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Am J Physiol Heart Circ Physiol 278: H698-H705, 2000;
0363-6135/00 $5.00
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Vol. 278, Issue 3, H698-H705, March 2000

Altered LV inotropic reserve and mechanoenergetics early in the development of heart failure

Sumanth D. Prabhu and Gregory L. Freeman

Department of Medicine, University of Texas Health Science Center at San Antonio, and South Texas Veterans Health Care System-Audie Murphy Division, San Antonio, Texas 78284


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

To test the hypothesis that alterations in left ventricular (LV) mechanoenergetics and the LV inotropic response to afterload manifest early in the evolution of heart failure, we examined six anesthetized dogs instrumented with LV micromanometers, piezoelectric crystals, and coronary sinus catheters before and after 24 h of rapid ventricular pacing (RVP). After autonomic blockade, the end-systolic pressure-volume relation (ESPVR), myocardial O2 consumption (MVO2), and LV pressure-volume area (PVA) were defined at several different afterloads produced by graded infusions of phenylephrine. Short-term RVP resulted in reduced preload with proportionate reductions in stroke work and the maximum first derivative of LV pressure but with no significant reduction in baseline LV contractile state. In response to increased afterload, the baseline ESPVR shifted to the left with maintained end-systolic elastance (Ees). In contrast, after short-term RVP, in response to comparable increases in afterload, the ESPVR displayed reduced Ees (P < 0.05) and significantly less leftward shift compared with control (P < 0.05). Compared with the control MVO2-PVA relation, short-term RVP significantly increased the MVO2 intercept (P < 0.05) with no change in slope. These results indicate that short-term RVP produces attenuation of afterload-induced enhancement of LV performance and increases energy consumption for nonmechanical processes with maintenance of contractile efficiency, suggesting that early in the development of tachycardia heart failure, there is blunting of length-dependent activation and increased O2 requirements for excitation-contraction coupling, basal metabolism, or both. Rather than being adaptive mechanisms, these abnormalities may be primary defects involved in the progression of the heart failure phenotype.

ventricular function; myocardial energetics; length-dependent activation; dog; pacing


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

WHEN RAPID TACHYCARDIA persists for several weeks, a dilated cardiomyopathy results with functional, hemodynamic, and neurohormonal changes closely resembling human heart failure (see Ref. 35 for review). This model is commonly used in animal studies to evaluate pathophysiological processes in the failing heart, although its exact pathogenesis remains unclear. At the chamber level, prior studies have reported that reduced left ventricular (LV) pump function in tachycardia heart failure is characterized by several distinct abnormalities, including a decreased capacity to increase contractile performance in response to increased preload, i.e., attenuation of the Frank-Starling mechanism (18), and disturbances in mechanoenergetics (39). Whether these factors are primary defects contributing to the development and progression of the heart failure phenotype or whether they are adaptive responses to more fundamental abnormalities remains unclear. Moreover, data regarding the temporal relationship of these derangements to overt ventricular mechanical dysfunction are few, although such information can yield important mechanistic insights.

In the canine model, the pressure-volume (P-V) plane provides a comprehensive assessment of LV inotropic and energetic reserve while maintaining an intact physiological state. Specifically, the end-systolic pressure-volume relation (ESPVR) and other related derived mechanical constructs are convenient windows on LV contractile performance (10, 22, 32). Additionally, steady-state increases in either preload (21, 38) or afterload (8) increase LV volume and induce concomitant increases in LV contractility. This phenomenon is postulated to be a manifestation of length-dependent activation (8, 21, 38), a primary determinant of the Frank-Starling mechanism (5). Finally, simultaneous measurement of myocardial O2 consumption (MVO2) and LV pressure-volume area (PVA) provides an assessment of contractile efficiency and MVO2 for nonmechanical processes (26, 29, 36).

