Arrhythmogenic potential of diuretic induced hypokalaemia in patients with mild hypertension and ischaemic heart disease.

In view of evidence suggesting an association of mild hypokalaemia with cardiac arrhythmia, the arrhythmogenic potentials of potassium losing and potassium sparing diuretic treatments were compared in a controlled prospective crossover study of 10 patients with mild hypertension and ischaemic heart disease. Mean (SEM) plasma potassium was 4.3(0.06) mmol/l and 3.3(0.07) mmol/l after potassium sparing and potassium losing treatments respectively. Blood pressure and volume depletion as assessed by weight change, plasma renin activity, and noradrenaline concentrations did not differ significantly in the two treatment periods. The potassium losing treatment phase was associated with an increased frequency of ventricular extrasystoles, a higher Lown grading during ambulatory electrocardiographic monitoring, prolonged duration and decreased phase 0 velocity of the monophasic action potential, a prolonged ventricular effective refractory period, and increased myocardial electrical instability as assessed by programmed ventricular stimulation. It is concluded that minor changes in plasma potassium concentration are associated with increased ventricular electrical instability in patients with ischaemic heart disease. Mild hypokalaemia in such patients may predispose to life threatening arrhythmias and should be avoided.     

Arrhythmogenic potential of diuretic induced hypokalaemia in patients with mild hypertension and ischaemic heart disease

In view of evidence suggesting an association of mild hypokalaemia with cardiac arrhythmia, the arrhythmogenic potentials of potassium losing and potassium sparing diuretic treatments were compared in a controlled prospective crossover study of 10 patients with mild hypertension and ischaemic heart disease. Mean (SEM) plasma potassium was 4.3(0.06) mmol/l and 3.3(0.07) mmol/l after potassium sparing and potassium losing treatments respectively. Blood pressure and volume depletion as assessed by weight change, plasma renin activity, and noradrenaline concentrations did not differ significantly in the two treatment periods. The potassium losing treatment phase was associated with an increased frequency of ventricular extrasystoles, a higher Lown grading during ambulatory electrocardiographic monitoring, prolonged duration and decreased phase 0 velocity of the monophasic action potential, a prolonged ventricular effective refractory period, and increased myocardial electrical instability as assessed by programmed ventricular stimulation. It is concluded that minor changes in plasma potassium concentration are associated with increased ventricular electrical instability in patients with ischaemic heart disease. Mild hypokalaemia in such patients may predispose to life threatening arrhythmias and should be avoided.     

Extracellular potassium activity changes in the canine myocardium after acute coronary occlusion and the influence of beta-blockade.

Extracellular potassium activity before and after coronary occlusion was measured in the canine heart by means of potassium-selective surface electrodes. In the ischaemic myocardium potassium activity rapidly increased from a preocclusion value of 3.2 +/- 0.3 mmol.litre-1 to 10 +/- 0.6 mmol.litre-1 within the first 5 min and to about 11.3 +/- 0.5 mmol.litre-1 after 10 min of ischaemia (range from 9.5 to 14.5 mmol.litre-1). Following the initial 10 min of ischaemia no further increase was measured. In the non-ischaemic area potassium activity remained constant. Acute beta-blockade significantly attenuated the initial rate of increase in potassium activity; however, beta-blockade did not influence maximal values of extracellular potassium activity measured after occlusion. Lowering of heart rate by vagal stimulation did not modify the pattern of increase in potassium during acute ischaemia. Following ventricular fibrillation, a slow but continuous rise in potassium activity was found. These results demonstrate that extracellular potassium activity in the acutely ischaemic myocardium is considerably higher than indicated by the technique of coronary vein sampling and is in the range necessary for the development of re-entrant arrhythmias in the early phase after coronary occlusion.     

