(Circulation. 1997;95:732-739.)
© 1997 American Heart Association, Inc.
Articles |
Effects of MCI-154, a Calcium Sensitizer, on Left Ventricular Systolic and Diastolic Function in Pacing-Induced Heart Failure in the Dog
the First Department of Internal Medicine, Mie University, Tsu, Japan.
Correspondence to Tetsu Yamakado, MD, First Department of Internal Medicine, Mie University, Edobashi 2-174, Tsu 514, Japan.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background MCI-154 is a positive inotropic agent that increases the myofilament response to Ca2+. Whether MCI-154 has beneficial effects on left ventricular dysfunction in chronic heart failure is not known. We examined the effects of MCI-154 on left ventricular systolic and diastolic function in pacing-induced heart failure in dogs.
Methods and Results We studied eight anesthetized dogs before and 2 to 4 weeks after rapid right ventricular pacing. Left cineventriculograms with simultaneous left ventricular pressures (tip manometer) were obtained before and during intravenous administration of MCI-154 (1.0 µg·kg-1·min-1 for 15 minutes) in the control and heart-failure states. Left ventricular volume dynamics was derived from frame-by-frame (20-ms) analyses of left ventricular angiograms. In heart failure, left ventricular contractility as assessed by shifts of the end-systolic pressure-volume ratio, evaluated by inferior vena cava occlusion, was improved by MCI-154 (+1.94 mm Hg/mL, P<.05) to an extent similar to that in the control state (+2.47 mm Hg/mL, P<.05). MCI-154 also accelerated left ventricular relaxation, assessed by the time constant of isovolumic pressure decay (T1/2), in both states. The absolute decrease in T1/2 with MCI-154 in heart failure was significantly greater than in the control state (-8.2 versus -3.1 ms, P<.05). In heart failure, MCI-154 shifted the left ventricular diastolic pressure-volume relation clearly downward, suggesting increased diastolic distensibility.
Conclusions MCI-154 improved not only left ventricular systolic function but also diastolic relaxation and distensibility in a chronic heart failure model.
Key Words: calcium • heart failure • systole • diastole • inotropic agents
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The cardiotonic agent MCI-154 has been identified and suggested as a possible alternative to inotropic agents such as cardiac glycosides and sympathomimetic amines. Several investigators have indicated that positive inotropism is primarily due to an increase in the Ca2+ sensitivity of the contractile apparatus.1 2 3 4 This compound has been shown to exert positive inotropy in isolated ventricular muscles from various mammalian species1 2 3 5 6 7 and in anesthetized or conscious intact dogs.8 9 Positive inotropic effects have also been demonstrated in canine models of acute cardiac dysfunction induced by pharmacological manipulations,8 ischemia,10 acidosis,10 and stunned myocardium.11 However, the effects of MCI-154 on LV systolic and diastolic function in chronic heart failure have not been documented. Furthermore, no data have been available comparing the effects of this agent in normal and failing hearts. Previous investigators have reported that pharmacological agents acting on the responsiveness of myofilaments to Ca2+ produce differential effects in myopathic myocardium compared with normal myocardium.12 13 It is therefore important to investigate these differential effects of the drugs on normal and myopathic hearts.
The purpose of this study was to examine the effects of MCI-154 on LV contractility and relaxation in an experimental chronic heart failure model, namely, pacing-induced heart failure in dogs. This model of heart failure produces hemodynamic, structural, and neurohumoral changes analogous to those seen in human congestive heart failure.14 15 16 In this model, we compared serially in the same animal the effects of MCI-154 in the control state and after the development of heart failure.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Pacemaker Implantation
Permanent pacemakers were implanted in adult mongrel dogs weighing 15.4±2.6 kg (range, 12.0 to 20.0 kg). The dogs were anesthetized with ketamine (10 mg/kg IM) and sodium pentobarbital (25 mg/kg IV), intubated, and placed on a volume-cycled respirator. The pericardium was opened through a sterile right thoracotomy at the fourth intercostal space. A ventricular pacing lead was sutured onto the midportion of the right ventricle of the exposed heart. The pacemaker lead was tunneled to the back and connected to a modified multiprogrammable pulse generator (Medtronics, Inc) implanted subcutaneously. The pericardium was loosely approximated, the thoracotomy was closed in layers, and the pleural space was evacuated. To avoid early postoperative effects on LV function,17 the dogs were allowed to recover for at least 4 weeks before the study protocol was begun.
Experimental Protocol
The effects of MCI-154 (Mitsubishi Chemical Corp) on LV systolic and diastolic function were studied before and 2 to 4 weeks after rapid right ventricular pacing (at 245 bpm). Hemodynamic data and left cineventriculograms were obtained before and during intravenous administration of MCI-154 at 1.0 µg·kg-1·min-1 for 15 minutes.
Previous studies demonstrated that doses of MCI-154 as low as 0.5 µg·kg-1·min-1 for 15 minutes have no or minimal hemodynamic effects.9 11 In the same studies, dogs treated with a dose of 1.0 µg·kg-1·min-1 showed significant hemodynamic improvement without the adverse hemodynamic effects observed with the 2.0 µg·kg-1·min-1 dose. On the basis of these observations, we believed that a dose of 1.0 µg·kg-1·min-1 was the optimal dose for the hemodynamic study on this agent.
