Alteration in Energetics in Patients With Left Ventricular Dysfunction After Myocardial Infarction
Increased Oxygen Cost of Contractility
Background Although the use of inotropic agents to treat congestive heart failure (CHF) in patients with coronary artery disease has yielded short-term hemodynamic improvement, long-term mortality has shown less improvement. The loss of cardiac muscle as a result of infarction not only decreases the pumping ability of the heart but also leads to some dramatic changes in myocardial energetics. However, little is known about the mechanoenergetics of the heart in patients with left ventricular (LV) dysfunction after myocardial infarction.
Methods and Results The present study was designed to compare, by means of the V̇o2-pressure-volume area relation (PVA, a measure of total mechanical energy) and Emax (LV contractility index), the incremental oxygen cost of contractility measured as nonmechanical energy per unit increment in contractility in patients with various kinds of LV dysfunction. We assessed Emax, V̇o2, and PVA using conductance and Webster catheters under control conditions and during different rates of dobutamine infusion (3 and 6 μg·kg−1·min−1) in 30 patients with coronary artery disease. Patients were divided into three groups according to LV ejection fraction (EF): 10 without LV dysfunction (EF ≥60%), 10 with mild LV dysfunction (40%≤EF<60%), and 10 with severe LV dysfunction (EF <40%). Under control conditions, the V̇o2-PVA relation was linear in each group. Contractile efficiency, the reciprocal of the slope of this relation, was comparable among the three groups. The oxygen cost of contractility in the severe LV dysfunction group was significantly greater than in the groups without and with mild LV dysfunction (0.022±0.014 versus 0.005±0.002 and 0.0012±0.005 mL O2 · mL · mm Hg−1 per beat, P<.05).
Conclusions These findings suggest that the alteration in mechanoenergetics in patients with severe LV dysfunction after myocardial infarction may result from the increased oxygen cost of excitation-contraction coupling rather than from a reduction in the efficiency of chemomechanical energy transduction.
CHF most frequently develops as a result of coronary artery disease. When pump performance is impaired by a large akinetic area after myocardial infarction, chronic overloading of active myocardial cells leads to biochemical abnormalities. These abnormalities result in an imbalance between energy production and energy use.1 Although inotropic therapy yields short-term hemodynamic improvement in the treatment of CHF, long-term mortality has shown less improvement.2 It may be that although inotropic intervention increases LV contractility, it also increases myocardial V̇o2. Therefore, an investigation of myocardial energetics in relation to inotropic intervention in patients with coronary artery disease should have clinical and therapeutic relevance.
The concepts of LV elastance (Emax) and systolic PVA proposed by Suga3 and others4 5 have facilitated research on myocardial mechanoenergetics in animal and human hearts. In more recent studies, the oxygen cost of contractility during inotropic intervention has been shown to be elevated in postischemic stunned myocardium,6 postacidotic heart,7 and pacing-induced heart failure.8 The purpose of the present study was to assess myocardial energetics in patients with various kinds of LV dysfunction after myocardial infarction in terms of the V̇o2-PVA relation and Emax.
Studies were performed in 30 patients with coronary artery disease (mean age, 58 years; range, 37 to 72 years; Table 1⇓). Patients with acute myocardial infarction, unstable angina, symptomatic CHF, and valvular heart disease were excluded. Administration of all diuretics, β-adrenergic blocking agents, and vasoactive agents was stopped 24 to 48 hours before, and administration of nitrate preparation was stopped 12 hours before catheterization. Complete informed written consent was obtained from each patient before the study, and there were no unfavorable complications throughout the study.
Cardiac catheterization was performed by the femoral approach on patients in the fasting state and without premedication. Patients underwent routine catheterization, including coronary angiography and left ventriculography, as described previously.9 10 After completion of routine catheterization, a 7F thermodilution Swan-Ganz catheter (Goodtech Inc) was advanced into the pulmonary artery, and an 8F conductance volume catheter (CardioDynamics) was advanced to the LV through the femoral artery. An 8F Webster catheter (Wilton Webster Manufacturing Co) was then advanced into the CS through the left subclavian sheath as confirmed by injection of contrast medium.
