Postextrasystolic Potentiation Research Articles

Modeling short-term interval-force relations in cardiac muscle.

This study employs two modeling approaches to investigate short-term interval-force relations. The first approach is to develop a low-order, discrete-time model of excitation-contraction coupling to determine which parameter combinations produce the degree of postextrasystolic potentiation seen experimentally. Potentiation is found to increase 1) for low recirculation fraction, 2) for high releasable fraction, i.e., the maximum fraction of Ca(2+) released from the sarcoplasmic reticulum (SR) given full restitution, and 3) for strong negative feedback of the SR release on sarcolemmal Ca(2+) influx. The second modeling approach is to develop a more detailed single ventricular cell model that simulates action potentials, Ca(2+)-handling mechanisms, and isometric force generation by the myofilaments. A slow transition from the adapted state of the ryanodine receptor produces a gradual recovery of the SR release and restitution behavior. For potentiation, a small extrasystolic release leaves more Ca(2+) in the SR but also increases the SR loading by two mechanisms: 1) less Ca(2+)-induced inactivation of L-type channels and 2) reduction of action potential height by residual activation of the time-dependent delayed rectifier K(+) current, which increases Ca(2+) influx. The cooperativity of the myofilaments amplifies the relatively small changes in the Ca(2+) transient amplitude to produce larger changes in isometric force. These findings suggest that short-term interval-force relations result mainly from the interplay of the ryanodine receptor adaptation and the SR Ca(2+) loading, with additional contributions from membrane currents and myofilament activation.

2,3-Butanedione monoxime suppresses primarily total calcium handling in canine heart.

Whether 2,3-butanedione monoxime (BDM, < or = 5mmol/l) suppresses primarily crossbridge cycling or total Ca(2+) handling in the blood-perfused whole heart remains controversial. Although BDM seems to suppress primarily total Ca(2+) handling in canine hearts, more evidence is lacking. We therefore analyzed the cardiac mechanoenergetics, namely, E(max) (contractility), PVA (total mechanical energy), and O(2) consumption of canine BDM-treated hearts by our recently developed integrative method to assess myocardial total Ca(2+) handling. This method additionally required the internal Ca(2+) recirculation fraction. We obtained this from the beat constant of the exponential decay component of the postextrasystolic potentiation. Our analysis indicated significant decreases in both internal Ca(2+) recirculation fraction and total Ca(2+) handling in the BDM-treated heart, but virtually no change in the reactivity of E(max) to total Ca(2+) handling. This result corroborates the view that BDM suppresses primarily total Ca(2+) handling rather than crossbridge cycling in the canine blood-perfused heart.

Influence of Transgenic Overexpression of Phospholamban on Postextrasystolic Potentiation

Twelve mice with PLB overexpression (PLBOE), and 11 isogenic FVB/N wild-type (WT) controls, were anesthetized and instrumented with a 1.4 F Millar catheter in the LV and a 1 F pacemaker in the right atrium. At a cycle length of 200 ms and a fixed extrastimulus of 120 ms, extrastimuli with increasing intervals (PESI) up to 1000 ms were introduced, and the peak rates of LV isovolumic contraction (±dP/dtmax) were normalized and fit to monoexponential equations. In a subset of animals, the protocols were repeated after ryanodine (4 ng/g) was given to deplete SR Ca2+stores. The time constant and the plateau of the exponential curve fits were significantly greater in PLBOE than WT (107.8±7.0v 75.2±5.5 ms and 1.39±0.03 v 1.08±0.02, both P<0.05). At 200, 600 and 1000 ms, the normalized dP/dt was significantly greater in PLBOE than WT. After ryanodine, normalized dP/dt was significantly decreased in PLBOE, but unchanged in WT. The protein levels of the sodium-calcium exchanger normalized to calsequestrin were increased 3.7±0.3-fold in PLBOE compared to controls. In conclusion, the phospholamban level is a critical determinant of postextrasystolic potentiation in this transgenic model, and is differentially impaired by ryanodine at long diastolic intervals in PLBOE v controls. These differences may be due in part to changes in the protein level and resultant activity of the sodium calcium exchanger.

