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A novel inotropic vasodilator, OPC-18790, reduces myocardial oxygen consumption and improves mechanical efficiency with congestive heart failure
Heart Failure
A novel inotropic vasodilator, OPC-18790, reduces myocardial oxygen consumption and improves mechanical efficiency with congestive heart failure Hirofumi Kanda, MD, a Mitsuhiro Yokota, MD, PhD, b Hitoshi Ishihara, MD, a Kohzo Nagata, MD, a Ryozo Kato, MD, a and Toshikazu Sobue, MD a Nagoya, Japan
We analyzed the left ventricular (LV) pressure-volume relation and obtained direct measurements of myocardial oxygen consumption (MVo2) before and after drug administration in 21 patients with New York Heart Association functional class II to III congestive heart failure to compare the mechanoenergetic effects of OPC-18790, a novel inotropic agent, and dobutamine. Pressure-volume data were obtained by the conductance method, and MVo2 measurements were obtained with a double-thermistor coronary sinus catheter before and after administration of OPC-18790 and dobutamine. The LV end-diastolic volume index decreased significantly without an increase in the heart rate after administration of OPC-18790, unlike that after administration of dobutamine. Both drugs significantly increased the LV contractility index (Emax)and caused similar improvements in ventricular-arterial coupling. OPC-18790 significantly reduced MVo2,whereas dobutamine increased MV02. The ratio of the pressure-volume area to myocardial oxygen consumption (PVA/MV02) remained unchanged after administration of 0PC-18790 and decreased after administration of dobutamine. The ratio of external work to the pressure-volume area (EW/PVA) was similarly increased by both drugs, resulting in an improvement in mechanical efficiency (EW/ MVo2)with OPC-18790 (p < 0.05) and in a deterioration with dobutamine (p < 0.05). OPC-18790 had an energetic advantage over dobutamine in spite of its positive inotropic effect. Our findings suggest that OPC-18790 may be useful for the treatment of patients with congestive heart failure. (Am Heart J 1996;132:361-8.)
From the aFirst Department of Internal Medicine, and the bDepartment of Clinical Laboratory Medicine, Nagoya University School of Medicine. Supported in part by research grants for cardiovascular diseases (4A-4) from the Ministry of Health and Welfare, and a Grant-in-Aid for Scientific Research (06670706) from the Ministry of Education, Science, and Culture of Japan. Received for publication Aug. 17, 1995; accepted Dec. 12, 1995. Reprint requests: Mitsuhiro Yokota, MD, PhD, Cardiovascular Section, Department of Clinical Laboratory Medicine, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan. Copyright © 1996 by Mosby-Year Book, Inc. 0002-8703/96/$5.00 + 0 4/1//2719
The usefulness of a number of new positive inotropic agents, in particular, the cyclic adenosine monophosphate (AMP)-phosphodiesterase (PDE) inhibitors, has been investigated in patients with congestive heart failure. 1-5 However, studies suggest that positive inotropic effects that are achieved mainly by increasing intracellular concentrations of cyclic AMP 6 may be deleterious because of the associated arrhythmogenicity and the adverse effects on myocardial energetics, with a resultant progression of disease. 7-9 New inotropic agents are therefore needed for treating patients with congestive heart failure. OPC-18790, (_+)-6-[3-(3,4-dimethoxybenzylamino)2-hydroxypropoxy]-2(1H)-quinolinone, is a watersoluble derivative ofvesnarinone that has been synthesized as a novel positive inotropic agent for the treatment of patients with heart failure. OPC-18790 increases contractile force without causing changes in heart rate in experimental animals. 1° Hosokawa et al. 1° reported that the positive inotropic effect of OPC-18790 was achieved in part by inhibition of type III PDE. However, unlike most PDE-III inhibitors, OPC-18790 prolongs the duration of action potentials in guinea pig ventricular muscles, 1° suggesting that it either increases the slow inward currents through the membrane that are carried mainly by calcium ions or reduces transmembrane potassiumrectifier currents as does vesnarinone, an oral inotropic agent, n Data obtained by right heart catheterization and noninvasive echocardiography demonstrated that OPC-18790 has beneficial dose-dependent effects on systolic and diastolic cardiac performance in patients with severe congestive heart failure. 12-14In addition to exerting a positive inotropic effect, OPC-18790 has 361
362
August 1996 American Heart Journal
Kanda et al.
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Fig, 1. Representative pressure-v•hime loops obtained by conductance catheter during inferior vena caval occlusion before and after administration of OPC-18790. Slope of the end-systolic pressure-volume relation (Emax) was increased by OPC-18790. ESPVR, End-systolic pressure-volume relation.
been found to reduce preload a n d afterload, as indicated by analysis of the p r e s s u r e - v o l u m e relation. 12 No previous clinical studies h a v e e v a l u a t e d the effects of OPC-18790 on m y o c a r d i a l energetics by directly m e a s u r i n g myocardial oxygen c o n s u m p t i o n (MVo2) a n d a n a l y z i n g the p r e s s u r e - v o l u m e relation. We c o m p a r e d the m e c h a n o e n e r g e t i c effects of OPC18790 a n d d o b u t a m i n e in p a t i e n t s with congestive h e a r t failure. METHODS
Study patients. We studied 21 Japanese patients with New York Heart Association hmctional class II to III congestive heart failure (mean age, 53 _+2 years). The patients' mean ejection fraction was 27% -+ 2%, and their mean left ventricular (LV) end-diastolic volume index was 134 -+ 6 ml/m 2. The underlying cause of congestive heart failure was idiopathic dilated cardiomyopathy (DCM) in 18 patients and coronary artery disease (CAD) in 3 patients. All patients had had cardiac failure at least once, and they complained of dyspnea at rest or on exertion. All patients were in normal sinus rhythm and had left ventriculographic evidence of dilated LV cavities. The study protocol was reviewed and approved by the appropriate institutional review committee, and all patients provided their written, informed consent before participating in the study. Study protocol. Patients underwent cardiac catheterization in the morning in the fasting state. All medications were withheld for at least 48 hours before catheterization. Left and right heart catheterization was performed by the femoral approach. A 7F Swan-Ganz thermodilution catheter was advanced to the pulmonary artery to measure pulmonary artery pressure, pulmonary artery wedge pressure, right atrial pressure, and cardiac output. A double-
thermistor catheter (model CCS/GOK; Wilton-Webster Laboratories, Los Angeles, CA) was placed percutaneously in the coronary sinus via the brachial or the subclavian vein to measure myocardial blood flow. After left ventriculography was performed, a 7F or 8F pigtail dual-field conductance catheter (Leycom, Oegstgeest, The Netherlands) with a 2F micromanometer tip (Millar, Instruments, Houston, Tex.) was inserted into the left ventricle to measure LV volume and pressure. A 8F catheter (model 62-080-8/22F; Edwards Laboratories, Santa Ana, CA) was placed in the inferior vena cava and was inflated transiently for determinations of the LV end-systolic pressurevolume relation. Arterial and coronary sinus blood samples were drawn simultaneously for determinations of oxygen saturation. After control measurements were obtained, OPC-18790 was administered in a dose of 5 pg/kg/min in 8 patients and in a dose of 10 pg/kg/min in 2 patients, and dobutamine was administered in a dose of 2.5 pg/kg/min in 9 patients and in a dose of 5 ~ag/kg/min in 2 patients. Data were collected 60 minutes after OPC-18790 administration and 15 minutes after dobutamine administration. There was no difference in mean age between patients who received OPC-18790 and patients who received dobutamine (53 +- 3 years vs 53 _+ 2 years). OPC-18790 was administered to 9 patients with DCM and i patient with CAD. Dobutamine was administered to 9 patients with DCM and 2 patients with CAD. There were no significant differences in hemodynamic variables before administration of inotropic agents between groups (Table I). After completion of the study protocols, selective coronary arteriography was performed, and a right ventricular biopsy was obtained. Cardiac biopsies were obtained to confirm the diagnosis of DCM. Left ventricular pressure-volume data analysis. The volume-conductance catheter was connected to a volumet-
Volume132,Number 2, Part 1 AmericanHeartJournal
Table
I.
Kanda et al.
