Biomedical subjects
M J Lab
Publications and source records attributed to M J Lab.
Characterisation of regional myocardial dynamics during mechanical alternans in heart of anaesthetised pig.
OBJECTIVE: The aim was to investigate the behaviour of regional myocardium during mechanical alternans in a multidirectional manner. METHODS: Mechanical alternans was induced in 12 anaesthetised open chested pigs by rapid atrial pacing. In contrast to previous studies, regional mechanical activity was simultaneously assessed at up to three different sites on the left ventricle using epicardial measuring devices able to provide multidirectional information on segment motion. Pressure-length loops were plotted to assess different patterns of segmental motion. The integral of pressure and length was calculated to obtain a regional work index for each beat. RESULTS: Pressure-length loops revealed profound abnormalities in segment motion and work index during regional mechanical alternans. Myocardial segments either performed alternate amounts of positive work on each beat or alternate amounts of positive and negative work on each beat. Alternating segments contracted out of phase with each other and were occasionally stretched during systole. CONCLUSIONS: The spatio-temporal heterogeneity of regional mechanical behaviour is greatly increased during mechanical alternans.
Mechanical restitution during alternans in guinea pig papillary muscles.
OBJECTIVE: The aim was to investigate alternate acceleration and retardation of mechanical restitution as a possible mechanism for mechanical alternans in isolated myocardium. METHODS: Mechanical alternans was induced in papillary muscles from the right ventricles of 11 guinea pigs (200-300 g) by rapid pacing under hypothermic conditions (T = 27 degrees C). Mechanical restitution curves were constructed by measuring the force responses to stimuli applied following variable test intervals during steady state pacing. Curves were obtained under control conditions (steady state stimulation interval 3 s), and for the beats following the large and small contractions during mechanical alternans. Monoexponentials were fitted to the restitution curves. RESULTS: The mean rate constant for restitution following the large beat in alternans was found to be slightly but significantly smaller than that following the small. Both rate constants obtained during alternans were significantly larger than the control rate constant (restitution was faster in alternans). In addition, as the alternation widened, the restitution curve of the beat following the small contraction developed a higher plateau than that following the large. CONCLUSIONS: The results confirm that the small beat in alternans is followed by faster restitution than the large. This alone is insufficient to explain the observed extent of alternans. The restitution curve for the beat following the small contraction must also rise to a higher plateau. Both the amount of calcium available for intracellular release and the rate at which it is made available vary from beat to beat.
Myocardial mechanics and arrhythmia.
The initiating cause of the first ectopic beat and its precipitation of sustained lethal arrhythmia in acute myocardial ischemia is not clear. Comparable uncertainties surround sudden death in myocardial failure. Progress in control of ventricular fibrillation has been slow, perhaps because diagnosis and treatment have been based on the premise that ischemic biochemical changes solely cause the alterations in electrophysiological behavior. Alternative approaches need exploration. Evidence that mechanical changes can initiate electrophysiological changes by a process sometimes referred to as "mechanoelectric feedback" is accumulating. It operates when any primary mechanical change in ventricular muscle, e.g., contraction produces a change in its electrical properties. Mechanical changes are prevalent in ischemia and cardiac failure. If mechanoelectric feedback operates here, it is not surprising that arrhythmias in some of these pathologies parallel the degree of mechanical myocardial dysfunction rather than electrophysiological changes, independent of etiology. This mechanoelectric feedback system may exist as an intrinsic property of normal myocardium, providing a feedback control of activation processes at both the cellular and gross levels. Its disruption during pathological events produces instability in the system and thus ventricular arrhythmia. This concept provides a new potential avenue for arrhythmia therapy.
Chaotic behavior in excitable systems.
This paper has dealt with biophysically accurate, or plausible, excitation systems. These are obtained from experiments, and so are complicated, often of high order, and are continually being updated by new experimental results. This is especially true for the excitation equations that represent cardiac tissue. Biophysically relevant problems require quantitatively accurate answers: What happens at what values of what parameter? Thus, numerical methods and results are important, and there is a strong tendency for both the model and the method of analysis to be given as computer algorithms; a current model for cardiac membrane dynamics is a computer package, and the use of path tracking procedures such as AUTO or PATH is becoming common. Perhaps the best way to proceed in the investigation of complicated and exotic dynamics in models of cardiac tissue would be to combine model formulation from voltage clamp data (the derivation of the excitation equations) with bifurcation, and even perhaps singularity theory analysis of dynamical systems, into an expert system.
