Ronald S. Aronson

Torsade de Pointes and Other Pause-Induced Ventricular Tachycardias: The Short-Long-Short Sequence and Early Afterdepolarizations

The early after depolarization, which is an interruption of repolarization, can evoke a second upstroke or a salvo of action potentials. It is suggested that the electrophysiological characteristics of the early after depolarization can produce a lengthening of the QT interval and that the second upstroke and salvo of activity that may follow, it can explain many features of torsade de pointes and of certain other ventricular tachycardias. The early after depolarization, torsade de pointes, and repetitive monomorphic idiopathic ventricular tachycardia are all induced hy bradycardia or by a preceding long RH interal. The R‐on‐T phenomenon is also discussed.

Electrophysiologic characteristics of single myocytes isolated from hypertrophied guinea-pig hearts

To determine whether the electrical changes associated with cardiac hypertrophy are due to alterations in the membrane properties of individual hypertrophied cells, we recorded action potentials in single myocytes isolated from normal and hypertrophied hearts. Cardiac hypertrophy was produced by a gradual pressure overload created by placing a band around the ascending aorta in young guinea-pigs (200-250 g). Almost half the animals that developed left ventricular (LHV) hypertrophy also developed evidence of cardiac dysfunction. Action potentials were recorded with standard microelectrodes in single ventricular myocytes isolated by enzymatic dispersion of the heart. The action potential duration at 1 Hz was significantly longer in hypertrophied cells than in control cells. The degree of action potential prolongation in isolated cells did not correlate with the degree of hypertrophy but did correlate with the degree of myocardial disease, the duration being longer in hypertrophied myocytes from dyspneic than in those from non-dyspneic animals. The resting potential was significantly lower in hypertrophied myocytes from dyspneic animals than in hypertrophied cells from non-dyspneic animals or control cells stimulated at 5 Hz. The relationship between the frequency of stimulation (0.33, 1, and 5 Hz) and action potential duration was steeper in hypertrophied than normal myocytes. The mean membrane capacitance (cm) of hypertrophied myocytes increased by 31% over the control value. Thus, isolated hypertrophied myocytes retain the prolonged duration of the action potential and the exaggerated dependence of duration on rate observed in intact hypertrophied muscle. The increased duration of the action potential in hypertrophied cells cannot be readily attributed to the observed increase in cm. Our results indicate that the membrane changes responsible for the altered electrical properties of hypertrophied myocardium are due to an effect of hypertrophy on individual myocytes and that the prolonged duration of the action potential is probably due to changes in active currents flowing during repolarization.

Altered myocardial response to ouabain in diabetic rats: Mechanics and electrophysiology

Diabetes induced by streptozotocin in rats is associated with changes in the mechanical function of isolated ventricular papillary muscle. Relaxation is slowed and shortening velocity is depressed. The effects of ouabain (10(-7) to 2 x 10(-4)M) and changes in extracellular calcium ([Ca2+]0 = 0.6 to 12 mM) on the mechanical and electrical properties of normal and diabetic papillary muscles were studied. High doses of ouabain caused a rise in resting tension and a fall in developed tension in both diabetic and control muscles. However, these changes were strikingly greater in diabetic muscles which developed partial contractures at 10(-4)M. The altered response to ouabain was observed in chronically (5 to 7 weeks or 3 months) but not acutely (less than 1 week) diabetic animals. Similarly, the response to ouabain was restored to normal after chronic (5 weeks) therapy with insulin but not after acute (4 days) therapy. In both normal and diabetic muscles, the mechanical effects of increasing [Ca2+]0 from 2.4 to 12.0 mM were qualitatively similar to those seen with ouabain at 10(-5) to 10(-4)M. Electrophysiologic studies showed that under control conditions action potentials of diabetic muscles were significantly longer than those of normal muscles. Treatment with progressively higher concentrations of ouabain (10(-7) to 10(-4)M) and [Ca2+]0 (2.4 to 12.0 mM) caused shortening of both normal and diabetic action potentials, but the effects of these interventions were much greater in the diabetics. These results suggest that the response of diabetic muscles to ouabain is markedly different from normal and that this altered response may be due to impaired regulation of intracellular Ca2+ levels in diabetic myocardium.