Accordingly, the purpose of this investigation was to examine the following parameters before and after a 24-h period of rapid ventricular pacing (RVP) in the intact dog: 1) the LV inotropic response to steady-state changes in afterload and 2) LV mechanoenergetic performance. The central hypothesis was that alterations in these fundamental mechanical parameters would manifest even at this early time point in the development of pacing-tachycardia cardiomyopathy before the establishment of overt heart failure, suggesting, at the chamber level, a central mechanistic role for these factors in the progression of the heart failure phenotype.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Surgical instrumentation. All animal studies were performed in accordance with the National Research Council's Guide for the Care and Use of Laboratory Animals (Revised 1996). Under 1-2% isoflurane general anesthesia, six mongrel dogs of either sex underwent left thoracotomy and surgical instrumentation for long-term monitoring as previously described (29, 30). The instrumentation consisted of 1) fluid-filled catheters in the descending aorta, left atrium (LA), and LV apex; 2) a high-fidelity micromanometer (Konigsberg Instruments) in the LV apex; 3) three sets of piezoelectric crystals (5-mm diameter, 5-MHz frequency) along the anterior-posterior (DAP), septal-lateral (DSL), and long-axis endocardial diameters (DLA); 4) pacing wires sutured to the LA and LV epicardium; 5) balloon occluder cuffs around the inferior vena cavae; and 6) Doppler flow probes (Division of Cardiovascular Sciences, Baylor College of Medicine, Houston, TX), 2.0-3.5 mm in size, around the proximal left circumflex (LCX) and left anterior descending (LAD) arteries. The animals recovered a minimum of 2 wk before experimentation.

Experimental protocol. On the day of the experiment, the dogs were anesthetized with a combination of thiopental sodium (25-30 mg/kg), droperidol (1.5-3.0 mg/kg), and fentanyl (0.03-0.06 mg/kg) and were mechanically ventilated with 100% O2. An external jugular venotomy was performed using sterile technique. Under fluoroscopic guidance, a modified multipurpose coronary catheter was placed via the jugular vein into the coronary sinus (CS). Heparin (5,000 units) was given systemically to minimize thrombus formation, and the catheter was flushed with heparinized saline at regular intervals. The following parameters were recorded on an eight-channel forced-ink oscillograph (Beckman Instruments) and simultaneously digitized at a sampling rate of 500 Hz: LV pressure (P), the first derivative of LVP (dP/dt), an electrocardiogram (ECG), LCX and LAD coronary flow, and the three LV dimensions. Hemodynamic data were collected during 10-s periods of apnea (to avoid respiratory effects on measured parameters) during two general conditions: steady state and caval occlusion. Arterial and CS blood sampling to determine O2 saturation were performed immediately before each steady-state run during normal mechanical ventilation. O2 saturation was measured using either a StatPal analysis system (SenDx Medical) or an AVOXimeter 1000E (A-VOX Systems).

After baseline hemodynamics and blood O2 saturations were measured, intravenous atropine (2 mg) and hexamethonium (20-25 mg/kg) were administered to produce autonomic blockade and minimize reflex effects. After a 15-min stabilization period, data were collected at steady state and during rapid caval occlusion to produce variably loaded beats and define the ESPVR. LV afterload was then increased incrementally by graded infusions of phenylephrine (dose range 1-4 µg · kg-1 · min-1) in three to four steps. After 10 min of stabilization at each dose, steady-state and caval occlusion measurements were repeated. Phenylephrine was subsequently discontinued, and data were reacquired after 15 min of stabilization. The oximetric catheter was then removed, the venotomy was repaired, and the skin was closed using surgical staples.

After animals had at least 2 days of recovery from the initial experiments, RVP was instituted at a heart rate of 210 beats/min for 24 h using customized pacemakers described previously (9). The pacemaker was then turned off for at least 30 min, and the entire experimental protocol was repeated. After this second set of experiments was completed, the animals were killed by lethal KCl injection following deep anesthesia with pentobarbital (50 mg/kg). The heart and great vessels were removed en bloc. The LCX and LAD were cannulated and injected distal to the flow probe with indocyanine green. The left and right ventricles were dissected and weighed individually. The stained LV myocardium, delineating the perfused LCX and LAD territories corresponding to measured flow, and unstained LV myocardium were weighed separately.

