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(Circulation. 1996;93:474-483.)
© 1996 American Heart Association, Inc.
Articles |
Acute Cardiovascular Effects of OPC-18790 in Patients With Congestive Heart Failure
Time- and Dose-Dependence Analysis Based on Pressure-Volume Relations
From the Divisions of Cardiology and the Departments of Internal Medicine, the Johns Hopkins Medical Institutions, Baltimore, Md, and the University of Virginia Health Sciences Center, Charlottesville.
Correspondence to David A. Kass, MD, Division of Cardiology, Halsted 500, Johns Hopkins University Hospital, 600 N Wolfe St, Baltimore, MD 21287.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion Appendix References |
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Background OPC-18790 is a water-soluble quinolinone derivative that shares the pharmacological properties of vesnarinone and that may be useful for treating heart failure. We studied the contribution and relative dose sensitivities of the inotropic, lusitropic, and vascular effects of OPC-18790 in patients with dilated cardiomyopathy.
Methods and Results Pressure-volume (PV)
analysis was performed in 17 patients who received either 5
µg·kg-1·min-1
(low dose, n=10) or 10
µg·kg-1·min-1
(high dose, n=7) OPC-18790 by 1-hour IV infusion. Right heart pressures
and flow and left heart PV relations (conductance catheter) were
measured at baseline and every 15 minutes during infusion. Transient
inferior vena caval obstruction was used to determine PV
relations. Both doses produced venodilation reflected by a 10% decline
in left ventricular end-diastolic volume
and a 30% fall in atrial and pulmonary artery pressures.
Arterial dilation was four times greater at the high dose,
with an 
40% fall in effective arterial elastance and
systemic resistance. Contractility rose by 25% to
100% (depending on PV index) with both doses.
Ventricular-arterial coupling (ratio of
ventricular end-systolic to
arterial elastances) was 0.25 at baseline and doubled
(or tripled) at low (or high) dose, correlating with improved
efficiency. Isovolumetric relaxation shortened, whereas the
diastolic PV relation was generally unchanged. Heart rate
was unaltered.
Conclusions OPC-18790 has potent venous and arterial vasodilator effects and moderate inotropic and lusitropic effects without a change in heart rate. These combined actions suggest a unique potential of OPC-18790 for heart failure treatment.
Key Words: cardiomyopathy • inotropic agents • heart failure • hemodynamics • quinolinone
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Introduction |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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A novel water-soluble quinolinone derivative, OPC-18790 (Otsuka America Pharmaceutical, Inc.), has been developed recently for intravenous treatment of patients with dilated heart failure.1 2 3 4 5 6 In experimental animals, the drug increases contractility and reduces venous and arterial pressures.2 3 These actions result in part from inhibition of PDE-III2 7 ; however, unlike most PDE-III inhibitors and ß-receptor agonists, OPC-18790 does not induce a significant rise in HR.2 3 5 6 8 This latter effect is thought to be due to simultaneous electrophysiological effects, specifically inhibition of potassium inward and delayed rectifier currents.9 10 Both mechanisms are shared by the oral agent vesnarinone.9
Prior clinical studies of OPC-18790 primarily reported right heart catheterization and noninvasive echocardiographic data.1 2 5 6 11 Such studies showed that the drug increases cardiac output while simultaneously lowering arterial resistance and central venous pressures. However, due to these marked simultaneous loading changes, the inotropic effects of the drug in vivo remain uncertain. More precise contractility assessments have been reported in isolated normal cardiac muscle,2 7 but this does not imply similar efficacy in failing myocardium. Inotropic responses to PDE-III inhibition in cardiomyopathic tissue are often much lower,12 and this appears to be true for OPC-18790 as well.13 Finally, a recent study suggested that OPC-18790 may also improve diastolic chamber compliance,5 although there are as yet no direct data to support such an effect.
The present investigation was designed to provide a more precise assessment of both time- and dose-dependent effects of OPC-18790 on vascular loading, ventricular systolic and diastolic function, and ventriculovascular coupling in patients with dilated cardiomyopathy. These properties were evaluated by PV relations, by use of the conductance catheter method14 and intermittent balloon occlusion of inferior vena caval inflow to measure the hemodynamic response during a 1-hour drug infusion.