On each study day, the dogs were anesthetized with 
-chloralose (50 mg/kg IV) and urethane (600 mg/kg IV), with supplemental doses given as necessary to maintain anesthesia. The dogs were allowed to breath spontaneously. We checked arterial blood gases and pH at intervals throughout the protocol and confirmed that these were maintained at a constant physiological level (pH, 7.37 to 7.43; PaCO2, 35 to 45 mm Hg; and PaO2, 80 to 100 mm Hg). The dogs were kept in a right lateral position throughout the study. Under fluoroscopic guidance, a thermodilution 7F Swan-Ganz catheter was inserted via the external jugular vein and advanced into the pulmonary artery for measurement of right atrial, pulmonary artery, and capillary wedge pressures. Thermodilution cardiac output values from three to five measurements were averaged. To obtain LV pressures and ventriculograms, a 7F angiographic micromanometer-tipped catheter (Millar Instruments) was positioned via the carotid artery in the left ventricle. To determine the LV end-systolic pressure-volume relation, a femoral vein was cannulated with a balloon-tipped catheter to occlude the inferior vena cava. Left ventriculograms were obtained after 20 mL of nonionic contrast material (iohexol) was injected into the left ventricle at a rate of 10 mL/s. Ventriculograms were recorded at 50 frames per second. LV pressures and dP/dt were recorded simultaneously during ventriculography at a paper speed of 200 mm/s (Nihon Kohden). Central aortic pressure was recorded immediately before each ventriculogram. The micromanometer-tipped catheter was calibrated with a fluid-filled system at intervals throughout the study. The zero-pressure manometer was set at the level of the right atrium.
For control studies, hemodynamic and angiographic measurements were first obtained under baseline conditions. To determine the LV end-systolic pressure-volume ratio (Ees), left ventriculography and simultaneous measurements of LV pressure were carried out after the inferior vena cava was occluded sufficiently to lower LV peak systolic pressure by 20 to 50 mm Hg. After the baseline data were recorded, MCI-154 was infused intravenously at a rate of 1.0 µg·kg-1·min-1 for 15 minutes in each dog. When the hemodynamic indexes had stabilized 15 minutes after the initiation of continuous MCI-154 infusion, hemodynamic and angiographic measurements were again carried out.
After control values had been established, the dogs were given 4 to 7 days to recover before prolonged rapid right ventricular pacing was started. The reason for this is that in our preliminary study, in which rapid pacing was initiated before recovery from the effects of general anesthesia, three of five dogs became anorexic and apathetic because of the long-lasting effects of urethane-chloralose anesthesia and died unexpectedly. We have learned that a period of 1 to 3 days is needed for the general anesthesia to wear off. Two to 4 weeks after the initiation of rapid ventricular pacing, baseline hemodynamic and ventriculographic measurements were made 1 hour after rapid ventricular pacing had been discontinued. Then the identical dose of MCI-154 as used in the control study was administered, and hemodynamic and ventriculographic measurements were repeated.
To avoid influences of contrast material on LV function, we waited at least 20 minutes after each ventriculography before continuing the protocol and confirmed that LV pressure had returned to baseline level.
This study protocol was approved by the Animal Research Committee of the Mie University. Specific attention was given to the appropriateness of the animal model, the welfare of the animals, the adequacy of anesthesia, and the methods of instrumentation.
Data Analysis
To assess LV volume, we digitized single-plane LV silhouettes frame by frame (50 frames per second) and calculated LV volumes by the single-plane area-length method.18 Premature and postextrasystolic beats were excluded from analysis. In seven dogs, cineangiograms could be satisfactorily digitized frame by frame over an entire cardiac cycle both before and after MCI-154 administration.
LV peak positive dP/dt was used as an isovolumic phase index of the inotropic state. For evaluation of the ejection phase indexes of LV contractility, we calculated LV ejection fraction and Ees. We could not assess Ees in two dogs because extrasystolic beats occurred during left ventriculography after inferior vena cava occlusion.
To assess LV relaxation, we calculated T1/2. To calculate T1/2, LV pressure was measured every 5 ms from the point of minimal dP/dt to a level 5 mm Hg above the end-diastolic pressure of the next beat. LV pressure data points were fitted to an exponential curve with variable asymptote in accordance with the equation P=aebt+c, where P is LV pressure (mm Hg), t is time (ms), c is the asymptote of pressure fall (mm Hg), and a and b are constants. By this equation, the time constant was calculated as the time required for LV pressure to decay to half (T1/2) the value at LV peak negative dP/dt, as proposed by Mirsky.19
LV relaxation rate may be influenced not only by the magnitude of afterload but also by the systolic load profile. As an index of afterload, LV global average circumferential stress (S, in g/cm2) at end systole was estimated as proposed by Mirsky: S=1.36(Pb/2h)(1-b2/2a2-h/b+h2/8a2), where P is LV end-systolic pressure (mm Hg), h is wall thickness (cm) at end systole, and a and b are LV semimajor axis and semiminor axis (cm) at end systole, respectively. The LV major axis and area (A) were measured in the right anterior oblique projection, and the semiminor axis (b) was calculated as b=A/
a. LV wall thickness was measured on an end-diastolic frame at the LV free wall, two thirds of the distance from the aortic valve to the apex in the right anterior oblique projection. For all frames subsequent to end diastole, LV wall thickness was calculated assuming constant mass for each frame.21 The time to peak wall stress, ie, the time from end diastole to the peak of the wall stress, was determined as an index of loading pattern.