Effects of [Na+]o, [Ca2+]o and cyclopiazonic acid on decline of post-extrasystolic potentiation and twitch kinetics in guinea-pig and human myocardial preparations.

The decline of post-extrasystolic potentiation was investigated in atrial and ventricular muscle of guinea-pigs and in human atrial muscle. This decline is described in terms of the recirculation fraction (RF) for calcium in myocardial cells. Under control conditions, the mean values for RF were as follows: 0.61 +/- 0.03 in the guinea-pig atrium, 0.32 +/- 0.05 in the guinea-pig ventricle and 0.51 +/- 0.10 in the human atrium. Upon increasing calcium concentrations within the range of 0.5-10 mM or decreasing the sodium to 70%, the steady-state force and recirculation fraction increased concomitantly in all three types of muscles. Cyclopiazonic acid (CPA), in a 5-20 microM concentration, decreased force in the guinea-pig preparations and decreased RF. The effects of CPA were great in atrial muscle, 20 microM CPA decreasing RF from 0.61 to 0. 39. In ventricular muscle, this effect was small and not statistically significant. When changing calcium or sodium concentrations, increased force was accompanied by slower relaxation in atrial muscle, but an unchanged or slightly faster relaxation in ventricular muscle. In guinea-pig myocardium, CPA (5-20 microM) prolonged the time to peak force (TPF), but it slowed relaxation only in the ventricle. Reducing the calcium outflow by Na/Ca exchange increased RF as expected, and reducing the SR calcium re-uptake decreased RF. These interventions were also expected to reduce the rate of decline of intracellular calcium, but relaxation was not consistently prolonged. This indicates that factors other than the SR calcium pump and sarcolemmal Na/Ca exchange determine, or at least influence, the rate of relaxation.

Myocardial mechanical restitution and potentiation partly underlie alternans decay of postextrasystolic potentiation: simulation.

We have reported that the postextrasystolic potentiation (PESP) decays in alternans or monotonically, respectively, depending on whether the first postextrasystolic beat interval has a compensatory pause or not, in the canine left ventricle. To get better mechanistic insight into the alternans PESP decay, we hypothesized that the myocardial mechanical restitution and potentiation could partly account for both types of PESP decay. To test this hypothesis, we simulated PESP decay on a computer using a documented equation combining myocardial mechanical restitution and potentiation. We changed the first postextrasystolic beat interval after a fixed extrasystolic beat interval without changing regular and other postextrasystolic beat intervals. The simulated PESP decayed in alternans or monotonically as a function only of the first postextrasystolic beat interval. Thus, the myocardial mechanical restitution and potentiation could partly account for both alternans and monotonic decay of PESP. We conclude that myocardial mechanical restitution and potentiation may partly underlie the initial two alternating beats, the first beat being the most potentiated and the second beat being the most depressed, of alternans PESP decay in the canine heart.

Myocardial Contractility Is Not Constant During Spontaneous Atrial Fibrillation in Patients

The variation in stroke volume and pulse pressure characteristic of atrial fibrillation is usually ascribed to time-dependent ventricular filling, implying a single positive relationship between end-systolic pressure and volume, which defines a single state of myocardial contractility. We tested the hypothesis that contractility also varies. We measured the left ventricular pressure and volume continuously with a conductance catheter with catheter-tip micromanometer introduced retrogradely into the left ventricle. The end-systolic pressure-volume relationship was determined in 6 patients in atrial fibrillation undergoing cardiac catheterization for diagnostic purposes and 4 control patients in sinus rhythm undergoing coronary artery bypass graft surgery. The normal positive relationship between end-systolic pressure and volume was found in the control patients, but no such positive relationship was found in any patient in atrial fibrillation. In the latter, the slopes of the linear regressions were either not significantly different from zero or significantly negative (r values <0.08), both results indicating a change in contractility from beat to beat. Significantly negative relationships were found between end-systolic volume and preceding R-R interval (-0.82<r<-0.24), indicating the presence of mechanical restitution. Significantly positive relationships were found between end-systolic volume and the R-R interval before the preceding R-R interval (0.35<r<0.74), indicating the presence of postextrasystolic potentiation. Myocardial contractility is constantly changing from beat to beat in atrial fibrillation because of the influence of the force-interval relationships.

