Samuel S. Wong

Electrophysiologic consequences of chronic experimentally induced left ventricular pressure overload

Cardiac electrophysiologic alterations were evaluated 1 to 8 months after partial supracoronary aortic constriction in cats. This procedure induced left ventricular systolic hypertension and hypertrophy with marked connective tissue infiltration. In situ, premature ventricular complexes were observed during or after vagal slowing of sinus rate in 8 (26%) of the 31 experimental animals, while an additional 3 of the 31 developed ventricular fibrillation. No arrhythmias were recorded in 31 normal or 7 sham-operated cats. In vitro, 29% of the left ventricular preparations from cats with pressure overload and 5% from control cats showed spontaneous ectopic activity. During stimulation at cycle lengths of 800 to 1,000 ms, multiple site impalements of subendocardial muscle cells within fibrotic regions revealed heterogeneous electrical abnormalities. These included short action potential duration, low amplitude action potentials generated from low resting potentials, split upstrokes and electrically silent areas. Impalements in nonfibrotic areas of the left ventricle showed prolongation of muscle action potential duration. Long-term disturbances in cellular electrophysiologic properties may favor the development of arrhythmias and thereby contribute to sudden cardiac death in left ventricular hypertension and hypertrophy.

Dissimilarities in the electrophysiological abnormalities of lateral border and central infarct zone cells after healing of myocardial infarction in cats

We studied the characteristics of an electrophysiological border zone detected after healing of experimental myocardial infarction in cats. Thirty-two isolated left ventricles were studied in tissue bath 2–7 months after distal left coronary artery ligation. Action potentials were recorded from endocardial ventricular muscle cells in normal, lateral border and central infarct zones. Action potential duration was prolonged in central infarct zone cells, while action potentials of lateral border zone cells had the shortest duration. Ventricular muscle cells in the border zone also had lower resting potential, action potential amplitude and Vmax. Slowly rising action potentials (Vmax ≪ 20 V/ sec) were noted in central infarct zone cells, but more consistently in border zone cells. Functional refractory period of cells in central infarct zone was significantly longer than that recorded from border and normal zone cells. Post-repolarization refractoriness occurred in the majority of border zone cells. Failure of a border zone cell to respond to a premature stimulus during repetitive activity was observed in ten of the 22 preparations in which repetitive activity could be induced. Furthermore, when the coupling interval between driving and premature stimuli was shortened, border zone cells were first to fail to be excited by the premature stimulus. These data indicate that conduction was impaired in the border zone, whereas normal conduction was still possible in central infarct and normal areas. The electrophysiological abnormalities in the endocardial lateral border zone cells of the healed myocardial infarction appear to be the most severe, and the border zone may play an important role in chronic electrophysiological instability observed both in situ and in vitro.

Electrophysiological effects or procainamide in acute and healed experimental ischemic injury of cat myocardium.

We studied the effects of a membrane-active antiarrhythmic agent, procainamide (PA), on cellular electrophysiological consequences of ischemic injury to cat ventricular muscle. The left ventricles of 90- to 120-minute acute myocardial infarctions (AMI) (n = 14), and 2- to 4-month healed myocardial infarctions (HMI) (n = 17), were studied by microelectrode techniques in isolated tissue bath. Control action potential duration at 90% repolarization (APD90) recorded from ventricular muscle cells in AMI areas were short (114 ± 4 msec) compared to recordings from cells in normal areas (136 ± 6 msec) (P < 0.001). In contrast, APD90 of cells surviving ischemia in HMI preparations were longer than normals (159 ± 5 vs. 140 ± 5 msec, P < 0.001). After 60 minutes of exposure to PA, the APD90 of all cells was prolonged, but the absolute and relative magnitudes of prolongation were greater in AMI cells (mean = +40 msec, +35%), than in HMI cells (mean = +19 msec, +13%), P < 0.001. The prolongation of APD90 of normal cells was intermediate. Local refractory period changes paralleled APD90 changes. In seven additional HMI preparations, sustained ventricular activity was induced by premature stimulation. APD90 of HMI cells prolonged less than APD90 of normal cells during exposure to PA in these preparations, and decreased differences of APD90 between normal and HMI cells was associated with loss of inducibility of sustained ventricular activity. The effect of tetrodotoxin (TTX) was compared to the effect of PA in four HMI preparations to determine whether impaired delivery of test substances caused only an apparent decreased responsiveness to PA in HMI zones. TTX caused nearly identical prolongations of conduction times in HMI zones and normal zones, whereas PA caused different effects on APD90 in the two zones. In conclusion, PA alters the time course of repolarization of AMI cells more than that of HMI cells, decreasing the dispersion of repolarization in a given AMI or HMI preparation. The decreased dispersion correlated with loss of ability to induce sustained ventricular activity. Finally, the decreased responsiveness of HMI cells to PA does not appear to be due to impaired delivery to cell membranes, but, rather, appears to be a membrane difference persisting in cells which have survived ischemic injury.