363
Effects of OPC-18790 and dobutamine on hemodynamics
0PC-18790
HR (beats/min) SBP (mm Hg) DBP (mm Hg) LVESP (ram Hg) LVEDP (ram Hg) PAWP(mmHg) CI (L/min/m2) SVR (dyn/sec/cm5) LVEDVI (ml/m2) LVESVI (m]/m2) EF (%) Em~x(ram Hg/ml) Ea (ram Hg/ml) EJE~x
Dobutamine
Before
After
Before
After
82 ± 3 138 __ 8 76 -+ 5 132 ± 7 1! ± 2 9±1 2.83 ± 0.14 1624 ± 150 129 ± 10 94 ± 10 28 ± 3 1.26 ± 0.12 2.63 ± 0.35 2.27 ± 0.43
88 ± 5 113 _+6t 68 ± 5# 107 _+6# 6 ± 15 6±1" 3.23 ± 0.23* 1226 ± 1229 109 ± 7t 70 ± 89 36 ± 4t 1.85 _+0.25* 2.07 ± 0.26 1.24 ± 0.229
79 ± 4 146 ± 6 75 ± 3 141 _+5 14 _+2 11±2 2.72 ± 0.14 1742 ± 118 144 ± 9 108 ± 9 26 ± 3 0.90 z 0.13 2.19 ± 0.19 2.72 ± 0.28
94 ± 55 171 ± 10t 74 ± 4 157 ± 9t 10 ± 2* 7±1" 4.04 _+0.175 1264 ± 885 135 _+ 11 91 ± 11 34 ± 39 1.73 ± 0.255 2.38 _+0.40 1.51 ± 0.229
HR, Heart rate; SBP, systolicbloodpressure;DBP, diastolicbloodpressure;LVESP, left ventricularend-systolicpressure;LVEDP, left ventricularenddiastolicpressure;PAWP, pulmonaryartery wedge pressure;CI, cardiac index;SVR, systemicvascularresistance;LVEDVI, left ventricularend-diastolic volume index;LVESVI, left ventricular end-systolicvolumeindex;EF, ejectionfraction. Values are expressed as mean value -+SEM. *p < 0.05. tp < 0.01. Sp < 0.001 versus before drug administration.
ric system (model Sigma 5, Leycom) to m e a s u r e LV volume conductance a n d to convert it to the LV volume. 15 A realtime pressure-volume diagram was generated, and 8-channel analog/digital conversion (at 200 Hz) was performed by using a 16-bit microcomputer system (PC-9801 VX; NEC Co., Tokyo). The catheter had eight electrodes spaced at 1 cm intervals and was excited by a n a l t e r n a t i n g current (30 DA, 20 kHz) across the distal and the proximal electrodes. The LV volume obtained by the conductance method was calibrated by biplane ventriculography (the area-length method) as described previously. 16 The stroke volume was defined as the difference between the LV end-diastolic volu m e a n d the LV end-systolic volume. The ejection fraction was calculated as the ratio of the stroke volume to the LV end-diastolic volume. LV pressure a n d volume signals were digitized at 3 msec intervals and analyzed with a PC-9801 VX. A n end-systolic pressure-volume line was drawn on the left upper corner of the pressure-volume loops during the t r a n s i e n t decrease in preload caused by inflation of a Fogarty catheter before and after a d m i n i s t r a t i o n of inotropic agents, as shown in Fig. 1. The LV contractility index (Ema~) was defined as the slope of the end-systolic pressure-volume line. Arterial characteristics were assessed in terms of the systemic vascular resistance a n d the effective arterial elastance (Ea), as proposed by S u n a g a w a et al. 17 The systemic vascular resistance represents only the m e a n vascular resistance, b u t Ea represents both the m e a n vascular resistance and the pulsatile components. We defined E~ as the ratio of the LV end-systolic pressure to the stroke volume before a n d after a d m i n i s t r a t i o n of inotropic agents. Ventricular-arterial coupling, the relation between the inotropic state a n d afterload, is useful for q u a n t i t a t i v e evaluation of their inter-
action. Ventricular-arterial coupling was calculated as the ratio of Ea to Em~x. PVA was defined as the area u n d e r the end-systolic pressure-volume line and the systolic pressure-volume trajectory and above the end-diastolic pressure-volume relation curve. EW was defined as the area within the pressure-volume diagrams. Both PVA a n d EW were calculated with a 32-bit microcomputer (PC-9801RA, NEC Co.) by using our original system of analysis. PVA and EW were measured i n millimeters of mercury times milliliters a n d converted to the dimensions of energy by the following formula: 1 m m Hg x milliliters = 1.33 x 10 -4 j.18 Myocardial oxygen consumption and energy conversion efficiency. Myocardial blood flow was measured by using a double-thermistor catheter. The coronary sinus flow was calculated according to the method of Ganz et al.19 by using a computer system (Thermo Flow; Goodman Co., Nagoya, Japan). The injectate was a normal saline solution m a i n t a i n e d at room t e m p e r a t u r e and delivered by a n infusion pump (Harvard Apparatus, Natick, Mass.) at a flow rate of 40 ml/min. The coronary sinus flow was recorded on a six-channel recorder (Unicorder; Nippon Denshi Kagaku Co., Kyoto, Japan) at a paper speed of 100 cm/min. MV02 was calculated as the product of myocardial blood flow and the difference between the arterial a n d coronary sinus oxygen content. Oxygen content was calculated as the product of the percentage oxygen saturation, the oxyhemoglobin binding capacity, and the hemoglobin Concentration. Myocardial oxygen consumption per beat (MVo2/beat) was calculated as follows: [MVo2/beat (J/beat)] = [20 x (MVo2/ min)/heart rate], where 1 ml 02 = 20 j.20 Mechanical efficiency was defined as the dimensionless ratio of EW to MV02. Suga et al. 21, 22 demonstrated t h a t this efficiency
August 1996 American Heart Journal
364 K a n d a et al. Table II, Effects of OPC-18790 and dobutamine on myocardial energetics 0PC-18790
Dobutamine
Before CSF (ml/min) Cao2 (vol%) Ccso2 (vol%) a-csDo2 (vol%) MVO2 (J/beat) PVA (J/beat) E W (J/beat)
133 17.23 4.57 12.66 3.97 1.92 0.67
-+ 24 -+ 0.84 ± 0.54 _+ 0.84 ± 0.58 ± 0.22 ± 0.06
CSF, Coronary sinus flow; Cao2,arterial oxygen content; Values are expressed as the mean value -+ SEM. *p < 0.05. tP < 0.01. Sp < 0.001 versus before drug administration.
After 130 16.50 5.90 10.60 2.96 1.12 0.58
± 22 -+ 0.72 ± 0.90 ± 1.38" -+ 0.49* _-_ 0.205 _-_0.10
Before 170 17.29 6.62 10.67 4.48 2.67 0.87
+_ 18 -+ 0.69 ± 0.88 _ 1.03 +_ 0.61 _+ 0.27 ± 0.10
After 273 17.22 6.09 11.13 6.30 2.33 1.16
_+ 305 ± 0.80 ± 0.46 _+ 0.91 ± 0.87t ± 0.35 ± 0.15"
Ccso2,coronary sinus oxygen content; a-csD02, arterial-coronary sinus oxygen content difference.
can be divided into two stages: (1) the efficiency of energy transfer from MVo2to PVA, and (2) the efficiencyof energy transfer from PVA to EW. We determined the energy-conversion efficiency of these two stages and the mechanical efficiency as a measure of the overall energy-conversion efficiency before and after administration of inotropic agents. Statistics. Complete data were obtained for 17 of 21 patients. The conductance-catheter data were incomplete in 1 patient who received OPC-18790. Analysis of MVo2 was incomplete in 1 patient who received OPC-18790 and in 2 patients who received dobutamine. Data are expressed as the mean + SEM. We obtained the end-systolic pressurevolume relations by linear regression analysis. Differences in paired variables before and after administration of OPC-18790 or dobutamine were analyzed by the paired t test. Comparisons of the variables between OPC-18790 and dobutamine studies were analyzed by the nonpaired t test. A p value of <0.05 was considered statistically significant. RESULTS Effects of OPC-18790 on hemodynamics and myocardial energetics. Ventricular arrhythmias either did
not appear or were not increased by administration of OPC- 18790. OPC- 18790 significantly reduced systolic and diastolic blood pressures (Table I). LV enddiastolic pressure and volume decreased significantly. The cardiac index increased slightly. The LV contractility index (Emax) increased significantly. The afterload index (Ea) decreased slightly but not significantly, resulting in a 41% improvement in ventricular-arterial coupling. These hemodynamic effects of OPC-18790 were not accompanied by an increase in heart rate. Coronary sinus flow remained unchanged and the arterial-coronary sinus oxygen content difference decreased slightly (Table II). The MVo2 per beat and PVA decreased significantly. The EW remained unchanged. The ratio of PVA to MVo2 decreased from 50% +_ 7% to 41% +_ 6% (p = not sig-
nificant INS]), and the ratio of EW to PVA increased from 36% +- 2% to 55% -+ 5% (p < 0.01), resulting in an increase in the mechanical efficiency (the ratio of EW to MVo2) from 18% _+ 2% to 22% + 3% (p < 0.05; Fig. 2). Effects of dobutamine on hemodynamics and myocardial energetics. Heart rate and systolic blood pres-
sure increased significantly after administration of dobutamine (Table I). Ventricular arrhythmias either appeared or increased in all patients. LV enddiastolic pressure and volume decreased slightly. The cardiac index and Ema~ increased significantly. Ea increased slightly but not significantly, resulting in a 45% improvement in ventricular-arterial coupling, which was similar to t h a t seen with OPC18790. Coronary sinus flow increased significantly, and the arterial-coronary sinus oxygen-content difference increased slightly (Table II). The MVo2 per beat and EW increased significantly, and PVA remained unchanged. The ratio of PVA to MVo2 decreased from 65% +_ 5% to 39% -+ 5% (p < 0.001), and the ratio of EW to PVA increased from 34% _+ 3% to 52% _+ 4% (p < 0.001), resulting in a deterioration of mechanical efficiencyfrom 22% _+ 3% to 19% + 3% (p < 0.05; Fig. 2). Fig. 3 shows the relation between ventricular-arterial coupling (EJEmax) and the ratio of EW to PVA before and after administration of inotropic agents. Comparable increases in the ratio of EW to PVA were observed after administration of OPC-18790 (52%) and dobutamine (56%) in proportion to similar improvements in ventricular-arterial coupling. Fig. 4 shows the relation between ventricular-arterial coupling and mechanical efficiency (EW/MVo2) before and after administration of inotropic agents. A 23% increase in mechanical efficiency after administration of OPC-18790 and an 11% decrease in mechanical efficiency after administration of dobutamine
Volume 132, Number 2, Part American Heart Journal
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Fig. 2. Changes in ratio of pressure-volume area to myocardial oxygen consumption (PVA/MV02) (A), ratio of external work to pressure-volume area (EW/PVA) (B), and ratio of external work to myocardial oxygen consumption (EW/MV02); (C) after administration of OPC-18790 (OPC) and dobutamine (DOB). *p < 0.05, tp < 0.01, Sp < 0.001 versus control (C). 30.