Local myocardial electrogram and potassium concentration changes in superficial and deep intramyocardium and their relations with early ischaemic ventricular arrhythmias

Bipolar myocardial electrograms and extracellular potassium concentrations were simultaneously monitored using double barrelled probes during 30 min of acute ischaemia in 15 dogs in vivo. The responsiveness of the time from the onset of the limb lead electrocardiogram to the peak deflection of the local electrogram to extracellular potassium changes was more prominent in superficial intramyocardium than in deep intramyocardium, despite similar changes in potassium concentration in both layers. The changes in electrogram duration and amplitude were related to extracellular potassium concentration both in superficial and deep intramyocardium. Immediate phase ventricular arrhythmias (within the first 10 min of acute ischaemia) were characterised by delayed activity mainly due to an increase in the time to peak of the electrogram in superficial intramyocardium. In contrast, in dogs showing delayed phase arrhythmias (within 10-30 min of acute ischaemia) delayed activity associated with pronounced changes in potassium concentration and electrogram duration and amplitude were noted in deep intramyocardium. Thus the two phasic appearances of early ischaemic ventricular arrhythmias with different origins seem to be related to the features of the conduction pathway in superficial intramyocardium and the severe local electrogram changes associated with a pronounced increase in extracellular potassium concentration in deep intramyocardium.     

The anti-arrhythmic effects of myocardial ischaemia. Relation to reperfusion arrhythmias?

Ventricular tachycardia was induced in the intact non-ischaemic pig heart by intramyocardial or intracoronary infusions of noradrenaline or N6, O2'-dibutyryl-cAMP. The chemically induced tachycardia was consistently stopped within 10 to 30 s by occluding the coronary artery supplying the infusion area. This ischaemic effect was readily reversed by coronary reperfusion, with ventricular tachycardia resuming within seconds after release of the occlusion. In contrast to the immediate effect of myocardial ischaemia, it took several minutes for the tachycardia to cease after the infusion of arrhythmogenic compounds was stopped. Pacing experiments showed that the effect of myocardial ischaemia on ventricular tachycardia was probably not due to a conduction block. The anti-arrhythmic property of myocardial ischaemia was separate from its known effect of decreasing the ventricular fibrillation threshold for electrical stimulation. The increased vulnerability of the acutely ischaemic myocardium to fibrillation was apparent in experiments in which ectopic activity was induced in the non-ischaemic part of the myocardium. In these experiments ventricular fibrillation consistently ensued within 6 min following distal occlusion of the anterior descending coronary artery. By contrast, ventricular fibrillation was not precipitated by coronary artery occlusion or local infusion of arrhythmogenic compounds alone. Cyclic AMP was shown to accumulate in ischaemic myocardium. An association existed between cAMP accumulation and the intensity of early ischaemic arrhythmias as well as reperfusion arrhythmias. The highest incidence of ventricular fibrillation was found during reperfusion, at peak myocardial cAMP levels. These findings suggest: (1) Noradrenaline and dibutyryl-cAMP exert arrhythmogenic effects preferentially in the intact, non-ischaemic myocardium, the effects being attenuated in ischaemic myocardium by a paradoxical anti-arrhythmic effect of ischaemia. (2) In the acutely ischaemic heart, ventricular fibrillation may be precipitated by the emergence of ectopic activity outside the ischaemic area. (3) Arrhythmias and fibrillation occurring early after reperfusion may be caused by unmasking the effects of excitants (eg, noradrenaline or cAMP) arising during the antecedent period of ischaemia.     

Characterisation of unipolar waveform alternation in acutely ischaemic porcine myocardium

The relation between electrical alternans recorded in acutely ischaemic myocardium, ventricular arrhythmias, and changes in the activation sequence was studied. Sixty three unipolar electrograms, simultaneously recorded from the epicardial surface of the in situ porcine heart during 6 min periods of coronary occlusion, were converted to a digital format and analysed by computer. The time integrals of the electrograms during their QRS complex, ST segment, and T wave were measured. Unipolar waveform alternation was then quantified by subtracting the values obtained for two consecutive beats showing alternans. The spatial distribution of unipolar waveform alternation was illustrated by isoarea difference maps. Isochronal maps of the local excitation detected on each electrogram were constructed. Of 52 occlusions in 27 preparations, unipolar waveform alternation was detected in 42 and was promptly followed by ventricular arrhythmias in 37. The magnitude of unipolar waveform alternation increased from the margin to the inner portion of the ischaemic zone but its correlation with activation delay was poor, and there was no change in the activation sequence. These results suggest that beat to beat alternation of the unipolar waveform is related to changes in the action potential configuration rather than to changes in the activation sequence. Furthermore, unipolar waveform alternation appears to be associated with the development of early post-occlusion ventricular arrhythmias.     