Comparative study of the effects of salinomycin and monensin on electrophysiologic and contractile properties of canine myocardium

The effects of the monocarboxylic ionophore, salinomycin (K+-selective), on isometric twitches, high K+-induced contracture and transmembrane action potentials were compared with those of the monocarboxylic ionophore, monensin (Na+-selective), in isolated canine right ventricular muscle. In a concentration (5 X 10(-6) M) which did not produce changes in resting force, salinomycin increased peak active force (Po, + 170 +/- 36%, mean % change from control +/- S.D., P less than 0.01), and maximal rates of force development (dP/dt max, + 123 +/- 33%, P less than 0.01) and relaxation (-dP/dt max, + 180 +/- 40%, P less than 0.01) of the isometric twitch. A similar response pattern was found for 5 X 10(-6) M monensin (Po, + 90 +/- 24%, P less than 0.01; dP/dt max, + 137 +/- 19%, P less than 0.01; -dP/dt max, + 145 +/- 20%, P less than 0.01). In contrast to their effects on isometric twitches, salinomycin reduced peak K+ contracture force (Pc, -35 +/- 14%, P less than 0.01) whereas monensin increased it (Pc, + 30 +/- 12%, P less than 0.02). Ventricular muscle action potential duration was shortened similarly by the ionophores. beta-Adrenergic receptor blockade with nadolol diminished salinomycins effects on the isometric twitch and K+ contracture, but not its effect to shorten the action potential. Monensins actions were unaffected by nadolol. These results suggest that salinomycins effects arise from both a direct modulation of K+ movement and the release of endogenous catecholamine. In contrast, monensin may act to alter intracellular Na+ which in turn leads to Na+-Ca2+ exchange and Ca2+-mediated modulation of K+ movement.

Regional variations in myosin heavy chain concentration after healing of experimental myocardial infarction in cats

Densitometric scanning of SDS-polyacrylamide gels was used to measure myosin heavy chain concentration in left ventricular specimens obtained from cat hearts 3 to 12 months after healing of small experimental myocardial infarctions. The study was designed to test the hypothesis that myosin concentration varies as a function of anatomic proximity to the infarct scar. Myosin heavy chain concentration was elevated in non-scarred areas adjacent to a healed infarct and normal in areas remote from the scar. The scar itself had reduced concentrations, reflecting the loss of muscle mass in this area. The increased myosin heavy chain concentration in regions adjacent to the scar may be an attempt to regulate or compensate for the decrease in mechanical function of the scarred area.

Electrophysiologic effects of encainide on acutely ischemic rabbit myocardial cells

The electrophysiologic effects of encainide were determined in normal and acutely ischemic (30 min) rabbit ventricular muscle cells. Encainide (10(-6), 5 X 10(-6) and 10(-5) M) had no effect on resting potential (RP); 10(-6) M encainide reduced overshoot and action potential (AP) amplitude of cells in normal left ventricles and cells in normal areas of ischemic ventricles. Encainide, 5 X 10(-6) M and 10(-5) M, depressed Vmax and prolonged AP duration of normal cells. Surviving cells within ischemic areas displayed AP with reduced RP, overshoot, AP amplitude, Vmax and shortened AP duration. All encainide concentrations reduced overshoot, AP amplitude and Vmax of depressed AP. Encainides lengthening of AP duration was greater in cells within ischemic areas than in surrounding normal cells. Encainide (10(-6) M) prolonged effective refractory period and often blocked AP in ischemic cells. Encainide also caused depression in membrane responsiveness. Encainides differential effect upon AP may significantly contribute to its antiarrhythmic activity in ischemic heart disease.