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were observed, in spite of similar improvements in ventricular-arterial coupling. DISCUSSION
This study provides the first detailed assessment of the effects of OPC-18790 on mechanoenergetics in patients with congestive h e a r t failure. OPC-18790 enhanced LV contractility in association with a reduction in preload and with arterial vasodilation. The most favorable effects of OPC-18790 observed were its effects on MVo2 and on mechanical efficiency, defined as the ratio of EW to MVo2. Dobutamine also enhanced LV contractility, but this effect was accompanied by an increase in MVo2 and a
0
1
2
3
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Ea/Emax Fig. 4. Changes in relation between ventricular-arterial coupling (Ea/Emax) and mechanical efficiency (EW/MV02) before and after administration of inotropic agents. White circle, Before OPC-18790; black circle, after OPC-18790; white square, before dobutamine; black square, after dobutamine. deterioration in mechanical efficiency. In addition, dobutamine increased the heart rate, whereas OPC18790 did not. Positive inotropic effect of OPC-18790. The positive inotropic effect ofOPC-18790 results in part from the accumulation of cyclic AMP induced by inhibition of PDE-III.10, 23 In addition to its inhibition of PDE-III, OPC-18790 has electrophysiologic effects t ha t result in a prolongation of the action potential duration. 1° As with vesnarinone, the electrophysiologic effects of OPC-18790 m ay be related to a reduction in the potassium repolarization currents, principally the inward and delayed rectifier currents. 11 These electrophysiologic effects m ay also contribute in part to the
366 K a n d a et al.
inotropic effects of OPC-18790. In our study, OPC18790 enhanced LV contractility without increasing the heart rate, in spite of a 17% decline in arterial pressure, which is consistent with the findings of previous experimental and clinical studies. 12-14 The findings of a recent study by Endoh et al. 23 suggest that these effects may contribute to the inotropic response. They found that OPC-18790 caused a small but significant increase in contractile force, even when cyclic AMP accumulation was abolished by carbacol.23 They found also that OPC-18790 caused a greater increase in contractile force than isoproterenol in isolated dog ventricular trabeculae for a given increase in the amplitude of Ca 2+ transients, suggesting that 0PC-18790 does not reduce the Ca 2+ sensitivity of contractile proteins. This effect may have contributed to the decrease in MVo2 induced by OPC-18790 in our study. Effects of OPC-18790 on ventricular and vascular loads. Ventricular preload, defined as the LV end-di-
astolic volume index, decreased after OPC-18790 administration. Although OPC-18790 was associated with a slight increase in the cardiac index, this effect may have resulted from a counteraction of the positive inotropic effect of OPC- 18790 induced by the preload reduction. Both 0PC-18790 and dobutamine had similar vasodilatory effects in terms of their effects on systemic vascular resistance. Afterload, defined as Ea, did not change significantly after 0PC18790 administration but tended to decrease, unlike that after administration of dobutamine. The afterload index, Ea, represents both the pulsation components and the mean arterial resistance. 17 Our findings suggest that the arterial vasodilatory effect of OPC-18790 and its lack of chronotropic action may have contributed to the tendency of Ea to decrease. Our findings support the results of a recent preliminary clinical trial of OPC-18790.12 Ventricular-arterial coupling, Evaluation of LV contractility and vascular loading conditions and their interaction is important in quantifying the effects of inotropic agents. Sunagawa et al. 17 first proposed that the interaction between these parameters could b e assessed by the ventricular-arterial coupling ratio of Ea to Emax. Under normal conditions, the ratio of Ea to Emax ranges from 0.5 to 1.0, and EW and mechanical efficiency are near their optimal values. 24 Recent studies have demonstrated that severely depressed hearts have a suboptimal interaction between the heart and the arterial system and can no longer maintain either maximal EW or maximal mechanical efficiency.25, 26 All patients in our study had dilated LV chambers, and the Ea/Emaxwas >2.0 because of the reduced Ema~ coupled with the in-
August 1996 American Heart Journal
creased Ea before administration ofinotropic agents. Thus both mechanical and energetic cardiovascular performance was severely depressed. The ratio close to 1.0 is expected to improve both EW and mechanical efficiencyat a given cardiac preload. The Ea/Emax improved after administration of OPC-18790 and dobutamine in our study. Mechanical efficiency was enhanced by OPC-18790, in spite of the unchanged EW, but was decreased by dobutamine. The decrease in cardiac preload induced by OPC-18790 is the likely explanation for the absence of changes in EW. The expected change in mechanical efficiency with dobutamine may have been offset by its positive inotropic effects, which reduce the mechanical efficiency. Effects of OPC-18790 on coronary circulation. Coronary sinus blood flow was unchanged, in spite of a reduction in arterial pressure, which is the "driving pressure" for coronary blood flow, and the arterialcoronary sinus oxygen content difference decreased as the result of the increase in coronary sinus blood oxygen content after administration of OPC-18790. Because myocardial blood flow is physiologically regulated to meet the metabolic demand of the myocardium without causing major changes in the rate of coronary sinus blood oxygen saturation, these results may have reflected primary rather than secondary (i.e., autoregulatory)27 vasodilation of the coronary vasculature or the shunting of blood flow within the myocardium. Although the clinical Significance of this primary coronary vasodilatory effect is unclear, the OPC-18790-induced decrease in MVo2 may have been related to this effect. Effects of OPC-18790 on myocardial oxygen consumption and mechanical efficiency. The notable differences
between the effects of OPC-18790 and dobutamine were their effects on MVo2 and mechanical efficiency (EW/MVo2). From a rather simplistic view, the pressure-volume data suggest that the heart is getting smaller and the arterial pressure is decreasing with OPC-18790, and therefore wall tension must be reduced. If loading conditions were kept constant, both OPC-18790 and dobutamine would be expected to increase M-Vo 2 concomitantly. The increase in MVo2 resulting from the increase in contractility after administration of OPC-18790 must be offset by a reduction in wall tension in our study. Although there was only a small difference in the change in mechanical efficiency induced by OPC18790 (+23%) and dobutamine (-11%), the efficiency increased in all OPC-18790-treated patients, except for 1 patient, and decreased in all dobutaminetreated patients. These findings suggest that these drugs have different effects on mechanical efficiency.
Volume 132, Number 2, Part 1 American Heart Journal
The effects of OPC-18790 and dobutamine on myocardial energetics can be assessed in terms of PVA proposed by Suga et al. 21, 22 Mechanical efficiency can be expressed as the product of the ratio of PVA to MV02 (the conversion efficiency of metabolic energy to mechanical energy) and the ratio of EW to PVA (the conversion efficiency of mechanical energy to external work). The increase in LV contractility induced by inotropic agents is commonly accompanied by an increase in the energy expenditure for intracellular calcium handling (the oxygen-wasting effect).21, 22 Previous studies have shown that inotropic agents, which increase Emax, shift the PVA-MVo2 relation upward so that production of the same PVA requires an increase in MVo2. 22' 28 Therefore it is assumed that the ratio of PVA to MVo2 decreases during administration ofinotropic agents. However, the decrease in the ratio of PVA to MV02 may be offset to some extent by the increase in the ratio of EW to PVA. In our study, OPC-18790 tended to reduce the ratio of PVA to MVo2 (12%), but the change was not significant. Dobutamine caused a significant decrease in the ratio of PVA to MVo2 (42%). The ratio of EW to PVA increased similarly with OPC-18790 and dobutamine, resulting in an improvement in mechanical efficiency with OPC-18790 and a deterioration of mechanical efficiency w i t h dobutamine. The ratio of PVA to MVo2 should be differentiated from the slope of the PVA-MVou relation. The total MVo2 at a given PVA consists of the sum of the PVA-dependent MVo2 and the PVA-independent MVo2 (the energy used for both basal metabolism and excitation-contraction coupling). The slope of the PVA-MVo2 relation indicates the ratio of the increase in PVA-dependent MVo2 to the increase in PVA. 22 Therefore, the ratio of PVA to MVo2 decreases as PVA decreases and as contractility is enhanced. In our study, OPC-18790 caused only a small decrease in the ratio of PVA to MV02, in spite of an increase in LV contractility and a marked decrease in PVA as a result of the OPC-18790-induced reductions in preload and arterial vasodilation. Dobutamine markedly reduced the ratio of PVA to MV02 in association with enhanced contractility, in spite of the absence of a change in PVA. These results may be related to relatively smaller oxygen-wasting effect of OPC-18790 compared with dobutamine. However, the difference in the change in contractility between OPC-18790 and dobutamine was not significant; OPC-18790 tended to increase contractility to a lesser extent than did dobutamine. Moreover, we were unable to analyze the PVA-MVo2 relation before and after administration of inotropic agents. Therefore it is unclear whether the oxygen-wasting
Kanda eta/.