For evaluation of alterations in LV diastolic distensibility, we plotted diastolic pressure-volume relations in seven dogs before and after MCI-154 administration in both the control and heart-failure states at four points in diastole: at minimal diastolic pressure, at points of one third and two thirds of the time from minimal pressure to end diastole, and at end-diastolic pressure. We also calculated passive elastic properties from minimal pressure to end-diastolic pressure by computing k from a simple elastic model as follows: P=aekV, where P is LV pressure (mm Hg), V is volume (mL), and a is the intercept (mm Hg).
Statistical Analysis
Values are expressed as mean±SD unless otherwise stated. Differences between the baseline values of the control and heart-failure states, data before and after MCI-154 administration in each state, and comparisons of the absolute changes from baseline after MCI-154 between the two states were analyzed by Student's paired t test. The effects with MCI-154 between the control and heart-failure states were compared by repeated-measures ANOVA. A value of P<.05 was considered statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Production of Experimental Heart Failure by Prolonged Rapid Ventricular Pacing
Systemic and LV hemodynamics and left ventriculographic data obtained in the control state and after rapid ventricular pacing are shown in the Table
. After 2 to 4 weeks of pacing, there was a significant increase in mean right atrial pressure (+3 mm Hg, P<.01) and pulmonary capillary wedge pressure (+7 mm Hg, P<.01) and a significant reduction in cardiac output (-26%, P<.05). There were no significant changes in heart rate and mean aortic pressure. LV peak systolic and end-systolic pressures were unchanged from the control state. LV end-diastolic pressure was markedly elevated (+15 mm Hg, P<.01) after rapid pacing. In addition, there was a significant decrease in LV peak positive dP/dt (-42%, P<.01). Prolonged rapid ventricular pacing led to increases in both LV end-diastolic volume (+19 mL, P<.05) and end-systolic volume (+19 mL, P<.01), resulting in a significant decrease in ejection fraction (-0.20, P<.01). There was a marked reduction in Ees (-4.02 mm Hg/mL, P<.05), suggesting a severe depression in myocardial contractility. LV relaxation and diastolic distensibility were also impaired, as evidenced by a significant prolongation in T1/2 (+6.9 ms, P<.01) and an upward shift in the diastolic pressure-volume relation. There was no significant change in k.
|
Effects of MCI-154 on Systemic and LV Hemodynamics
After MCI-154 administration, heart rate remained almost unchanged in both the control and heart-failure states. In the control state, MCI-154 produced no change (-1 mm Hg, P=NS) in mean pulmonary capillary wedge pressure but in heart failure, a significant decrease (-5 mm Hg, P<.01). In addition, MCI-154 caused a significant reduction in mean right atrial pressure in both the control state (-2 mm Hg, P<.05) and heart failure (-3 mm Hg, P<.01), with no significant differences between the two states. After MCI-154, mean aortic pressure was unchanged in both states. In the control state, MCI-154 produced no change (-0.1 L/min, P=NS) in cardiac output but in heart failure, a significant increase (+0.7 L/min, P<.05). After MCI-154, systemic vascular resistance remained unchanged in the control state (30.1±8.3 to 31.1±6.5 units, P=NS), but it was significantly decreased in heart failure (37.5±14.5 to 29.2±9.8 units, P<.05). The change in pulmonary vascular resistance did not reach statistical significance in the control state (3.7±1.2 to 3.2±1.3 units, P=NS) but was significantly decreased in heart failure (4.5±1.3 to 3.7±1.6 units, P<.05). These results suggested that MCI-154 exerted vasorelaxant effects in heart failure. In both states, there was no significant change in LV peak systolic pressure after MCI-154. LV end-systolic pressure was decreased in six of eight dogs in the control state and decreased in four of eight dogs in heart failure, but both decreases were not statistically significant (-9 mm Hg for the control state and -3 mm Hg for heart failure, P=NS). After MCI-154 infusion, LV end-diastolic pressure did not change significantly in the control state (-1 mm Hg, P=NS), but it was markedly reduced in heart failure (-9 mm Hg, P<.01). The change in LV end-diastolic volume failed to achieve statistical significance in the control state (-6 mL, P=NS) but was significantly decreased in heart failure (-5 mL, P<.05).
Effects of MCI-154 on LV Systolic Function
MCI-154 caused a substantial and comparable increase in LV peak positive dP/dt in both the control state (+37%, P<.01) and heart failure (+40%, P<.01). In addition, MCI-154 resulted in a significant and comparable reduction in LV end-systolic volume in both the control state (-7 mL, P<.05) and heart failure (-10 mL, P<.01). Ejection fraction was also significantly and comparably increased by MCI-154 in both the control state (+0.14, P<.05) and heart failure (+0.14, P<.01). After MCI-154, Ees was significantly increased, from 6.04 to 8.51 mm Hg/mL (P<.05), in the control state. In heart failure, Ees was similarly increased, from 2.02 to 3.96 mm Hg/mL (P<.05). The mean value of intercept on the x axis of LV end-systolic pressure-volume relationships was -4 mL for baseline and -2 mL for after MCI-154 in the control state (P=NS). In heart failure, it was -10 mL for baseline and +3 mL for after MCI-154 (P=NS) (Fig 1). There was no difference in the absolute increase from baseline in Ees between the values in the control state and in heart failure (Fig 2). Thus, MCI-154 augmented systolic performance in heart failure, as evidenced by increases in LV peak positive dP/dt, ejection fraction, and Ees to an extent similar to that in the control state.