Data analysis. The digitized data were analyzed using custom-developed computer software. Calculated dP/dt (mmHg/s) was derived from instantaneous LVP using a running five-point Lagrangian fit. The mean velocity of circumferential fiber shortening (VCF, circumferences/s) was defined as the systolic excursion of DAP (mm) divided by the ejection time (s), normalized for end-diastolic DAP (24). LV volume (V, ml) was calculated from the three orthogonal diameters using the equation for an ellipse
V = (&pgr;/6) ⋅ <IT>D</IT><SUB>AP</SUB> ⋅ <IT>D</IT><SUB>SL</SUB> ⋅ <IT>D</IT><SUB>LA</SUB>
End diastole was defined as occurring at the peak of the QRS complex and end systole at the upper left corner of the LV P-V loop. The ESPVR was determined using least-squares linear regression (20). The data were fit to the equation
ESP = <IT>E</IT><SUB>es</SUB> (ESV − V<SUB>0</SUB>)
where Ees (mmHg/ml) is the slope and V0 (ml) is the volume-axis intercept. V100 (ml) was defined as the ESV derived at an ESP of 100 mmHg to allow for comparisons between animals without excessive extrapolation in the P-V plane. Instantaneous circumferential force (F, in g) was determined from the method of Suga and Sagawa (37) using the equation F = 1.64 · P · (V)2/3, and end-systolic force (ESF) was used as an additional index of afterload.

Stroke work (SW, mmHg · ml) was defined as the area bound by the P-V loop. The SW-end-diastolic volume (EDV) and maximum dP/dt (dP/dtmax)-EDV relations were also determined using linear least-squares regression. The SW-EDV data were fit to the equation
SW = M<SUB>W</SUB>(EDV − V<SUB>W</SUB>)
where MW (mmHg) is the slope and VW (ml) is the volume-axis intercept (10). The dP/dtmax-EDV data were fit to the equation
dP/d<IT>t</IT><SUB>max</SUB> = d<IT>E</IT>/d<IT>t</IT><SUB>max</SUB>(EDV − V<SUB>D</SUB>)
where dE/dtmax (mmHg · ml-1 · s-1) is the slope and VD (ml) is the volume-axis intercept (22). VW 1,000 (ml) and VD 2,000 (ml) were defined as EDV derived at an SW of 1,000 mmHg · ml and a dP/dtmax of 2,000 mmHg/s, respectively, again to allow for comparisons in the physiological range.

Isovolumic relaxation was defined as occurring between the time of peak negative dP/dt to the time when LVP fell to 5 mmHg above the end-diastolic pressure (EDP) for that beat. The time constant of LV relaxation (tau ) was determined by nonlinear regression analysis of the pressure and time data during isovolumic relaxation using the equation
LVP = (P<SUB>0</SUB> − P<SUB>B</SUB>) ⋅ exp (−<IT>t</IT>/&tgr;) + P<SUB>B</SUB>
where P0 (mmHg) is an estimate of LVP at peak negative dP/dt, t is time (ms), tau  is the time constant of relaxation (ms), and PB (mmHg) is the floating pressure asymptote as t approaches infinity (28).

The PVA (mmHg · ml), or total ventricular mechanical energy, was defined as the area bound by the ESPVR, the systolic segment of the P-V loop, and the EDPVR (36). Because steady-state changes in afterload shift the ESPVR relation to the left (8), P-V loops obtained during steady-state runs at different afterloads were not used to determine PVA. Instead, the PVA of the steady-state P-V loop was determined by matching the steady-state loop to a nearly identical loop obtained during each corresponding caval occlusion run, as described by Nozawa et al. (26). Generally, such a beat occurred within the first four beats of caval occlusion.