367
effect of OPC-18790 was less than that of dobutamine in our study. The ratio of EW to PVA (the conversion efficiency of mechanical energy to external work) also affects mechanical efficiency. A previous study showed that if the ejection portion of the pressure-volume loop is assumed to be flat and the end-diastolic pressure is negligible, the ratio of EW to PVA can theoretically be expressed by the following equation: EW/PVA = 1/ (1 + 0.5 Ea/Emax), so that the ratio of EW to PVA increases in proportion to the decrease in ventriculararterial coupling. 24 Studies have suggested that this equation may be relevant to the depressed human heart, in spite of the limitations of the assumption. 16,29 In our study, both OPC-18790 and dobutamine caused similar improvement in ventricular-arterial coupling, resulting in comparable increases in the ratio of EW to PVA. These findings suggest that the difference in the effects of these drugs on mechanical efficiency was not primarily related to improved ventricular-arterial coupling in our study. Several new positive inotropic agents improve short-term cardiac performance, resulting in increased LV contractility induced by an increase in the intracellular concentrations of cyclic AMP. Howe~ler, these agents have oxygen-wasting and arrhythmogenic effects in the failing heart and thus are not appropriate for long-term therapy in patients with congestive heart failure. The quinolinone derivative vesnarinone, a new inotropic agent, has been reported to improve mortality and morbidity in patients with congestive heart failure, 3° but it has a narrow therapeutic range and is associated with a 2.5% incidence of neutropenia. 3° Although there are only a few reports of clinical trials of OPC-18790, no serious complications have been reported. In our study, OPC-18790 exhibited positive inotropic effects without increasing heart rate or MVo2. OPC18790 may have an important role in the short-term treatment of patients with congestive heart failure. Future clinical trials are needed to evaluate its effects in patients with chronic heart failure. Study limitations. There are several limitations to our study. First, we used relatively low doses of dobutamine and OPC-18790. However, most patients who received higher doses ofdobutamine complained of severe palpitations associated with an increase in heart rate or with ventricular arrhythmias, and some patients who received OPC-18790 experienced episodes of asymptomatic hypotension at 60 minutes. In addition, our study population included 3 patients with CAD. Therefore it is possible that the inotropic agents had an effect on myocardial ische-
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K a n d a et al.
mia. However, no patients had chest pain or ST-segment changes on electrocardiograms. Conclusions. OPC-18790 had favorable mechanoenergetic effects in patients with congestive heart failure. Its effect on contractility was balanced by its effect on loading conditions. In spite of enhancing contractility, OPC-18790 reduced myocardial oxygen consumption and improved mechanical efficiency. Our findings suggest that OPC-18790 may be useful for short-term treatment of patients with congestive heart failure. We thank Dr. Shinichiro Morimoto (Department of Internal Medicine, Fujita Health University, Toyoake, Japan) for making the histopathologic diagnoses of biopsy specimens; Drs. Takashi Miyahara, Mitsunori Iwase, Masahiko Ukai, Takeshi Machii, Keiko Matsubara, Yasuto Nishinaka, Hideo Izawa, and Takaharu Fujimura for their cooperation; and Sadako Ichihashi for preparing the manuscript. REFERENCES 1. Monrad ES, Bairn DS, Smith HS, Lanoue A, Braunwald E, Grossman W. Effects of milrinone on coronary hemodynamics and myocardial energetics in patients with congestive heart failure. Circulation 1985; 71:972-9. 2. Asanoi/H, Sasayama S, Iuchi K, Kameyama T. Acute hemodynamic effects of a new inotropic agent (OPC-8212) in patients with congestive heart failure. J Am Coll Cardiol 1987;9:865-71. 3. Hasenfuss G, Holubarsch C, Heiss HW, Just H. Influence of UDCG-115 on hemodynamics and myocardial energetics in patients with idiopathic dilated cardiomyopathy. Am Heart J 1989;118:512-9. 4. Feldman AM, Becker LC, Llewellyn MP, Baughman KL. Evaluation of a new inotropic agent, OPC-8212, in patients with dilated cardiomyopathy and heart failure. Am Heart J 1988;116:771-7. 5. Yokota M, Matsui H, Ishihara H, Nishinaka Y, Sobue T. MS-857: a new inotropic vasodilator. Cardiovasc Drug Rev 1992;10:425-45. 6. Feldman AM. Classification of positive inotropic agents. J Am Coll Cardiol 1993;22:1223-7. 7. Packer M, Medina N, Yushak M. Hemodynamic and clinical limitations of long-term inotropic therapy with amrinone in patients with severe chronic heart failure. Circulation 1984;70:1038-47. 8. Uretsky BF, Jessup M, Konstam MA, et al. Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure: lack of benefit compared with placebo. Circulation 1990; 82:774-80. 9. Packer M, Carver JR, Rodeheffer RJ, et aL Effect of oral milrinone on mortality in severe chronic heart failure. N Engi J Med 1991;325:146875. 10. Hosokawa T, Mori T, Fujiki H, et al. Cardiovascular actions of OPC-18790: a novel positive inotropic agent with little chronotropic action. Heart Vessels 1992;7:66-75. 11. Iijima T, Taira N. Membrane current changes responsible for the positive inotropic effect of OPC-8212, a new positive inotropic agent, in single ventricular cells of the guinea pig heart. J Pharmacol Exp Ther 1987;240:657-62.
August 1996 American Heart Journal
12. Feldman MD, Haber HL, Wu CC, et al. Clinical determination of myocardial vs. load effects ofOPC-18790, a novel intravenous agent for the treatment of patients with congestive heart failure [abstract]. Circulation 1993;88:I-301. 13. Cody RJ, Leier CV, Bristow MR, et al. OPC-18790 produces titratable hemodynamic benefit in hospitalized patients with severe congestive heart failure [abstract]. Circulation 1993;88:I-300. 14. Holt BD, Burwig S, Eppert D, Bhat G, Walsh RA. Effects of a novel inotropic agent (OPC-18790) on systolic and diastolic function in patients with severe heart failure. Am Heart J 1994;128:1156-63. 15. Baan J, van der Velde ET, de Bruin HG, et al. Continuous measurement of left ventricular volume in animals and humans by conductance catheter. Circulation 1984;70:812-23. 16. Ishihara H, Yokota M, Sobue T, Saito H. Relation between ventriculoarterial coupling and myocardial energetics in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 1994;23:406-16. 17. Sunagawa K, Maughan WL, Burkhoff D, Sagawa K. Left ventricular interaction with arterial load studied in isolated canine ventricle. Am J Physiol 1983;245:H773-80. 18. Gibbs CL. Cardiac energetics. Physiol Rev 1978;58:174-254. 19. Ganz W, Tamura K, Marcus HS, Donoso R, Yoshida S, Swan HJC. Measurement of coronary sinus blood flow by continuous thermodilution in man. Circulation 1971;4:!81-95. 20. Gibbs CL, Chapman JB. Cardiac energetics. In: Berne RM, Sperlakis N, Geiger SR, editors. Handbook of physiology: the cardiovascular system, the heart. Washington, DC: American Physiology Society, 1979: 775-804. 21. SugaH, HayashiT, Shirahata M.Ventricular systolic pressure-volume area as a predictor of cardiac oxygen consumption. Am J Physiol 1981; 240:H39-44. 22. Suga H. Ventricular energetics. Physiol Rev 1990;70:247-77. 23. Endoh M, Kawabata Y, Katano Y, Norota I. Effects of a novel cardiotonic agent (_+)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]2(1H)-qninolinone (OPC-18790) on contractile force, cyclic AMP level, and aequorin light transients in dog ventricular myocardium. J Cardiovasc Pharmacol 1994;23:723-30. 24. Burkhoff D, Sagawa K. Ventricular efficiency predicted by an analytical model. Am J Physiol 1986;250:R1021-7. 25. Asanoi H, Sasayama S, Kameyama T. Ventriculoarterial coupling in normal and failing heart in humans. Circ Res 1989;65:483-93. 26. Nozawa T, Yasumura Y, Futaki N, Tanaka N, Uenishi M, Suga H. Efficiency of energy transfer from pressure-volume area to external mechanicai work increases with contractile state and decreases with afterload in the left ventricle of the anesthetized closed-chest dog. Circulation 1988;77:1116-24. 27. Rouleau J, Boerboom LE, Surjadhana A, Hoffman JIE. The role ofautoregulation and tissue diastolic pressures in the transmural distribution of left ventricular blood flow in anesthetized dogs. Circ Res 1979;45:804-15. 28. Suga H, Hisano R, Goto Y, Yamada O, Igarashi Y. Effect of positive inotropic agents on the relation between oxygen consumption and systolic pressure volume area in canine left ventricle. Circ Res 1983;53:30618. 29. Takaoka H, Takeuchi M, Odake M, Hayashi Y, Mori M, Hata K, Yokoyama M. Comparison of the effects on arterial-ventricular coupling between phosphodiesterase inhibitor and dobutamine in the diseased human heart. J Am Coll Cardiol 1993;22:598-606. 30. Feldman AM, Bristow MR, Parmley WW, et al. Effects ofvesnarinone on morbidity and mortality in patients with heart failure. N Engl J Med 1993;329:149-55.