|
|
Effects of MCI-154 on LV Relaxation
MCI-154 significantly accelerated LV pressure decay, as measured by T1/2, in both the control (-12%, P<.01) and heart-failure (-26%, P<.01) states. The absolute decrease in T1/2 in heart failure was significantly (P<.05) greater than that in the control state (Fig 3). The relation between the absolute changes in Ees and T1/2 before and after MCI-154 administration in both states is shown in Fig 4.
|
|
After prolonged rapid ventricular pacing, LV end-systolic wall stress was markedly elevated (135±48 to 224±53 g/cm2, P<.01) and the time to peak wall stress was significantly increased (79±19 to 110±19 ms, P<.01). MCI-154 caused a substantial and comparable decrease in end-systolic wall stress in both the control (-47 g/cm2, P<.05) and heart-failure states (-55 g/cm2, P<.01). In the control state, MCI-154 produced no significant change (-12 ms, P=NS) in the time to peak wall stress but in heart failure, a significant reduction (-24 ms, P<.05). The magnitude of changes in T1/2 was closely related to changes in end-systolic volume (r=.70) and end-systolic wall stress (r=.67) in heart failure (Fig 5). In contrast, the changes in T1/2 did not correlate with the magnitude of reduction in the time to peak wall stress (r=.29) in heart failure. Thus, the magnitude of wall stress rather than the time course of wall stress seemed to play the predominant role in the improvement in the relaxation rate.
|
Effects of MCI-154 on LV Diastolic Distensibility and Passive Elastic Properties
In the control state, the pressure at the one-third point and the volume at minimal pressure and at the two-thirds point were significantly decreased (P<.05), but the other coordinates did not significantly shift after MCI-154. In heart failure, in contrast, MCI-154 resulted in a significant decrease in LV pressure with a concomitant decrease in LV volume at the four diastolic points (all P<.05), producing a clear leftward and downward shift of the diastolic pressure-volume curve (Fig 6).
|
MCI-154 significantly decreased k in heart failure (P<.05) but not in the control state, assessed by the diastolic pressure-volume relationship from the point of minimal pressure to end diastole. The intercept did not change significantly in either state (Table
). However, when k was computed from the point of minimal pressure to the beginning of atrial contraction, it remained unaltered after MCI-154 in heart failure (0.028±0.017 to 0.027±0.013, P=NS). Thus, the decrease in k seemed to be largely due to the change in the slope in the steep portion of the diastolic pressure-volume curve during atrial contraction, when ventricular interaction and the pericardium affect the diastolic pressure-volume relation.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
We investigated the effects of MCI-154 on LV dysfunction in pacing-induced heart failure in dogs. We found that MCI-154 exerted similar inotropic effect as assessed by shifts of the end-systolic pressure-volume relations (Ees) in the heart-failure and control states. MCI-154 also accelerated LV relaxation, evaluated by T1/2, more in the heart-failure than in the control state and produced a clear downward shift of the diastolic pressure-volume relation consistent with increased diastolic distensibility in heart failure.
Effects of MCI-154 on LV Systolic Function
Most of the inotropic agents currently available are less effective both clinically and experimentally in failing hearts than in controls.22 23 24 25 MCI-154, however, caused similar improvement of LV contractility assessed by Ees in heart failure and in the control state. There are several possible explanations for the observed preservation of the inotropic effects of MCI-154 in heart failure. First, recent studies have reported that Ca2+ sensitivity of failing human and animal myocardium is unaltered25 26 27 28 29 or increased30 31 32 compared with that of normal myocardium. Wolff et al32 observed increased Ca2+ sensitivity in experimental pacing-induced heart failure in dogs. O'Leary et al26 reported no significant difference in tension-pCa relations obtained from skinned ventricular strips in the same heart failure model compared with control myocardium. This may help to explain why MCI-154 shifted the end-systolic pressure-volume relation to the left (increased contractility) in failing hearts. Second, MCI-154 has been shown to increase maximal Ca2+-activated tension as well as to enhance Ca2+ sensitivity.1 3 Generally, Ca2+ responsiveness of the myofilaments can be modulated by two primary determinants, Ca2+ sensitivity and maximal Ca2+-activated tension.33 Perreault et al25 reported that maximal Ca2+-activated tension in a pacing-induced heart failure model was substantially reduced compared with that in nonfailing myocardium. An increase in the maximal Ca2+-activated tension may represent another potential explanation for augmentation of contractility by MCI-154 in myopathic hearts. In a recent study on pacing-induced heart failure, the positive inotropic response to another Ca2+ sensitizer, pimobendan, was markedly attenuated under failing conditions compared with normal conditions.34 Recent experimental studies have shown that pimobendan affected only myofibrillar Ca2+ sensitivity but not maximal Ca2+-activated tension.35 36 Thus, the difference between the effects of MCI-154 and pimobendan on pacing-induced heart failure may be due in part to differences in the mechanisms underlying their positive inotropic actions. Finally, Kitada et al5 and Bethke et al37 reported that the inotropic mechanism of MCI-154 may operate by additional inhibition of phosphodiesterase, with concomitant accumulation of cAMP. They documented that MCI-154 apparently acted as a Ca2+ sensitizer at low concentrations, but at high concentrations its action as a phosphodiesterase inhibitor contributed to positive inotropic effects. At relatively low concentrations, as present during intravenous infusion of MCI-154 at a rate of 1.0 µg·kg-1·min-1 for 15 minutes, this compound may not inhibit cAMP phosphodiesterase. In addition, the positive inotropic effects of most cAMP-dependent cardioactive agents in failing hearts are markedly diminished because of deficient production of cAMP in myopathic myocardium.22 23 24 25 Therefore, it seems unlikely that MCI-154 improves systolic performance in the present study because of its action as a phosphodiesterase inhibitor.