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Methods |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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Patient Group
Eighteen patients with dilated cardiomyopathy referred for elective cardiac catheterization to either Johns Hopkins University or University of Virginia hospitals were entered into the study. In 1 patient, high-dose OPC-18790 infusion resulted in sustained ventricular alternans, and these data were excluded from analysis. The remaining patients were randomly assigned to one of two dose groups: 10 patients who received 5 µg·kg-1·min-1 (low dose) and 7 who received 10 µg·kg-1·min-1 (high dose). All patients had a history of exertional dyspnea or fatigue secondary to LV systolic dysfunction and were in New York Heart Association functional class III (n=16) or class IV (n=1). Twelve patients had idiopathic cardiomyopathy, whereas the remaining 5 patients (4 in the high-dose group, 1 in the low-dose group) had ischemic cardiomyopathy. All subjects had a baseline pulmonary capillary wedge pressure
15 mm Hg and EF 
35%.
Patients were excluded from the study if they had atrial fibrillation,
active myocardial ischemia or a myocardial infarction within
the past 3 months, exposure to inotropic therapy (other than digoxin)
within 4 weeks before the study, sustained or symptomatic
ventricular tachycardia, LV apical thrombus, or
primary valvular heart disease. Chronic medications included an angiotensin-converting enzyme inhibitor (16 patients), digoxin (12), nitrates or diltiazem (6), and oral hypoglycemic or lipid-reducing agents (8). The mean chronic diuretic dose (expressed as milligrams of furosemide) for each dose group was similar (66.5±38.5 mg, low dose; 57.1±31.5 mg, high dose; P=NS). All vasodilators were withheld for at least 24 hours before the cardiac catheterization. Written informed consent was obtained from all patients, and the identical protocol was approved by the human investigation committees at both the Johns Hopkins University Medical Institutions and the Hospital of the University of Virginia at Charlottesville.
Instrumentation and Protocol
Patients underwent routine right
and left heart
catheterization, left ventriculography, and
coronary angiography. Nonionic contrast was used to minimize
potential negative inotropic effects of the contrast media. After the
routine study, conductance and micromanometer
catheters were advanced into the LV apex as described
previously.14 Baseline hemodynamic
parameters were recorded at least 30 minutes after the
diagnostic cardiac catheterization and
included HR, mRaP, PaP, AoP, LV pressures (EDP and ESP), thermodilution
CO, and SV. Transient balloon-catheter (SP-9168, Cordis)
obstruction of inferior vena cava inflow was performed to
generate PV relations from beats at various preloads. Steady state
conditions were rapidly restored after balloon deflation. Data were
digitized at 200 Hz by use of custom acquisition and display software.
After baseline data were measured, OPC-18790 was infused at low or high
dose with a constant IV infusion rate of 100 mL/h for a total of 1
hour. Hemodynamic measurements including both steady
state and PV relations (transient preload reduction) were repeated
every 15 minutes during the drug infusion. Peripheral
venous blood samples were drawn at each time point to measure plasma
drug concentration.15
Conductance Catheter Technique
A full description of the
principles and technique of the
conductance catheter method has been provided
elsewhere.14 16 The present study used a 7F or 8F
conductance catheter (Webster Labs) with a 2F
micromanometer catheter (Millar Instruments) fully
extended within its lumen. Catheters were positioned under fluoroscopic
guidance along the long axis of the LV and connected to a digital
stimulator microprocessor (Sigma V, Leycom [dual-field system],
or VCU, Cardiac Pacemakers Inc). An excitation current was applied to
electrodes at the cardiac apex and aortic root, and resistance
differences were measured between intervening electrode pairs. The
inverse of each resistance is proportional to segmental volume, and the
segments were added to yield total volume. Selection of intracavitary
segments was based on the pattern of segmental PV loops, as previously
described.14 Prior studies have shown that the catheter
accurately measures changes in chamber volume throughout the cardiac
cycle in patients with both normally and abnormally contracting
ventricles.17
The conductance catheter signal was calibrated by matching the average width of the PV loop to SV calculated from thermodilution CO divided by HR. This correspondence was made at each 15-minute time point during the drug infusion, and the results were averaged to provide a single mean calibration gain for each patient. The calibration offset (parallel conductance) was corrected by matching the average catheter signal during isovolumic contraction (ie, EDV) either with EDV measured by ventriculography or to the quotient of thermodilution SV divided by ventriculographic EF (EDV=SV/EF). Single-plane ventriculographic volumes were derived by the Kennedy-Dodge regression.18 These volume estimates have been shown to correlate well with those determined by biplane ventriculography, even in patients with dyskinetic or depressed ventricles.19
Data Analysis
Digitized hemodynamic data were analyzed
off-line with custom software. PV data were smoothed with a
three-point moving average to eliminate any 60-Hz noise. Steady
state hemodynamic measurements were determined from
signal-averaged cardiac cycles, combining 5 to 10 sequential beats.