Measurement of LV Pressure and Volume
LV pressure-volume relations were determined simultaneously by the conductance catheter attached to a stimulator-processor (Sigma-5, CardioDynamics) with a 2F Millar catheter (Millar Instruments, Inc) advanced into the LV through the lumen of the conductance catheter. Heparinized saline solution was infused slowly and continuously through the lumen of the conductance catheter to prevent hemostasis. The principle and accuracy of LV volume measurements with the conductance catheter were described earlier.11 12 13 The indicator technique (injection of hypertonic saline solution) was used to determine parallel conductance, ie, the correcting volume for the conductance of the surrounding tissues.
On completion of calibration, a large balloon-occlusion catheter (Baxter Healthcare, Inc) was advanced to the right atrium–inferior vena caval junction through the 9F femoral sheath. The balloon was inflated rapidly in the right atrium and pulled back to occlude venous return. Pressure-volume loops of the next 8 to 10 cardiac cycles were recorded; LV systolic pressure dropped 30 to 40 mm Hg during this interval. The balloon was then deflated, and both pressure and volume rapidly returned to baseline. This procedure was repeated at least twice to obtain ESPVRs. The LV contractile state was defined by the slope (Emax) of the ESPVR as shown in Fig 1A⇓. Pressure-volume data during the fall in LV pressure were fitted by use of the least-squares technique to
where ESP is the LV end-systolic pressure, V0 is the intercept of the volume axis,14 15 and ESV is end-systolic volume. For comparison among various patients, Emax (mm Hg·mL−1·m2) and V0 (mL/m2) were normalized by body surface area.15
Measurement of V̇o2
V̇o2 in milliliters of O2 per minute was calculated as the product of coronary sinus flow (milliliters per minute) and coronary arteriovenous oxygen-content difference (vol %) and was divided by heart rate to yield V̇o2 per beat. Coronary sinus flow was measured with the Webster catheter, which was advanced into the CS; it was measured at least twice during a 30-second continuous injection of room-temperature indicator (5% glucose) through the catheter lumen at a rate of 40 mL/min with a Mark IV angiographic injector (Medrad Inc).16 17
After adequate placement of both the conductance and Webster catheters, blood resistivity, ρ, was measured and entered into the signal coordinator, and volume correction by the parallel conductance was performed. HR was maintained at approximately the control rate by CS pacing (mean HR, 90±10 beats per minute). After steady state hemodynamics, pressure-volume loops, and V̇o2 were measured, transient vena caval occlusions were performed several times. Dextran was then infused continuously (100 to 200 mL for 5 minutes). After stabilization of hemodynamics was confirmed, steady state hemodynamics, pressure-volume loops, and V̇o2 were measured. Volume loading was repeated twice, and the same measurements were performed at each volume-loading stage. At the end of this protocol, transient vena caval occlusion was repeated. We measured 114 whenever >400 mL dextran was infused and entered 114 into the signal coordinator. Our previous study showed that dextran infusion does not alter myocardial contractility or induce myocardial ischemia.4
Next, dobutamine was administered intravenously stepwise (first, 3 μg·kg−1·min−1; second, 6 μg·kg−1·min−1) to increase contractility. At each level of dobutamine infusion, steady state hemodynamics, pressure-volume loops, and V̇o2 were measured. At the end of each protocol, transient vena caval occlusion was repeated to obtain Emax. To confirm that there was no myocardial ischemia during dobutamine infusion, blood was sampled from the CS and the femoral artery, and lactate concentrations were measured. There were no signs of pulmonary congestion or other side effects during these procedures.
Calculation of PVA
PVA in millimeters of mercury per milliliter per beat represents the total mechanical energy generated by contraction of the LV. PVA was calculated as an area circumscribed by the ESPVR, EDPVR, and systolic pressure-volume trajectory of each beat, as shown in Fig 1A⇑.3
V̇o2-PVA Relation and Contractile Efficiency
where a is the slope of the regression line and b is the V̇o2 intercept, aPVA is the PVA-dependent V̇o2 term, and b is the PVA-independent V̇o2 term. PVA-independent V̇o2 includes the V̇o2 for excitation-contraction coupling and basal metabolism.3 The reciprocal of the slope of the V̇o2-PVA relation (1/a) represents the chemomechanical energy transduction efficiency from PVA-dependent V̇o2 to total mechanical energy.3 This is called contractile efficiency and is calculated in percent.3
Oxygen Cost of Contractility
When V̇o2-PVA relations are obtained at different levels of contractility or Emax, the V̇o2 intercept values vary, but their slopes are virtually the same, as shown schematically in Fig 1C⇑.3 The V̇o2 intercept of the V̇o2-PVA relation increases with an increase in Emax. When the PVA-independent V̇o2 values or V̇o2 intercept values of the V̇o2-PVA relations at different Emax levels were plotted against Emax values, the relation was linear, as shown schematically in Fig 1D⇑.20 The relation was formulated as
where c is the slope of this relation and d is the PVA-independent V̇o2 extrapolated to zero Emax. Suga3 showed that the slope c represents the oxygen cost of contractility, which indicates the increment in V̇o2 per unit increment in contractility.