Furthermore, this agent augmented systolic performance in heart failure, as evidenced by greater increases in stroke volume and cardiac output than in the control state. In addition to augmented LV contractility, the reduction in mitral regurgitation after MCI-154 in failing hearts might have contributed to the increased LV pump performance. We observed that prolonged rapid ventricular pacing led to increases in both LV end-diastolic and end-systolic volumes, resulting in a production of secondary mitral regurgitation. It was angiographically evident that MCI-154 substantially decreased the regurgitation volume in failing hearts with mitral regurgitation. Augmentation of LV contractility with MCI-154 could decrease the regurgitation by reducing the size of the regurgitant orifice, presumably by decreasing ventricular volume, with resultant improvement in forward cardiac output and stroke volume.38
Effects of MCI-154 on LV Relaxation
There is little or no information on the effects of MCI-154 on LV isovolumic relaxation in myopathic hearts. Theoretically, Ca2+-sensitizing agents should prolong relaxation by shifting the relationship between pCa and force to the left on the pCa axis.39 In fact, a recent experimental study reported that another Ca2+ sensitizer, EMD 57033, impaired relaxation in the beating heart.40 In the present study, however, we observed that MCI-154 accelerated LV relaxation as assessed by T1/2 in both states and that the absolute decrease in T1/2 was significantly larger in heart failure than in the control state. Several possible explanations exist for the positive lusitropic effects of MCI-154. First, Liao and Gwathmey,41 by measuring Mg-ATPase activity of failing human myocardium, showed that MCI-154 produced Ca2+ sensitization only at the higher systolic Ca2+ range, and at the diastolic Ca2+ range it decreased Mg-ATPase activity. They also revealed that the selective Ca2+ sensitization by MCI-154 at higher systolic Ca2+ range may be due to the Ca2+-induced exposure of hydrophobic patches on troponin C that facilitates the interaction of MCI-154 to contractile proteins.42 As for EMD 57033, Solaro et al43 showed that it did not increase Ca2+ binding to troponin C and suggested that EMD 57033 reverses the inhibition of formation of strong cross-bridges by troponin-tropomyosin complex. Therefore, the Ca2+-sensitizing action of EMD 57033 may be most prominent during diastole, resulting in prolongation of myocardial relaxation. Second, relaxation is regulated not only by inactivation but also by loading conditions and nonuniformity (asynchrony).44 45 46 47 Changes in loading conditions may be responsible for improved relaxation. In our study, a reduction in end-systolic volume and end-systolic wall stress was observed with MCI-154 in both states. In addition, changes in T1/2 were closely correlated to changes in end-systolic volume and wall stress. Reduction in end-systolic volume could cause heightened systolic deformation of the elastic elements. The resultant increased potential energy may be released as elastic recoil and may speed the rate of the fall in LV pressure.45 48 Eichhorn et al49 suggested that contraction and relaxation are intimately coupled and relate hyperbolically: relaxation occurs more rapidly as ventricular systolic function improves below the inflection point. According to this, similar improvements in contractility may result in larger lusitropic improvements in failing hearts. This concept may explain why in this study, the lusitropic effect of MCI-154 in heart failure was greater than that in control. Several investigators have shown that ventricular relaxation depends not only on the magnitude of afterload changes but also on the pressure waveform during ejection.50 51 A recent study has reported that loading sequence rather than elastic recoil plays the predominant role in enhanced load sensitivity of the failing heart.52 However, our data suggested that the lusitropic effects with MCI-154 were parallel to a reduction in the magnitude of afterload rather than changes in the time course of afterload. Finally, MCI-154 might reduce the asynchrony of LV relaxation in heart failure. Nonuniformity of the ventricle may be partly responsible for impaired relaxation in heart failure.44 46 Analysis of regional LV function, which was not performed in the present study, could further elucidate this mechanism. These might counterbalance a negative lusitropic effect of a Ca2+-sensitizing agent, explaining the improved LV relaxation after MCI-154 in the failing hearts in the present study.
Effects of MCI-154 on LV Diastolic Distensibility
To date, no data have been available regarding the effect of MCI-154 on LV diastolic distensibility. In the normal heart, we did not observe a significant shift in the LV diastolic pressure-volume relation after MCI-154. In heart failure, in contrast, MCI-154 produced a downward shift of the diastolic pressure-volume curve, suggesting increased distensibility. It has been postulated that both the pericardium and the right ventricle are important determinants of LV distensibility. In congestive heart failure, the rapid shift toward normal of the diastolic pressure-volume relation observed after vasodilating or inotropic drugs may be related to relief of extrinsic compression of the distended left ventricle by the pericardium and right ventricle.53 54 55 Tyberg et al54 demonstrated that right atrial pressure accurately reflects intrapericardial pressure over a wide range. Accordingly, the decrease in right atrial pressure might have contributed to the downward shift in the pressure-volume curves. The constant k was significantly decreased with MCI-154 in heart failure, assessed by the diastolic pressure-volume relationship from the point of minimal pressure to end diastole. However, we observed that the decrease in k in heart failure was largely due to the change in late diastole, when ventricular interaction and the pericardium exert their influence.56 Therefore, the downward shift of LV pressure-volume relationship and the decrease in k in failing hearts might possibly be associated with decreased extrinsic compression by the pericardium and right ventricle.