The AVO2 difference (ml O2/ml blood) representing the difference between arterial (SaO2) and CS O2 saturation content (SCSO2) was calculated from the respective steady-state O2 saturations using the formula
AVO<SUB>2</SUB> difference = 1.36 ⋅ Hb ⋅ (Sa<SUB>O<SUB>2</SUB></SUB> − S<SC>cs</SC><SUB>O<SUB>2</SUB></SUB>) ⋅ 10<SUP>−2</SUP>
MVO2 (ml O2/beat) was calculated using the Fick principle (11) as follows
M<A><AC>V</AC><AC>˙</AC></A><SC>o</SC><SUB>2</SUB> = CF<SUB>avg</SUB> ⋅ AVO<SUB>2</SUB> difference ⋅ HR<SUP>−1</SUP>
where CFavg is the average coronary flow to the LV (ml blood/min) and HR is heart rate (beats/min). The MVO2-PVA relation was described by its slope and MVO2 intercept, representing the contractile efficiency and load-independent MVO2, respectively (36). To allow comparison between animals, MVO2 and PVA were normalized per 100 g of LV and converted to joules (J) using standard conversion factors (1 mmHg · ml = 0.000133 J, and 1 ml O2 consumed = 20 J). After conversion to joules, the slope was rendered dimensionless and the MVO2 intercept was expressed as joules per beat per 100 g of LV. Contractile efficiency (%) was expressed as 1 divided by (slope × 100).

Statistical analysis. Comparisons of mechanical and energetic parameters before and after RVP were made using the paired t-test. Comparisons of mechanical parameters at low and high afterload were also made using the paired t-test. A P value <0.05 was considered significant. All group data are expressed as means ± SE.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Effect of short-term RVP on steady-state LV mechanical parameters. Analog tracings recorded before autonomic blockade from a representative animal before and after 24 h of RVP are shown in Fig. 1. Note the modest reductions in the end-diastolic DAP, DSL, and DLA after RVP. Table 1 summarizes mechanical data for the group at control and after 24 h of RVP, measured before autonomic blockade. Short-term tachycardia pacing (tachypacing) resulted in significant reductions in dP/dtmax (P = 0.004), SW (P = 0.005), and LVEDV (P = 0.02) but no significant changes in HR, LVEDP, LVESP, LVESV, LVESF, VCF, or tau . Table 2 shows parameters of LV performance derived from P-V plane analysis after autonomic blockade before and after RVP. There were no significant differences in the slopes (Ees, MW, dE/dtmax) or the relative positions at physiological ranges (V100, VW 1,000, VD 2,000) of either the ESPVR, SW-EDV, or dP/dtmax-EDV relations, indicating no change in LV contractile performance after 24 h of tachypacing. For further confirmation, dP/dtmax was also calculated from each dP/dtmax-EDV relation before and after RVP at a matched EDV, defined as the baseline EDV in the control state for each animal. As shown in Table 2, there was no significant difference in dP/dtmax at matched EDV. Figure 2 shows a composite EDPVR for the group (after autonomic blockade) before and after RVP. Tachypacing resulted in a modest leftward and upward shift of the EDPVR, indicating reduced passive chamber compliance. Thus, after 24 h of RVP, the LV operated at a lower EDV or preload, with proportionate reductions in SW and dP/dtmax. There was no significant reduction in baseline LV contractile function or relaxation, although the LV diastolic chamber compliance was decreased.


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  		Fig. 1.   Analog tracings from a representative animal showing steady-state measurements before (control) and after 24 h of rapid ventricular pacing (RVP). Note that after RVP there were modest reductions in end-diastolic anterior-posterior (AP), septal-lateral (SL), and long-axis (LA) diameters as well as in maximal value of first derivative of left ventricular (LV) pressure (dP/dt). ECG, electrocardiogram; LCX, left circumflex artery; LAD, left anterior descending artery.


                              
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  		Table 1.   Baseline mechanical parameters before and after 24 h of RVP


                              
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  		Table 2.   Effect of 24 h of RVP on derived parameters of LV performance



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  		Fig. 2.   Composite LV end-diastolic pressure-volume relation after autonomic blockade for group before (control) and after 24 h of RVP. After RVP there was a leftward and upward shift of this relation, indicating reduced LV diastolic chamber compliance. All data points are expressed as means ± SE.