Postextrasystolic potentiation echocardiography in predicting reversible myocardial dysfunction by surgical coronary revascularization

Sustained inotropic stimulation, such as dobutamine infusion, has the potential to cause an additional contractile deterioration in viable but chronically hypoperfused and dysfunctioning myocardium, by inducing ischemia. Postextrasystolic potentiation (PESP) represents a potent inotropic stimulus without risk of provoking ischemia, as it is instantaneous. In this study, we assessed the role of PESP-echocardiographic examination in predicting the recovery of regional contractility after coronary revascularization. We examined 105 consecutive patients with multivessel coronary artery disease who were candidates for bypass surgery; 79 were included in this prospective study. Preoperative reversibility of contractile dysfunction in asynergic myocardial regions was determined by PESP, with a coupling interval of 500 msec decreasing to 300 msec, with a progressive decrease by 10 msec. The examination was accompanied by continuous 2-dimensional (2D) echocardiographic monitoring. The assessed sensitivity and specificity were 92% and 87%, respectively; the predictive accuracy was 90%. These results demonstrated that PESP echocardiography is a useful and cost-effective method for identifying viable myocardium in patients undergoing myocardial revascularization.

Evidence for an influence of mechanical restitution on beat-to-beat variations in haemodynamics during chronic atrial fibrillation in patients.

We tested the hypothesis that beat-to-beat changes in haemodynamics during atrial fibrillation include an effect of each preceding R-R interval through the interval-strength relationship (mechanical restitution). The variation in stroke volume and pulse pressure characteristic of atrial fibrillation is usually ascribed to time dependent ventricular filling. We measured the maximum rate of rise of left ventricular pressure (LVdP/dtmax), and aortic blood velocity and its integral in patients with atrial fibrillation undergoing cardiac catheterisation. The contractile response of isometric human myocardial trabeculae to sequences of atrial fibrillation was also studied, using the recorded ECGs as stimuli. The trabeculae were obtained from the resected right ventricular outflow tracts of patients with Fallot's tetralogy undergoing operative correction. Beat-to-beat variations in contractile function during atrial fibrillation in the patients were recorded as LVdP/dtmax and left ventricular ejection (ascending aortic) velocity integral (proportional to stroke volume). Both these indices correlated well with the response to the same ECG (R wave) sequences in the isometric model measured as the maximum rate of rise of force, dF/dtmax, r = 0.72 to 0.81, p, 0.0001. When short pre-preceding intervals were excluded (minimizing the effect of post-extrasystolic potentiation), these variables showed a positive curvilinear relationship to preceding interval typical of mechanical restitution. Mechanical restitution, which causes beat-to-beat changes in inotropic state, accounts in part for the changes in stroke volume in atrial fibrillation.

Modeling the cellular basis of altered excitation–contraction coupling in heart failure