Study Limitations
We cannot exclude the possibility that the use of contrast material influenced LV function. However, we confirmed that LV pressure had returned to baseline values after a pause of at least 20 minutes so that the cardiodepressant effects of the contrast material could wear off after each ventriculography.
Conclusions
We demonstrated in anesthetized dogs that MCI-154 exerted a similar positive inotropic action in pacing-induced heart failure and in the control state. Despite its Ca2+-sensitizing actions, MCI-154 improved LV relaxation and diastolic distensibility in heart failure more than in the control state. MCI-154 may therefore have possible beneficial effects on left ventricular systolic and diastolic function in chronic heart failure.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This work was supported in part by grant-in-aid for Scientific Research C-06670650 from the Ministry of Education and Culture, Tokyo, Japan.
|
Footnotes |
|---|
Presented in part at the 44th Scientific Sessions of the American College of Cardiology, New Orleans, La, March 22, 1995.
Received August 22, 1996; accepted September 24, 1996.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Kitada Y, Narimatsu A, Matsumura N, Endo M. Increase in Ca++ sensitivity of the contractile system by MCI-154, a novel cardiotonic agent, in chemically skinned fibers from the guinea pig papillary muscles. J Pharmacol Exp Ther. 1987;243:633-638.
2.
Kitada Y, Kobayashi M, Narimatsu A, Ohizumi Y. Potent stimulation of myofilament force and adenosine triphosphatase activity of canine cardiac muscle through a direct enhancement of troponin C Ca++ binding by MCI-154, a novel cardiotonic agent. J Pharmacol Exp Ther. 1987;250:272-277.
3. Perreault C, Brozovich FV, Ransil BJ, Morgan JP. Effects of MCI-154 on Ca2+ activation of skinned human myocardium. Eur J Pharmacol. 1989;165:305-308.[Medline] [Order article via Infotrieve]
4.
Sata M, Sugiura S, Yamashita H, Fujita H, Momomura S, Serizawa T. MCI-154 increases Ca2+ sensitivity of reconstituted thin filament: a study using a novel in vitro motility assay technique. Circ Res. 1995;76:626-633.
5.
Kitada Y, Narimatsu A, Suzuki R, Endoh M, Taira N. Does the positive inotropic action of a novel cardiotonic agent, MCI-154, involve mechanisms other than cyclic AMP? J Pharmacol Exp Ther. 1987;243:639-645.
6. Hosono M, Taira N. Cardiac and coronary vasodilator effects of the novel cardiotonic agent, MCI-154, assessed in isolated, blood-perfused dog heart preparations. J Cardiovasc Pharmacol. 1987;10:692-698.[Medline] [Order article via Infotrieve]
7. Allert JA, Adams HR. Inotropic and chronotropic profile of MCI-154: comparison with isoproterenol and imazodan in guinea pig cardiac preparations. J Cardiovasc Pharmacol. 1990;16:59-67.[Medline] [Order article via Infotrieve]
8. Narimatsu A, Kitada Y, Satoh N, Suzuki R, Okushima H. Cardiovascular pharmacology of 6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride, a novel and potent cardiotonic agent with vasodilator properties. Arzneimittelforschung. 1987;37:398-406.[Medline] [Order article via Infotrieve]
9. Al-Wathiqui MH, Shimshak TM, Brooks HL, Preuss KC, Wynsen JC, Gross GJ, Warltier DC. Comparative effects of inotropic agents on coronary and systemic hemodynamics of conscious dogs: actions of milrinone, dopamine, ouabain and MCI-154. Pharmacology. 1988;36:217-227.[Medline] [Order article via Infotrieve]
10.
Abe Y, Kitada Y, Narimatsu A. Beneficial effect of MCI-154, a cardiotonic agent, on ischemic contractile failure and myocardial acidosis of dog hearts: comparison with dobutamine, milrinone and pimobendan. J Pharmacol Exp Ther. 1992;261:1087-1095.
11. Wynsen JC, Shimshak TM, Preuss KC, Gross GJ, Brooks HL, Warltier DC. Stimulation of myocardium during reperfusion injury by a new inotrope-vasodilator agent, MCI-154. Fundam Clin Pharmacol. 1987;1:335-345.[Medline] [Order article via Infotrieve]
12. Hajjar RJ, Gwathmey JK, Briggs GM, Morgan JP. Differential effect of DPI 201-106 on the sensitivity of the myofilaments to Ca2+ in intact and skinned trabeculae from control and myopathic human hearts. J Clin Invest. 1988;82:1578-1584.
13.
Ventura-Clapier R, Baudet S. Differential effects of caffeine on skinned fibers from control and hypertrophied ferret hearts. Am J Physiol. 1990;259:H1803-H1808.
14. Moe GW, Stopps TP, Angus C, Forster C, De Bold AJ, Armstrong PW. Alterations in serum sodium in relation to atrial natriuretic factor and other neuroendocrine variables in experimental pacing-induced heart failure. J Am Coll Cardiol. 1989;13:173-179.[Abstract]
15.
Spinale FG, Zellner JL, Tomita M, Crawford FA, Zile MR. Relation between ventricular and myocyte remodeling with the development and regression of supraventricular tachycardia-induced cardiomyopathy. Circ Res. 1991;69:1058-1067.
16.
Shannon RP, Komamura K, Stambler BS, Bigaud M, Manders WT, Vatner SF. Alterations in myocardial contractility in conscious dogs with dilated cardiomyopathy. Am J Physiol. 1991;260:H1903-H1911.
17.