Cardiac damage in athlete's heart: When the “supernormal” heart fails!

Intense exercise may cause heart remodeling to compensate increases in blood pressure or volume by increasing muscle mass. Cardiac changes do not involve only the left ventricle, but all heart chambers. Physiological cardiac modeling in athletes is associated with normal or enhanced cardiac function, but recent studies have documented decrements in left ventricular function during intense exercise and the release of cardiac markers of necrosis in athlete's blood of uncertain significance. Furthermore, cardiac remodeling may predispose athletes to heart disease and result in electrical remodeling, responsible for arrhythmias. Athlete's heart is a physiological condition and does not require a specific treatment. In some conditions, it is important to differentiate the physiological adaptations from pathological conditions, such as hypertrophic cardiomyopathy, arrhythmogenic dysplasia of the right ventricle, and non-compaction myocardium, for the greater risk of sudden cardiac death of these conditions. Moreover, some drugs and performance-enhancing drugs can cause structural alterations and arrhythmias, therefore, their use should be excluded.     

Arrhythmias in the athlete

Regular exercise provides substantial health benefits, mostly by reducing cardiovascular risk factors. However, it may also trigger acute cardiac events and cause sudden cardiac death in individuals with a pre-existing condition. In an otherwise healthy population, intense regular exercise may lead to morphological and electrical cardiac adaptations commonly referred as "athlete's heart." Recent data suggest that this may itself produce structural changes of atrial and ventricular myocardium with enlargement and fibrosis, creating the substrate for development of arrhythmias in apparently healthy athletes. The state of the art in this controversial issue is reviewed.     

Myocardial potassium loss after acute coronary occlusion in humans

Animal studies have established that there is a rapid increase in extracellular potassium concentration in myocardial tissue after the onset of ischemia. To study this phenomenon in humans, coronary sinus plasma potassium concentration was measured in five patients undergoing therapeutic coronary angioplasty. Recordings were obtained during a total of 22 coronary artery occlusions lasting between 5 and 50 seconds. Though little change was observed during angioplasty balloon inflation, all occlusions that lasted more than 15 seconds were followed by a transient elevation in coronary sinus potassium concentration of between 0.18 and 1.55 mmol X liter-1. The majority of occlusions (n = 17) were not accompanied by chest pain, electrocardiographic (ECG) changes or alteration of heart rate. The increase in coronary sinus potassium concentration after angioplasty balloon deflation is attributable to a washout of accumulated extracellular potassium during reperfusion. Redistribution of human myocardial potassium occurs within 15 seconds of the onset of myocardial ischemia and may be an important factor accounting for early electrophysiologic changes.     

Mechanisms of Arrhythmias in Ventricular Hypertrophy

Mechanisms of Arrhythmias in Ventricular Hypertrophy. Cardiac hypertrophy is an adaptative process by which the heart accommodates to abnormal pressure and volume overloads. However, hypertrophy of the left ventricle is associated with a high incidence of ventricular arrhythmias and sudden death. The cellular mechanisms responsible for the abnormal rhythmic activity in hypertrophied myocardium has not been clearly defined, but left ventricular hypertrophy is associated with characteristic electrical abnormalities in experimental models and in hypertrophied human tissue. The most consistent electrical alteration is prolonged duration of the action potential in hypertrophied myocardium. The prolonged duration of depolarization predisposes hypertrophied tissue to develop early afterdepolarizations, which can encourage the development of arrhythmias by a variety of mechanisms. Early afterdepolarizations interrupt repolarization and can lead directly to sustained triggered activity. Early afterdepolarizations can depolarize adjacent excitable fibers and thereby induce triggered activity. The prolonged duration of repolarization can enhance influx of calcium, which can in turn lead to delayed afterdepolarizations that can give rise to triggered activity. Early afterdepolarizations can also produce conduction block or delay, which could contribute to the development of reentrant arrhythmias. Early afterdepolarizations are the most likely electrical abnormality to arise from the prolonged time course of repolarization in hypertrophied myocardium. Therefore, therapeutic measures aimed at preventing the development of early afterdepolarizations in hypertrophied myocardium could prove to be a fruitful approach to inhibiting the development of arrhythmias. The development of agents that selectively reduce the duration of the action potential requires a better understanding of the ionic mechanisms responsible for prolonging the action potential in hypertrophied myocardium. In the meantime, avoiding factors known to favor the development of afterpotentials (e.g., extremes of heart rate, electrolyte abnormalities, certain antiarrhythmic drugs) in patients with left ventricular hypertrophy seems prudent.     