Regional changes in ventricular excitability during load manipulation of the in situ pig heart.
1. The effect of load manipulation on myocardial excitability was studied in the anaesthetized, in situ pig heart. 2. A 33% increase in systolic left ventricular pressure achieved by aortic clamping reduced the mean effective refractory period by 11 ms (7.6%, P less than 0.01); whereas a 15% reduction in ventricular pressure achieved by intravenous infusion of sodium nitroprusside increased the mean effective refractory period by 4 ms (3.2%, P less than 0.05). 3. Changes in action potential duration, measured to 70% repolarization, roughly paralleled those of the effective refractory period. 4. The changes in effective refractory period were inhomogeneous, with a greater change occurring at the apex compared to the base in response to an increase in load, i.e. there was an increase in regional dispersion of refractoriness across the left ventricle. 5. Since inhomogeneity of repolarization and refractoriness is known to be potentially arrhythmogenic, these findings suggest that mechanical factors may contribute directly to the arrhythmias commonly seen clinically in high load states such as congestive cardiac failure and may also have consequences for the treatment of such arrhythmias.
Changes in intracellular calcium during mechanical alternans in isolated ferret ventricular muscle.
Alternans in heart is important as pulsus alternans in cardiac failure and electrophysiological alternans in myocardial ischemia. The explanation of this phenomenon is still unclear. We attempted to investigate the cellular mechanisms of alternans by measuring intracellular free calcium concentration [( Ca2+]i) with the photoprotein aequorin in isolated ferret papillary muscles. Tension and length were also recorded simultaneously. Transient mechanical alternans lasting five to 20 contractions could be reliably induced in this preparation by following a 30-second rest period with stimulation at a fast rate (2-4 Hz). Production of sustained mechanical alternans, which lasted longer than 20 contractions and could persist for several hundred contractions, required additional interventions, consisting of a lower temperature (25 degrees C), a lower external calcium concentration (1 mM), and a lower pH (6.91) than control conditions (0.33-0.5 Hz, 30 degrees C, 2 mM Ca2+, pH 7.36). Transient mechanical alternans was associated with transient in-phase alternation of aequorin light and, hence, [Ca2+]i. Sustained mechanical alternans was associated with sustained in-phase alternation of aequorin light as well as incomplete relaxation of tension. However, when muscles were switched from isometric to unloaded isotonic contraction, relaxation between stimuli was complete but contraction and the aequorin light signal continued to alternate. The addition of 10 mM caffeine or 10 microns ryanodine abolished transient and sustained mechanical alternans and also abolished the associated alternation of aequorin light. Commensurate with the action of ryanodine, which allows the sarcoplasmic reticulum to reaccumulate calcium to a limited extent after a period of rapid stimulation, sustained mechanical alternans sometimes reappeared in an attenuated form 30 to 50 contractions after the addition of ryanodine. These results demonstrate that incomplete muscle relaxation between beats need not be present for alternans to occur, and support the hypothesis that alternans is caused by intracellular calcium cycling involving the sarcoplasmic reticulum.
Arrhythmia in heart failure: role of mechanically induced changes in electrophysiology.
Various mechanisms have been suggested to explain the high prevalence of ventricular arrhythmia in patients with heart failure, but as yet there is no unifying theory. There is growing evidence that changes in myocardial mechanical properties may directly alter cardiac electrophysiology by a process of mechanoelectric feedback. Moreover, when changes in cardiac loading similar to those seen in heart failure are produced experimentally in normal heart, there is a greater tendency to arrhythmogenesis. The intimate relation between changes in mechanical function and arrhythmia in heart failure could account for the lack of effect of most conventional antiarrhythmic drugs on arrhythmogenesis, and the beneficial effect of peripheral vasodilators. This paper argues that mechanically induced changes in electrophysiology are very important in the development of arrhythmia in cardiac failure; there may be no need to implicate other mechanisms, such as relative ischaemia, metabolic changes, or changes in sympathetic tone.