Our previous findings led us to expect that the V̇o2-PVA relations in human heart would also be shifted in a parallel manner despite dobutamine-induced changes in Emax.4 In the present study, the PVA-independent V̇o2 values at different Emax levels after dobutamine infusion were calculated by assuming an identical slope and were plotted against Emax values to obtain the oxygen cost of contractility.
ANOVA21 was applied to compare Emax, PVA-independent V̇o2, the slope of the V̇o2-PVA relations, and other variables for the control and positive inotropic states between groups. When ANOVA showed statistical significance according to the F test, the differences in mean values among the groups were tested by the Fisher protected least significant difference method. Differences in the paired variables in each group were tested by paired t tests. Values of P<.05 were considered statistically significant. All data are presented as mean±SD.
We divided 30 patients into three groups according to their LVEFs. The normal LV function group consisted of 10 patients with coronary artery disease and normal LVEF (>60%; mean, 69%). The mild LV dysfunction group consisted of 10 patients with previous myocardial infarction whose LVEFs ranged from 40% to 60% (mean, 49%). The severe LV dysfunction group consisted of 10 patients with previous myocardial infarction whose LVEF was <40% (mean, 34%).
Table 1⇑ lists the demographic data and hemodynamic variables under control conditions. There were no significant differences in age, HR, end-systolic pressure, or end-diastolic pressure among the three groups. End-systolic and end-diastolic volume indexes in the severe LV dysfunction group were larger than those in the normal LV function (P<.0001 and P=.0001 for end-systolic and end-diastolic volume indexes, respectively) and the mild LV dysfunction groups (P<.0001 and P=.009). Emax in the severe LV dysfunction group was smaller than that in the normal LV function group (P=.0001), but it was not significantly different from that in the mild LV dysfunction group (P=.09). End-systolic volume index in the mild LV dysfunction group was larger than that in the normal LV function group (P=.002), but end-diastolic volume index in this group was not different from that in the normal LV function group. Emax in the mild LV dysfunction group was smaller than that in the normal LV function group (P=.007).
Comparison of the Relation Between V̇o2 and PVA Under Control Conditions
Volume loading with dextran was successfully completed in 25 of 30 patients. Because of the complex preparations, we skipped volume loading in 5 patients to prevent unfavorable complications such as hemostasis and administered dobutamine intravenously after control measurements. Dextran infusion increased PVA by 28±17% in the normal LV function group, 37±15% in the mild LV dysfunction group, and 25±21% in the severe LV dysfunction group (Table 2⇓). It increased V̇o2 by 32±30%, 31±19%, and 27±21% in the respective groups. The V̇o2-PVA relations during control condition were highly linear in each of the groups. The mean values of the correlation coefficient were .92 in the normal LV function group, .95 in the mild LV dysfunction group, and .88 in the severe LV dysfunction group. The slope and the V̇o2 intercept of the V̇o2-PVA relation showed no difference among the three groups, nor was there any difference among the three groups in contractile efficiency, the chemomechanical energy transduction efficiency, which was ≈45%.