PV relations were derived from a set of cardiac cycles at various
preload volumes, starting with the beat just prior to the onset of LV
systolic pressure decline and ending with the nadir of preload
reduction or with a reflex rise in HR (>5% HR change for three
consecutive beats). Extrasystoles and at least two
postextrasystolic beats that may have occurred
during the transient preload reduction were excluded from
analysis.
Hemodynamic analysis was subdivided into chronotropy, preload, arterial vascular load, ventricular systolic function, ventricular diastolic relaxation and compliance, and ventricular-arterial coupling and energetics.
Ventricular preload was defined as EDV. As noted above, this was measured by averaging volumes during the midportion of isovolumic contraction for the steady state PV loop. This definition used several data points and therefore was less susceptible to signal noise. None of the patients had significant mitral regurgitation that would invalidate the method. EDP was the pressure at the lower right-hand corner of the PV loop.
Arterial loading was calculated by systemic vascular resistance [SVR=(mAoP-mRaP)/CO] and by the effective arterial elastance (Ea =ESP/SV). SVR quantifies mean resistance only, whereas Ea incorporates both mean and pulsatile components of the arterial load.20 21
Systolic pump function parameters included CO, SV, SW, and ESP and ESV. SW was digitally calculated. The end-systolic PV point of each loop was selected as the point of maximal [P/(V-Vo)], where P and V are LV pressure and volume and Vo is the zero-pressure volume intercept of the end-systolic PV relation (ESPVR).22 Vo was determined by an iterative method.14
Contractility change was assessed by four indexes: the ratio of maximal dP/dt to EDV (dP/dtmax/EDV),23 the slope of the ESPVR (Ees),22 the slope of the SW-EDV relation,24 and the ratio of maximal LV power to EDV2 (PWRmx/EDV2).25 dP/dt was derived digitally by use of a five-point weighted slope. ESPVR points were fit by perpendicular regression to derive Ees. SW and EDV were measured for the same set of beats, and the relation was fit by linear regression to yield a slope (Msw). Finally, maximal ventricular power (PWRmx) was the peak product of instantaneous ventricular pressure and flow (LVP and dV/dt). PWRmx was divided by EDV2 to minimize load dependence, as previously described and validated.25
Diastolic parameters included the end-diastolic PV relation (EDPVR) and time constant of isovolumic relaxation. The time constant was calculated by regressing LV pressure versus dP/dt during the isovolumic relaxation phase.24 Estimates derived from regressions with correlation coefficients <.94 were excluded from analysis. Diastolic PV relations were measured during transient preload reduction, as previously described.14
Ventriculoarterial coupling was indexed by the ratio of
ventricular to arterial elastances
(Ees/Ea).20 21 This ratio
reflects the matching of cardiac systolic properties with the
arterial system. In normal subjects, the ratio is typically
1.5, and it declines to <0.5 in patients with dilated heart
failure.26 Such reduced ratios generally reflect a
depressed LV inotropic state (low Ees) coupled with a high
vascular resistance (high Ea). Increases in the ratio are
predicted to improve ventricular work and
efficiency.27 28 To explore this hypothesis,
M
o2 was estimated by the PWI of
Rooke and
Feigl,29 calculated by
PWI=4.08x10-4x(sAoPxHR)+3.25x10-4x(0.8sAoP-0.2dAoP)x(HRxSV/BW)+1.43,
where sAoP and dAoP are systolic and
diastolic arterial pressure and BW is body
weight in kilograms. We chose this estimate of
Mo2
because it was based solely on directly measured parameters
as opposed to extrapolated values required to calculate the total PV
area,30 and it correlates reasonably well with directly
measured Mo2.31 To
derive chamber
efficiency, both Mo2 and SW were
expressed in
joules, and the ratio of SW/Mo2 was
calculated.
