may form in the blood and tissues (1). These may exert mechanical pressure on nerve endings or may cause pain by some other mechanism (2). Our investigations were initiated with the explicit desire to provide (a) classification procedures for selection of high altitude flyers on the basis of gas exchange rates; (b) information on methods of prevention of bends by accelerating the elimination of nitrogen or inert gas or by pre-breathing oxygen. In attempting to solve these two problems, which were of immediate practical importance, we could spend relatively little time on the study of the fundamental mechanisms of inert gas exchange. Answers to the problems a and b have been given elsewhere (3, 4) and the purpose of this paper is to describe some experiments which pertain to the mechanism of inert gas exchange in the human body.

Dispersion of ventricular activation and refractoriness in patients with idiopathic dilated cardiomyopathy

We sought to evaluate the electrophysiologic substrate for ventricular arrhythmias and sudden cardiac death in patients with idiopathic dilated cardiomyopathy. When compared with controls, patients with cardiomyopathy had prolonged activation times, increased dispersion of activation and recovery, and prolonged duration of monophasic action potential recordings at 70%, but not at 90%, of repolarization.

Regional Treatment Effects in Studies of Cardiorenal Drugs: A Summary of Recent Clinical Trials

To the Editor: The global treatment effect in a multinational trial design can be difficult to interpret when that global treatment effect does not reflect a consistent finding within the trial regional sites. This global treatment effect may not apply to the populations of each of the countries