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Am J Physiol Heart Circ Physiol 294: H481-H489, 2008. First published November 16, 2007; doi:10.1152/ajpheart.00962.2006
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Aortic wave intensity analysis of ventricular-vascular interaction during incremental dobutamine infusion in adult sheep

Daniel J. Penny,1,2,3 Jonathan P. Mynard,1 and Joseph J. Smolich1,2

1Australia and New Zealand Children's Heart Research Center, Murdoch Children's Research Institute, 2Institute of Reproduction and Development, Monash University, and 3Department of Cardiology, Royal Children's Hospital, Melbourne, Australia

Submitted 5 September 2006 ; accepted in final form 16 November 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
This study undertook a detailed examination of the ventricular-vascular interaction of the predominant β-adrenergic agonist dobutamine using wave intensity analysis. Eight anesthetized open-chest ewes were instrumented with an aortic micromanometer to measure central aortic blood pressure (P) and an ultrasonic flow probe to obtain ascending aortic blood velocity (U). Hemodynamics were recorded during incremental dobutamine infusion (0.5, 1, 2.5, 5, 7.5, and 10 µg·kg–1·min–1). Wave intensity (dIW) was calculated as the product of the rates of change of P and U with customized software using ensemble-averaged signals. Forward and backward components of dIW, P, and U were determined after calculation of wave speed. As well as the typical initial forward compression wave (FCW), midsystolic backward compression wave (BCW), and late-systolic forward expansion wave (FEWes), two minor and previously unheralded waves were also detectable in the wave intensity profile at baseline. The first was an early systolic backward expansion wave (BEW), which reduced P but increased peak U. The second was a mid-systolic forward expansion wave (FEWms), which reduced P and U. During dobutamine infusion FCW dIW increased 18-fold (P < 0.001), but BCW dIW rose 12-fold (P < 0.001) while FEWes dIW fell by 70% (P < 0.001). However, the latter changes were accompanied by a 44-fold increase in BEW dIW (P = 0.005) that augmented the initial aortic forward flow and a >100-fold rise in FEWms dIW (P < 0.001) that produced earlier and enhanced aortic blood deceleration. These findings provide new insights into the ventricular-vascular interaction of dobutamine.

hemodynamics; wave propagation; arterial circulation; blood velocity

DOBUTAMINE, A CATECHOLAMINE with predominant β-adrenoceptor activity, is widely used in clinical practice to improve cardiovascular performance (32). Dobutamine not only has inotropic effects that increase the briskness, force, and degree of left ventricular (LV) myocardial contraction (35) and the extent of LV torsion (9, 24, 33) but also lusitropic actions that augment LV myocardial relaxation processes (15), including the restoring forces that promote chamber untwisting (24, 33). In addition, dobutamine has vasodilator actions that serve to facilitate systemic perfusion (1, 35). Because dobutamine has both ventricular and vascular effects, knowledge about the interaction of these effects during LV ejection is integral to understanding the cardiovascular actions of this agent. However, although aspects of the ventricular-vascular interaction of dobutamine have been analyzed using the pressure-volume framework (8, 20) and spectral analysis (2), neither of these approaches provides temporal or quantitative information about the specific components that contribute to this interaction.

One potential means of gaining greater insight into the ventricular-vascular interaction of dobutamine is the relatively new method of wave intensity analysis (WIA) (3). The basis of this approach, which is founded on a treatment of the basic equations for fluid flow using the method of characteristics without assumptions about periodicity or linearity, is that the cardiac cycle is associated with the propagation of infinitesimal wavefronts defined by changes in pressure (P) and velocity (U) (27). Time domain analysis of P and U waveforms enables calculation of the product of changes in P and U, termed the "wave intensity," which represents the instantaneous energy carried by the wavefront (17, 43). WIA can distinguish between "forward-running" waves arising from the heart and "backward-running" waves propagating from the vasculature, as well as between "compression" waves which increase pressure and "expansion" waves that decrease pressure (3). Moreover, calculation of wave speed permits the separation of total wave intensity into the four potential wave types that may simultaneously exist in an overall profile, namely "forward compression waves" that increase pressure and velocity, "forward expansion waves" that decrease pressure and velocity, "backward compression waves" that increase pressure but decrease velocity, and "backward expansion waves" that decrease pressure but increase velocity (3, 17).