Statistical Analysis
Data are expressed as mean±SEM.
In most tables, the baseline
data are provided followed by the mean±SEM change from baseline at
each 15-minute drug infusion point. Drug-induced changes over time
in each parameter were tested by repeated measures ANOVA
with Dunnett's test for multiple comparisons. This was applied
separately to each dose group. Testing for differences in the time
response of a given parameter as a function of low- or
high-dose OPC-18790 and testing interactions between dose and time
effects was performed by use of a two-way repeated measures ANOVA.
Comparisons of the baseline characteristics between patients in the
low- and high-dose groups were performed with an unpaired
Student's t test.
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Results |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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Baseline Characteristics: Low- and High-Dose Groups
Baseline values for virtually all measured hemodynamic parameters in the patients receiving low- compared with high-dose OPC-18790 were not significantly different. The one exception was a slightly higher mRaP in the high-dose group. These results are provided under the "Baseline" heading of Tables 1 through 4
.
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Effect of OPC-18790 on HR and Vascular Load
The effects of
intravenous OPC-18790 on HR, preload,
and arterial afterload are summarized in Table 1
. HR was not
altered at either low or high dose.
Ventricular preload (EDV) significantly declined as early
as 30 minutes after drug infusion was started in both dosage groups.
Right heart load as assessed by mRaP and by mean and systolic
PaP also fell after 15 minutes of drug infusion. These changes were
consistent with a venous pooling effect of the drug. They were
observed at both doses, although somewhat more so at the low dose.
In contrast to preload reduction, systemic vasodilation was much more pronounced with high-dose OPC-18790 infusion. Mean systemic resistance and mean and systolic arterial pressure all declined four times more in the high- than the low-dose group (P<.001). Ea, which incorporates both mean and pulsatile components of vascular load, was unchanged in the low-dose group but fell by 40% in the high-dose group (P<.001). Even with marked venodilation and vasodilation, there was no reflex-induced chronotropic response.
Fig 1
displays steady state loops at baseline and at
each 15-minute time point during drug infusion for two patients, one
who received low-dose (left) and the other high-dose (right)
OPC-18790. Preload reduction was observed in both patients, indicated
by the leftward shift of the PV loops. A high dose also led to a
greater systolic pressure decline and to a fall in
arterial load.
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Effect of OPC-18790 on Systolic Function
Table
2 provides systolic function
responses to both low- and high-dose OPC-18790. There was no change
in SV or CO in the low-dose group. However, both variables rose
significantly in the high-dose group. EF increased slightly with
low-dose infusion but rose more prominently and earlier with the
high dose (P<.05 by ANOVA). SW was unchanged at either
dose.
Inotropic enhancement was observed similarly at both doses. dP/dtmax/EDV increased by 16% to 34% after 60 minutes of infusion, whereas Ees more than doubled and PWRmx/EDV2 rose by 30% to 40% (all P<.05). Msw, perhaps the least sensitive of the various inotropic indexes to a given contractile change,23 rose significantly, but only at the high dose.
Fig 2 displays PV loops and relations recorded at
baseline and after 30 and 60 minutes of 5
µg · kg-1 ·min-1
OPC-18790 in a representative patient. The data show a
steepening of the ESPVR (increased Ees) with
simultaneous reduction in chamber preload and
diastolic pressures. Although the rise in Ees
was nearly 100% comparing baseline with 60-minute infusion data, there
was a relatively small net leftward shift of the systolic
boundary due to a simultaneous rightward shift of the
Vo intercept. This limited the net impact of the inotropic
change on cardiac workload. This observation was fairly common among
the patients. Overall, ESVs declined by 13% (Table 2), and this
change
was similar between dose groups. Fig 3 displays the
relations between SW and EDV derived from the same PV loop data shown
in Fig 2. The slopes of these relations also progressively rose
with
drug infusion, confirming a positive inotropic effect.
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Effect of OPC-18790 on Diastolic Function
Table
3 provides summary diastolic
data. EDP declined by 5 to 6 mm Hg in both groups (25% fall),
corresponding to the EDV decrease reported in Table 1. The
isovolumic
relaxation time constant was prolonged at baseline in both groups at
between 70 to 80 ms. OPC-18790 shortened this time-constant rate by
15 ms (20%). As with the inotropic response, this change was
similar at both doses.