Ca transients measured in failing human ventricular myocytes exhibit reduced amplitude and slowed relaxation [Beuckelmann, D.J., Nabauer, M., Erdmann, E., 1992. Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure. Circulation 85, 1046–1055; Gwathmey, J.K., Copelas, L., MacKinnon, R., Schoen, F.J., Feldman, M.D., Grossman, W., Morgan, J.P., 1987. Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ. Res. 61, 70–76; Kaab, S., Nuss, H. B., Chiamvimonvat, N., O'Rourke, B., Pak, P.H., Kass, D.A., Marban, E., Tomaselli, G.F., 1996. Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circ. Res. 78(2); Li, H.G., Jones, D.L., Yee, R., Klein, G.J., 1992. Electrophysiologic substrate associated with pacing-induced hert failure in dogs: potential value of programmed stimulation in predicting sudden death. J. Am. Coll. Cardiol. 19(2), 444–449; Vermeulen, J.T., McGuire, M.A., Opthof, T., Colonel, R., Bakker, J.M.T.d., Klopping, C., Janse, M.J., 1994. Triggered activity and automaticity in ventricular trabeculae of failing human and rabbit hearts. Cardiovasc. Res. 28, 1547–1554.] and blunted frequency dependence [Davies, C.H., Davia, K., Bennett, J.G., Pepper, J.R., Poole-Wilson, P.A., Harding, S.E., 1995. Reduced contraction and altered frequency response of isolated ventricular myocytes from patients with heart failure. Circulation, 92, 2540–2549; Hasenfuss, G., Reinecke, H., Studer, R., Meyer, M., Pieske, B., Holtz, J., Holubarsch, C., Posival, H., Just, H., Drexler, H., 1994. Relation between myocardial function and expression of sarcoplasmic reticulum Ca–ATPase in failing and nonfailing human myocardium. Circ. Res. 75, 434–442; Hasenfuss, G., Reinecke, H., Studer, R., Pieske, B., Meyer, M., Drexler, H., Just, H., 1996. Calcium cycling proteins and force–frequency relationships in heart failure. Basic Res. Cardiol. 91, 17–22; Monte, F.D., O'Gara, P., Poole-Wilson, P.A., Yacoub, M., Harding, S.E., 1995. Cell geometry and contractile abnormalities of myocytes from failing human left ventricle. Cardiovasc. Res. 30, 281–290; Philips, P.J., Gwathmey, J.K., Feldman, M.D., Schoen, F.J., Grossman, W., Morgan, J.P., 1990. Post-extrasystolic potentiation and the force–frequency relationships: differential augmentation of myocardial contractility in working myocardium from patients with end-stage heart failure. J. Mol. Cell. Cardiol. 22, 99–110; Pieske, B., Hasenfuss, G., Holubarsch, C., Schwinger, R., Bohm, M., Just, H., 1992. Alterations of the force–frequency relationship in the failing human heart depend on the underlying cardiac disease. Basic Res. Cardiol. 87, 213–221.]. Analyses of protein levels in these failing hearts reveal that the SR Ca–ATPase is down-regulated on average by 50% and that the Na/Ca exchanger is up-regulated on average by a factor of two. In this paper, we test the hypothesis that this altered pattern of expression of Ca handling proteins is sufficient to account for changes in excitation–contraction coupling properties measured experimentally at the cellular level. To do this, we present an integrated model of excitation–contraction coupling in the guinea pig ventricular cell. The model is used to determine the effects of SR Ca–ATPase down-regulation and Na/Ca exchanger up-regulation on action potential duration, Ca transient shape and amplitude, and isometric force. Model analyses demonstrate that changes in Ca handling proteins play a direct and critical role in prolongation of action potential duration, and in reduction of contractile force in heart failure.

Characterization of excitation-contraction coupling in conscious dogs with pacing-induced heart failure.

In isolated cardiac preparations of non-failing hearts from different species, including man, there is a positive force-frequency relation which is reversed into a negative relation in preparation from failing hearts. Whether or not such relations between ventricular function and heart rate hold true in the in situ heart is not clear at present. Mechanical restitution and postextrasystolic potentiation might serve as alternative measures of excitation-contraction coupling. Eleven dogs were instrumented with a left ventricular micromanometer, ultrasonic crystals for the measurement of regional wall thickness, two hydraulic occluders around the descending aorta and the inferior caval vein, and left atrial and ventricular pacing leads with a subcutaneous pacemaker. Left ventricular dP/dtmax, as an isovolumic phase index, and systolic wall thickening, as an ejection phase index, were plotted versus heart rate, and heart rate was increased by left atrial pacing from rest to 200 min-1 in increments of 25 min-1. In a subset of dogs, left ventricular filling was controlled and the frequency range expanded by the bradycardic agent UL-FS 49. Measurements were performed in the presence and absence of autonomic blockade (hexamethonium, atropine). Mechanical restitution and postextrasystolic potentiation were determined as normalized dP/dtmax and systolic wall thickening, respectively, of the extra- and postextrasystolic beat versus defined variations of the extrasystolic time interval (250-550 ms). Following control studies, heart failure was induced by rapid left ventricular pacing at 250 min-1 for 20 days +/- 6 (SD) and measurements repeated. Isolated left ventricular trabeculae from non-failing and failing hearts were studied during stimulation at 0.2-4 Hz. Only with filling control and in the absence of autonomic blockade, was there a slightly positive relation between dP/dtmax and heart rate in the control state. Otherwise, the relation of dP/dtmax to heart rate was flat both in the control state and in heart failure. The relation between systolic wall thickening and heart rate in the control state was negative, unless filling was controlled, and it was flat in heart failure. In contrast, the time constants of mechanical restitution and postextrasystolic potentiation were increased significantly with heart failure from 91 +/- 25 (SD) to 164 +/- 13 ms and from 107 +/- 18 to 156 +/- 4 ms, respectively, for dP/dtmax and from 76 +/- 22 to 162 +/- 10 ms and from 101 +/- 17 to 160 +/- 17 ms, respectively, for systolic wall thickening. These time constants were, however, insensitive to UL-FS 49 and autonomic blockade. There was a negative force-frequency relation in left ventricular trabeculae from non-failing hearts at higher calcium concentrations, where it was flat in trabeculae from failing hearts. Time constants of mechanical restitution and postextrasystolic potentiation are more sensitive than the steady state relation of ventricular function and heart rate to characterize the impairment of excitation-contraction coupling in heart failure.