A novel inotropic vasodilator, OPC-18790, reduces myocardial oxygen consumption and improves mechanical efficiency with congestive heart failure Hirofumi Kanda, MD, a Mitsuhiro Yokota, MD, PhD, b Hitoshi Ishihara, MD, a Kohzo Nagata, MD, a Ryozo Kato, MD, a and Toshikazu Sobue, MD a Nagoya, Japan
We analyzed the left ventricular (LV) pressure-volume relation and obtained direct measurements of myocardial oxygen consumption (MVo2) before and after drug administration in 21 patients with New York Heart Association functional class II to III congestive heart failure to compare the mechanoenergetic effects of OPC-18790, a novel inotropic agent, and dobutamine. Pressure-volume data were obtained by the conductance method, and MVo2 measurements were obtained with a double-thermistor coronary sinus catheter before and after administration of OPC-18790 and dobutamine. The LV end-diastolic volume index decreased significantly without an increase in the heart rate after administration of OPC-18790, unlike that after administration of dobutamine. Both drugs significantly increased the LV contractility index (Emax)and caused similar improvements in ventricular-arterial coupling. OPC-18790 significantly reduced MVo2,whereas dobutamine increased MV02. The ratio of the pressure-volume area to myocardial oxygen consumption (PVA/MV02) remained unchanged after administration of 0PC-18790 and decreased after administration of dobutamine. The ratio of external work to the pressure-volume area (EW/PVA) was similarly increased by both drugs, resulting in an improvement in mechanical efficiency (EW/ MVo2)with OPC-18790 (p < 0.05) and in a deterioration with dobutamine (p < 0.05). OPC-18790 had an energetic advantage over dobutamine in spite of its positive inotropic effect. Our findings suggest that OPC-18790 may be useful for the treatment of patients with congestive heart failure. (Am Heart J 1996;132:361-8.)
From the aFirst Department of Internal Medicine, and the bDepartment of Clinical Laboratory Medicine, Nagoya University School of Medicine. Supported in part by research grants for cardiovascular diseases (4A-4) from the Ministry of Health and Welfare, and a Grant-in-Aid for Scientific Research (06670706) from the Ministry of Education, Science, and Culture of Japan. Received for publication Aug. 17, 1995; accepted Dec. 12, 1995. Reprint requests: Mitsuhiro Yokota, MD, PhD, Cardiovascular Section, Department of Clinical Laboratory Medicine, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan. Copyright © 1996 by Mosby-Year Book, Inc. 0002-8703/96/$5.00 + 0 4/1//2719
The usefulness of a number of new positive inotropic agents, in particular, the cyclic adenosine monophosphate (AMP)-phosphodiesterase (PDE) inhibitors, has been investigated in patients with congestive heart failure. 1-5 However, studies suggest that positive inotropic effects that are achieved mainly by increasing intracellular concentrations of cyclic AMP 6 may be deleterious because of the associated arrhythmogenicity and the adverse effects on myocardial energetics, with a resultant progression of disease. 7-9 New inotropic agents are therefore needed for treating patients with congestive heart failure. OPC-18790, (_+)-6-[3-(3,4-dimethoxybenzylamino)2-hydroxypropoxy]-2(1H)-quinolinone, is a watersoluble derivative ofvesnarinone that has been synthesized as a novel positive inotropic agent for the treatment of patients with heart failure. OPC-18790 increases contractile force without causing changes in heart rate in experimental animals. 1° Hosokawa et al. 1° reported that the positive inotropic effect of OPC-18790 was achieved in part by inhibition of type III PDE. However, unlike most PDE-III inhibitors, OPC-18790 prolongs the duration of action potentials in guinea pig ventricular muscles, 1° suggesting that it either increases the slow inward currents through the membrane that are carried mainly by calcium ions or reduces transmembrane potassiumrectifier currents as does vesnarinone, an oral inotropic agent, n Data obtained by right heart catheterization and noninvasive echocardiography demonstrated that OPC-18790 has beneficial dose-dependent effects on systolic and diastolic cardiac performance in patients with severe congestive heart failure. 12-14In addition to exerting a positive inotropic effect, OPC-18790 has 361
362
August 1996 American Heart Journal
Kanda et al.
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been found to reduce preload a n d afterload, as indicated by analysis of the p r e s s u r e - v o l u m e relation. 12 No previous clinical studies h a v e e v a l u a t e d the effects of OPC-18790 on m y o c a r d i a l energetics by directly m e a s u r i n g myocardial oxygen c o n s u m p t i o n (MVo2) a n d a n a l y z i n g the p r e s s u r e - v o l u m e relation. We c o m p a r e d the m e c h a n o e n e r g e t i c effects of OPC18790 a n d d o b u t a m i n e in p a t i e n t s with congestive h e a r t failure. METHODS
Study patients. We studied 21 Japanese patients with New York Heart Association hmctional class II to III congestive heart failure (mean age, 53 _+2 years). The patients' mean ejection fraction was 27% -+ 2%, and their mean left ventricular (LV) end-diastolic volume index was 134 -+ 6 ml/m 2. The underlying cause of congestive heart failure was idiopathic dilated cardiomyopathy (DCM) in 18 patients and coronary artery disease (CAD) in 3 patients. All patients had had cardiac failure at least once, and they complained of dyspnea at rest or on exertion. All patients were in normal sinus rhythm and had left ventriculographic evidence of dilated LV cavities. The study protocol was reviewed and approved by the appropriate institutional review committee, and all patients provided their written, informed consent before participating in the study. Study protocol. Patients underwent cardiac catheterization in the morning in the fasting state. All medications were withheld for at least 48 hours before catheterization. Left and right heart catheterization was performed by the femoral approach. A 7F Swan-Ganz thermodilution catheter was advanced to the pulmonary artery to measure pulmonary artery pressure, pulmonary artery wedge pressure, right atrial pressure, and cardiac output. A double-
thermistor catheter (model CCS/GOK; Wilton-Webster Laboratories, Los Angeles, CA) was placed percutaneously in the coronary sinus via the brachial or the subclavian vein to measure myocardial blood flow. After left ventriculography was performed, a 7F or 8F pigtail dual-field conductance catheter (Leycom, Oegstgeest, The Netherlands) with a 2F micromanometer tip (Millar, Instruments, Houston, Tex.) was inserted into the left ventricle to measure LV volume and pressure. A 8F catheter (model 62-080-8/22F; Edwards Laboratories, Santa Ana, CA) was placed in the inferior vena cava and was inflated transiently for determinations of the LV end-systolic pressurevolume relation. Arterial and coronary sinus blood samples were drawn simultaneously for determinations of oxygen saturation. After control measurements were obtained, OPC-18790 was administered in a dose of 5 pg/kg/min in 8 patients and in a dose of 10 pg/kg/min in 2 patients, and dobutamine was administered in a dose of 2.5 pg/kg/min in 9 patients and in a dose of 5 ~ag/kg/min in 2 patients. Data were collected 60 minutes after OPC-18790 administration and 15 minutes after dobutamine administration. There was no difference in mean age between patients who received OPC-18790 and patients who received dobutamine (53 +- 3 years vs 53 _+ 2 years). OPC-18790 was administered to 9 patients with DCM and i patient with CAD. Dobutamine was administered to 9 patients with DCM and 2 patients with CAD. There were no significant differences in hemodynamic variables before administration of inotropic agents between groups (Table I). After completion of the study protocols, selective coronary arteriography was performed, and a right ventricular biopsy was obtained. Cardiac biopsies were obtained to confirm the diagnosis of DCM. Left ventricular pressure-volume data analysis. The volume-conductance catheter was connected to a volumet-
Volume132,Number 2, Part 1 AmericanHeartJournal
Table
I.
Kanda et al.