In the resting state, WIA in the ascending aorta typically reveals an early systolic forward compression wave associated with the initial impulsive ejection of blood from the LV in the aorta a midsystolic, reflected backward compression wave of variable magnitude that augments aortic pressure and opposes forward flow and a late-systolic forward expansion wave that decelerates aortic flow and reduces aortic blood pressure just before aortic valve closure (13, 16, 17, 19). Because dobutamine enhances LV contraction (8, 14, 30, 35) and relaxation processes (15, 33), and reduces vascular wave reflection (2), it might be expected that this agent would increase forward compression and expansion wave intensities but decrease backward compression wave intensity. However, the sole study of the actions of dobutamine using WIA, which was confined to an evaluation of total intensity at a single infusion rate, observed an increase in forward compression wave intensity but no change in the amplitude of other waves (13).

Accordingly, the aim of this study, performed in anesthetized, open-chest adult sheep, was to undertake a detailed examination of the ventricular-vascular interaction of dobutamine with WIA, incorporating separation of total intensity into forward and backward components and measurement of responses over a range of incremental infusion rates. As expected, dobutamine increased forward compression wave intensity but, contrary to expectation, midsystolic backward compression wave intensity also increased while late-systolic forward expansion wave intensity fell. However, these changes were accompanied by increasing prominence of two previously unheralded waves in the ascending aortic WIA, namely an early systolic backward expansion wave that augmented aortic forward flow and a midsystolic forward expansion wave that produced earlier and enhanced aortic blood deceleration.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Experiments were approved by the institutional Animal Ethics Committee and conformed to guidelines of the National Health and Medical Council of Australia.

Acute surgical preparation. The surgical preparation was similar to that previously described (30, 31). In brief, eight Border-Leicester cross ewes weighing 46.4 ± 3.2 kg (mean ± SD) were anesthetized with 5 mg/kg im ketamine and 0.1 mg/kg im xylazine followed by 25–50 mg/kg iv {alpha}-chloralose. Anesthesia was maintained with intravenous {alpha}-chloralose infused at a rate of 12–25 mg·kg–1·h–1. Animals were intubated and ventilated with oxygen-enriched air using a large animal respirator (model 607; Harvard Apparatus, Dover, MA). On the basis of frequent blood gas analysis, ventilation was adjusted to maintain arterial O2 tension at 100–120 mmHg and arterial CO2 tension at 35–40 mmHg, whereas base deficits were corrected with sodium bicarbonate as required. Body temperature was maintained at 39–40°C with a heating pad and towel covering.

The neck was incised in the midline, and polyvinyl catheters were advanced through the left external jugular vein to the superior vena cava for fluid and drug infusion. A 5-Fr. micromanometer-tipped catheter (MPC-500; Millar Instruments, Houston, TX) was inserted in the right common carotid artery, and its tip was advanced in the ascending aorta. A left thoracotomy was performed in the fourth intercostal space, and a Teflon cannula was inserted through a purse-string suture in the aortic arch and connected to polyvinyl tubing. After incision of the pericardium over the pulmonary trunk and left atrium, a 20- to 24-mm ultrasonic flow probe (Transonics Systems, Ithaca, NY) was placed around the ascending aorta. A second 5-Fr. micromanometer-tipped catheter (MPC-500; Millar Instruments) was inserted through the roof of the left atrium and passed across the mitral valve into the LV cavity. The edges of the pericardial incision were then loosely reapproximated with a continuous suture.

Experimental protocol. Hemodynamics were allowed to stabilize for {approx}15 min after completion of surgery. Subsequently, baseline hemodynamic variables were recorded, and dobutamine (David Bull, Victoria, Australia) was then infused continuously in the superior vena cava in incremental steps of 0.5, 1, 2.5, 5, 7.5 and 10 µg·kg–1·min–1 using a roller pump (model MS 4-Reglo; Ismatec, Zürich, Switzerland). After steady-state conditions had been attained 5–10 min into each dobutamine dose, hemodynamic measurements were repeated, and the dobutamine infusion was increased to the next dose. At the end of the experiment, the animal was killed with an overdose of pentobarbitone sodium.