Effect of short-term RVP on afterload-induced enhancement of LV performance. Figure 3 shows the effect of increased afterload on the ESPVR in a representative animal before (Fig. 3A) and after (Fig. 3B) short-term RVP. The increases in LVESP (51-mmHg increase at control, 56-mmHg increase after RVP) and LVESF (925-g increase at control, 1,099-g increase after RVP) produced under each experimental condition were comparable. Under control conditions, increased afterload shifted the ESPVR to the left (V100 decreasing from 28.2 to 23.7 ml), indicating improved LV performance without a significant change in the slope (Ees). After pacing, the slope and volume intercept of the ESPVR at baseline were similar to control. However, with equivalent increases in afterload, the leftward shift of the ESPVR was less pronounced (V100 decreasing from 25.9 to 23.3 ml) and was associated with a mild reduction in slope (Ees decreasing from 8.7 to 7.1 mmHg/ml), indicating attenuated load-induced enhancement of LV performance compared with control. Table 3 shows group data for afterload-induced alterations in LV performance before and after pacing. Data from low and high load are presented along with percent change in V100 with high afterload for each condition. Under control conditions, increased afterload was associated with maintenance of Ees with a significant shift of the ESPVR to the left (V100, P = 0.006). After pacing, increased afterload was associated with reduced Ees (P = 0.03). Also, a significant leftward shift of the ESPVR was still present (V100, P = 0.009) but was much less pronounced compared with control (Delta V100 pacing vs. control, P = 0.04). The increase in afterload was comparable for both conditions (Delta LVESP and Delta LVESF pacing vs. control, P = not significant). Thus, after 24 h of RVP, afterload-induced enhancement of LV performance was significantly attenuated.


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  		Fig. 3.   End-systolic pressure-volume (ESPVRs) relations from a representative animal showing response to steady-state changes in afterload at baseline (A) and response after 24 h of RVP (B). Also delineated in each panel is V100, the ESV corresponding to an ESP of 100 mmHg. A: at baseline, increased afterload resulted in a leftward shift of ESPVR with V100 decreasing from 28.2 to 23.7 ml, indicating improved LV performance without a significant change in end-systolic elastance (Ees, slope of ESPVR). B: with equivalent increases in afterload after pacing, leftward shift of ESPVR was less pronounced (V100 decreased from 25.9 to 23.3 ml) and was associated with a reduction in Ees from 8.7 to 7.1 mmHg/ml, indicating attenuated load-induced enhancement of LV performance compared with control.


                              
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  		Table 3.   Effect of 24 h of RVP on afterload-induced enhancement of LV performance

Effect of short-term RVP on LV mechanoenergetics. As shown in Table 4, short-term RVP resulted in a significant reduction of total LV coronary blood flow (P = 0.03) but no change in SCSO2 saturation or baseline MVO2. Figure 4 shows the relationship between MVO2 and PVA before and after RVP from a representative animal. Under both conditions, the relationship was highly linear with correlation coefficients of 0.962 and 0.952 before and after RVP, respectively. In this animal, pacing resulted in an increase in the MVO2-axis intercept with little change in slope, indicating increased O2 consumption for nonmechanical processes with maintenance of contractile efficiency. Table 4 shows group data for variables from the MVO2-PVA relations determined in each animal. Under control conditions, contractile efficiency was 41.6 ± 4.3% for the group. After pacing, there was a significant increase in the MVO2-axis intercept (P = 0.044) but no significant change in contractile efficiency. Thus 24 h of tachypacing resulted in increased load-independent MVO2 but no change in the efficiency of conversion of consumed O2 to mechanical work.