Fig 4 displays three examples of
diastolic
PV relations at baseline and after 15 and 60 minutes of drug infusion.
These data are highly representative of the group data.
Generally, EDPVRs fell along a single nonlinear relation, as shown by
the examples in the top and bottom panels of Fig 4. In such
patients,
there was no evidence for any change in the EDPVR but simply a
corresponding decline in chamber pressures and volumes along the
baseline relation. In several patients, the drug also led to a parallel
downward shift of the EDPVR (eg, Fig 4, middle panel). This
shift, when
it occurred, likely reflected a decline in external loading
constraints, as the drug also markedly reduced right heart filling
pressures along with LV volumes (cf Table 1).
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Effects on Ventricular-Vascular Coupling and
Efficiency
Baseline ventricular-arterial coupling
was characterized by an Ees/Ea ratio.
This ratio was low (0.25) at baseline in both groups, similar to
ratios previously reported in heart failure patients.26 By
increasing Ees at a similar or reduced Ea,
OPC-18790 considerably improved the coupling ratio at both doses (Table
4). In the high-dose group, the combined
effects of inotropic and vasodilator responses led to a threefold rise
in the Ees/Ea ratio. Enhancement of this
ratio was aided by the lack of chronotropic response, since
Ea is also proportional to HR20 27 and any
rate increase would offset the benefits from arterial
vasodilation on ventricular-vascular coupling.
Increasing the ratio of
Ees/Ea from a
baseline value of near 0.25 is predicted to increase cardiac SW and
efficiency.28 As shown in Table 2, SW did not
change, but
this likely reflected the simultaneous decline in preload
that reduces SW (cf Fig 3).24 However, chamber
efficiency,
which is less preload sensitive, increased along with the
Ees/Ea ratio. Estimated cardiac
efficiency rose from 39.2% to 43.5% in the low-dose group and
from 34.4% to 49.5% in the high-dose group (both
P<.01). Fig 5 displays efficiency as a
function of the Ees/Ea ratio for each
dose group at each time point. In both groups, efficiency was highly
correlated with the Ees/Ea ratio.
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OPC-18790 Plasma Concentrations
Table 5
provides plasma concentrations of OPC-18790
for both dose groups. Consistent with the doubling of infusion
rate, high-dose concentrations were at least twice the respective
low-dose values at all measured time points. The largest rise in
plasma concentration was observed after 15 minutes of drug infusion,
with proportionately smaller increments thereafter.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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The present study provides the first detailed assessment of temporal and dose-dependent effects of OPC-18790 on cardiovascular function in intact patients with dilated cardiomyopathy. We found that at a low dose (5 µg·kg-1·min-1), the drug had substantial effects on reducing ventricular preload, whereas at a higher dose (10 µg·kg-1·min-1), the drug had more pronounced arterial vasodilation effects. Inotropic and lusitropic improvements were generally similar at both doses. Ventricular-vascular coupling improved, particularly at the high dose, and this resulted in an increase in estimated chamber efficiency. Most importantly, OPC-18790 achieved all of these changes without a concomitant rise in HR. This is unusual, particularly for an agent that can lower arterial afterload by as much as 40%. The combined effects from OPC-18790 were that CO increased without changing SW, while cardiac filling pressures were markedly lowered and ventricular-arterial coupling and chamber efficiency were enhanced.
Positive Inotropic Effect of OPC-18790
Quantitative estimates
of the in vivo inotropic increase due to
OPC-18790 varied somewhat among the four contractile indexes. Most
indexes suggested only a modest rise averaging 25% to 35%, whereas
the largest change was evident in Ees (>100%). This
variability likely reflected the differential sensitivities of the
individual parameters to contractile change and possibly
signal artifacts. Yet even the apparently greater rise in
Ees yielded only modest increases in systolic pump
function. As shown in Fig 2, the ESPVRs tended to pivot such
that the
steeper Ees was accompanied by a rightward shift of the
volume-axis intercept (Vo). This behavior has
been observed in intact animals and humans both with
pharmacological32 and chronotropic33 34
stimuli and may be due to an underlying nonlinearity of the
ESPVR.32 Most prior studies using clinical PV
analysis to assess novel inotropic agents measured only a
single cardiac cycle after the experimental
intervention,35 36 so it is impossible to know
whether
similar pivoting occurred.