Physiological variables. Aortic blood pressure was measured through the fluid-filled catheter with a silicon chip pressure transducer (CDX-111; COBE Laboratories, Lakewood, CO) that was referenced to atmospheric pressure at the level of the midthoracic vertebral spines and calibrated against a manometer before each experiment. High-fidelity aortic and LV pressures were measured by interfacing micromanometers with transducer control units (TCB-500; Millar Instruments). Ascending aortic flow was measured with an ultrasonic flowmeter (model T206; Transonic Systems). Flow and pressure signals were amplified using an eight-channel programmable signal conditioner (Cyberamp 380; Axon Instruments, Foster City, CA) and displayed continuously on a direct-writing recorder (Neotrace 800Z; Neomedix Systems, New South Wales, Australia). All phasic physiological signals were digitized at a sampling rate of 500 Hz for 20 s, and data were stored on computer for later off-line analysis using commercially available programmable software (Spike2, Cambridge Electronic Design, Cambridge, UK). No filtering was employed during acquisition or analysis of high-fidelity pressure or flow data, apart from application of a 48-Hz low-pass filter at the time of analysis to remove high-frequency electrical interference from signals. Changes in LV contractility were assessed by calculating the rate of change of LV pressure with a running three-point linear differentiation algorithm and measuring its maximal positive value (dP/dtMAX).

Wave intensity analysis. Because WIA is undertaken in the pressure-velocity domain, ascending aortic blood flow values were converted to U using aortic cross-sectional area derived from the nominal size of the flow probe (10, 11, 40). After generation of an ensemble average of the high-fidelity aortic P and U signals, the rates of change of aortic blood pressure (dP/dt) and velocity (dU/dt), as well as the product of these differentials, wave intensity (dIW), were derived. Note that this calculation yields a "time-corrected" dIW (i.e., dP/dt·dU/dt) that is independent of the digitizing sample rate (6, 13, 34), which contrasts with wave intensity defined by absolute changes in P and U between samples (i.e., dP·dU) used in a number of previous reports (10, 11, 16, 17, 19, 27, 38, 40, 43). However, the latter can be derived from time-corrected wave dIW by dividing by the square of the sampling frequency (19).

To separate P, U, and dIW into their forward and backward components, wave speed was obtained by derivation of dP/dU and subsequent use of the relation {rho}c = dP/dU (17), where {rho} is the density of blood (assumed to be 1,050 kg/m3) and c is the wave speed. Using ensemble-averaged P and U data, dP/dU was calculated with least-squares linear regression from the slope of the P-U relation during early systole, when the contribution of backward-running waves is minimal (17, 18). Hardware-related time lags between P and U data points were corrected by aligning the peak second derivatives of these signals, resulting in a highly linear dP/dU (R2 = 0.9997 ± 0.0002). The required shift of U relative to P was unaffected by dobutamine infusion, and its magnitude (5 ± 4 ms) was close to the value of 3.5 ms reported previously for the combination of a Millar catheter-tipped micromanometer and a Transonics flow probe-flowmeter system (11).

As per convention (3), the direction of waves was referenced to the direction of blood flow, such that waves arising from the heart were defined as forward running and those arising from the vasculature as backward running. Using established methodology (6, 10, 11), the intensity of forward-running waves (dIW+) was calculated as (dP/dt + {rho}c·dU/dt)2/(4{rho}c) and that of backward-running waves (dIW–) as –(dP/dt – {rho}c·dU/dt)2/(4{rho}c). Waves causing an increase in pressure were classified as compression waves and those causing a decrease in pressure as expansion waves, and this characteristic was defined by the sign of the pressure difference across the respective forward-running wave front, given by (dP/dt)+ = 1/2(dP/dt + {rho}c·dU/dt) and the backward-running wave, given by (dP/dt)– = 1/2(dP/dt – {rho}cd·U/dt). Thus, a forward-running wave was deemed a compression wave if (dP/dt)+ was greater than zero and an expansion wave if (dP/dt)+ was less than zero. Similarly, a backward-running wave was categorized as a compression wave if (dP/dt)– was greater than zero and an expansion wave if (dP/dt)– was less than zero (10, 11).

For backward-running waves, the distance to the site of wave reflection was calculated as the product of wave speed and one-half of the time interval between the peak of the backward compression or expansion wave and the peak of the preceding forward compression wave (11). The cumulative intensity of forward-running (IW+) and backward-running waves (IW–) was calculated by integrating the respective dIW over the duration of the wave (6). In addition, because forward-running expansion and backward-running compression waves had both major and minor components, total IW for these waveforms was also calculated. The magnitude of wave reflection was obtained from the reflection coefficient, defined as the ratio of the backward-running wave IW to forward compression wave IW, with the reflection coefficient being negative if the reflected wave was an expansion wave and positive if the reflected wave was a compression wave (11).

