Test Pulse Interval Research Articles

Sympathomimetic modulation of load-dependent changes in the action potential duration in the in situ porcine heart

Increased sympathetic stimulation is known to be arrhythmogenic. Likewise increased loading of the myocardium can directly generate arrhythmias. The interaction between the two on the electrophysiology of the myocardium has not been investigated before. We investigated the effect of dobutamine infusion on the shortening of the monophasic action potential duration secondary to increased loading. This was investigated during steady-state pacing and during an alteration in beat-to-beat interval in the form of a restitution curve. Pigs were anaesthetised and their hearts exposed. Monophasic action potentials and segment lengths were recorded from the anterior surface of the left ventricle. The loading of the ventricle was increased by transiently occluding the aorta. Steady-state pacing and a restitution curve were performed. Recordings were taken before and during dobutamine infusion. At steady state, increased loading of the heart shortened the monophasic action potential duration by a mean (+/- s.e.m.) of 4.0 (+/- 0.5) ms (P < 0.001). During dobutamine infusion this shortening of the monophasic action potential increased. Shortening of the action potential duration increased with the dose of dobutamine up to 10 micrograms/kg/min after which a plateau was reached. By comparison to control, dobutamine depressed the electrical restitution curve at short test pulse intervals did not significantly alter the plateau. Increased loading elevated the initial section of the electrical restitution curve at short test pulse intervals and depressed the plateau in both the control recordings and those taken during dobutamine infusion. Increased loading increased the amplitude of the supernormal phase of the electrical restitution curve in control recordings and those taken during dobutamine infusion. Sympathetic stimulation by dobutamine during the steady state potentiates the effect of mechanoelectric feedback on the myocardium. The effect on the restitution curve varies with test pulse interval. At short test pulse intervals the effect of sympathetic stimulation dominates with only minor antagonistic modification by increased loading. However, at longer test pulse intervals the effect of mechanoelectric feedback is equal to that of sympathetic stimulation and is synergistic with it. The mechanically induced changes we describe in the normal pig heart in situ are relatively small. However, they are in the right direction to possibly contribute to arrhythmia under pathological conditions where mechanical as well as electrophysiological inhomogeneity is prominent.

The force-interval relationship of the left ventricle: A quantitative description in patients with ischemic heart disease

Quantitative descriptions of the mechanical restitution curve as a description of variability in ventricular performance with coupling interval in isolated tissue preparations are widely available. In humans, however, in vivo examination of the force-interval relationship is restricted to test pulse intervals shorter than the sinus cycle length (ie, incomplete mechanical restitution). The primary objectives in this investigation were therefore to examine this aspect of mechanical restitution in patients with ischemic heart disease and to develop a quantitative description of the phenomenon. Mechanical restitution curves were constructed in 40 patients, most of whom had well-preserved left ventricular (LV) systolic function, undergoing diagnostic cardiac catheterization for the investigation of chest pain, using a single premature test pulse interval during baseline atrial pacing. The mechanical restitution curve, the relationship between LV+dP/dt max and test pulse interval, was fitted to a rectangular hyperbolic function. From this, the parameter c, the calculated proportional decrease in LV+dP/dt max at 60% of the resting cycle length, was derived. The mechanical restitution curve-fitting model (involving determination of c) satisfactorily described the force-interval relationship in 37 of the 40 patients studied (as a rectangular hyperbola in 31 and with simple linear regression in 6 patients). The refractory period of the atria/atrioventricular node limited accurate use of the model in the remaining three patients. The parameter c was inversely proportional to both baseline atrial pacing cycle length ( P < .001) and LV ejection fraction ( P < .02) In patients with normal LV ejection fractions, the derived value of c at a cycle length of 800 ms (c 800) was 29.0% baseline LV+dP/dt max (95% confidence interval, 23.0, 35.0). The presence of hemodynamically significant ischemic heart disease was not a predictor of the parameters of the model. After intravenous injection of the beta-adrenoreceptor antagonist metoprolol in seven patients, there was a significant ( P < .05) reduction in both c and LV+dP/dt max at the baseline atrial pacing cycle length. Thus, the force-interval relationship can be quantitatively studied using incomplete mechanical restitution curves in humans in vivo. This quantitative description probably reflects relative intracellular calcium availability via slow channel activity and can be used to assess effects of cardioactive drugs on frequency-dependent inotropic mechanisms in humans. The predictive value of this mechanical restitution curve model for hemodynamic instability during tachycardia in patients with impaired LV function remains to be determined.