Myocardial Dysfunction and Adrenergic Cardiac Innervation in Patients With Insulin-Dependent Diabetes Mellitus

Background. Insulin-dependent diabetes mellitus (IDDM) is associated with an increased incidence of heart failure due to several factors, and in some cases a specific cardiomyopathy has been suggested.Objectives. This study sought to assess the mechanisms of exercise-induced left ventricular (LV) dysfunction in asymptomatic patients with IDDM in the absence of hypertensive or coronary artery disease.Methods. Fourteen consecutive patients with IDDM were enrolled (10 men, 4 women; mean [±SD] age 28.5 ± 6 years); 10 healthy subjects matched for gender (7 men, 3 women) and age (28.5 ± 3 years) constituted the control group. LV volume, LV ejection fraction (LVEF) and end-systolic wall stress were calculated by two-dimensional echocardiography at rest and during isometric exercise. LV contractile reserve was assessed by post-extrasystolic potentiation (PESP) obtained by transesophageal cardiac electrical stimulation and dobutamine infusion. Myocardial iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy was performed to assess adrenergic cardiac innervation.Results. Diabetic patients were classified into group A (n = 7), with an abnormal LVEF response to handgrip (42 ± 7%), and group B (n = 7), with a normal response (72 ± 8%). Baseline LVEF was normal in both group A and B patients (60 ± 6% vs. 61 ± 7%, p = NS). In group A patients, the LV circumferential wall stress–LVEF relation showed an impairment in LVEF disproportionate to the level of LV afterload. No significant changes in LVEF occurred during dobutamine (60 ± 6% vs. 64 ± 10%, p = NS), whereas PESP significantly increased LVEF (60 ± 6% vs. 74 ± 6%, p < 0.001); PESP at peak handgrip normalized the abnormal LVEF (42 ± 7% vs. 72 ± 5%, p < 0.001); and MIBG uptake normalized for body weight or for LV mass was lower than that in normal subjects (1.69 ± 0.30 vs. 2.98 ± 0.82 cpm/MBq per g, p = 0.01) and group B diabetic patients (vs. 2.79 ± 0.94 cpm/MBq per g, p = 0.01). Finally, a strong linear correlation between LVEF at peak handgrip and myocardial MIBG uptake normalized for LV mass was demonstrated in the study patients.Conclusions. Despite normal contractile reserve, a defective blunted recruitment of myocardial contractility plays an important role in determining exercise LV dysfunction in the early phase of diabetic cardiomyopathy. This abnormal response to exercise is strongly related to an impairment of cardiac sympathetic innervation.

Effects of Ca2+ and epinephrine on Ca2+ recirculation fraction and total Ca2+ handling in canine left ventricles.