Water and electrolyte alterations during the life course of the BIO 14.6 Syrian golden hamster. A disease model of a hereditary cardiomyopathy

In a hereditary cardiomyopathy of the Syrian hamster, changes in water and electrolyte metabolism were investigated. Four age groups were differentiated histopathologically. Body weight of cardiomyopathic animals was initially decreased but later exceeded that of controls. The total extracellular fluid volume was larger than in controls, with a decreased haematocrit; these changes were especially pronounced in the oldest hamsters. The myocardial extracellular space and water content underwent similar changes to those in total extracellular volume. Besides a tendency to hyponatraemia there were no alterations of the serum potassium and sodium levels in the youngest three groups. However, in animals with congestive heart failure, serum potassium was decreased and serum sodium increased. Initially serum calcium was increased and the magnesium value was normal. In prenecrotic tissue myocardial magnesium was markedly decreased but calcium only slightly increased. In the necrotizing myocardium, however, calcium was greatly elevated; in the later stages, calcium tended to decrease. Surprisingly, magnesium was unchanged in necrotizing tissue, and decreased later. Myocardial sodium and potassium did not exhibit changes during the prenecrotic but in the following stages, when potassium was lowered and sodium was elevated. A distinct rise of the extracellular sodium concentration was observed in animals with obvious congestive heart failure.Disturbed myocardial calcium and magnesium metabolism is restricted to cardiomyopathic cells and is thought to play an essential role in the necrotic process. Succeeding changes, especially in sodium and potassium, are thought to occur in myocardial cells developmentally normal but subjected to a sustained volume overload. Secondary aldosteronism is believed to be the cause for the terminal fluid and electrolyte changes in serum and myocardium.     

Strenuous exercise, plasma fibrinogen, and factor VII activity.

OBJECTIVE--To assess the effect of physical activity on plasma fibrinogen and factor VII activity and thus on the risk of ischaemic heart disease. DESIGN--Cross sectional survey. SETTING--Ten group practices in the Medical Research Council's General Practice Research Framework. PATIENTS--3967 men aged 45-69 attending screening clinics for the thrombosis prevention trial. METHODS--Structured interview to elicit the intensity and frequency of physical exercise during past month. Measurement of fibrinogen, factor VII activity, cholesterol concentration, blood pressure, and other indices of ischaemic heart disease risk. RESULTS--Strenuous exercise was associated with significantly lower fibrinogen concentrations than mild exercise, implying a difference of about 15% in the risk of ischaemic heart disease. Strenuous exercise was also associated with lower cholesterol concentrations. More frequent strenuous exercise was associated with lower factor VII activity. CONCLUSIONS--With the recognition of plasma fibrinogen as a strong index of ischaemic heart disease risk the results of this and other studies suggest a pathway through which the protective effect of strenuous exercise may partly be mediated and they provide doctors and patients with a valuable incentive towards prevention, particularly in those whose risk of ischaemic heart disease is substantially due to raised fibrinogen concentrations.     

Strenuous exercise, plasma fibrinogen, and factor VII activity.

OBJECTIVE--To assess the effect of physical activity on plasma fibrinogen and factor VII activity and thus on the risk of ischaemic heart disease. DESIGN--Cross sectional survey. SETTING--Ten group practices in the Medical Research Council's General Practice Research Framework. PATIENTS--3967 men aged 45-69 attending screening clinics for the thrombosis prevention trial. METHODS--Structured interview to elicit the intensity and frequency of physical exercise during past month. Measurement of fibrinogen, factor VII activity, cholesterol concentration, blood pressure, and other indices of ischaemic heart disease risk. RESULTS--Strenuous exercise was associated with significantly lower fibrinogen concentrations than mild exercise, implying a difference of about 15% in the risk of ischaemic heart disease. Strenuous exercise was also associated with lower cholesterol concentrations. More frequent strenuous exercise was associated with lower factor VII activity. CONCLUSIONS--With the recognition of plasma fibrinogen as a strong index of ischaemic heart disease risk the results of this and other studies suggest a pathway through which the protective effect of strenuous exercise may partly be mediated and they provide doctors and patients with a valuable incentive towards prevention, particularly in those whose risk of ischaemic heart disease is substantially due to raised fibrinogen concentrations.     

