C. Frank Starmer

Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation

The function of the 12 positive charges in the 53-residue III/IV interdomain linker of the cardiac Na(+) channel is unclear. We have identified a four-generation family, including 17 gene carriers with long QT syndrome, Brugada syndrome, and conduction system disease with deletion of lysine 1500 (DeltaK1500) within the linker. Three family members died suddenly. We have examined the functional consequences of this mutation by measuring whole-cell and single-channel currents in 293-EBNA cells expressing the wild-type and DeltaK1500 mutant channel. The mutation shifted V(1/2)h( infinity ) to more negative membrane potentials and increased k(h) consistent with a reduction of inactivation valence of 1. The shift in h( infinity ) was the result of an increase in closed-state inactivation rate (11-fold at -100 mV). V(1/2)m was shifted to more positive potentials, and k(m) was doubled in the DeltaK1500 mutant. To determine whether the positive charge deletion was the basis for the gating changes, we performed the mutations K1500Q and K1500E (change in charge, -1 and -2, respectively). For both mutations, V(1/2)h was shifted back toward control; however, V(1/2)m shifted progressively to more positive potentials. The late component of Na(+) current was increased in the DeltaK1500 mutant channel. These changes can account for the complex phenotype in this kindred and point to an important role of the III/IV linker in channel activation.

Multiple effects of KPQ deletion mutation on gating of human cardiac Na+ channels expressed in mammalian cells

Several aspects of the effect of the KPQ deletion mutation on Na+ channel gating remain unresolved. We have analyzed the kinetics of the early and late currents by recording whole cell and single-channel currents in a human embryonic kidney (HEK) cell line (HEK293) expressing wild-type and KPQ deletion mutation in cardiac Na+ channels. The rate of inactivation increased three- to fivefold between -40 and -80 mV in the mutant channel. The rate of recovery from inactivation was increased twofold. Two modes of gating accounted for the late current: 1) isolated brief openings with open times that were weakly voltage dependent and the same as the initial transient and 2) bursts of opening with highly voltage-dependent prolonged open times. Latency to first opening was accelerated, suggesting an acceleration of the rate of activation. The ΔKPQ mutation has multiple effects on activation and inactivation. The aggregate effects may account for the increased susceptibility to arrhythmias.Several aspects of the effect of the KPQ deletion mutation on Na+ channel gating remain unresolved. We have analyzed the kinetics of the early and late currents by recording whole cell and single-channel currents in a human embryonic kidney (HEK) cell line (HEK293) expressing wild-type and KPQ deletion mutation in cardiac Na+ channels. The rate of inactivation increased three- to fivefold between -40 and -80 mV in the mutant channel. The rate of recovery from inactivation was increased twofold. Two modes of gating accounted for the late current: 1) isolated brief openings with open times that were weakly voltage dependent and the same as the initial transient and 2) bursts of opening with highly voltage-dependent prolonged open times. Latency to first opening was accelerated, suggesting an acceleration of the rate of activation. The delta KPQ mutation has multiple effects on activation and inactivation. The aggregate effects may account for the increased susceptibility to arrhythmias.

The nature of treatment selection in coronary artery disease. Experience with medical and surgical treatment of a chronic disease.

This report presents our experience with the medical and surgical management of patients with coronary heart disease and uses this experience to document the role of a computerized medical information system in the long-term management of patients with a chronic disease. Of 781 consecutively evaluated patients, 402 were treated medically and 379 were treated with aortocoronary bypass surgery. At two years post-zero time, more than twice as many surgical survivors were pain free, but the survival was the same in the medical (83%) and surgical (85%) cohorts. The medically and surgically treated patients were compared with respect to 89 baseline characteristics. The cohorts were remarkably similar. Correction for baseline inequalities did not affect the fact that two-year survival was the same in both cohorts. One subgroup was identified in which surgically treated patients had a higher two-year survival. Other subgroups were identified in which therapy did not appear to affect two-year survival.