We investigated the effects of intracoronary Ca2+ and epinephrine on the intracellular Ca2+ recirculation fraction (RF) and total Ca2+ handling in the left ventricle (LV) of the excised cross-circulated canine heart preparation. We analyzed LV postextrasystolic potentiation (PESP) following a spontaneous extrasystole that occurred sporadically under constant atrial pacing. All PESPs decayed in alternans and none decayed monotonically. We extracted an exponential decay component from the alternans PESP, determined its beat constant (taue), and calculated RF = exp(-1/taue). Increased intracoronary Ca2+ slightly increased taue and RF, but epinephrine did not change them, although both agents enhanced LV contractility 2-3 times. Neither Ca2+ nor epinephrine affected the sinusoidal decay of the alternans PESP. These results indicate that RF via the sarcoplasmic reticulum was slightly augmented by Ca2+, but not by epinephrine. We combined these RF data with LV Ca2+ handling O2 consumption data and obtained 40-110 micromol/kg as the total amount of Ca2+ handled in one cardiac cycle in the control and enhanced contractile states. These results indicate that this new LV-level approach seems to better the understanding of the Ca2+ mass dynamics responsible for the mechanoenergetics enhanced by inotropic interventions.

Contractile Failure in Chronic Doxorubicin-induced Cardiomyopathy

The mechanisms for the progression of the anthracycline-induced cardiomyopathy to contractile failure has not been defined.In vitro, doxorubicin (DOX) appears to modify calcium-mediated excitation–contraction coupling, which depresses cardiac contractility. This study characterizes the onset of contractile failure associated with the development of DOX-induced cardiomyopathy. Rabbits were treated with DOX (1 mg/kg i.v. twice weekly, 12–18 doses; DOX-treated group) and compared with a pair-fed Control group infuse with saline vehicle. The severity of the cardiomyopathy was determined by numerically-scored histopathology. Myocardial contractility was determined in thin fiber bundles from right ventricular (RV) papillary muscles and left atria that were removed and mounted on a force transducer in oxygenated Krebs-bicarbonate buffer (pH=7.4 at 30°C) to record the amplitude (DT) and maximum rate (+dT/dt) of isometric tension. Myofibrillar and calcium loading properties were determined by the calcium and caffeine-activated tension responses respectively in chemically-permeabilized fibers. With the onset of the cardiomyopathy (score <2) DT at low frequency (0.5 Hz) was depressed (0.61±0.01 mN/mg;n=14) compared to Control (0.93±0.09 mN/mg;n=15). Contractility at higher rates (1 Hz) was not different in this DOX-treated and Control groups. Maximum calcium and caffeine-activated force and the pCa to half-maximum force of permeabilized fibers were comparable in DOX-treated and Control groups. The loss of contractility of the DOX-treated group was related to reduction in sacroplasmic reticulum calcium release channel density, as determined by Bmaxfor3H-ryanodine binding in cardiac microsomal membrane fraction. Post-rest potentiation of contractility, as well as frequency-dependent (0.25–1.5 Hz) and post-extrasystolic potentiation of contractility were preserved in the DOX-treated group.In vitro, DOX depressed post-rest potentiation of contractility. Thus, the onset of contractile failure of the DOX-induced cardiomyopathy is characterized by effects consistent with disordered calcium-mediated excitation–contraction coupling and these effects are qualitatively different thanin vitroeffects of DOX.

Postextrasystolic potentiation and dobutamine echocardiography in predicting recovery of myocardial function after coronary bypass revascularization.

Identification of viable but hibernating myocardium remains a relevant issue in the current era of myocardial revascularization. Echocardiography can be helpful in detecting reversible contractile dysfunction and optimizing the selection of patients for coronary bypass surgery. Eighty-four consecutive candidates for bypass surgery with chronic multivessel coronary artery disease were screened, and 60 were included in this prospective study. Preoperative evaluation of a reversible contractile dysfunction in asynergic myocardial regions was performed by dobutamine infusion at 5 (low dose) and 10 (intermediate dose) microg x kg(-1) x min(-1) with each stage lasting at least 5 minutes; postextrasystolic potentiation (PESP), with a coupling interval ranging from 500 to 300 ms with a progressive 10-ms decrease; or a combination of both dobutamine infusion and PESP. Sensitivity (92% versus 86%) and predictive accuracy (89% versus 84%) were higher with PESP than dobutamine (P=.009 and P=.001, respectively), but the combination did not improve sensitivity or accuracy. Dobutamine induced ischemic dysfunction in 15% of patients at the intermediate dose; however, the low dose resulted in loss of sensitivity. PESP echocardiography is a useful and cost-effective method to identify viable myocardium in patients with multivessel coronary disease undergoing revascularization and is more sensitive and accurate than dobutamine infusion.