The antiarrhythmic effect of the ACE inhibitor captopril in patients with congestive heart failure largely is due to its potassium sparing effects.

OBJECTIVE: To evaluate the mechanisms by which the angiotensin converting enzyme (ACE) inhibitor captopril may modify the presence of ventricular arrhythmias in patients with chronic heart failure. PATIENTS: Forty-seven patients with chronic stable congestive heart failure. METHODS: Twenty-four hour Holter monitoring was done prior to and after one month of therapy with the ACE inhibitor captopril. In a first group of 25 patients, changes in the incidence of ventricular arrhythmias were correlated with changes in cardiac hemodynamics (assessed invasively). In a second group of 22 patients, changes in ventricular arrhythmias were correlated with changes in echocardiographic measurements. In all patients serum potassium was kept constant, and changes in exercise tolerance and serum noradrenaline levels were assessed prior to and after captopril. RESULTS: One month of captopril therapy caused an improvement in cardiac hemodynamics and in exercise tolerance. It also led to a tendency for improved echocardiographic measurements and serum noradrenaline levels, similar to those already published by others. However, no change in the incidence or severity of ventricular arrhythmias was detected. No correlation could be found between changes in ventricular arrhythmias and any of the variables measured. CONCLUSIONS: As the only obvious difference between this and previous studies that documented a decrease in ventricular arrhythmias when ACE inhibitors were started in patients with congestive heart failure is a lack of change in serum potassium in this study, the current results suggest that the major antiarrhythmic effect of ACE inhibitors in patients with congestive hear failure is the result of their potassium sparing effects.     

Electrophysiologic Basis for T Wave Alternans as an Index of Vulnerability to Ventricular Fibrillation

Electrophysiologic Basis for T Wave Alternans. Substantial evidence indicates that T wave alternans is an intrinsic property of ischemic myocardium. The electrophysiologic basis appears to be spatial and temporal heterogeneity of repolarization resulting from changes in action potential morphology rather than in activation sequence. Ischemia-induced changes in postrepolarization refractoriness and depressed electrical restitution of action potential duration have also been implicated. The main underlying ionic basis for T-wave alternans during coronary occlusion appears to be derangements in intracellular cycling of calcium. Accumulation of potassium in the extracellular space adjoining ischemic cells and disruption in electro-genie sodium-calcium exchange may also be involved. In humans, T wave alternans has been observed in Prinzmetal's and classical angina, angioplasty, and bypass graft occlusion. Under these conditions associated with acute myocardial ischemia, alternans is restricted to the ischemic zone, and alternation in action potential morphology is an underlying factor. Recently, repolarization alternans has been shown to be a statistically significant predictor of the results of electro physiologic testing and arrhythmia-free survival in individuals with and without organic heart disease. Collectively, these observations provide a rationale for quantitation of T-wave alternans magnitude for assessment of vulnerability to life-threatening ventricular arrhythmias both in response to and independent of the effects of myocardial ischemia.     

Heart rate and metabolic response to competitive squash in veteran players: identification of risk factors for sudden cardiac death

We studied 10 older males during a competitive game and the early post-exercise period to define the metabolic response to squash in veteran players. For comparison, all subjects were also studied during exhaustive treadmill exercise. Squash caused a dramatic increase in heart rate (150%), and circulating levels of noradrenaline (164%), adrenaline (93%), lactate (202%) and free fatty acids (67%). These effects were independent of haemoconcentration. The early post-exercise period (5 min) was characterized by persistent elevation of plasma catecholamines, lactate, and free fatty acids, hypokalaemia and ventricular arrhythmias. The heart rate and metabolic responses to squash were similar in pattern and magnitude to those observed during treadmill exercise, highlighting the strenuous nature of squash as a recreation sport. While these changes may represent appropriate physiological adaptation to exercise in health, each has been implicated in the pathogenesis of fatal ventricular arrhythmias in subjects with ischaemic heart disease. These data support the contention that squash may be an inappropriate form of exercise for older men with coronary artery disease.     