363
Effects of OPC-18790 and dobutamine on hemodynamics
0PC-18790
HR (beats/min) SBP (mm Hg) DBP (mm Hg) LVESP (ram Hg) LVEDP (ram Hg) PAWP(mmHg) CI (L/min/m2) SVR (dyn/sec/cm5) LVEDVI (ml/m2) LVESVI (m]/m2) EF (%) Em~x(ram Hg/ml) Ea (ram Hg/ml) EJE~x
Dobutamine
Before
After
Before
After
82 ± 3 138 __ 8 76 -+ 5 132 ± 7 1! ± 2 9±1 2.83 ± 0.14 1624 ± 150 129 ± 10 94 ± 10 28 ± 3 1.26 ± 0.12 2.63 ± 0.35 2.27 ± 0.43
88 ± 5 113 _+6t 68 ± 5# 107 _+6# 6 ± 15 6±1" 3.23 ± 0.23* 1226 ± 1229 109 ± 7t 70 ± 89 36 ± 4t 1.85 _+0.25* 2.07 ± 0.26 1.24 ± 0.229
79 ± 4 146 ± 6 75 ± 3 141 _+5 14 _+2 11±2 2.72 ± 0.14 1742 ± 118 144 ± 9 108 ± 9 26 ± 3 0.90 z 0.13 2.19 ± 0.19 2.72 ± 0.28
94 ± 55 171 ± 10t 74 ± 4 157 ± 9t 10 ± 2* 7±1" 4.04 _+0.175 1264 ± 885 135 _+ 11 91 ± 11 34 ± 39 1.73 ± 0.255 2.38 _+0.40 1.51 ± 0.229
HR, Heart rate; SBP, systolicbloodpressure;DBP, diastolicbloodpressure;LVESP, left ventricularend-systolicpressure;LVEDP, left ventricularenddiastolicpressure;PAWP, pulmonaryartery wedge pressure;CI, cardiac index;SVR, systemicvascularresistance;LVEDVI, left ventricularend-diastolic volume index;LVESVI, left ventricular end-systolicvolumeindex;EF, ejectionfraction. Values are expressed as mean value -+SEM. *p < 0.05. tp < 0.01. Sp < 0.001 versus before drug administration.
ric system (model Sigma 5, Leycom) to m e a s u r e LV volume conductance a n d to convert it to the LV volume. 15 A realtime pressure-volume diagram was generated, and 8-channel analog/digital conversion (at 200 Hz) was performed by using a 16-bit microcomputer system (PC-9801 VX; NEC Co., Tokyo). The catheter had eight electrodes spaced at 1 cm intervals and was excited by a n a l t e r n a t i n g current (30 DA, 20 kHz) across the distal and the proximal electrodes. The LV volume obtained by the conductance method was calibrated by biplane ventriculography (the area-length method) as described previously. 16 The stroke volume was defined as the difference between the LV end-diastolic volu m e a n d the LV end-systolic volume. The ejection fraction was calculated as the ratio of the stroke volume to the LV end-diastolic volume. LV pressure a n d volume signals were digitized at 3 msec intervals and analyzed with a PC-9801 VX. A n end-systolic pressure-volume line was drawn on the left upper corner of the pressure-volume loops during the t r a n s i e n t decrease in preload caused by inflation of a Fogarty catheter before and after a d m i n i s t r a t i o n of inotropic agents, as shown in Fig. 1. The LV contractility index (Ema~) was defined as the slope of the end-systolic pressure-volume line. Arterial characteristics were assessed in terms of the systemic vascular resistance a n d the effective arterial elastance (Ea), as proposed by S u n a g a w a et al. 17 The systemic vascular resistance represents only the m e a n vascular resistance, b u t Ea represents both the m e a n vascular resistance and the pulsatile components. We defined E~ as the ratio of the LV end-systolic pressure to the stroke volume before a n d after a d m i n i s t r a t i o n of inotropic agents. Ventricular-arterial coupling, the relation between the inotropic state a n d afterload, is useful for q u a n t i t a t i v e evaluation of their inter-
action. Ventricular-arterial coupling was calculated as the ratio of Ea to Em~x. PVA was defined as the area u n d e r the end-systolic pressure-volume line and the systolic pressure-volume trajectory and above the end-diastolic pressure-volume relation curve. EW was defined as the area within the pressure-volume diagrams. Both PVA a n d EW were calculated with a 32-bit microcomputer (PC-9801RA, NEC Co.) by using our original system of analysis. PVA and EW were measured i n millimeters of mercury times milliliters a n d converted to the dimensions of energy by the following formula: 1 m m Hg x milliliters = 1.33 x 10 -4 j.18 Myocardial oxygen consumption and energy conversion efficiency. Myocardial blood flow was measured by using a double-thermistor catheter. The coronary sinus flow was calculated according to the method of Ganz et al.19 by using a computer system (Thermo Flow; Goodman Co., Nagoya, Japan). The injectate was a normal saline solution m a i n t a i n e d at room t e m p e r a t u r e and delivered by a n infusion pump (Harvard Apparatus, Natick, Mass.) at a flow rate of 40 ml/min. The coronary sinus flow was recorded on a six-channel recorder (Unicorder; Nippon Denshi Kagaku Co., Kyoto, Japan) at a paper speed of 100 cm/min. MV02 was calculated as the product of myocardial blood flow and the difference between the arterial a n d coronary sinus oxygen content. Oxygen content was calculated as the product of the percentage oxygen saturation, the oxyhemoglobin binding capacity, and the hemoglobin Concentration. Myocardial oxygen consumption per beat (MVo2/beat) was calculated as follows: [MVo2/beat (J/beat)] = [20 x (MVo2/ min)/heart rate], where 1 ml 02 = 20 j.20 Mechanical efficiency was defined as the dimensionless ratio of EW to MV02. Suga et al. 21, 22 demonstrated t h a t this efficiency
August 1996 American Heart Journal
364 K a n d a et al. Table II, Effects of OPC-18790 and dobutamine on myocardial energetics 0PC-18790
Dobutamine
Before CSF (ml/min) Cao2 (vol%) Ccso2 (vol%) a-csDo2 (vol%) MVO2 (J/beat) PVA (J/beat) E W (J/beat)
133 17.23 4.57 12.66 3.97 1.92 0.67
-+ 24 -+ 0.84 ± 0.54 _+ 0.84 ± 0.58 ± 0.22 ± 0.06
CSF, Coronary sinus flow; Cao2,arterial oxygen content; Values are expressed as the mean value -+ SEM. *p < 0.05. tP < 0.01. Sp < 0.001 versus before drug administration.
After 130 16.50 5.90 10.60 2.96 1.12 0.58
± 22 -+ 0.72 ± 0.90 ± 1.38" -+ 0.49* _-_ 0.205 _-_0.10
Before 170 17.29 6.62 10.67 4.48 2.67 0.87
+_ 18 -+ 0.69 ± 0.88 _ 1.03 +_ 0.61 _+ 0.27 ± 0.10
After 273 17.22 6.09 11.13 6.30 2.33 1.16
_+ 305 ± 0.80 ± 0.46 _+ 0.91 ± 0.87t ± 0.35 ± 0.15"
Ccso2,coronary sinus oxygen content; a-csD02, arterial-coronary sinus oxygen content difference.
can be divided into two stages: (1) the efficiency of energy transfer from MVo2to PVA, and (2) the efficiencyof energy transfer from PVA to EW. We determined the energy-conversion efficiency of these two stages and the mechanical efficiency as a measure of the overall energy-conversion efficiency before and after administration of inotropic agents. Statistics. Complete data were obtained for 17 of 21 patients. The conductance-catheter data were incomplete in 1 patient who received OPC-18790. Analysis of MVo2 was incomplete in 1 patient who received OPC-18790 and in 2 patients who received dobutamine. Data are expressed as the mean + SEM. We obtained the end-systolic pressurevolume relations by linear regression analysis. Differences in paired variables before and after administration of OPC-18790 or dobutamine were analyzed by the paired t test. Comparisons of the variables between OPC-18790 and dobutamine studies were analyzed by the nonpaired t test. A p value of <0.05 was considered statistically significant. RESULTS Effects of OPC-18790 on hemodynamics and myocardial energetics. Ventricular arrhythmias either did
not appear or were not increased by administration of OPC- 18790. OPC- 18790 significantly reduced systolic and diastolic blood pressures (Table I). LV enddiastolic pressure and volume decreased significantly. The cardiac index increased slightly. The LV contractility index (Emax) increased significantly. The afterload index (Ea) decreased slightly but not significantly, resulting in a 41% improvement in ventricular-arterial coupling. These hemodynamic effects of OPC-18790 were not accompanied by an increase in heart rate. Coronary sinus flow remained unchanged and the arterial-coronary sinus oxygen content difference decreased slightly (Table II). The MVo2 per beat and PVA decreased significantly. The EW remained unchanged. The ratio of PVA to MVo2 decreased from 50% +_ 7% to 41% +_ 6% (p = not sig-
nificant INS]), and the ratio of EW to PVA increased from 36% +- 2% to 55% -+ 5% (p < 0.01), resulting in an increase in the mechanical efficiency (the ratio of EW to MVo2) from 18% _+ 2% to 22% + 3% (p < 0.05; Fig. 2). Effects of dobutamine on hemodynamics and myocardial energetics. Heart rate and systolic blood pres-
sure increased significantly after administration of dobutamine (Table I). Ventricular arrhythmias either appeared or increased in all patients. LV enddiastolic pressure and volume decreased slightly. The cardiac index and Ema~ increased significantly. Ea increased slightly but not significantly, resulting in a 45% improvement in ventricular-arterial coupling, which was similar to t h a t seen with OPC18790. Coronary sinus flow increased significantly, and the arterial-coronary sinus oxygen-content difference increased slightly (Table II). The MVo2 per beat and EW increased significantly, and PVA remained unchanged. The ratio of PVA to MVo2 decreased from 65% +_ 5% to 39% -+ 5% (p < 0.001), and the ratio of EW to PVA increased from 34% _+ 3% to 52% _+ 4% (p < 0.001), resulting in a deterioration of mechanical efficiencyfrom 22% _+ 3% to 19% + 3% (p < 0.05; Fig. 2). Fig. 3 shows the relation between ventricular-arterial coupling (EJEmax) and the ratio of EW to PVA before and after administration of inotropic agents. Comparable increases in the ratio of EW to PVA were observed after administration of OPC-18790 (52%) and dobutamine (56%) in proportion to similar improvements in ventricular-arterial coupling. Fig. 4 shows the relation between ventricular-arterial coupling and mechanical efficiency (EW/MVo2) before and after administration of inotropic agents. A 23% increase in mechanical efficiency after administration of OPC-18790 and an 11% decrease in mechanical efficiency after administration of dobutamine
Volume 132, Number 2, Part American Heart Journal
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were observed, in spite of similar improvements in ventricular-arterial coupling. DISCUSSION
This study provides the first detailed assessment of the effects of OPC-18790 on mechanoenergetics in patients with congestive h e a r t failure. OPC-18790 enhanced LV contractility in association with a reduction in preload and with arterial vasodilation. The most favorable effects of OPC-18790 observed were its effects on MVo2 and on mechanical efficiency, defined as the ratio of EW to MVo2. Dobutamine also enhanced LV contractility, but this effect was accompanied by an increase in MVo2 and a
0
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2
3
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Ea/Emax Fig. 4. Changes in relation between ventricular-arterial coupling (Ea/Emax) and mechanical efficiency (EW/MV02) before and after administration of inotropic agents. White circle, Before OPC-18790; black circle, after OPC-18790; white square, before dobutamine; black square, after dobutamine. deterioration in mechanical efficiency. In addition, dobutamine increased the heart rate, whereas OPC18790 did not. Positive inotropic effect of OPC-18790. The positive inotropic effect ofOPC-18790 results in part from the accumulation of cyclic AMP induced by inhibition of PDE-III.10, 23 In addition to its inhibition of PDE-III, OPC-18790 has electrophysiologic effects t ha t result in a prolongation of the action potential duration. 1° As with vesnarinone, the electrophysiologic effects of OPC-18790 m ay be related to a reduction in the potassium repolarization currents, principally the inward and delayed rectifier currents. 11 These electrophysiologic effects m ay also contribute in part to the