                              
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  		Table 4.   Effect of 24 h of RVP on LV mechanoenergetics



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  		Fig. 4.   Myocardial O2 consumption-pressure-volume area (MVO2-PVA) relations from a representative animal at baseline (control) and after 24 h of RVP. RVP resulted in an increased MVO2-axis intercept, indicating increased O2 consumption for nonmechanical processes and minimal change in slope, consistent with maintenance of contractile efficiency.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Our study shows for the first time that despite unchanged baseline LV contractile and relaxation indexes, short-term tachypacing results in 1) attenuation of afterload-induced increases in LV performance and 2) increased MVO2 for nonmechanical processes but with maintenance of contractile efficiency. The findings suggest that these defects and their underlying cellular determinants, rather than being adaptive mechanisms, are primary abnormalities involved in the development and progression of the heart failure phenotype at the chamber level.

Mechanical effects of short-term tachypacing. Numerous prior investigations have demonstrated that 3-5 wk of tachypacing reliably produces LV dilatation, depressed contractility, and slowed relaxation (17-19, 30, 35, 39). In contrast, as shown in Tables 1 and 2, 24 h of RVP resulted in reduced dP/dtmax and SW in association with reduced preload (LVEDV) and no change in LV relaxation or filling pressure. Surprisingly, on examination of LV contractile performance in the P-V plane (Table 2), no significant differences were seen in slopes or relative positions of the ESPVR, SW-EDV, and dP/dtmax-EDV relations, suggesting that baseline LV contractility was not reduced. Indeed, both VCF, which is preload independent (24), and dP/dtmax adjusted for EDV did not change after short-term RVP (Tables 1 and 2).

Prior studies examining LV function after brief (24-48 h) rapid pacing are few (17, 19, 34). In contrast to our data, these studies reported depression of LV systolic function and relaxation and no change in LV size. The reasons for these discrepancies are not fully clear but may be related to differences in experimental design. First, we used rapid tachypacing of the LV, whereas previous studies used the RV as the pacing site. Although speculative, it is possible that differences in pacing site during the production of tachycardia heart failure may have divergent effects on early ventricular remodeling. Indeed, in our study the EDPVR was consistently shifted upward and to the left, indicating decreased chamber compliance (Fig. 2), whereas studies using RV pacing showed no change (34). Second, to allow sequential catheterization of the CS, the animals in our study were studied under anesthesia and mechanical ventilation. Also, LV performance was evaluated after autonomic blockade to obviate reflex effects. Although these manipulations allowed for careful control of loading conditions and autonomic tone, they may also have contributed to the divergence of our results with prior studies, especially because neural sympathetic tone and plasma norepinephrine are already significantly increased by 1 day of rapid pacing (17).

Alterations of afterload-induced enhancement of LV performance with short-term tachypacing. The Frank-Starling mechanism describes the increase in myocardial contractile force resulting from an increase in initial muscle length or preload. An important determinant of this relationship is length-dependent activation of the contractile elements (1, 5). Several underlying mechanisms for length-dependent activation have been proposed, including stretch-induced increases in myofilament and troponin C Ca2+ sensitivity (1, 5), length-dependent increases in intracellular Ca2+ transients (2, 5), and alterations of stretch-activated ion channels (5). In isolated cardiac muscle preparations, this phenomenon manifests as a significantly steeper steady-state tension-length relation compared with the instantaneous tension-length relation such that abrupt increases in initial muscle length produce an immediate increase in peak tension followed by a delayed further increase in peak tension over several minutes (2). Analogous to cardiac muscle preparations, steady-state increases in either preload or afterload in the intact LV result in improved performance manifested by increased LVESP at any given end-systolic diameter or volume, i.e., a leftward shift of the ESPVR (8, 21, 38). The time course of this shift (~10 min) is similar to the time course of length-dependent activation in isolated cardiac muscle and thus is thought to be a manifestation of this phenomenon in the intact LV.

As shown in Fig. 3 and Table 3, under control conditions, acute increases in afterload produced a significant leftward shift of the ESPVR with maintenance of Ees, indicating improved LV performance and confirming prior studies from this laboratory (8). After short-term RVP, however, similar increases in load produced a much smaller leftward shift and decreased Ees, indicating significant attenuation of afterload-induced enhancement of LV performance and reduced inotropic reserve. These results suggest that length-dependent activation is reduced after short-term RVP and may afford one mechanism by which the Frank-Starling effect is altered in the failing heart in vivo. Indeed, in dogs with pacing-tachycardia heart failure, Komamura et al. (18) demonstrated that the failing LV is unable to increase stroke volume in response to an acute volume load. Similarly, the failing human heart is less able to recruit the Frank-Starling mechanism in the face of increased afterload (31).