Postextrasystolic potentiation in patients with ischaemic heart disease: influence of inotropic agents.

1. The extent of postextrasystolic potentiation (PESP) has been considered a useful parameter for evaluating myocardial contractile reserve in the presence of myocardial stunning or hibernation. Extent of PESP appears to reflect an interaction between myofibrillar calcium concentration and function of the contractile apparatus. However, potential for cardiovascular drugs including agents modifying adenosine 3' 5'-cyclic monophosphate concentration to influence the extent of PESP in man has not been extensively studied. 2. In 35 patients undergoing diagnostic coronary angiography, we investigated the relationship between the extrasystolic test pulse interval (ETPI) and left ventricular (LV) +dP/dtmax of a postextrasystolic contraction. The influence of three inotropically active agents on this relationship was examined following intravenous bolus injection (metoprolol, 4 mg; sotalol, 20 mg; and milrinone, 1 mg). 3. The patient group examined had predominantly preserved LV function (LVEF 67% with 95% confidence intervals 63%, 71%). In the doses utilized, all agents exerted significant effects on LV+dP/dtmax during atrial pacing: reduction of 12.3% (6.4, 18.2) for metoprolol (P < 0.0005), and 10.9% (4.2, 17.6) for sotalol (P < 0.005); and increase of 11.8% (1.3, 22.3) for milrinone (P < 0.05). 4. With the postextrasystolic interval identical to baseline pacing cycle length, postextrasystolic potentiation of LV+dP/dtmax varied inversely with ETPI. None of the three agents investigated significantly affected this relationship. 5. These results demonstrate that the extent of PESP is unaffected by 'pure' beta-adrenoceptor antagonism, (+/-)-sotalol or phosphodiesterase inhibition in man. Hence pharmacotherapy with these agents is unlikely to affect assessment of extent of PESP.

Interplay between adrenaline and interbeat interval on ventricular repolarisation in intact heart in vivo

The aim was to examine the hypothesis that an interaction between adrenaline and change in heart rate may alter the normal time sequence of ventricular repolarisation (and hence refractoriness) in a manner that (1) may favour arrhythmia formation, (2) may partly explain conflicting reports of the effect of adrenaline, ie, there are two opposing effects on action potential duration, and (3) be relevant to T wave abnormalities that sometimes occur in normal people. As a measure of the time course of repolarisation, monophasic action potentials were recorded simultaneously from three epicardial sites in the porcine heart (left ventricular apex, left ventricular base, and mid right ventricle). During steady state pacing, test pulse intervals were interposed at progressively shorter intervals in order to construct restitution curves. Adrenaline infusion (0.4-1.5 micrograms.kg-1.min-1) resulted in earlier repolarisation in the beats after shorter interbeat intervals, and delayed repolarisation after longer interbeat intervals, tending to turn the restitution curve anticlockwise (ie, there were two opposing effects on action potential duration). The effects were not homogeneous between regions. To show this inhomogeneity, pairs of monophasic action potentials from different regions were subtracted using a differential input amplifier to produce an ECG like waveform at the amplifier output. The resulting T wave was thereby a measure of the time difference in repolarisation between the monophasic action potentials from which it was derived. The inhomogeneity of repolarisation induced by adrenaline and rate change was reflected in the morphology of this derived T wave, particularly at early (premature) beats. These T wave changes correlated closely with the true T wave changes in bipolar electrograms recorded between the same recording sites (R = 0.89; p less than 0.0001). These results show that adrenaline altered the normal relationship between interbeat interval and the timing of repolarisation. The effect was not homogeneous and when regional differences were observed they were reflected in changes in T wave morphology. These were marked at short intervals. It is possible that in addition to increased excitability observed with adrenaline, a combination of raised sympathetic activity and early beats predisposes to arrhythmias by exaggerating dispersion of repolarisation.