The time interval between waves and aortic valve closure, as well as between the various peak wave intensities, was obtained from the separated WIA profiles. The point of aortic valve closure was defined as the zero crossing of the aortic dP/dt waveform after the negative peak that immediately preceded the aortic incisura.

Statistical analysis. Statistical analyses were performed using the Statistical Package for the Social Sciences Version 12.0.1 (SPSS, Chicago, IL). Physiological responses to dobutamine were evaluated using repeated-measures ANOVA, with calculation of the Greenhouse-Geisser adjustment for multisample asymmetry (21). Specific effects were evaluated by partitioning the sums of squares from the analysis of variance into individual degrees of freedom. Logarithmic transformation was performed before analysis, as required, where data had a nonnormal distribution. Relationships between variables were evaluated using least-squares regression. Results are expressed as means ± SD, and significance was taken at the P < 0.05 level.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Hemodynamic effects of dobutamine. Dobutamine administration was accompanied by no change in aortic systolic blood pressure (P =0.4), a fall in aortic diastolic blood pressure (P = 0.007), and increases in aortic pulse pressure (P < 0.001), heart rate (P < 0.001), LV dP/dtMAX (P < 0.001), and ascending aortic blood flow (P < 0.001; Table 1).


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  		Table 1. Hemodynamic variables during incremental dobutamine infusion

 
Wave intensity patterns. As in previous reports (16, 17, 19), three main waves were readily distinguishable in the separated ascending aortic dIW waveform at baseline, namely an initial forward compression wave (FCW) that increased P and U, a midsystolic backward compression wave (BCW) that increased P but reduced U, and a late-systolic forward expansion wave (FEWes) occurring just before aortic valve closure that decreased P and U. Two additional minor, but clearly discernible waves were also present. The first was a small early systolic backward expansion wave (BEW) that reduced P but increased peak U. The second was a small, midsystolic forward expansion wave (FEWms) that reduced P and U just after their peak (Fig. 1). Incremental dobutamine infusion was associated with striking and progressive changes in the morphology of all dIW waveforms, with substantial increases in the intensities of FCW, FEWms, BCW, and BEW but a reduction in the intensity of FEWes (Fig. 2).


Figure 1
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  		Fig. 1. Representative example, in descending order from top to bottom, of aortic blood pressure, aortic blood velocity, total wave intensity, forward wave intensity, and backward wave intensity at baseline. BCW, backward compression wave; BEW, backward expansion wave; FCW, forward compression wave; FEWes, late-systolic forward expansion wave; FEWms, midsystolic forward expansion wave. Note that 1) measured aortic blood pressure and velocity (heavy line) are separated into forward (medium line) and backward (stippled line) components; 2) scales differ for forward and backward wave intensities; and 3) dashed vertical lines correspond to the point of peak intensity of the various waves.

 

Figure 2
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  		Fig. 2. Representative examples, in descending order from top to bottom, of changes in aortic blood pressure, aortic blood velocity, total wave intensity, forward wave intensity, and backward wave intensity during incremental dobutamine infusion. Note that 1) measured aortic blood pressure and velocity (heavy line) have been separated into forward (medium line) and backward (stippled line) components; 2) to highlight the change in wave intensity morphology, the scale for total wave intensity has been increased during incremental dobutamine infusion; 3) scales differ for forward and backward wave intensities; 4) dashed vertical lines correspond to the point of peak intensity of the various waves; and 5) data for dobutamine infusion rates of 0.5 and 1.0 µg·kg–1·min–1 have been omitted for clarity of presentation.

 
Wave intensity analysis. Data on the effect of dobutamine on wave speed and wave intensities are presented in Table 2. The resting wave speed (2.7 ± 0.8 m/s) was initially unchanged with dobutamine infusion but increased by {approx}20% at a dobutamine infusion rate of 5 µg·kg–1·min–1 (P = 0.01) and then plateaued.