366 K a n d a et al.
inotropic effects of OPC-18790. In our study, OPC18790 enhanced LV contractility without increasing the heart rate, in spite of a 17% decline in arterial pressure, which is consistent with the findings of previous experimental and clinical studies. 12-14 The findings of a recent study by Endoh et al. 23 suggest that these effects may contribute to the inotropic response. They found that OPC-18790 caused a small but significant increase in contractile force, even when cyclic AMP accumulation was abolished by carbacol.23 They found also that OPC-18790 caused a greater increase in contractile force than isoproterenol in isolated dog ventricular trabeculae for a given increase in the amplitude of Ca 2+ transients, suggesting that 0PC-18790 does not reduce the Ca 2+ sensitivity of contractile proteins. This effect may have contributed to the decrease in MVo2 induced by OPC-18790 in our study. Effects of OPC-18790 on ventricular and vascular loads. Ventricular preload, defined as the LV end-di-
astolic volume index, decreased after OPC-18790 administration. Although OPC-18790 was associated with a slight increase in the cardiac index, this effect may have resulted from a counteraction of the positive inotropic effect of OPC- 18790 induced by the preload reduction. Both 0PC-18790 and dobutamine had similar vasodilatory effects in terms of their effects on systemic vascular resistance. Afterload, defined as Ea, did not change significantly after 0PC18790 administration but tended to decrease, unlike that after administration of dobutamine. The afterload index, Ea, represents both the pulsation components and the mean arterial resistance. 17 Our findings suggest that the arterial vasodilatory effect of OPC-18790 and its lack of chronotropic action may have contributed to the tendency of Ea to decrease. Our findings support the results of a recent preliminary clinical trial of OPC-18790.12 Ventricular-arterial coupling, Evaluation of LV contractility and vascular loading conditions and their interaction is important in quantifying the effects of inotropic agents. Sunagawa et al. 17 first proposed that the interaction between these parameters could b e assessed by the ventricular-arterial coupling ratio of Ea to Emax. Under normal conditions, the ratio of Ea to Emax ranges from 0.5 to 1.0, and EW and mechanical efficiency are near their optimal values. 24 Recent studies have demonstrated that severely depressed hearts have a suboptimal interaction between the heart and the arterial system and can no longer maintain either maximal EW or maximal mechanical efficiency.25, 26 All patients in our study had dilated LV chambers, and the Ea/Emaxwas >2.0 because of the reduced Ema~ coupled with the in-
August 1996 American Heart Journal
creased Ea before administration ofinotropic agents. Thus both mechanical and energetic cardiovascular performance was severely depressed. The ratio close to 1.0 is expected to improve both EW and mechanical efficiencyat a given cardiac preload. The Ea/Emax improved after administration of OPC-18790 and dobutamine in our study. Mechanical efficiency was enhanced by OPC-18790, in spite of the unchanged EW, but was decreased by dobutamine. The decrease in cardiac preload induced by OPC-18790 is the likely explanation for the absence of changes in EW. The expected change in mechanical efficiency with dobutamine may have been offset by its positive inotropic effects, which reduce the mechanical efficiency. Effects of OPC-18790 on coronary circulation. Coronary sinus blood flow was unchanged, in spite of a reduction in arterial pressure, which is the "driving pressure" for coronary blood flow, and the arterialcoronary sinus oxygen content difference decreased as the result of the increase in coronary sinus blood oxygen content after administration of OPC-18790. Because myocardial blood flow is physiologically regulated to meet the metabolic demand of the myocardium without causing major changes in the rate of coronary sinus blood oxygen saturation, these results may have reflected primary rather than secondary (i.e., autoregulatory)27 vasodilation of the coronary vasculature or the shunting of blood flow within the myocardium. Although the clinical Significance of this primary coronary vasodilatory effect is unclear, the OPC-18790-induced decrease in MVo2 may have been related to this effect. Effects of OPC-18790 on myocardial oxygen consumption and mechanical efficiency. The notable differences
between the effects of OPC-18790 and dobutamine were their effects on MVo2 and mechanical efficiency (EW/MVo2). From a rather simplistic view, the pressure-volume data suggest that the heart is getting smaller and the arterial pressure is decreasing with OPC-18790, and therefore wall tension must be reduced. If loading conditions were kept constant, both OPC-18790 and dobutamine would be expected to increase M-Vo 2 concomitantly. The increase in MVo2 resulting from the increase in contractility after administration of OPC-18790 must be offset by a reduction in wall tension in our study. Although there was only a small difference in the change in mechanical efficiency induced by OPC18790 (+23%) and dobutamine (-11%), the efficiency increased in all OPC-18790-treated patients, except for 1 patient, and decreased in all dobutaminetreated patients. These findings suggest that these drugs have different effects on mechanical efficiency.