In vitro studies, however, have yielded conflicting results as to the status of the Frank-Starling mechanism in the failing heart. Schwinger et al. (33) reported that isolated papillary muscle strips from terminally failing human hearts were unable to use the Frank-Starling mechanism because of a failure of length-dependent activation. This finding was attributed to increased myofilament Ca2+ sensitivity in failing versus nonfailing myocardium that did not increase further with stretch. Wolff et al. (40) also reported increased myofilament Ca2+ sensitivity in canine pacing-tachycardia heart failure. In contrast, other studies have reported that the Frank-Starling mechanism, although possibly attenuated, is preserved in both human (15) and experimental (7) heart failure and that myofilament Ca2+ sensitivity is unchanged (12). As pointed out by de Tombe (6), these discrepancies may be secondary to experimental conditions and technical considerations in isolated muscle preparations, especially the level of phosphorylation of contractile proteins during the studies. Furthermore, the functional significance of reported changes is not entirely clear as most studies have been performed after the establishment of an advanced or end-stage heart failure phenotype, which limits insights into the causal mechanisms underlying its development. In our study, using an animal model that reproducibly produces heart failure over a well-defined time period, we have demonstrated reduced inotropic reserve in the face of increased afterload before overt mechanical dysfunction or LV dilatation. This suggests that alteration of length-dependent activation is a fundamental defect in the development and progression of the heart failure phenotype in vivo.

Alterations of LV mechanoenergetics with short-term tachypacing. Mechanoenergetic performance of the LV can be assessed using the relationship between MVO2 and PVA (26, 29, 36). The MVO2 intercept of this relation represents MVO2 for nonmechanical processes (unloaded MVO2), consisting primarily of energy requirements for excitation-contraction (EC) coupling and basal metabolism. The inverse of the slope of the relation reflects the efficiency of chemomechanical energy transduction of the myofilaments (contractile efficiency). As shown in Fig. 4 and Table 4, short-term RVP resulted in increased unloaded MVO2 and unchanged contractile efficiency. Tachycardia is associated with increased transsarcolemmal Ca2+ flux resulting from increased magnitude and slower inactivation of inward Ca2+ current (27) as well as increased intracellular Na+ activity favoring Ca2+ influx via Na+/Ca2+ exchange (4). This results in increased peak systolic and end-diastolic Ca2+ (14), increased sarcoplasmic reticulum (SR) Ca2+ loading (3), and increased SR Ca2+ available for myofilament activation. As detailed by Suga (36), interventions that increase myofilament Ca2+ delivery also increase MVO2 requirements for EC coupling. Additionally, because basal metabolic MVO2 is thought to primarily reflect energy requirements for maintenance of the intracellular ionic environment and cellular structures (36), the marked increase in intracellular Na+ with tachycardia (4) would also be expected to increase energy requirements for the Na+-K+ pump needed to maintain intracellular Na+ concentration. Thus the increase in unloaded MVO2 after short-term RVP is likely secondary to increased energy requirements for both EC coupling and basal metabolism.

Contractile efficiency represents the product of the metabolic efficiency of O2 conversion to ATP and the efficiency of cross-bridge cycling (36). Because contractile efficiency was unchanged after short-term RVP, this may represent no change or reciprocal changes in either of these components. Although failing myocardium does display increased glycolytic metabolism compared with normal myocardium (25), this shift from normal aerobic metabolism is modest and without significant quantitative change in the efficiency of conversion of O2 to ATP (13, 16). These studies argue against a prominent role for alterations in the overall efficiency of energy metabolism in heart failure, and the unchanged contractile efficiency in our study probably represents maintained efficiency of both ATP synthesis and cross-bridge cycling.