Effect of changes in load on monophasic action potential and segment length of pig heart in situ.
There is increasing evidence that mechano-electric feedback, defined as a change in mechanical state that precedes and alters transmembrane potential, operates in a wide variety of preparations and species including man. Load reduction is becoming a common therapeutic tool in a variety of clinical settings but the electrophysiological effects of these manoeuvres is not known. In this study the effect of changes in loading conditions on the time course of ventricular repolarisation were examined in the in situ heart in 13 pigs anaesthetised with halothane. Monophasic action potentials, electrocardiograms and segment length changes were recorded from the left ventricular epicardium using suction operated devices. Afterload was decreased by intravenous infusion of sodium nitroprusside, and increased by aortic cross clamping. Infusion of sodium nitroprusside resulted in a rise in action potential duration (measured at 70% repolarisation) in all 21 infusions (mean 3.4 ms), which was linearly related to the fall in systolic left ventricular pressure (r = 0.72, p less than 0.001) and the change in minimum systolic segment length (r = 0.46, p less than 0.05), but not to the change in maximum diastolic length (r = 0.33, NS). Aortic constriction, sufficient to elevate peak systolic left ventricular pressure back to the control level, restored the changes in action potential duration to normal. In addition, there were concomitant changes in the QT interval and T wave of the epicardial ECG. These findings show that mechano-electric feedback operates in the in situ heart and has potential importance in the clinical setting where changes in systemic blood pressure may directly alter cardiac electrophysiology.
Contribution of mechano-electric coupling to ventricular arrhythmias during reduced perfusion.
The monophasic action potential may have a better relationship to reduced myocardial perfusion than the S-T segment of the electrocardiogram. This was addressed because of the need to monitor ischaemic areas in open chest surgery. The precise relationship between the action potential and myocardial motion during reduced perfusion also requires addressing because of the potential importance in arrhythmias. Landrace pigs were anaesthetised and their chests opened to expose the heart. Snares were placed around a branch of descending coronary artery, and the ascending aorta. Arterial and intraventricular pressures were monitored. Monophasic action potentials and local segment mechanical behaviour were recorded from predefined areas. Radiolabeled microspheres were used to measure regional myocardial blood flow. After 60 min ischaemia, regional blood flow showed a good relationship with action potential duration, reducing with blood flow reductions, whereas the S-T segment of the ECG showed no correlation. Both regional ischaemia, and aortic constriction in normal heart, produced paradoxical wall motion, (lengthening instead of shortening during electrical systole and contraction), associated with early afterdepolarisations. The latter were occasionally accompanied by ventricular ectopic beats. Alternans was regularly noted with ischaemia. All the observations could be seen in the period preceding arrhythmia. The results suggest that the monophasic action potential per se may be used in monitoring ischaemia during cardiac surgery, and the 'Mechano-electric feedback' interactions could have implications for arrhythmias.
Electrophysiological alternans and restitution during acute regional ischaemia in myocardium of anaesthetized pig.