Electrophysiologic Effects of Verapamil on Cells Bordering Healed Myocardial Infarction in the Cat

Abstract Verapamil (1 μg/ml) completely abolished a population of markedly depressed action potentials of cells (BZ-1) in border zones around healed infarcts. Even at higher concentrations, verapamil had no such inhibitory effect on other border zone cells (BZ-2), normal and central infarct zones cells. BZ-1 cells demonstrated a severely depressed V max (<20 V/sec), accompanied by partial depolarization, while BZ-2 cells were characterized by abbreviated duration. Verapamil only significantly depressed V max of BZ-1 cells. Action potential amplitude and action potential duration at 50% repolarization of all cells were abbreviated by verapamil. These results indicate slow inward currents may be involved in the genesis of action potentials in BZ-1 cells.

Cellular electrophysiology of coronary artery ligation in chronic pressure overload

We evaluated ischemia-induced cellular electrophysiologic abnormalities in chronic pressure overload ventricular myocardium in vitro. Left ventricular systolic hypertension was induced in cats via partial supracoronary aortic constriction (overload); at 1 1/2-3 months, resulting pressure overload was accompanied by ventricular hypertrophy (25-35% by weight) and patchy endocardial fibrosis. Two hours of subsequent acute myocardial ischemia (ischemia) was imposed on overload (ischemia/overload) via total occlusion of distal branches of the left coronary artery system. Spontaneous premature depolarizations in vitro were increased in ischemia/overload compared to control, ischemia or overload alone; bursts of spontaneous, repetitive depolarizations were also unique to these preparations. Multiple site recordings of endocardial transmembrane action potentials overlying the borders (interface) of fibrotic areas in ischemia/overload demonstrated numerous electrophysiologic abnormalities, including several not observed in control, ischemia or overload. Unique to the border areas of ischemia/overload preparations was the presence of maintained but depressed resting potential without action potentials; also, the incidence of depolarizations at the onset of the plateau phase was highest in these preparations. In non-fibrotic areas, electrophysiologic properties including resting potential and action potential amplitude and rate of rise were diminished in ischemia/overload compared to ischemia or overload preparations. These data demonstrate that acute myocardial ischemia in the setting of chronic pressure overload leads to additional cellular electrophysiologic abnormalities compared to ischemia or overload alone.

Early electrophysiologic and anatomic alterations in cat ventricular muscle after coronary artery ligation

The effect of coronary artery ligation on electrophysiologic properties of cat ventricular muscle cells was studied. Depression of resting potential, action potential rate of rise and amplitude was observed in infarcted cells, 30 min to 5 days after ligation. Action potential duration was markedly shortened in acute stages (30-120 min) but gradually lengthened to above control by 48 h. Anatomic sequelae included oedema, loss of fibre striation and cellular necrosis.

Regional sensitivity to verapamil in ventricular myocardium

The effects of verapamil (0.1-4.0 micrograms/ml) on transmembrane action potential configuration was examined in various regions of the normal cat left ventricular endocardium. Surface electrograms showed that the sequence of activation of anterior papillary muscle fibers was from the base of the muscle to its apex, while overlying Purkinje fibers were activated in the opposite direction. Action potential duration in basal muscle fibers was relatively unaffected by verapamil, while cells at the tip of the papillary muscle showed increased slope in phase 2 and a more rapid rate of early repolarization. Regional sensitivity to verapamil may reflect disparate patterns of endocardial activation, and could influence the effectiveness of the drug against ventricular arrhythmias.