Force-frequency and relaxation-frequency relationships in neonatal goats: Physiologic mirrors of changes in cytosolic calcium. • 94

Force-frequency (FFR) and relaxation-frequency relationships (RFR) and post-extrasystolic potentiation (PESP) act as physiologic mirrors reflecting changes in Ca2+ release and uptake by sarooplasmic reticulum (SR). It has been proposed that SR is relatively immature in neonatal animal and FFR and RFR may be impaired in them. We studed certain new aspects of FFR and RFR in 4 neonatal goats (Age: 4 weeks) and 3 adult goats. Left ventricular (LV) dP/dtmax and time constant of relaxation (τ) were calculated from micromanometric LV pressure tracings at increasing heart rates (HR) generated by right ventricular pacing. The phenomenon of PESP was studied by pacing at a constant cycle length(400ms) and by introducing an extrasystole and post-extrasystole at cycle lengths of 250ms and 600 ms, respectively. Both FFR(dP/dtmax vs HR) and RFR (τ vs HR) have biphasic relationships separated by a critical HR at which this transition occurs. Critical HR was nearly identical for both FFR and RFR. Mean critical HR was higher in neonatal vs adult goats (250± 35 vs 180±22 beats/min, p, 0.05). Following ryanodine (a SR Ca2+-release channel blocker), critical HR was shifted to the left in both neonatal and adult goats (170±34 vs 140±28 beats/min). Fig. 1

Ryanodine decreases internal Ca2+ recirculation fraction of the canine heart as studied by postextrasystolic transient alternans.

We tested our hypothesis that the O2 wasting of Ca2+ handling in the excitation-contraction (E-C) coupling in ryanodine-treated failing hearts could be reflected by a decrease in the internal Ca2+ recirculation fraction (RF). We have reported, using canine excised cross-circulated hearts, that intracoronary ryanodine (40 nmol/l blood) halved left ventricular contractility without decreasing myocardial O2 consumption for the E-C coupling. We previously suspected this mechanoenergetic state to manifest energy wasting of Ca2+ handling due to ryanodine causing leakage of Ca2+ from the sarcoplasmic reticulum. To test this hypothesis, we analyzed all the sporadic spontaneous cases of postextrasystolic potentiation (PESP) obtained during the ryanodine experiments. We calculated RF from the beat constant of the exponential decay component of not only the monotonic type but also the transient alternans type of PESP. Results showed that ryanodine significantly decreased the beat constant in both types of PESP from about 2 to 1.5 beats and hence RF from 0.6 to 0.5 on the average, supporting the hypothesis. This organ-level systems approach to Ca2+ handling using transient alternans PESP as well as monotonic PESP may help obtain better insights into the mechanoenergetics of failing hearts.

Influence of ryanodine on the mechanical restitution and on the post-extrasystolic potentiation of the guinea-pig ventricular myocardium.