The role of magnesium in cardiac arrhythmias

T HE RELATIONSHIP between electrolyte deficiencies and the development and prevention of cardiac arrhythmias has been a subject of continued interest in the medical literature. Studies have suggested a correlation between certain electrolyte deficiencies, such as hypokalemia, and the occurrence of arrhythmias and sudden death.le6 Recent interest, however, has focused on magnesium (Mg) deficiency and its role in this area. Interest in Mg may be related to the recognition of the extensive role this cation plays in a multitude of human physiological processes. Mg is the second most abundant intracellular cation in the human body and is involved in over 300 different enzymatic reactions including: glucose use; the synthesis of fat, protein, and nucleic acids; the metabolism of adenosine triphosphate (ATP); muscle contraction; and some membrane transport systems. Effects of Mg on atrioventricular (AV) nodal conduction, the transmembrane potential, and arrhythmias have also been postulated.‘*7-12 Total body Mg stores approximate 1,000 mmol/L with 1% present extracellularly, 60% present in skeletal tissue, and 39% present intracellularly.’ A normal homeostatic level of Mg is maintained via a balance between gastrointestinal absorption and renal excretion. Gastrointestinal net absorption is approximately 35% to 40% of an orally administered load and occurs almost exclusively via the small intestine. Mg loss occurs primarily via renal excretion and averages only 3% to 5% of a filtered load. Over 65% of Mg reabsorption occurs in the thick ascending limb of Henle and, depending on the Mg concentration in plasma, excretion may range from 10 to 5,000 mg over a 24-hour period.274F7,97’0*‘3-15 Despite the apparent ability of the human body to maintain Mg homeostasis through intestinal and renal processes, Mg deficient states occur and are being increasingly recognized. Two studies have documented the prevalence of Mg deficiency in hospitalized patients.‘6-‘8 In one study the prevalence of hypomagnesemia was determined in 2,300 patients in a Veteran’s Administration hospital.16*” When hypomagnesemia was defined as a serum Mg concentration less than 1.25 mEq/L the prevalence of hypomagnesemia was 6.9%. In another study Wong et all8 determined serum magnesium levels in 621 samples of randomly selected hospitalized patients and found hypomagnesemia (< 1.2 mEq/ L) in 11%. The causes of hypomagnesemia are many and varied and include: nutritional causes secondary to prolonged parenteral fluid administration, starvation with metabolic acidosis, protein-calorie malnutrition, Kwashiorkor, or alcoholism; intestinal causes secondary to chronic diarrhea or a malabsorption syndrome; renal causes secondary to disease-related states such as renal tubular acidosis, the diuretic phase of acute tubular necrosis, chronic glomerulonephritis, chronic pyelonephritis, or familial and sporadic renal Mg losses; drug-related causes secondary to diuretics, antibiotic therapy including gentamicin, tobramyocin, ticarcillin, carbenicillin, or amphoteritin B, antineoplastic drugs including cisplatin and cyclosporine; endocrine and metabolic causes including primary and secondary aldosteronism, hyperthyroidism, excessive lactation, pregnancy, hypercalcemia, primary hyperparathyroidism, uncontrolled diabetes mellitus with glucosuria, and acute intermittent porphyria; and congenital causes including maternal diabetes, maternal hyperparathyroidism, maternal hypothyroidism and exchange transfusions.7’9”0~1’7’7*‘9’20 In light of the multitude of etiologies of hypomagnesemia and its prevalence in hospitalized patients, it is possible that reduced Mg often goes undetected by the unsuspecting physician. The symptoms of hypomagnesemia are as varied as its causes, yet these may often be absent or vague. 9*21 Documented manifestations include: neuromuscular symptoms including tremor, myoclonic jerks, convulsions, Chvostek sign, Trous-

Torsades de pointes and early afterdepolarizations

SummaryIt is suggested that torsades de pointes may be only one of a group of arrhythmias that are characterized by being pause induced or bradycardia induced. A distinction is made between the cause of the “twisting of the points” and the cause of the action potentials that initiate and sustain the tachycardia. It is pointed out that torsades de pointes and other pause-induced arrhythmias share many features with rhythmic activity arising from early afterdepolarizations. Both are seen after pauses or at low rates, both are seen in quinidine intoxication, and both are seen in hypokalemia. The short-long-short sequence that is seen in torsades de pointes and certain other pauseor bradycardia-induced arrhythmias can be fully explained by the behavior of rhythmic activity initiated and sustained by early afterdepolarizations, as can the abrupt onset and termination of pause-induced arrhythmias and their tendency to show initial warming up and terminal slowing down.

Arrhythmogenic interaction between low potassium and ouabain in isolated guinea-pig ventricular myocytes.