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  		Table 2. Wave intensity analysis during incremental dobutamine infusion

 
FCW peak dIW+ increased 18-fold (P < 0.001) and FCW IW+ rose 10-fold (P < 0.001) during dobutamine infusion, with both variables displaying an exponential relationship with LV dP/dtMAX (Fig. 3). By contrast, peak FEWes dIW+ and FEWes IW+ fell by {approx}70% during dobutamine infusion (P < 0.001), whereas peak FEWms dIW+ and FEWms IW+ increased >100-fold (P ≤ 0.001). However, total FEW IW+ rose sixfold between baseline and the highest dobutamine infusion rate (P = 0.001), with the contribution of FEWes IW+ decreasing from 92 ± 6 to 5 ± 4% (P < 0.001) and that of FEWms IW+ increasing from 4 ± 3 to 84 ± 12% (P < 0.001). In conjunction with these changes, an inverse relationship was evident between FEWes and FEWms IW+, as well as between FEWes and FCW IW+, but a direct relationship with a slope of 0.28 was present between FEWms and FCW IW+ (Fig. 4).


Figure 3
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  		Fig. 3. Relationships between forward compression wave peak intensity (FCW peak dIW+, A) and cumulative intensity (FCW IW+, B) and the maximal rate of rise of left ventricular pressure (LV dP/dtMAX) before and during dobutamine infusion.

 

Figure 4
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  		Fig. 4. Relationships between cumulative intensities of midsystolic (FEWms IW+) and late-systolic (FEWes IW+) forward expansion waves (A) as well as between FEWms IW+ ({circ}) and FEWes IW+ (bullet) and the cumulative intensity of the forward compression wave (FCW IW+, B).

 
Peak BCW dIW– and BCW IW– increased 12-fold and 9-fold, respectively (P ≤ 0.001), by the highest dobutamine infusion. Moreover, the contribution of BCW IW– to total backward compression wave IW– rose from 58 ± 25 to 90 ± 14% (P = 0.01) during dobutamine infusion. However, neither the BCW reflection coefficient (overall 0.08 ± 0.04) nor the distance to the BCW reflection point (overall 7.0 ± 2.9 cm) was affected by dobutamine.

Peak BEW dIW– and BEW IW– increased 44-fold (P = 0.005) and 23-fold (P = 0.003), respectively, between baseline and the highest dobutamine infusion rate. The BEW reflection coefficient increased almost fivefold up to a dobutamine infusion rate of 5 µg·kg–1·min–1 (P < 0.05), and then did not change further, whereas the distance to the BEW reflection point was unaltered (overall 2.1 ± 1.3 cm).

The WIA time interval data are presented in Table 3. Apart from a lack of change in the interval between peak FCW and BEW dIW, other dIW intervals decreased with incremental dobutamine infusion. Of particular note, peak FEWms dIW+ occurred 35–65 ms after peak FCW dIW+ but 57–129 ms before peak FEWes dIW+ and 74–143 ms before aortic valve closure.


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  		Table 3. Wave intensity time intervals during incremental dobutamine infusion

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
WIA is a powerful technique that has provided increased understanding about a diverse range of cardiovascular phenomena, including ventricular function, vascular physiology, and ventricular-vascular interaction (3, 6, 10, 11, 16, 18, 34, 38, 40, 43). The results of this study, which is the first to have used WIA with wave separation to examine systemic responses to an incremental infusion of the β-adrenergic agonist dobutamine, has yielded a number of new insights about the ventricular-vascular interaction of this agent.

The early systolic FCW is the manifestation of an LV contraction wave that is generated at the beginning of systole and provides the forward momentum for blood movement from the LV in the aorta (40). Although our observation of an increase in the peak intensity of FCW during dobutamine infusion confirmed the observations of a previous study (13), the latter noted less than a twofold increase in peak FCW intensity, with a linear relation between this intensity and LV dP/dtMAX at a dobutamine infusion rate of 10–15 µg·kg–1·min–1, whereas an 18-fold rise in peak FCW intensity (Table 2) with an exponential relationship between this intensity and LV dP/dtMAX (Fig. 3) was observed with a comparable infusion rate in the present study. The smaller FCW responses in the previous study (13) most likely reflected a combination of a lesser inotropic effect (55% increase in LV dP/dtMAX vs. more than a doubling in the present study) and a blunting of FCW associated with a higher LV afterload (aortic blood pressure >140/120 vs. 90/60 mmHg in the present study).