Isolated heart studies in both the canine tachycardia heart failure model (39) and a rat heart failure model (16) have revealed that in established heart failure there is improved contractile efficiency, probably representing depressed cross-bridge cycling and reduced energy requirements for cross bridge-level events, and no change in unloaded MVO2. Because failing myocardium has deficient energy reserves (25), increased contractile efficiency was postulated to be a beneficial adaptation to limited energy supply and increased stress (16, 39). Additionally, although unloaded MVO2 was unchanged, given that unloaded MVO2 is positively correlated with contractile state, it was still increased relative to the depressed contractility of the failing heart (39). Our data indicate that increased O2 consumption for nonmechanical processes occurs early in the development of heart failure before overt mechanical dysfunction, suggesting that O2 wasting is a primary defect contributing to the reduced energy reserves seen in advanced disease. Conversely, the absence of early changes in contractile efficiency would support the hypothesis that improved efficiency in advanced heart failure is a compensatory adaptation to reduced energy reserves.

Study limitations. First, in a prior study examining LV mechanoenergetics in the intact animal, we used transient changes in loading conditions to define the MVO2-PVA relation on a beat-by-beat basis (29). More recently, Nozawa et al. (26) demonstrated that the MVO2-PVA relation in intact dogs determined during transient load alterations was less linear and not coincident with the relation determined during steady-state load changes. In view of these results, we chose to use the steady-state method in this study. Using this protocol, we calculated an overall efficiency of 41.6% at baseline, well within the wide range of efficiencies (23-50%) reported by others (16, 26, 36, 39). Second, it was not always possible to place the LAD flow probe proximal to the first septal perforator branch. Thus we assumed that coronary flow was proportional per unit mass throughout the LV (26, 29) both before and after short-term RVP. This assumption is reasonable given that chronic pacing has not been shown to result in significant regional alterations in blood flow, ischemia, or LV hypertrophy (34). Finally, as in many prior studies, our analysis assumes linearity of the ESPVR. In the intact canine model, Little et al. (23) showed that although a slight but consistent curvilinearity of the ESPVR exists regardless of inotropic state, this degree of nonlinearity does not prevent the relation from being well approximated by a straight line. In our study, the linear regression correlation coefficients were high, and it is doubtful that a significant quantitative error resulted. Consistent with this, Nozawa et al. (26) demonstrated that the MVO2-PVA relation is the same whether the ESPVR is assumed to be linear or nonlinear.

In summary, we have demonstrated that a short-term, 24-h period of RVP in the intact dog results in attenuation of afterload-induced enhancement of LV performance and alterations of mechanoenergetics consisting of increased energy consumption for nonmechanical processes but maintenance of contractile efficiency. This suggests that early in the development of tachycardia heart failure, before the appearance of ventricular dilatation and overt mechanical dysfunction, there is blunting of length-dependent activation and increased O2 wasting in the processes of EC coupling, basal metabolism, or both. These defects may contribute to attenuation of the Frank-Starling mechanism in vivo and reduction in myocardial energy reserves seen in advanced disease. Given their manifestation in the early formative stages of cardiomyopathy, rather than being adaptive mechanisms, these abnormalities may be primary defects involved in the progression of the heart failure phenotype.


    ACKNOWLEDGEMENTS

We gratefully acknowledge the excellent technical assistance of Danny Escobedo and Cindy Ramirez.


    FOOTNOTES

This work was supported by a Grant-in-Aid from the American Heart Association, the Research Service of the Department of Veterans Affairs, a grant from the South Texas Health Research Center, and a grant from the San Antonio Area Foundation. S. Prabhu is an Established Investigator of the American Heart Association.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Address for reprint requests and other correspondence: S. D. Prabhu, Division of Cardiology, Univ. of Louisville, ACB, 3rd Flr., 550 S. Jackson St., Louisville, KY 40292.

Received 19 May 1999; accepted in final form 23 August 1999.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Heart Circ Physiol 278(3):H698-H705
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