Pressure-flow studies in man. An evaluation of the duration of the phases of systole

This study was designed to assess the independent effects of stroke volume and heart rate on the phases of systole and other selected hemodynamic parameters. By means of the pressure gradient technique instantaneous blood pressure and flow were recorded in the ascending aorta at fixed ventricular rates in five patients with complete heart block and in four patients with atrio-ventricular dissociation induced by ventricular pacing. Because of the variable contribution of atrial systole to ventricular filling, a wide range of stroke volumes were observed at each heart rate. The results indicate that the duration of ejection bears a close direct linear relationship to stroke volume while heart rate has only a weak but independent relation. On the other hand, the duration of total systole is related chiefly to the heart rate but stroke volume exerts an important independent effect. In a given patient, both duration of ejection and pulse pressure reflect changes of stroke volume and the product of the duration of ejection and the pulse pressure shows a good correlation with the stroke volume.

ELECTRICAL HAZARDS ASSOCIATED WITH CARDIAC PACEMAKING

The success1*2 of implantable cardiac pacemakers has served to focus attention on methods of maintaining an adequate heart rate before implantation can be accomplished. While drug therapy is effective in many cases, electrical stimulation of the heart has assumed an increasingly more important role-especially in the management of patients in the period immediately preceding and during the surgical implantation of a pacemaker. Because pacing with external electrodes presents certain problems, internal pacing either by an electrode catheter in the right ventricle or by previously placed myocardial electrodes is now used routinely in many centers. Electrode catheters or myocardial electrodes carry certain inherent dangers because they afford a low resistance path directly to the myocardium by circumventing the usually protective resistance provided by the skin and other body tissues. Thus the possibility of inducing ventricular fibrillation by introducing usually harmless voltages, but now dangerous currents, to a patient has become a real one. Zoll and Linenthal,3 B ~ r c h e l l , ~ and other^^.^ have emphasized these dangers. The purpose of this discussion is: ( 1 ) to document the current levels which will cause ventricular fibrillation in the experimental animal and man (2 ) , to demonstrate that many pieces of routine hospital equipment are capable of delivering dangerous currents, and ( 3 ) to suggest certain precautions designed to prevent the accidental electrocution of patients with intracardiac electrodes.

Evaluation of several methods for computing stroke volume from central aortic pressure.

Six pulse-contour methods for estimating stroke volume from a single central aortic blood pressure were evaluated in 8 dogs and 17 patients. In the dogs, wide variations in stroke volume, measured with an electromagnetic flowmeter, were obtained by pacing the heart at various rates during a control period and during several pharmacologic interventions. Good correlations existed between measured stroke volume and most estimators when the data from each intervention were analyzed separately. However, regression analysis revealed considerable variation in the individual slopes and intercepts, and thus a poor correlation was obtained when all data for one dog were combined in a single analysis. Similar evaluations were carried out in two groups of patients in whom the pressure-gradient technique was used to measure stroke volume. In the group with minimal variations in hemodynamic status, the correlations between estimated and true stroke volume were reasonably good. In the patients having a wide range of hemodynamic conditions, considerable variation in both slopes and intercepts was observed, and the combined correlation coefficients were generally poor. Although pulse contour methods of estimating stroke volume may work reasonably well over a range of stroke volumes when the variation is induced by a single perturbing agent, none of these methods perform adequately when the variation is induced by multiple perturbing agents; thus their clinical usefulness is markedly limited.