The significance of an apparent rightward
shift in Vo with
an increase in Ees is related to the fact that although the
slope may have risen by 100% (as with OPC-18790), cardiac ejection
capacity, SW, and Mo2 were less than
would otherwise
be predicted. Indeed, the measured ESV decline was modest (13%) and
could be mostly attributed to simultaneous declines in
vascular loading (see "Appendix"). If the ESPVR pivoting had not
occurred, the same 100% rise in slope likely would have lowered ESV
more and increased metabolic demands.
The present data, which reveal a relatively modest influence of OPC-18790 on inotropic state as opposed to rather pronounced vascular loading effects, are supported by several prior experimental studies. In normal canine heart2 and in normal and failing human myocardium,13 the inotropic potency of OPC-18790 stems primarily (but not entirely) from inhibition of PDE-III. The relative potency of this effect is about 5 times lower than milrinone or enoximone2 13 but greater than that of the related oral compound vesnarinone.6 Like other PDE-III inhibitors, the positive inotropic response to OPC-18790 is blunted in failing compared with nonfailing myocardium,13 and this disparity can be reversed by pretreatment with forskolin, consistent with downregulation of adenylate cyclase.12 13 In normal canine myocardium, the rise in force from OPC-18790 correlates directly with an increase in the Ca2+ transient.7 However, both responses are <40% of that maximally obtained with isoproterenol. Similarly, in human normal and failing myocardium, the contractile response to isoproterenol was nearly 15 times greater than that produced by OPC-18790.13
The inotropic effect of OPC-18790 does not entirely depend on PDE-III inhibition. The agent also has electrophysiological effects that result in a prolonged action potential2 4 and reduced potassium repolarization currents, principally the inward and delayed rectifier currents.37 These changes may also contribute to the inotropic response. Such non-cAMP–dependent effects have been demonstrated by coadministration of OPC-18790 with the muscarinic receptor agonist carbachol. Under these conditions, a small but significant rise in contractile force is still observed despite negligible change in cAMP level.7
Increasing intracellular cAMP also generally increases HR, yet this did not occur with OPC-18790. This behavior is also thought to stem from the electrophysiological action of the drug. OPC-18790 has direct negative chronotropic effects on isolated blood perfused sinoatrial node preparations2 and in vivo, this activity is sufficient to counter reflex changes in HR due to vasodilation.1 2 5 6 This was evident in the present study, in which a 25-mm Hg decline in arterial pressure at the high dose failed to elicit any HR increase. This important property differentiates OPC-18790 from prior PDE-III inhibitors and from conventional ß-agonists.6 35 36 38 39 40 For example, enoximone also was found to increase inotropic state as indexed by PV analysis, yet this occurred with a near 16% increase in HR. Lack of an HR rise has been shown to play a key role in minimizing changes in high-energy phosphate metabolism when OPC-18790 is administered to a globally ischemic heart.41 This contrasted with dobutamine or amrinone, which raised HR and exacerbated ischemic declines in pH, ATP, and the phosphocreatine/inorganic phosphate ratio.
This lack of HR change with modest inotropic activity is shared by the oral quinolinone derivative vesnarinone.42 43 44 Furthermore, chronic oral administration of vesnarinone at a dose of 60 mg per day has been found to significantly reduce 6-month morbidity and mortality in heart failure patients.43 Many acute studies of PDE-III inhibitors demonstrated hemodynamic benefits35 36 38 39 40 only to reveal an increased mortality when they were administered chronically.45 46 Whether or not chronic OPC-18790 will prove different in this regard, particularly in light of its lack of chronotropic response and minimal influence on QTc interval,1 remains to be determined.
Dose-Dependent Load Alteration
Increasing the OPC-18790 dose
had its greatest influence on
enhancing afterload reduction. Such dose effects on vascular loading
are consistent with another recent preliminary
report.11 Interestingly, both myocardial inotropic and
lusitropic effects of the drug were similar at low and high doses. This
suggests that the relative contribution of peripheral
arterial vasodilation may be titratable independently of
the primary cardiac actions of OPC-18790. Plasma levels between 400 and
800 ng/mL appear to be required to generate a significant systemic
arterial effect. The value of 800 ng/mL also seems near the
upper clinical therapeutic range, since higher doses tended to produce
hypotension.