Effects of Dobutamine on Hemodynamics, ECG, and Lactate Extraction
We administered dobutamine in 20 of 30 patients. Dobutamine infusion increased PVA by 79±29% in the normal LV function group, 51±34% in the mild LV dysfunction group, and 23±34% in the severe LV dysfunction group. It increased V̇o2 by 81±25%, 82±44%, and 51±44% in the respective groups. Dobutamine increased both Emax and PVA-independent V̇o2 (Table 3⇓). A linear relation between PVA-independent V̇o2 and Emax was observed in individual patients in all groups (Fig 2⇓). The mean values of the correlation coefficient of the regression line were .98 in the normal LV function group, .92 in the mild LV dysfunction group, and .96 in the severe LV dysfunction group (Table 3⇓). The mean value of the oxygen cost of contractility was significantly greater in the severe LV dysfunction group than in the normal and mild LV dysfunction groups (P=.0012 versus the normal LV function group and P=.038 versus the mild LV dysfunction group; Fig 3⇓ and Table 3⇓). The oxygen cost in the mild LV dysfunction group tended to be greater than in the normal LV function group, but the difference did not reach statistical significance (P=.092; Fig 3⇓).
There was no change in either lactate extraction or ECG, which would indicate developing myocardial ischemia during either volume loading with dextran infusion (31±16% to 38±11%, n=12; P=NS) or dobutamine infusion (48±18% to 36±10%, n=4; P=NS).
Our aim was to study abnormal myocardial energetics in patients with various kinds of LV dysfunction by using the concepts of Emax and PVA. The principal findings of the present study are that (1) the slope and the PVA-independent V̇o2 of the V̇o2-PVA relation during control conditions were comparable among the three groups despite the differences in Emax, (2) a highly linear correlation between PVA-independent V̇o2 and Emax was observed during inotropic intervention in individual patients, and (3) the oxygen cost of contractility in the severe LV dysfunction group was significantly greater than in modest LV dysfunction groups.
Oxygen Cost of Contractility
Increased oxygen cost of contractility means that for a given value of Emax, more PVA-independent V̇o2 is needed for calcium handling. The PVA-independent V̇o2 is believed to represent the V̇o2 for nonmechanical work that is used for basal metabolism and excitation-contraction coupling.3 Because V̇o2 for basal metabolism has been reported to remain constant with changes in loading conditions and inotropic state in the dog,22 increased PVA-independent V̇o2 is thought to indicate a greater oxygen-wasting cost of excitation-contraction coupling or calcium handling.
There are conflicting results in earlier studies on the oxygen cost of contractility in the failing myocardium.8 23 Although elucidation of the precise mechanism of the increased oxygen cost of contractility is beyond the goal of the present study, we have speculated on some mechanisms. One possible mechanism is that the responsiveness of the contractile machinery to free calcium is decreased. In such circumstances, more Ca2+ would be needed to maintain a given Emax, and thus more oxygen would be consumed. In support of this, an increased oxygen cost of contractility was demonstrated recently in acidotic and postischemic stunned myocardium in which decreased Ca2+ sensitivity was reported.6 7 However, the Ca2+ sensitivity of myofibrils from human hearts in end-stage failure is identical to that in nonfailing human hearts.24 25 26 Therefore, decreased Ca2+ sensitivity probably is not the main factor responsible for the increased oxygen cost of contractility in patients with severe LV dysfunction.
Another possible mechanism is altered sarcoplasmic reticulum function, eg, a decreased coupling ratio of calcium to ATP in the Ca2+-ATPase pump of the sarcoplasmic reticulum.27 28 29 It has been well documented that depressed cardiac function in chronically infarcted hearts induces compensatory hypertrophy in the surviving LV myocardium.30 31 Recently, depressed sarcoplasmic reticulum function in hypertrophied viable cardiac tissue induced by regional myocardial infarction was reported.32 Furthermore, altered Ca2+ handling has been shown even at quite an early stage in experimental heart failure models.33 Therefore, impaired sarcoplasmic reticulum function may account for the increased oxygen cost of contractility in patients with severe LV dysfunction.
We should consider the influence of plasma catecholamine levels on LV contractility and the oxygen cost of contractility. It would have been expected that Emax was high in proportion to catecholamine levels. Data from our laboratory34 showed a weak positive correlation between Emax and catecholamine level (Fig 4⇓), but it did not reach statistical significance. This may result partly because some patients with severe heart failure had relatively high catecholamine levels and low LV contractility. Few studies have focused on the correlation between the oxygen cost and catecholamine level. A previous experimental study showed that plasma catecholamine levels did not correlate with the oxygen cost of contractility or Emax in excised blood-perfused dog hearts.35 Further studies are needed to clarify these issues.