Block of Wild-Type and Inactivation-Deficient Cardiac Sodium Channels IFM/QQQ Stably Expressed in Mammalian Cells

The role of inactivation as a central mechanism in blockade of the cardiac Na(+) channel by antiarrhythmic drugs remains uncertain. We have used whole-cell and single channel recordings to examine the block of wild-type and inactivation-deficient mutant cardiac Na(+) channels, IFM/QQQ, stably expressed in HEK-293 cells. We studied the open-channel blockers disopyramide and flecainide, and the lidocaine derivative RAD-243. All three drugs blocked the wild-type Na(+) channel in a use-dependent manner. There was no use-dependent block of IFM/QQQ mutant channels with trains of 20 40-ms pulses at 150-ms interpulse intervals during disopyramide exposure. Flecainide and RAD-243 retained their use-dependent blocking action and accelerated macroscopic current relaxation. All three drugs reduced the mean open time of single channels and increased the probability of their failure to open. From the abbreviation of the mean open times, we estimated association rates of approximately 10(6)/M/s for the three drugs. Reducing the burst duration contributed to the acceleration of macroscopic current relaxation during exposure to flecainide and RAD-243. The qualitative differences in use-dependent block appear to be the result of differences in drug dissociation rate. The inactivation gate may play a trapping role during exposure to some sodium channel blocking drugs.

Hazards of electric shock in cardiology

Abstract The danger of inducing ventricular fibrillation is present during certain commonly used diagnostic and therapeutic procedures. Electrode catheters employed for intracardiac electrocardiography, the detection of intracardiac shunts or cardiac pacing provide a current path of low resistance directly to the heart. In the presence of such paths, small voltages from improperly functioning or improperly used electrical equipment can generate fibrillatory currents. Proper grounding of all equipment coming in contact with patients will eliminate the danger of inducing ventricular fibrillation in the vast majority of cases. Since proper grounding is not always possible, battery-powered rather than line-powered pacemakers should be used in conjunction with myocardial electrodes or electrode catheters. Electrocardiographic monitoring of pericardiocentesis is unlikely to cause ventricular fibrillation because the resistance within the V lead circuit of the electrocardiograph and the resistance of the body tissues act to prevent significant currents from entering the heart. Cardioversion, if improperly programmed, may cause ventricular fibrillation. Because certain D. C. cardioversion units have a grounded rather than an isolated countershock circuit, burns can be induced at the site of the indifferent electrode of the electrocardiographic monitoring circuit.

Complete and incomplete revascularization at aortocoronary bypass surgery: Experience with 392 consecutive patients

Abstract This report presents our experience with “complete” and “incomplete” revascularization in 392 consecutive patients undergoing aortocoronary artery bypass surgery. Patients were considered to have had “complete” revascularization only if all major coronary arteries with 70 per cent occlusion received at least one bypass graft. Patients were considered “incompletely” revascularized if any vessel with a 70 per cent or more occlusion did not receive at least one bypass graft. The “completely” revascularized cohort contained 186 patients and the “incompletely” revascularized cohort contained 206 patients. The survival of the “completely” and “incompletely” revascularized cohorts was compared postoperatively and at 6, 12, and 24 months using the Chi-square test. Relief of anginal pain rates were compared at 6, 12, and 24 months using the Chi-square test. Analyses were repeated after stratifying for number of vessels diseased. The subgroup with one vessel diseased was, by definition, “completely” revascularized. No significant difference in survival or relief of anginal pain was demonstrated in the total group or in subgroups with 2 and with 3 vessels diseased. The data indicate that “complete” revascularization is not closely coupled to two-year survival or relief of anginal pain.

Vulnerability in one-dimensional excitable media

Abstract Potentially life-threatening cardiac arrhythmias can be iniated with stimuli timed to occur during the “vulnerable window (VW)”. We defined VW as the time interval between the “conditioning” and “test” stimuli following in sequence, during which the test stimulus response propagates in only one direction. We show that the VW is a generic feature of excitable media and describe the relationship between the properties of an excitable medium and the VW. We present asymptotic results that reveal the sensitivity of the VW to both the propagation velocity of the conditioning wavefront and the recovery process parameters. We also have identified a critical length of medium that must be excited in order to reveal vulnerability. Analytical results are in agreement with numerical studies.