Ihara T, Shannon RP, Komamura K, Pasipoularides A, Patrick T, Shen YT, Vatner SF. Effects of anaesthesia and recent surgery on diastolic function. Cardiovasc Res. 1994;28:325-336.
18. Dodge HT, Sandler H, Baxley WA, Hawley RR. Usefulness and limitations of radiographic methods for determining left ventricular volume. Am J Cardiol. 1966;18:10-24.[Medline] [Order article via Infotrieve]
19.
Mirsky I. Assessment of diastolic function: suggested methods and future considerations. Circulation. 1984;69:836-841.
20. Mirsky I. Elastic properties of the myocardium: a quantitative approach with physiological and clinical applications. In: Berne RM, ed. Handbook of Physiology. Section 2. The Cardiovascular System. Volume 1. The Heart. Bethesda, Md: American Physiological Society: 1979:497.
21. Hugenholtz PA, Kaplan E, Hall E. Determination of left ventricular wall thickness by angiocardiography. Am Heart J. 1969;78:513-522.[Medline] [Order article via Infotrieve]
22.
Fowler MB, Laser JA, Hopkins GL, Minobe W, Bristow MR. Assessment of the ß-adrenergic receptor pathway in the intact failing human heart: progressive receptor down-regulation and subsensitivity to agonist response. Circulation. 1986;74:1290-1302.
23.
Feldman MD, Copelas L, Gwathmey JK, Phillips P, Warren SE, Schoen FJ, Grossman W, Morgan JP. Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulation. 1987;75:331-339.
24.
Parker JD, Landzberg JS, Bittl JA, Mirsky I, Colucci WS. Effects of ß-adrenergic stimulation with dobutamine on isovolumic relaxation in the normal and failing human left ventricle. Circulation. 1991;84:1040-1048.
25. Perreault CL, Shannon RP, Komamura K, Vatner SF, Morgan JP. Abnormalities in intracellular calcium regulation and contractile function in myocardium from dogs with pacing-induced heart failure. J Clin Invest. 1992;89:932-938.
26. O'Leary EL, Colston JT, Freeman GL. Maintained length-dependent activation of skinned myocardial fibers in tachycardia heart failure. Circulation. 1992;86(suppl I):I-284. Abstract.
27.
D'Agnolo A, Luciani GB, Mazzucco A, Gallucci V, Salviati G. Contractile properties and Ca2+ release activity of the sarcoplasmic reticulum in dilated cardiomyopathy. Circulation. 1992;85:518-525.
28.
Gwathmey JK, Hajjar RJ. Relation between steady-state force and intracellular [Ca2+] in intact human myocardium: index of myofibrillar responsiveness to Ca2+. Circulation. 1990;82:1266-1278.
29.
Hajjar RJ, Gwathmey JK. Cross-bridge dynamics in human ventricular myocardium: regulation of contractility in the failing heart. Circulation. 1992;86:1819-1826.
30. Kapelko VI, Veksler VI, Popovich MI, Ventura-Clapier R. Energy-linked functional alterations in experimental cardiomyopathies. Am J Physiol. 1991;261:39-44.
31.
Schwinger RHG, Bohm M, Koch A, Schmidt U, Morano I, Eissner H-J, Uberfuhr P, Reichart B, Erdmann E. The failing human heart is unable to use the Frank-Starling mechanism. Circ Res. 1994;74:959-969.
32.
Wolff MR, Whitesell LF, Moss RL. Calcium sensitivity of isometric tension is increased in canine experimental heart failure. Circ Res. 1995;76:781-789.
33. Morgan JP. Abnormal intracellular modulation of calcium as a major cause of cardiac contractile dysfunction. N Engl J Med. 1991;325:625-632.[Medline] [Order article via Infotrieve]
34. Asanoi H, Ishizaka S, Kameyama T, Ishise H, Sasayama S. Disparate inotropic and lusitropic responses to pimobendan in conscious dogs with tachycardia-induced heart failure. J Cardiovasc Pharmacol. 1994;23:268-274.[Medline] [Order article via Infotrieve]
35.
Kitada Y, Abe Y, Narimatsu A, Tobe A. MCI-154, a novel cardiotonic agent, reverses the acidic pH-induced decrease in responses of cardiac myofilaments to Ca++: comparison with sulmazole and pimobendan. J Pharmacol Exp Ther. 1991;257:812-819.
36.
Fujino K, Sperelakis N, Solaro RJ. Sensitization of dog and guinea pig heart myofilaments to Ca2+ activation and the inotropic effect of pimobendan: comparison with milrinone. Circ Res. 1988;63:911-922.
37. Bethke T, Meyer W, Schmitz W, Scholz H, Wenzlaff H, Armah BI, Bruckner R, Raap A. High selectivity for inhibition of phosphodiesterase III and positive inotropic effects of MCI-154 in guinea pig myocardium. J Cardiovasc Pharmacol. 1993;21:847-855.[Medline] [Order article via Infotrieve]
38. Yoran C, Yellin EL, Becker RM, Gabbay S, Frater RWM, Sonnenblick EH. Mechanism of reduction of mitral regurgitation with vasodilator therapy. Am J Cardiol. 1979;43:773-777.[Medline] [Order article via Infotrieve]
39. Hajjar RJ, Gwathmey JK. Calcium-sensitizing inotropic agents in the treatment of heart failure: a critical view. Cardiovasc Drugs Ther. 1991;5:961-966.[Medline] [Order article via Infotrieve]
40.