Diastolic Influences of OPC-18790
As with PDE-III inhibitors
and ß-agonists,
OPC-18790 has been found to shorten the diastolic
relaxation time in isolated muscle.7 In humans, the drug
has been shown to increase posterior wall thinning rate and maintain
the early diastolic velocity-time integral despite a
decline in preload.5 These findings were attributed to
enhanced relaxation, reduced end-systolic dimensions, and
improved chamber compliance.5 The present study
confirmed both a shortened isovolumic relaxation time and lower ESV.
However, we did not find a change in the diastolic PV
relations. Rather, these data were generally superimposable, with the
data falling along a single curvilinear relation at gradually declining
volumes. Some patients displayed a downward displacement as well, but
this most likely was due to simultaneous declines in right
heart and pericardial loading.
Ventriculoarterial Coupling
Recent
studies26 30 demonstrated that patients with
severe cardiac dysfunction have a suboptimal interaction between the
heart and arterial system. This generally takes the form of
systolic cardiac depression (reduced Ees) coupled
with high systemic vascular resistance (elevated Ea).
Sunagawa et al20 27 first proposed that this
interaction
between the heart and arterial system could be assessed by
the Ees/Ea ratio. Normally,
ventricular and vascular properties are such that this
ratio is >1.0, and cardiac work and efficiency are near
optimal.26 28 47 In failing human hearts,
however, this
ratio declines to <0.5, and the result is that both work and
efficiency are compromised.26 30 Experimental studies
have
shown that at a baseline ventriculovascular coupling ratio of 0.25,
such as observed in the present study, both work and efficiency are
reduced from their optimal values by as much as 50%.28
Increasing the ratio toward 1.0 is anticipated to elevate both
parameters (assuming other variables, such as cardiac
preload, are held constant). This can be accomplished by a rise in
inotropic state,48 a decline in afterload,49
or both.
At both doses, OPC-18790 increased the
Ees/Ea ratio, but this was most
prominent at the 10
µg·kg-1·min-1
dose. The simultaneous decline in cardiac preload likely
explained the lack of change in SW. Estimated chamber efficiency,
defined as the ratio of SW/Mo2, is
less
preload dependent, and this ratio increased with higher
Ees/Ea ratios. The
Mo2 data in the present study are
admittedly
indirect estimates, and the exact efficiency values should be viewed
cautiously. However, the conclusions from this analysis are
very consistent with recent preliminary clinical data in which
Mo2 was directly
measured50 during
OPC-18790 infusion. In both that study50 and the
present study, Mo2 declined with
OPC-18790, in
part because of preload reduction, and the ratio of
SW/Mo2 increased. Finally, it is
worth noting that
the lack of chronotropic response played an important role in the
enhancement of the Ees/Ea ratio.
Ea rises with HR, reflecting the higher
arterial pressures that result when a given SV is ejected
into the arterial system more times per minute. Agents such
as dobutamine have been shown to have less beneficial
effects on coupling and efficiency, due in part to their positive
chronotropic effects.30
Methodological and Experimental Design Limitations
Thermodilution-derived COs and ventriculogram EDV and EF are
subject to error, and these errors can be exacerbated in patients with
depressed LV function. In this respect, we recognize that baseline
catheter volumes were no better or worse than these external
calibrations dictated. The catheter method, however, provides greater
consistency than most other volume approaches, so temporal
changes are more accurate. Calibration of the catheter can vary if
volumes are greatly reduced from baseline. However, EDV reduction from
OPC-18790 was less than resting SV, so this error should have been
minimal.51 Right ventricular volumes, which
are lowered by the inferior vena caval balloon obstruction
method, can influence the conductance signal.51 However,
these effects are much reduced in human-sized hearts, particularly
dilated hearts, due to the increased distance of the right
ventricular blood pool from the stimulating current
field.52 Large chamber diastolic volumes with
relatively small SVs can pose a signal-to-noise limitation for
the conductance catheter. However, by increasing the distance between
sense electrodes (1.5 versus the usual 1.0 cm) and combining several
segments into larger ones, this problem is reduced. Use of
dual-field excitation improves current-field homogeneity,
further stabilizing the signal.52 Still, there are
limitations to the method, and very dilated or hypocontractile hearts
and/or hearts with very high right heart pressures remain difficult to
study.