1. Alternate long and short action potential durations, or electrical alternans, has only been sporadically observed in ischaemic myocardium in situ. We systematically studied alternans in the latter to characterize the phenomenon, relate it to ventricular arrhythmia and suggest possible mechanisms. 2. Sixteen Landrace pigs were anaesthetized (Azaperone, N2O and O2), ventilated and the hearts exposed. A branch of the left coronary artery was ligated. Left intraventricular and systemic pressures were monitored. Monophasic action potentials were recorded simultaneously with up to five suction electrodes in and around the proposed ischaemia area. 3. A computer measured the duration of every action potential, at several phases of repolarization, throughout the first hour of ischaemia. This allowed the systematic study of the alternans. Measurements during defined stimulus protocols were also made for the construction of electrical restitution curves. 4. Alternans was found in all recordings within the ischaemic area and in two-thirds of those in the 'border' area. There was no alternans in non-ischaemic areas. 5. The alternans, when action potential duration was plotted for every beat, appeared as an oscillation which was pleomorphic. It could be: (a) stable for hundreds of beats; (b) switched or triggered (by one extraneous beat having a different cycle length) between one stable state with high and one with low or absent alternans; (c) damped; (d) undamped to take a crescendo form, sometimes preceding ventricular fibrillation. 6. The alternans in general showed an ill-defined peak incidence between about 200 to 1500 beats after the onset of ischaemia, and a clearer late peak at about 3000 beats. These periods occurred at about 2-7 min and 15-40 min, corresponding to so-called phase 1A and 1B arrhythmia respectively. Only the late peak was seen with triggered alternans. 7. The electrical restitution curve for the action potential duration during ischaemia when compared with curves, constructed with data from non-ischaemic myocardium, showed a progressive depression in plateau, a reduction in magnitude and was flattened at 1 h. However, there was a reversal or reduction in decline at about 15-45 min. 8. We propose that electrical alternans is a distinctive electrophysiological characteristic of ischaemic myocardium which may be causally related to ventricular arrhythmia and fibrillation, and that at least two mechanisms contribute to the alternans: (i) electrical restitution of the action potential and (ii) changes in intracellular calcium cycling.
Changes in monophasic action potential duration during the first hour of regional myocardial ischaemia in the anaesthetised pig.
The effects of ischaemia on monophasic action potential duration and conformation were studied using suction electrodes on the in situ left ventricle in anaesthetised pigs. Action potentials were recorded throughout the first hour of ischaemia and their behaviour studied on a beat to beat basis by computer analysis. The natural history of action potential duration changes in the ischaemic area was based on the presence or absence of four events. Typically, ischaemic segments showed a brief increase in action potential duration after coronary ligation (event 1), followed by a rapid fall in action potential duration (event 2), a temporary, partial, spontaneous recovery of action potential duration after about 15 min (event 3), and, finally, a decay towards inexcitability of the segment (event 4). An increase in variability of action potential duration was associated with event 2, sometimes manifest as electrical alternans. Simultaneous records from control segments of non-ischaemic myocardium were relatively unchanged. Segments of myocardium bridging the cyanotic border sometimes showed the events. Non-uniform or dispersed event 3 in ischaemia, coupled with the increased beat to beat variability after event 2, could establish the conditions for ventricular arrhythmias and fibrillation.
Relation between monophasic action potential duration, ST segment elevation, and regional myocardial blood flow after coronary occlusion in the pig.
There is mounting interest in the use of the monophasic action potential for electrophysiological investigation of regional myocardial ischaemia. There is, however, no systematic study of the relation between the changes in monophasic action potential and regional myocardial blood flow. In this study monophasic action potential and, for comparison, epicardial electrograms were recorded by suction electrode at 14 selected sites on the anterior surface of the normal left ventricle of the intact pig heart in situ (n = 16). The monophasic action potential duration varied across the left ventricle; it was shortest close to the left anterior descending coronary artery, increased laterally across the left ventricle, and was longer at the apex than at the base. This variation was independent of regional myocardial blood flow (measured with radiolabelled microspheres). After coronary occlusion, in nine of these pigs monophasic action potential duration significantly decreased in proportion to the reduction in regional myocardial blood flow. The ST segment of the epicardial electrogram was elevated in relation to the reduction in regional myocardial blood flow but correlated less well. The reduction in regional myocardial blood flow of approximately 50% produced maximal ST elevation. The monophasic action potential could be recorded from some sites within the border zone for up to 5 h but could not be recorded from the centre of an ischaemic zone. With ischaemic episodes of this duration there was, however, a return to baseline of the elevated ST segment for all sites within the compromised region. Monophasic action potential duration, unlike epicardial electrogram ST elevation, discriminates between central ischaemic and non-ischaemic and ischaemic sites on either side of the zone with a reduced blood flow. The results suggest that monophasic action potential duration measured by suction electrode may be a simple and reliable index of transmural-epicardial myocardial ischaemia in experimental studies and in surgery.
The effects of shortening on myoplasmic calcium concentration and on the action potential in mammalian ventricular muscle.