Suga3 reported that various inotropic interventions shift the linear V̇o2-PVA relation upward or downward in a parallel manner. In other words, the contractile efficiency remains constant regardless of inotropic interventions. Changes in the slope of the V̇o2-PVA relation have been interpreted as alterations in myofibrillar energy efficiency.3 A recent study on the hyperthyroid rabbit heart demonstrated depressed contractile efficiency along with a marked increase in the myosin isoform Vl/V3 ratio, ie, increased ATPase activity.19 Extrapolation of the results suggests that the myosin ATPase activity or cross-bridge cycling rate may not be impaired in patients with LV dysfunction.
In the present study, to determine the oxygen cost of contractility, we assumed that the slope for the V̇o2-PVA relation did not change during inotropic intervention. This assumption is based on the parallelism of the V̇o2-PVA relations, one at control Emax and others at stable dobutamine-enhanced Emax. This assumption appears justified in that our previous study showed that this parallelism holds true even in diseased human hearts.4
Several methodological problems must be discussed. First, we obtained the slope and the V̇o2 intercept of the V̇o2-PVA relation during volume loading by applying linear regression analysis. Extrapolation of the V̇o2 intercept of the V̇o2-PVA relation might have caused some errors in the assessment of the oxygen cost of contractility. However, it is impossible to measure the V̇o2 intercept of zero PVA directly in the clinical setting.
Second, LV wall motion abnormalities in patients with LV dysfunction might also have caused some errors in the assessment of the oxygen cost of contractility. A previous study showed that Emax was influenced by asynchronous contraction.36 If asynchronous contraction had been augmented in patients with LV dysfunction during inotropic intervention, the measured Emax would have been an underestimation of the true Emax, and this possible underestimation of Emax would result in an apparent increased oxygen cost of contractility. In the present study, however, no patient had dyskinetic LV wall motion. Furthermore, during dobutamine infusion, there was no significant alteration in ESP, which might have strongly affected LV wall motion abnormalities.
Finally, the number of patients enrolled in the present study was small. Therefore, the results cannot be widely extrapolated to other subgroups of patients with LV dysfunction such as patients with more severe LV dysfunction (LVEF <25%) or patients with idiopathic dilated cardiomyopathy. Further studies of larger numbers of patients and patients in other subgroups are needed before these conclusions can be applied more generally to patients with LV dysfunction.
The results of the present study may have important pathophysiological and clinical significance. In the treatment of CHF, inotropic agents yield short-term hemodynamic improvement, but they increase V̇o2. That increase in V̇o2 is particularly critical among patients with coronary artery disease because the energy supply to the myocardium often is quite limited. The present study suggests that the increased oxygen cost of contractility in patients with severe LV dysfunction may contribute to the adverse effect of inotropic agents on long-term mortality. Further studies are needed to find ideal inotropic agents that increase myocardial force with less oxygen-wasting effect.
In conclusion, by measuring Emax and PVA, we were able to assess the oxygen cost of contractility in patients with various kinds of LV dysfunction after myocardial infarction and found that the oxygen cost of contractility was significantly greater in patients with severe LV dysfunction than with modest LV dysfunction. Our results demonstrate that although inotropic interventions improve LV mechanics, the oxygen-wasting effects of these agents may be energetically crucial, especially in patients with severe LV dysfunction. These findings may reflect a possible alteration in calcium handling in failing human hearts.
Selected Abbreviations and Acronyms
|CHF||=||congestive heart failure|
|EDPVR||=||end-diastolic pressure-volume relation|
|ESPVR||=||end-systolic pressure-volume relation|
This study was supported in part by Grant-in-Aid 04670535 for Scientific Research from the Ministry of Education, Culture and Science of Japan. We gratefully acknowledge Kaoru Yoshizawa (Taisho Biomed Instruments Co, Ltd) and Teruo Nakatsuka (Goodman Co, Ltd) for their technical assistance in our catheterization laboratory.
Presented in part at the 65th Scientific Sessions of the American Heart Association, New Orleans, La, November 18, 1992, and previously published in abstract form (Circulation. 1992;86[suppl I]:I-647).
- Received July 11, 1995.
- Revision received October 2, 1995.
- Accepted October 6, 1995.
- Copyright © 1996 by American Heart Association
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