OPC-18790 reduced arterial pressures, particularly at the high dose, and one could speculate that if this altered coronary perfusion, it might also have influenced the volume signal. Furthermore, several patients (four in the high-dose group, one in the low-dose group) had ischemic heart disease, which also might modify regional flow and thus the volume signal. However, prior studies showed that total coronary occlusion at various sites and distribution beds,53 as well as global flow reduction (lowering total mean perfusion pressure from 100 to <50 mm Hg),51 has small and often insignificant effects on the catheter calibration. Human studies in patients with prior myocardial infarctions and coronary disease have found excellent correlations between conductance volumes and those obtained by ventriculography.17 Finally, mean arterial pressures after OPC-18790 did not decline below 70 mm Hg in any patient, making it highly unlikely that coronary blood volume was ever critically reduced. There was also no evidence of ischemia, either by symptoms or ECG, in any patient.
One limitation of our study is that data were not obtained in a placebo group to test the acute effects of catheterization itself on left heart PV dynamics during the first 90 minutes. Packer and colleagues54 reported significant hemodynamic changes mimicking vasodilator effects after right heart catheterization, in the absence of drug therapy. However, after 2 hours, many of these changes were small and much less than the responses observed after infusion of OPC-18790. More substantial changes in filling pressure and CO, reported after 6 to 24 hours of right heart catheter placement,54 would not apply to our more acute investigation.
Summary
We evaluated the time- and dose-dependent
cardiovascular effects of OPC-18790, a novel
intravenous agent for clinical treatment of dilated
cardiomyopathy. Unique properties of this agent
were potent venodilation, inotropic and lusitropic responses evident at
a lower dose, and arterial vasodilation that was prominent
only at the higher dose. Most importantly, these responses were not
accompanied by any change in HR. Future clinical trials are needed to
directly compare the utility of this agent to existing drugs for
chronic heart failure treatment. On the basis of the present data,
OPC-18790 appears promising.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
|---|
This research was supported by National Public Health Service grants HL-47511, AG-12249 (Dr Kass), HL-47046 (Dr Feldman), an American Heart Association Established Investigator Award (Dr Kass), an American Heart Association Virginia Affiliate Fellowship Award (Dr Haber), a Merck clinician scientist award (Dr Pak), and a grant from Otsuka America Pharmaceutical, Inc. The authors gratefully acknowledge the excellent nursing support of Christine Tedesco and Marykris Carnivale.
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Appendix |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
|---|
OPC-18790 increased the Ees, but as shown in Fig 2
, this was often associated with a pivoting of the
relation, such
that the apparent volume-axis intercept (Vo)
increased. Thus, even though ESV declined, much of this change was
related to the simultaneous venous and arterial
loading changes. This can be demonstrated by the following
analysis, based on previously published coupling
equations.23 The equation for the ESPVR is related to
Ea by their definition expressions:
 | (1) |
Rearranging, one gets the equation:
 | (2) |
To
predict a given ESVpred that would result solely
from a change in EDV (
EDV) and/or Ea
(Ea), one can write:
 | (3) |
From
the first equation and the initial baseline values provided
in Tables 1 and 2, we can obtain values for
(EDV-Vo)
of 271 mL for low dose and 288 mL for high dose. Substituting these
values and the corresponding changes in EDV and Ea after 60
minutes of OPC-18790 infusion (provided in Table 1), and
maintaining
Ees at its baseline value, we obtain:
 |
 |
 |
 |
From
Table 2, the ESV measured 60 minutes after low-dose
OPC-18790 was 195 mL, slightly less than the 200 mL predicted from
unloading influences alone. For high-dose OPC-18790, measured ESV
declined to an average of 186 mL. So at both doses, the majority of the
ESV decline could be explained purely on the basis of venous and
arterial unloading rather than by an inotropic change. Had
ESPVR pivoting not occurred, then the measured ESV would have been
lower and this disparity greater.
Received May 10, 1995; revision received September 11, 1995; accepted September 14, 1995.
|
References |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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