The midsystolic BCW constitutes the main vascular reflection of FCW (16, 17, 19). Although BCW increased in amplitude during dobutamine infusion (Table 2), the associated lack of change in the reflection coefficient implied that this increase was primarily a consequence of the rise in FCW. The unaltered reflection point for BCW before and during dobutamine infusion also indicated that reflection occurred from a constant anatomical location that, with a reflection distance of {approx}7 cm, most likely corresponded to the bifurcation of the ascending aorta into the aortic arch and the brachiocephalic trunk (its only cephalic branch in sheep). Moreover, our finding that the cumulative BCW intensity constituted {approx}60% of the total cumulative wave intensity of all backward compression waves at rest, and that this increased to 90% at the highest dobutamine infusion rate, suggests that reflected waves from other sites had a relatively minor effect on raising central aortic blood pressure and reducing ascending aortic flow, particularly during dobutamine infusion.

As well as a characteristic FEWes (3, 13, 16, 17, 19, 27, 34), a FEWms was also observed within the ascending aorta at rest in our study. Such a wave has previously been described in the carotid, brachial, and radial arteries but has been considered to be absent from the ascending aorta (43). However, this view most likely reflects the relatively small magnitude of FEWms under baseline conditions (Fig. 1), which renders it liable to be overlooked even though clearly present, as, for example, in Figs. 2 and 3 of Koh et al. (19). FEWms was much more evident during dobutamine infusion and indeed became the dominant forward expansion wave at dobutamine infusion rates ≥5 µg·kg–1·min–1 (Fig. 2 and Table 2). FEWms was thus not only directly implicated in the augmented aortic blood deceleration and rate of fall in blood pressure occurring during LV ejection with dobutamine infusion, but also the temporal shift in this augmentation from late systole to midsystole.

The simultaneous but discrete presence of a small FEWms and a large FEWes under resting conditions, as well as the reciprocal changes in the magnitude of these waves during dobutamine infusion in the present study, imply that different mechanisms underpinned these waves. The recent finding that FEWes corresponds with the generation of a rarefaction wave by the left ventricle just before aortic valve closure (40), coupled with the observation that LV untwisting starts 13–27 ms before aortic valve closure (7, 25), suggests that FEWes is related to myocardial relaxation processes. Although it has also been previously suggested that FEWes represents evidence of the LV decelerating blood flowing out of the ventricle under its own momentum (12), two findings from our study are not in accord with this notion. First, if momentum was a major factor in FEWes, then this wave should have increased during infusion of dobutamine, which increases aortic blood flow (Table 1) and velocity (13) and, therefore, aortic blood momentum (the product of mass and velocity). Instead, however, a marked reduction in FEWes intensity occurred (Table 2). Second, if momentum was a major basis for FEWes, then a direct relation should have been present between the FCW and FEWes cumulative intensities, whereas the opposite was observed (Fig. 4).

On the other hand, three observations are in strong accord with the proposition that FEWms arose as a consequence of aortic momentum. First, a highly linear relationship was evident between the cumulative FEWms and FCW intensities during dobutamine infusion (Fig. 4). Second, the occurrence of FEWms in the midportion of LV ejection, {approx}140 and {approx}75 ms before aortic valve closure at rest and at the highest dobutamine infusion rate, respectively, would place this wave in the midst of myocardial shortening (14) and the initial LV rotation related to contraction (9), and thus considerably before the onset of myocardial lengthening or LV untwisting. Third, one input in the calculation of aortic wave intensity, namely dU/dt, is directly related to the magnitude of blood inertial effects within the aorta (5). Moreover, inertial components are particularly evident with rises in blood momentum, such as occurs during inotropic stimulation, with not only an enhanced early systolic positive peak during the initial ventricular impulse (29) but, consistent with the presence of a large FEWms (Fig. 2), also a prominent midsystolic negative peak (5).

Our conclusion that the origin of FEWms was related to aortic momentum thus implies that the enhanced aortic blood deceleration and rate of fall in blood pressure occurring during LV ejection with dobutamine infusion were not because of any augmentation of myocardial relaxation processes per se. Moreover, the slope of the relation between the cumulative FEWms and FCW intensities (Fig. 4) suggests that, during dobutamine infusion, {approx}30% of the energy transmitted in the aorta from LV contraction in the initial part of the cardiac cycle contributes to blood deceleration and blood pressure lowering in the subsequent part of systole of the same cycle via a momentum effect.

It has been suggested that a FEWms evident in peripheral arteries is the result of reflection of early systolic BCW from a proximal open-end-type reflection site (43). However, FEWms could not have been a reflection of BCW during dobutamine infusion in our study because the cumulative intensity of FEWms exceeded that of BCW by an infusion rate of 5 µg·kg–1·min–1 (Table 2).