This paper records the results of an investigation into potentiation and staircase phenomena in rightventricular guinea-pig papillary muscles with particular reference to the sarcoplasmic Ca(2+)-channel. As a tool to isolate the second ('late', 'tonic') component of isoproterenol-induced biphasic contractions ryanodine was used. On the evidence at present available the monophasic ryanodine-resistant component of the twitch represents that portion of the activator calcium which reaches the troponin C directly, that is, not taking the roundabout way through the intracellular storage structures. In order to avoid functional instabilities of the isolated muscle preparation a short-time double rest stimulation programme was used which combines a number of different tests and gives information on (1) the post-rest potentiation, (2) the post-extrasystolic potentiation, (3) the mechanical post-rest recovery, (4) the interval-strength relationship, and (5) the mechanical restitution. The results of the present work show that under the influence of ryanodine (1) the Bowditch staircase, a typical feature of normodynamic mammalian ventricular preparations as well as of hypodynamic frog heart preparations, does not exist, (2) the post-extrasystolic potentiation disappears, (3) the curve reflecting the mechanical restitution, under normal in vitro conditions a monotonically increasing function, becomes biphasic within the relative refractory period, (4) the conspicuous depression of the isometric post-rest contraction for long lasting pauses interrupting the regular pacing rhythm, a typical feature of isolated guinea-pig ventricular tissue, is clearly diminished, and (5) the characteristic curve, reflecting the potentiation of the post-extrasystolic post-rest contraction as a function of the delay time preceding the extrastimulus, becomes displaced to the premature interstimulus interval. The concept of an 'extended 2-calcium-store model' is supported by this work.

Correlation of fatty acid metabolism and contractile reserve assessed by BMIPP SPECT and postextrasystolic potentiation in acute myocardial infarction

Correlation of fatty acid metabolism and contractile reserve assessed by BMIPP SPECT and postextrasystolic potentiation in acute myocardial infarction

Evidence of myocardial dysfunction in Bartter's syndrome.

Bartter's syndrome (BS) is characterized by arterial normohypotension despite biochemical and hormonal abnormalities generally associated with hypertension. An abnormal intracellular calcium homeostasis due to a reduced capacity to increase intracellular calcium has been demonstrated by us in BS and proposed as the main pathophysiological factor of the vascular hyporeactivity in BS. The present study was designed to assess whether this altered intracellular calcium homeostasis could also impair contractile recruitment at the myocyte level. Left-ventricular function of patients with BS and normal subjects (C) were studied by quantitative 2-D echocardiography at rest and by postextrasystolic potentiation (PESP), an inotropic stimulus able to recruit the maximal contractile reserve. A group of patients with hypokalemia other than BS (PB) was also included in the study to evaluate the effect of hypokalemia on myocardial contractile recruitment. Baseline left-ventricular end-diastolic volume (EDV) and ejection fraction (EF) did not differ in the 3 groups: EDV: 62 +/- 6 vs. 64 +/- 9 and 60 +/- 12 ml/m2; EF: 64 +/- 9 vs. 67 +/- 8 and 64 +/- 8%. PESP determines an increase of EF in C and PB: 82 +/- 5%, p < 0.01 and 76 +/- 6%, p < 0.01, while in BS it is unchanged: 69 +/- 9% and is reduced in comparison with the increment of myocardial function shown by C and PB (p < 0.01). This study is the first demonstration in BS of a depressed inotropic recruitment causing an exercise-induced left-ventricular dysfunction likely due to an abnormal intracellular calcium homeostasis in the myocytes.

Mechanisms contributing to pulsus alternans in pressure-overload cardiac hypertrophy.

The mechanisms underlying pulsus alternans in pressure-over-load (POL) cardiac hypertrophy were investigated. Simultaneous measurements of force and intracellular Ca2+ (using fura 2) in right ventricular papillary muscles under conditions that produced mechanical alternans, revealed alternation of the amplitude of the Ca2+ transient together with alternation of force in some POL muscles. Instances when alternation of force occurred without any apparent alternation of the Ca2+ transient were also observed. Exposure of muscles to 5 microM ryanodine significantly attenuated mechanical alternans, thereby implicating a role for the sarcoplasmic reticulum (SR) in this process. The time course of restitution of force and the intracellular Ca2+ transient were, however, unchanged in POL hearts, indicating that SR Ca2+ cycling was not appreciably slowed. The fraction of Ca2+ recirculated intracellularly was derived from studies of postextrasystolic potentiation and was significantly reduced in the POL hearts, suggesting additional differences in cellular Ca2+ regulation. We conclude that changes in Ca2+ handling play an important role in the onset of mechanical alternans in POL hypertrophy, but that additional factors, most likely a slowing of crossbridge cycling rate, are also likely to be important.