Hgashiyama A, Watkins MW, Chen Z, LeWinter MM. Effects of EMD 57033 on contraction and relaxation in isolated rabbit hearts. Circulation. 1995;92:3094-3104.
41. Liao R, Gwathmey JK. Mg-ATPase activity in ventricular myofibrils from non-failing and failing human myocardium: effects of calcium sensitizing agents. Circulation. 1993;88(suppl I):I-135. Abstract.
42.
Liao R, Gwathmey JK. Effects of MCI-154 and caffeine on Ca++-regulated interactions between troponin subunits from bovine heart. J Pharmacol Exp Ther. 1994;270:831-839.
43.
Solaro RJ, Gambassi G, Warshaw DM, Keller MR, Spurgeon HA, Beier N, Lakatta EG. Stereoselective actions of thiadiazinones on canine cardiac myocytes and myofilaments. Circ Res. 1993;73:981-990.
44.
Brutsaert DL, Rademarkers FE, Sys SU. Triple control of relaxation: implications in cardiac disease. Circulation. 1984;69:190-196.
45. Gaasch WH, Blaustein AS, Andrias CW, Donahue RP, Avitall B. Myocardial relaxation, II: hemodynamic determinants of rate of left ventricular isovolumic pressure decline. Am J Physiol. 1980;239:H1-H6.
46.
Gillebert TC, Lew WYW. Nonuniformity and volume loading independently influence isovolumic relaxation rates. Am J Physiol. 1989;257:H1927-H1935.
47.
Paulus WJ, Heyndrickx GR, Buyl P, Goethals MA, Andries E. Wide-range load shift of combined aortic valvuloplasty-arterial vasodilation slows isovolumic relaxation of the hypertrophied left ventricle. Circulation. 1990;81:886-898.
48.
Udelson JE, Bacharach SL, Cannon RO, Bonow RO. Minimum left ventricular pressure during ß-adrenergic stimulation in human subjects: evidence for elastic recoil and diastolic `suction' in the normal heart. Circulation. 1990;82:1174-1182.
49.
Eichhorn EJ, Willard JE, Alvarez L, Kim AS, Glamann DB, Risser RC, Grayburn PA. Are contraction and relaxation coupled in patients with and without congestive heart failure? Circulation. 1992;85:2132-2139.
50. Hori M, Inoue M, Kitakaze M, Tsujioka K, Ishida Y, Fukunami M, Nakajima S, Kitabatake A, Abe H. Loading sequence is a major determinant of afterload-dependent relaxation in intact canine heart. Am J Physiol. 1985;249:H747-H754.
51.
Gillebert TC, Lew WYW. Influence of systolic pressure profile on rate of left ventricular pressure fall. Am J Physiol. 1991;261:H805-H813.
52.
Ishizaka S, Asanoi H, Wada O, Kameyama T, Inoue H. Loading sequence plays an important role in enhanced load sensitivity of left ventricular relaxation in conscious dogs with tachycardia-induced cardiomyopathy. Circulation. 1995;92:3560-3567.
53. Grossman W, Barry WH. Diastolic pressure volume relations in the diseased heart. Fed Proc. 1980;39:148-155.[Medline] [Order article via Infotrieve]
54.
Tyberg JV, Taichman GC, Smith ER, Douglas NWS, Smiseth OA, Keon WJ. The relationship between pericardial pressure and right atrial pressure: an intraoperative study. Circulation. 1986;73:428-432.
55.
Carroll JD, Lang RM, Neumann AL, Borow KM, Rajfer SI. The differential effects of positive inotropic and vasodilator therapy on diastolic properties in patients with congestive cardiomyopathy. Circulation. 1986;74:815-825.
56.
Gilbert JC, Glantz SA. Determinants of left ventricular filling and of the diastolic pressure-volume relation. Circ Res. 1989;64:827-852.
This article has been cited by other articles:
 |
|
 |
|
  S. Takahashi, S. Cho, T. Hara, H. Ureshino, S. Tomiyasu, and K. Sumikawa The Interaction of MCI-154, a Calcium Sensitizer, and Isoflurane on Systemic and Coronary Hemodynamics in Chronically Instrumented Dogs Anesth. Analg., January 1, 2004; 98(1): 30 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ishitani, Y. Hattori, F. Sakuraya, H. Onozuka, T. Makino, N. Matsuda, S. Gando, and O. Kemmotsu Effects of Ca2+ Sensitizers on Contraction, [Ca2+]i Transient and Myofilament Ca2+ Sensitivity in Diabetic Rat Myocardium: Potential Usefulness as Inotropic Agents J. Pharmacol. Exp. Ther., August 1, 2001; 298(2): 613 - 622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Kumamoto, H. Okamoto, M. Watanabe, H. Onozuka, K. Yoneya, I. Nakagawa, S. Chiba, S. Watanabe, T. Mikami, K. Abe, et al. Beneficial effect of myocardial angiogenesis on cardiac remodeling process by amlodipine and MCI-154 Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1117 - H1123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Asai, M. Uechi, N. Sato, W. Shen, T. Meguro, M. A. Mathier, R. P. Shannon, and S. F. Vatner Lack of desensitization and enhanced efficiency of calcium channel promoter in conscious dogs with heart failure Am J Physiol Heart Circ Physiol, December 1, 1998; 275(6): H2219 - H2226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.A Lee and D.G Allen Calcium sensitisers: mechanisms of action and potential usefulness as inotropes Cardiovasc Res, October 1, 1997; 36(1): 10 - 20. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||