Force interval relationship (FIR) related to the global function of the left ventricle: a computer study

A model which relates the left ventricular (LV) geometry, structure and sarcomere properties to its global function, recently proposed by the authors, is extended to account for contractility changes which are a function of the heart rate, prematurity of the beat and calcium transients within the cell. To characterise LV function and relate it to fibre function under varying rhythm conditions, a model of muscle force restitution, based on calcium kinetics, was used to calculate the maximum fibre stress at the optimum sarcomere length sigma o as the parameter which depends on the heart rate, the test pulse interval TPI, the action potential duration APD and the restitution time constant. The global LV force interval relationship FIR was then calculated, and by comparing the calculated FIR to the experimental measurement (in dogs) at the ventricular level, the constants of the restitution of force at the fibre level were derived. Based on these constants, the LV function under ejecting conditions at various rhythm disturbances was calculated and related to the local, distributed parameters. This approach provides a tool to describe ventricular function as well as transmural distribution of stress and sarcomere length at a wide variety of loading and rhythm conditions based on given 'muscle level' parameters.

Relation of human cardiac action potential duration to the interval between beats: implications for the validity of rate corrected QT interval (QTc).

Fourteen patients undergoing routine cardiac catheterisation were paced at a steady frequency; after this test, stimuli were introduced with a variable preceding interval (test pulse interval). The QT interval of the electrocardiogram and the duration of the monophasic action potential of the right ventricle were measured. QT interval is a function of action potential duration; the two variables were very closely correlated in this study. Both these variables increased in duration with increasing test pulse interval. A biphasic response, as previously reported, was not seen. An increase in steady state pacing frequency caused QT interval and action potential duration to decrease for any given R-R interval. When frequency of stimulation was suddenly increased and then maintained, there was an immediate action potential shortening followed by a further more gradual shortening occurring over several minutes. These results imply that a simple correction of QT interval for heart rate (QTc) is inadequate. It is concluded that the relation between action potential duration (or QT interval) and heart rate depends on both the instantaneous interval between beats and the duration of the prevailing heart rate.

On the change of cardiac action potential with age: a study in dogs.

The action potential duration (APD) was measured using an Ag-AgCl electrode, in open chest anaesthetised dogs (n = 8) and puppies, 4 to 6 months old (n = 8), with complete atrio-ventricular dissociation and beta-adrenergic blockade. They were paced in the control period at a frequency of 120 beats . min-1. Both adults and puppies showed maximum action potential duration at a test pulse interval of over 700 ms. Below this the adult dogs showed a progressive shortening of the action potential duration (mean APD 81.5% at 200 ms). In contrast, the puppies showed much less shortening (91% at 200 ms; p less than 0.001). Measurements of Na+, K+-ATPase activity by the Rb uptake method gave values of 13.4 +/- 1.3 (puppies, n = 4) and 6.1 +/- 1.1 (adults, n = 6). These results may be consistent with the idea of a greater influx and efflux of sodium in the myocardial cells of the puppy compared with the adult dog.

Mechanical restitution of isolated perfused canine left ventricles.

We measured cardiac mechanical restitution curves, which describe the time course of recovery of ventricular contractile strength following a steady-state beat. In the first series of experiments, we studied left ventricles that beat isovolumically throughout the experiment, allowing use of dP/dtmax as a reliable index of contractile strength independent of the influence of changing ventricular pre- and afterload. The commencement of mechanical restitution was found to be associated with the onset of electrical diastole; thereafter, contractile strength rose monoexponentially to a plateau that was maintained for test pulse intervals as long as 15 s. The time constant of restitution (typically 245 ms) was independent of priming frequency and ventricular volume. These findings were interpreted in terms of a model of intracellular calcium fluxes within the myocardial cells. In a second series of experiments, we measured mechanical restitution curves from isolated ventricles that ejected against a simulated arterial impedance system. Under this condition, we did not observe the monoexponential time course of mechanical restitution as was measured under isovolumic conditions. The differences between the mechanical restitution curves measured under isovolumic and ejecting conditions were attributed to the influences of changing hemodynamic conditions on dP/dtmax that caused it to be an unreliable index of contractile strength.

The relationship between the strength of the human heart beat and the interval between beats.

In 15 patients undergoing cardiac catheterization and pacing tests, the left ventricular (LV) pressure and its maximum rate of rise (LV dP/dt max) were measured with catheter-tip manometers. Atrial or ventricular pacing at a single steady frequency (the priming frequency) was followed by a test pulse at a varying interval (test pulse interval). In 14 subjects in whom it was examined, the contractile response after the test pulse increased with test pulse interval to reach a maximum plateau value--the optimum contractile response (OCR). In five cases, further prolongation of the test pulse interval decreased the contractile response. The optimum test pulse interval occurred at 800-900 msec. An increase in the priming frequency before the introduction of the test pulse caused a progressive increase in OCR, in contrast to the minor effects on LV dP/dt max of the control beats. Similar results were recorded in four other patients in whom contractile response was assessed from the rate of rise of right ventricular pressure. These results indicate that with tachycardia, the interval between beats is insufficient to allow maximum contractile performance (presumed to be activated by calcium ions) to develop. The true effect of increasing heart rate is only revealed by the relationship between OCR and the preceding frequency of contraction.