When cardiac muscle shortens during a contraction, the duration of mechanical activity is abbreviated (shortening deactivation), but the duration of the action potential is prolonged. Neither of these phenomena is fully understood, but both may be related to changes in the myoplasmic free calcium concentration. In these experiments, isolated papillary muscles from cats and ferrets were allowed to contract under various mechanical conditions while myoplasmic calcium was monitored with aequorin, or in parallel experiments the membrane potential was recorded with microelectrodes or a sucrose gap. When shortening occurred, myoplasmic calcium was increased and the membrane potential was more positive than in isometric contractions. The changes in calcium apparently precede the depolarization. We propose that muscle shortening reduces calcium binding to the contractile proteins and leads to a rise in myoplasmic calcium, and that this rise in myoplasmic calcium activates an inward current leading to the observed changes in the action potential. These processes may be important contributory factors in some arrhythmias.
Analogue computation of indices of contraction from regional measurements in intact hearts.
Computation of indices of regional myocardial contractility such as the shortening, or the work done by or on a segment of myocardium in a single cardial cycle is tedious to perform manually, and complex interfacing and software is needed for digital computation. We describe the principles of an on-line, analogue device to perform these computations . The accuracy of the machine is demonstrated, and examples of the uses of the devices are given.
The effects of low sodium solutions on intracellular calcium concentration and tension in ferret ventricular muscle.
Papillary muscles from the right ventricles of ferrets were micro-injected with the photoprotein aequorin. Both tension and the light emitted by the aequorin, which is a measure of the free intracellular Ca concentration [( Ca2+]i), were monitored. Exposure of the papillary muscle to a solution in which all the Na had been replaced by K (0 Na(K) solution) resulted in an increase in tension which subsequently slowly decreased. This contracture was associated with a large increase in [Ca2+]i followed by a decrease to a steady-state-level which was often significantly greater than that in Na-containing solutions. If choline, Li or Tris was used instead of K as a substitute for Na, both the contracture and the associated increase of [Ca2+]i were reduced. The effects of depolarization alone (by raising external K at constant Na concentration) were compared with those of Na removal alone (at constant external K concentration). Na removal contributes more than depolarization to the effects of a Na-free, K-containing solution on the contracture and rise of [Ca2+]i. Increasing intracellular Na concentration [( Na+]i), by exposure to strophanthidin (10 mumol/l), increased the magnitude of both the contracture and [Ca2+]i in 0 Na(K) solutions. Conversely, decreasing [Na+]i by exposure to a solution containing a decreased extracellular Na concentration [( Na+]o), decreased the contracture and [Ca2+]i. When contractures were produced by solutions with various [Na+]o, the size of the resulting contracture and [Ca2+]i were inversely related to [Na+]o. No contracture was seen unless [Na+]o was reduced to below 70 mmol/l. A decrease in the extracellular Ca concentration [( Ca2+]o) from 2 to 0.5 mmol/l or an increase to 8 mmol/l produced, respectively, large decreases and increases of the twitch and accompanying Ca transient. However, if [Ca2+]o was changed at the same time as Na was replaced by K there was little effect on either the contracture or the rise of [Ca2+]i. If [Ca2+]o was changed before replacing Na by K then increasing [Ca2+]o from 2 to 8 mmol/l decreased, and decreasing [Ca2+]o from 2 to 0.5 mmol/l increased, the rise of [Ca2+]i produced by replacing Na by K. The difference between this result and that obtained when [Ca2+]o was changed at the same time as Na was removed may be due to changes of [Na+]i produced by prolonged exposure to an altered [Ca2+]o.(ABSTRACT TRUNCATED AT 400 WORDS)
Myocardial liposome uptake in the early stages of myocardial infarction.
Multiply-labelled neutral or positively-charged liposomes were given iv to open-chested dogs or pigs 0.5 h or 5 h after coronary artery occlusion. Myocardial blood flow was measured by labelled microspheres. Animals were killed 3.5 h or 6 h after coronary artery occlusion and the myocardial distribution of liposomal labels was correlated with that of the microspheres. No evidence was found that liposomes are taken up preferentially by ischaemic myocardium. The results suggest that liposomes have limited potential as a means of drug delivery in myocardial infarction.
Contraction-excitation feedback in myocardium. Physiological basis and clinical relevance.
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