Cyclic AMP levels in the plasma and ischemic myocardium and free fatty-acid levels in the serum following coronary artery ligation in dogs: relation to ventricular fibrillation

This study was designed to shed light on the biochemical causes of serious ventricular arrhythmias in the early stage of acute myocardial infarction (AMI). Fourteen mongrel dogs were divided into 2 groups. One group was subjected to coronary ligation by placing silk sutures around the LAD coronary artery about 1.5 cm from its origin. All the dogs of this group were found to have ventricular tachycardia and fibrillation, starting approximately 18 min. After ligation, associated with regional accumulation of myocardial cAMP in the ischaemic zone. The increase of cAMP started about 10-15 min. before the onset of the arrhythmia. In contrast, the control group had only sutures placed without ligation and was not found to have change in myocardial cAMP within 35 min and arrhythmias at the same time. Both plasma cAMP and serum FFA were studied, but no significant changes were found. It is concluded that myocardial cAMP may play an important role in the genesis of ventricular arrhythmias in the acute ischaemic heart and it may be one of the arrhythmogenic factors to evoke ventricular arrhythmias.     

Exogenous substrate preference of the post-ischaemic myocardium

Myocardial exogenous substrate preference was studied under conditions of increased plasma lactate concentration before and after a severe (halving of tissue ATP concentration, sixfold increase in tissue lactate concentration) but reversible (less than 1% necrosis on reperfusion) global ischaemic stress produced by continuous hypothermic electromechanical arrest of the heart of four hours' duration by aortic cross clamping and multidose potassium cardioplegia. Fatty acid oxidation was studied using 1-14C-palmitate under steady state conditions and under similar isovolumic fixed pressure conditions with the heart at a constant rate using a left ventricular intracavitary balloon. Exogenous free fatty acid oxidation during the pre-ischaemic period with an increased lactate concentration (3.9-5.8 mmol . litre-1) was 0.62(0.21) mumol . min-1 X 100 g-1 (mean (SEM)). This represented a mean of 32% of the total carbon dioxide produced in contrast to a post-ischaemia free fatty oxidation rate of 2.67(0.87) mumol . min-1 X 100 g-1, in the presence of even further increased plasma lactate concentrations (8.47-11.17 mmol . litre-1), representing a mean of 82% of the total carbon dioxide output. These data suggest that the substrate preference of the myocardium, under conditions of increased plasma lactate concentration, shifts to greater oxidation of exogenous free fatty acids after ischaemic stress.     

Plasma noradrenaline concentrations during isometric exercise.

Blood was collected simultaneously from the left ventricle and pulmonary artery in 12 patients undergoing routine cardiac catheterisation and was analysed for noradrenaline concentrations at rest, during, and after isometric stress (hand grip). Moderate isometric exercise resulted in a significant rise in plasma noradrenaline with a return to basal values 10 minutes after discontinuing the grip test. There were no significant differences in noradrenaline levels between the left ventricular and pulmonary arterial samples either at rest or during exercise. Three patients with evident left ventricular dysfunction had the highest plasma noradrenaline concentrations, in contrast to the much lower levels in 2 patients on beta-blockers and in 1 patient with a normal heart. As moderate isometric effort results in an important increase in noradrenaline level, this form of exercise could be dangerous in subjects suffering from ischaemic heart disease or in those with impaired left ventricular function since these patients are particularly susceptible to arrhythmias.     

Internal potassium balance and the control of the plasma potassium concentration

The plasma potassium concentration is determined both by external potassium balance and by the distribution of potassium between extracellular and intracellular fluid compartments, i.e., "internal potassium balance." Whenever external potassium balance is altered, the resultant change in the plasma potassium concentration is strongly influenced by concomitant alterations in internal potassium balance. Several factors alter internal potassium balance independently of changes in external balance. Acid-base disturbances produce shifts of potassium into or out of cells, but attempts to quantify these effects are not likely to be clinically useful. Hypertonicity produces a shift of potassium out of cells. Several hormones (insulin, aldosterone, catecholamines, glucagon, and growth hormone) may have roles in internal potassium balance. Digitalis and succinylcholine, by producing efflux of potassium from cells, may cause hyperkalemia. Potassium is released from skeletal muscle during exercise, causing an increase in the plasma potassium concentration. The periodic paralyses are associated with well-defined transient alterations in internal potassium balance.