A BEW was first described in the pulmonary circulation, where it was proposed to be due to the presence of "open-end" reflection sites that result from the large increases in vascular cross-sectional area occurring over a short distance (10, 11). Up until the present study, it has been considered that a BEW does not occur in the systemic circulation, because most reflecting sites here are "closed end" in type and thus produce backward compression waves (3). However, our finding of a consistent BEW in the ascending aorta under baseline conditions (Fig. 1 and Table 2) is supported by a previous observation (17). Clearly, however, the ascending aortic BEW is quite small at baseline, with the reflection coefficient (0.006, equivalent to 0.6% of the cumulative intensity of the FCW) being more than an order of magnitude smaller than in the pulmonary circulation (11). Nonetheless, the ascending aortic BEW had a discernible "pulling" effect at baseline that enhanced aortic forward blood velocity and thus complemented this action of FCW (Fig. 1). Both the peak and cumulative intensity of BEW rose strikingly during dobutamine infusion, however, with a fivefold increase in the reflection coefficient at an infusion rate of 5 µg·kg–1·min–1, associated with correspondingly greater effects on aortic forward blood velocity. Generation of a progressively larger BEW therefore appears to be one means whereby a vascular action of dobutamine can supplement the increase in cardiac output arising from the inotropic effect of this agent (1, 8, 35).

The small distance to the BEW reflection point ({approx}2 cm) and the lack of change in this distance (Table 2) not only implies that BEW originated from a constant location before and during dobutamine infusion but also that an open-end reflection site related to an anatomical increase in vascular cross-sectional area (10, 11) was not the mechanism that underpinned BEW in our study. However, based on the close relationship evident between aortic diameter and blood pressure (26), the increase in pulse pressure (Table 1) suggests that a progressively greater cyclical expansion of the aorta occurred during incremental dobutamine infusion. This raises the possibility of a physiological basis for BEW, namely the functional increase in aortic vascular cross-sectional area occurring during each cardiac systole, a proposition indirectly supported by a strong correlation (R2 = 0.98) between aortic pulse pressure and BEW intensity during dobutamine infusion in our study.

Several methodological issues require comment. First, the relatively low levels of aortic blood pressure measured in our study are quite typical for sheep, even in the conscious state (4, 22, 26, 28). Importantly, with such levels of blood pressure in sheep, derived vascular and cardiac parameters are quite valid (36), and there is no evidence of compromised myocardial function, perfusion and energetics, or systemic perfusion, oxygen delivery, oxygen consumption, and oxygen delivery/consumption relationships (30, 31). Second, calculated wave speed in the ascending aorta of sheep in the present study (2.7–3.3 m/s) was lower than the range of 5.1–6.3 m/s reported in previous WIA studies performed in dogs (17, 18). This would appear to largely reflect a species difference, since our finding accords with a low-pulse wave velocity (3.2–4.6 m/s) reported in large-conduit systemic arteries of sheep (23, 41, 42). Moreover, consistent with our observed rise in wave speed, an increase in pulse wave velocity has been reported with dobutamine (37), presumably related to the {alpha}-adrenoceptor effects of this agent (35). Third, separation of total wave intensity was an essential part of WIA during dobutamine administration because of the simultaneous but disproportionate effects of this agent on the various wave types. Thus, in the total wave intensity profile, changes in BEW were overwhelmed by increases in FCW, whereas BCW and FEWms occurred at similar time points in midsystole, thereby blunting the overall change (Fig. 2). Finally, because general anesthesia and open-chest conditions with mechanical ventilation may alter aortic blood pressure and velocity/flow (39) and thus the rates of change of these variables, wave intensity findings may differ quantitatively, but should not be qualitatively different, from those obtained in the conscious, closed-chest setting with spontaneous respiration.

Summary

WIA with separation of total intensity has provided new insights into ventricular-vascular interactions occurring with incremental dobutamine infusion. In particular, this approach has highlighted the role of two previously unheralded waves in this interaction, namely an early systolic BEW that augmented forward aortic flow and a FEWms that produced earlier and enhanced aortic blood deceleration.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was performed with the assistance of a Grant-in-Aid from the National Heart Foundation of Australia.


   ACKNOWLEDGMENTS
 
We thank Karyn Forster for technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. J. Smolich, Dept. of Cardiology, Royal Children's Hospital, Flemington Road, Parkville, Victoria, Australia, 3052 (e-mail: joe.smolich{at}mcri.edu.au)

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. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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