The action‐potential duration and contractile response of the intact heart related to the preceding interval and the preceding beat in the dog and cat

1. Simultaneous measurements were made in anaesthetized dogs of monophasic action potentials from the right ventricle and of the maximum rate of rise of left ventricular pressure (dP(lv)/dt(max)). Atrio-ventricular dissociation was induced and the heart paced via right ventricular electrodes.2. A control period of steady pacing was followed by a test stimulus after a variable interval called the ;test-pulse interval'. The duration of the action potential of the test beat (measured at 70% repolarization) increased with test-pulse interval and reached an approximately steady value at intervals of 1.0-1.5 sec. This constitutes the ;electrical restitution curve'.3. An increase in the frequency of stimulation prior to the introduction of the test pulses caused a downward displacement of the electrical restitution curve.4. Stimulation at 2 Hz and paired pulse stimulation at 1 Hz (same number of stimuli per min) were introduced prior to the test pulses and produced very similar electrical restitution curves.5. For a constant frequency of stimulation in the control period, adrenaline produced downward displacement of the restitution curve.6. It is concluded that there is no obvious relationship between the restitution of the action potential duration and of the contractile response. We suggest therefore that electrical and mechanical restitution occur through separate processes, the former through time-dependent recovery in membrane conductances and the latter through time-dependent increase in availability of intracellular calcium for release.7. Contractions were introduced with a test-pulse interval shorter than the optimum, and were followed by a second test pulse fixed at the optimum interval of 0.8-1.0 sec. The second test beats were potentiated (post-extrasystolic potentiation). In isolated ejecting cat hearts, there was an optimum interval for the first test pulse to produce the greatest potentiation of the second test beat. This interval was 0.2-0.3 sec, and was shortened by an increase in frequency of stimulation prior to the first test beat.8. The interval preceding the first test pulse was then varied within a range (0.8-2.0 sec) which did not produce potentiation. These first test pulses were sometimes preceded by one extrasystole. The timing of this extrasystole was altered to vary the post-extrastolic potentiation of the first test pulse.9. Multiple regression analysis, carried out between dP(lv)/dt(max) of the second test pulse (DP(2), the dependent variable) and the action potential duration (AP(1)) and dP(lv)/dt(max) (DP(1)) of the first test pulse (independent variables) yielded correlation coefficients between 0.88 and 0.99. Each determination of the coefficient included data from beats with and without post-extrasystolic potentiation.10. It is postulated that the coefficient relating DP(2) to DP(1) in the multiple regression analysis (mean value 0.75) is an index of the proportion of calcium stored during relaxation which is released again on the next beat.11. When the decay of post-extrasystolic potentiation was examined in consecutive beats at the optimum interval, the action potential durations of these beats were found to be nearly constant. A plot of dP(lv)/dt(max) of each beat against dP(lv)/dt(max) of the previous beat yielded a curvilinear relationship which was less steep than that relating DP(2) to DP(1) in the two test pulse analysis; this was attributed to inconstancy of calcium ion entry during the action potential.

Assessment of refractoriness of the human Purkinje system.

In 35 unselected patients premature right ventricular stimulation during a constant right ventricular drive rhythm was performed at the rates of 80, 100, and 120 per min. Several surface ECG leads and intracardiac electrograms were simultaneously recorded. To assess the beginning of decreased conductivity of the His-Purkinje system for retrograde conduction the premature test pulse interval was measured when the retrograde intraventricular conduction to the bundle of His prolonged for the first time. This interval was defined as the beginning of relative refractoriness of the Purkinje system. Additionally, the effective refractory period of the right ventricular muscle was determined. A rate dependancy between the beginning of relative refractoriness of the Purkinje system and the effective refractory period of the right ventricular muscle, as it is known from animal experiments, could be established with significantly different (P less than 0.001) mean values at the three different heart rates. The method described may be the only means by which to obtain approximate information about normal and abnormal conductivity of the human Purkinje system. It is inferred that critical prolongation of refractoriness of the Purkinje system relative to the refractoriness of the myocardium may be relevant to the occurrence of ventricular arrhythmias.