1. The two‐microelectrode method of voltage clamp was used in single myocytes isolated from guinea‐pig ventricles to investigate the mechanism underlying the arrhythmogenic interaction between low external K+ and digitalis. 2. We investigated the effects of ouabain (10(‐6) M) with 4 mM‐K+ or 2 mM‐K+ on the peak magnitude of the inward component of oscillatory current (Iti) recorded upon repolarization to the resting potential after depolarizing clamps to ‐5 mV, and on the characteristics of the steady‐state current‐voltage relationship. 3. Whereas ouabain with 4 mM‐K+ did not alter the current‐voltage relationship from its control shape, ouabain with 2 mM‐K+ caused marked changes in the curve: the zero‐current intercept was shifted in a negative direction, the region of low slope conductance was extended to more negative potentials, and the curve was shifted downward relative to the control current‐voltage relationship. The changes in the current‐voltage relationship induced by ouabain with 2 mM‐K+ were very similar to those induced by 2 mM‐K+ alone. 4. The functional consequence of the changes in the current‐voltage relationship induced by ouabain with 2 mM‐K+ was a highly significant reduction in the amount of outward current (Ith) needed to reach the threshold for excitation; Ith was reduced from 1.6 +/‐ 0.4 nA (n = 6) in ouabain with 4 mM‐K+ to 0.8 +/‐ 0.3 nA (n = 5) in ouabain with 2 mM‐K+. 5. The mean value for Iti was larger in ouabain with 2 mM‐K+ (0.58 +/‐ 0.41 nA, mean +/‐ S.D., n = 4) than in ouabain with 4 mM‐K+ (0.42 +/‐ 0.38 nA, n = 5). Although the increase in Iti was not statistically significant because of the large variability of the measurement, it is possible that the increase might be physiologically significant. 6. Our results suggest that the arrhythmogenic interaction between digitalis and low K+ is due to the combined effects of low K+ on the current‐voltage relationship and on the size of the peak inward current induced by ouabain. Whereas the effect of low K+ and ouabain on the inward current was highly variable, the effects on the current‐voltage curve were far more consistent, pointing to an important role for alterations in the current‐voltage relationship in the arrhythmogenic interaction between low K+ and ouabain.

Effects of Verapamil on Ventricular Tachycardia Induced by Ouabain in Guinea Pigs

Calcium ions appear to play a central role in the development of ventricular arrhythmias associated with digitalis intoxication. Therefore, the effects of the calcium channel antagonist, verapamil, on ouabain‐induced ventricular tachycardia were investigated. Ventricular tachycardia (three or more consecutive wide QRS complexes) was induced in guinea pigs by intravenous infusion of ouabain (1 μg/ min) and bursts of rapid ventricular stimulation. Of seven guinea pigs given the infusion of ouabain, all developed ventricular tachycardia at a dose of 82 ± 17 μg/kg (mean ± SD) and none developed heart block or asystole. Eight guinea pigs were treated with verapamil (2 μg/min for 30 minutes) prior to exposure to ouabain. Of those eight animals, only two developed ventricular tachycardia but six developed heart block or asystole at a significanlly higher dose of ouabain (154 ± 47 μg/kg), None of three control guinea pigs given an infusion of normal saline for 90 minutes developed ventricular tachycardia. These results show that pretreatmenf with verapamil inhibits ouabain‐induced ventricular tachycardia in guinea pigs. Combined treatment with verapamil and ouabain is associated with a high incidence of heart block and asystole, which may limit the usefulness of verapamil.

Effects of Amrinone on Atrioventricular Conduction in the Intact Canine Heart

Abstract: The effects of amrinone on conduction in the intact canine heart were studied. Intracardiac His‐electrode catheter recordings were used to measure the functional refractory period (FRP) of the AV node and conduction time through the AV node (A2H2 interval) and in the His‐Purkinje system (H2V2 interval). Amrinone (2.5 to 10 mg/kg) shortened the FRP and A2H2 in a dose‐dependent manner but had no significant effect on H2V2. In hearts where AV conduction was depressed by treatment with verapamil, propranolol, or ouabain, amrinone partially reversed this depression. Amrinone also shortened the recovery time of spontaneous sinoatrial (SA) node activity following a train of rapid atrial stimulation. This effect was also observed after depression of SA nodal recovery with verapamil, propranolol, or ouabain. These results indicate that amrinone enhances AV conduction and SA nodal activity in the normal heart and may favorably influence depressed AV conduction and SA nodal activity induced by a variety of cardioactive agents.

The role of reduced potassium conductance in generating triggered activity in guinea-pig ventricular muscle

This study investigates the role of reducing potassium conductance (gK) in generating delayed afterdepolarizations and triggered activity in small preparations of ventricular muscle from guinea-pig hearts. We used agents believed to reduce gK (low or absent K0, tetraethylammonium (TEA), CsCl) and we used ouabain (10(-6) M) to induce delayed afterdepolarizations. Treatment with ouabain only caused subthreshold delayed afterdepolarizations or occasionally non-sustained triggered activity. Exposure to Tyrodes solution with K reduced from 4 to 2 mM or K-free Tyrodes solution, with or without ouabain, caused subthreshold delayed afterdepolarizations and sometimes non-sustained triggered activity. Exposure to Tyrodes solution containing TEA and ouabain caused sustained triggered activity, supporting the hypothesis that accumulation of extracellular K inhibits the development of triggered activity. Presumably, the reduction in gK caused by TEA is not reversed by accumulation of extracellular K so that the delayed afterdepolarizations in the presence of persistently reduced gK are large enough to induce sustained triggered activity. Under extreme conditions, when Cs replaced K and half the NaCl was replaced by TEA, delayed afterdepolarizations occurred in the presence of markedly reduced gK, the result being the rapid development of sustained triggered activity, even at the basic drive rate of 1 Hz. Our results suggest that reduced gK plays an important role in the development of triggered activity.