Volume 132, Number 2, Part 1 American Heart Journal
The effects of OPC-18790 and dobutamine on myocardial energetics can be assessed in terms of PVA proposed by Suga et al. 21, 22 Mechanical efficiency can be expressed as the product of the ratio of PVA to MV02 (the conversion efficiency of metabolic energy to mechanical energy) and the ratio of EW to PVA (the conversion efficiency of mechanical energy to external work). The increase in LV contractility induced by inotropic agents is commonly accompanied by an increase in the energy expenditure for intracellular calcium handling (the oxygen-wasting effect).21, 22 Previous studies have shown that inotropic agents, which increase Emax, shift the PVA-MVo2 relation upward so that production of the same PVA requires an increase in MVo2. 22' 28 Therefore it is assumed that the ratio of PVA to MVo2 decreases during administration ofinotropic agents. However, the decrease in the ratio of PVA to MV02 may be offset to some extent by the increase in the ratio of EW to PVA. In our study, OPC-18790 tended to reduce the ratio of PVA to MVo2 (12%), but the change was not significant. Dobutamine caused a significant decrease in the ratio of PVA to MVo2 (42%). The ratio of EW to PVA increased similarly with OPC-18790 and dobutamine, resulting in an improvement in mechanical efficiency with OPC-18790 and a deterioration of mechanical efficiency w i t h dobutamine. The ratio of PVA to MVo2 should be differentiated from the slope of the PVA-MVou relation. The total MVo2 at a given PVA consists of the sum of the PVA-dependent MVo2 and the PVA-independent MVo2 (the energy used for both basal metabolism and excitation-contraction coupling). The slope of the PVA-MVo2 relation indicates the ratio of the increase in PVA-dependent MVo2 to the increase in PVA. 22 Therefore, the ratio of PVA to MVo2 decreases as PVA decreases and as contractility is enhanced. In our study, OPC-18790 caused only a small decrease in the ratio of PVA to MV02, in spite of an increase in LV contractility and a marked decrease in PVA as a result of the OPC-18790-induced reductions in preload and arterial vasodilation. Dobutamine markedly reduced the ratio of PVA to MV02 in association with enhanced contractility, in spite of the absence of a change in PVA. These results may be related to relatively smaller oxygen-wasting effect of OPC-18790 compared with dobutamine. However, the difference in the change in contractility between OPC-18790 and dobutamine was not significant; OPC-18790 tended to increase contractility to a lesser extent than did dobutamine. Moreover, we were unable to analyze the PVA-MVo2 relation before and after administration of inotropic agents. Therefore it is unclear whether the oxygen-wasting
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effect of OPC-18790 was less than that of dobutamine in our study. The ratio of EW to PVA (the conversion efficiency of mechanical energy to external work) also affects mechanical efficiency. A previous study showed that if the ejection portion of the pressure-volume loop is assumed to be flat and the end-diastolic pressure is negligible, the ratio of EW to PVA can theoretically be expressed by the following equation: EW/PVA = 1/ (1 + 0.5 Ea/Emax), so that the ratio of EW to PVA increases in proportion to the decrease in ventriculararterial coupling. 24 Studies have suggested that this equation may be relevant to the depressed human heart, in spite of the limitations of the assumption. 16,29 In our study, both OPC-18790 and dobutamine caused similar improvement in ventricular-arterial coupling, resulting in comparable increases in the ratio of EW to PVA. These findings suggest that the difference in the effects of these drugs on mechanical efficiency was not primarily related to improved ventricular-arterial coupling in our study. Several new positive inotropic agents improve short-term cardiac performance, resulting in increased LV contractility induced by an increase in the intracellular concentrations of cyclic AMP. Howe~ler, these agents have oxygen-wasting and arrhythmogenic effects in the failing heart and thus are not appropriate for long-term therapy in patients with congestive heart failure. The quinolinone derivative vesnarinone, a new inotropic agent, has been reported to improve mortality and morbidity in patients with congestive heart failure, 3° but it has a narrow therapeutic range and is associated with a 2.5% incidence of neutropenia. 3° Although there are only a few reports of clinical trials of OPC-18790, no serious complications have been reported. In our study, OPC-18790 exhibited positive inotropic effects without increasing heart rate or MVo2. OPC18790 may have an important role in the short-term treatment of patients with congestive heart failure. Future clinical trials are needed to evaluate its effects in patients with chronic heart failure. Study limitations. There are several limitations to our study. First, we used relatively low doses of dobutamine and OPC-18790. However, most patients who received higher doses ofdobutamine complained of severe palpitations associated with an increase in heart rate or with ventricular arrhythmias, and some patients who received OPC-18790 experienced episodes of asymptomatic hypotension at 60 minutes. In addition, our study population included 3 patients with CAD. Therefore it is possible that the inotropic agents had an effect on myocardial ische-
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mia. However, no patients had chest pain or ST-segment changes on electrocardiograms. Conclusions. OPC-18790 had favorable mechanoenergetic effects in patients with congestive heart failure. Its effect on contractility was balanced by its effect on loading conditions. In spite of enhancing contractility, OPC-18790 reduced myocardial oxygen consumption and improved mechanical efficiency. Our findings suggest that OPC-18790 may be useful for short-term treatment of patients with congestive heart failure. We thank Dr. Shinichiro Morimoto (Department of Internal Medicine, Fujita Health University, Toyoake, Japan) for making the histopathologic diagnoses of biopsy specimens; Drs. Takashi Miyahara, Mitsunori Iwase, Masahiko Ukai, Takeshi Machii, Keiko Matsubara, Yasuto Nishinaka, Hideo Izawa, and Takaharu Fujimura for their cooperation; and Sadako Ichihashi for preparing the manuscript. REFERENCES 1. Monrad ES, Bairn DS, Smith HS, Lanoue A, Braunwald E, Grossman W. Effects of milrinone on coronary hemodynamics and myocardial energetics in patients with congestive heart failure. Circulation 1985; 71:972-9. 2. Asanoi/H, Sasayama S, Iuchi K, Kameyama T. Acute hemodynamic effects of a new inotropic agent (OPC-8212) in patients with congestive heart failure. J Am Coll Cardiol 1987;9:865-71. 3. Hasenfuss G, Holubarsch C, Heiss HW, Just H. Influence of UDCG-115 on hemodynamics and myocardial energetics in patients with idiopathic dilated cardiomyopathy. Am Heart J 1989;118:512-9. 4. Feldman AM, Becker LC, Llewellyn MP, Baughman KL. Evaluation of a new inotropic agent, OPC-8212, in patients with dilated cardiomyopathy and heart failure. Am Heart J 1988;116:771-7. 5. Yokota M, Matsui H, Ishihara H, Nishinaka Y, Sobue T. MS-857: a new inotropic vasodilator. Cardiovasc Drug Rev 1992;10:425-45. 6. Feldman AM. Classification of positive inotropic agents. J Am Coll Cardiol 1993;22:1223-7. 7. Packer M, Medina N, Yushak M. Hemodynamic and clinical limitations of long-term inotropic therapy with amrinone in patients with severe chronic heart failure. Circulation 1984;70:1038-47. 8. Uretsky BF, Jessup M, Konstam MA, et al. Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure: lack of benefit compared with placebo. Circulation 1990; 82:774-80. 9. Packer M, Carver JR, Rodeheffer RJ, et aL Effect of oral milrinone on mortality in severe chronic heart failure. N Engi J Med 1991;325:146875. 10. Hosokawa T, Mori T, Fujiki H, et al. Cardiovascular actions of OPC-18790: a novel positive inotropic agent with little chronotropic action. Heart Vessels 1992;7:66-75. 11. Iijima T, Taira N. Membrane current changes responsible for the positive inotropic effect of OPC-8212, a new positive inotropic agent, in single ventricular cells of the guinea pig heart. J Pharmacol Exp Ther 1987;240:657-62.
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12. Feldman MD, Haber HL, Wu CC, et al. Clinical determination of myocardial vs. load effects ofOPC-18790, a novel intravenous agent for the treatment of patients with congestive heart failure [abstract]. Circulation 1993;88:I-301. 13. Cody RJ, Leier CV, Bristow MR, et al. OPC-18790 produces titratable hemodynamic benefit in hospitalized patients with severe congestive heart failure [abstract]. Circulation 1993;88:I-300. 14. Holt BD, Burwig S, Eppert D, Bhat G, Walsh RA. Effects of a novel inotropic agent (OPC-18790) on systolic and diastolic function in patients with severe heart failure. Am Heart J 1994;128:1156-63. 15. Baan J, van der Velde ET, de Bruin HG, et al. Continuous measurement of left ventricular volume in animals and humans by conductance catheter. Circulation 1984;70:812-23. 16. Ishihara H, Yokota M, Sobue T, Saito H. Relation between ventriculoarterial coupling and myocardial energetics in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 1994;23:406-16. 17. Sunagawa K, Maughan WL, Burkhoff D, Sagawa K. Left ventricular interaction with arterial load studied in isolated canine ventricle. Am J Physiol 1983;245:H773-80. 18. Gibbs CL. Cardiac energetics. Physiol Rev 1978;58:174-254. 19. Ganz W, Tamura K, Marcus HS, Donoso R, Yoshida S, Swan HJC. Measurement of coronary sinus blood flow by continuous thermodilution in man. Circulation 1971;4:!81-95. 20. Gibbs CL, Chapman JB. Cardiac energetics. In: Berne RM, Sperlakis N, Geiger SR, editors. Handbook of physiology: the cardiovascular system, the heart. Washington, DC: American Physiology Society, 1979: 775-804. 21. SugaH, HayashiT, Shirahata M.Ventricular systolic pressure-volume area as a predictor of cardiac oxygen consumption. Am J Physiol 1981; 240:H39-44. 22. Suga H. Ventricular energetics. Physiol Rev 1990;70:247-77. 23. Endoh M, Kawabata Y, Katano Y, Norota I. Effects of a novel cardiotonic agent (_+)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]2(1H)-qninolinone (OPC-18790) on contractile force, cyclic AMP level, and aequorin light transients in dog ventricular myocardium. J Cardiovasc Pharmacol 1994;23:723-30. 24. Burkhoff D, Sagawa K. Ventricular efficiency predicted by an analytical model. Am J Physiol 1986;250:R1021-7. 25. Asanoi H, Sasayama S, Kameyama T. Ventriculoarterial coupling in normal and failing heart in humans. Circ Res 1989;65:483-93. 26. Nozawa T, Yasumura Y, Futaki N, Tanaka N, Uenishi M, Suga H. Efficiency of energy transfer from pressure-volume area to external mechanicai work increases with contractile state and decreases with afterload in the left ventricle of the anesthetized closed-chest dog. Circulation 1988;77:1116-24. 27. Rouleau J, Boerboom LE, Surjadhana A, Hoffman JIE. The role ofautoregulation and tissue diastolic pressures in the transmural distribution of left ventricular blood flow in anesthetized dogs. Circ Res 1979;45:804-15. 28. Suga H, Hisano R, Goto Y, Yamada O, Igarashi Y. Effect of positive inotropic agents on the relation between oxygen consumption and systolic pressure volume area in canine left ventricle. Circ Res 1983;53:30618. 29. Takaoka H, Takeuchi M, Odake M, Hayashi Y, Mori M, Hata K, Yokoyama M. Comparison of the effects on arterial-ventricular coupling between phosphodiesterase inhibitor and dobutamine in the diseased human heart. J Am Coll Cardiol 1993;22:598-606. 30. Feldman AM, Bristow MR, Parmley WW, et al. Effects ofvesnarinone on morbidity and mortality in patients with heart failure. N Engl J Med 1993;329:149-55.