Quantitative analysis of exercise-induced enhancement of early- and late-systolic retrograde coronary blood flow

Abstract

Coronary blood flow (CBF) is reduced and transiently reversed during systole via cardiac contraction. Cardiac contractility, coronary tone, and arterial pressure each influence systolic CBF (CBF_SYS), particularly by modulating the retrograde component of CBF_SYS. The effect of concurrent changes in these factors on CBF_SYS during dynamic exercise has not been examined. Using chronically instrumented swine, we hypothesized that dynamic exercise enhances retrograde CBF_SYS. Phasic CBF was examined at rest and during treadmill exercise [2–5 miles/h (mph)]. Absolute values of mean CBF over the cardiac cycle (CBF_CYCLE) as well as mean CBF in diastole (CBF_DIAS) and mean CBF_SYS were increased by exercise, while relative CBF_DIAS and CBF_SYS expressed as percentage of mean CBF_CYCLE were principally unchanged. Early retrograde CBF_SYS was present at rest and increased in magnitude (−33 ± 4 ml/min) and as a percent of CBF_CYCLE (−0.6 ± 0.1%) at 5 mph. This reversal was transient, comprising 3.7 ± 0.3% of cardiac cycle duration at 5 mph. Our results also reveal that moderately intense exercise (>3 mph) induced a second CBF reversal in late systole before aortic valve closure. At 5 mph, late retrograde CBF_SYS amounted to −53 ± 11 ml/min (−3.1 ± 0.7% of CBF_CYCLE) while occupying 11.1 ± 0.3% of cardiac cycle duration. Wave-intensity analysis revealed that the second flow reversal coincided with an enhanced aortic forward-going decompression wave (vs. rest). Therefore, our data demonstrate a predictable increase in early-systolic CBF reversal during exercise and additionally that exercise induces a late-systolic CBF reversal related to the hemodynamic effects of left ventricular relaxation that is not predictable using current models of phasic CBF.

the phasic nature of coronary blood flow (CBF) is attributable to unique interactions between the continuously beating heart and coronary vessels, especially during ventricular systole when coronary flow is impeded and often transiently reversed (2, 24). This systolic reduction and reversal of flow, the coronary systolic flow impediment, results from the compressive effect of cardiac contraction and increased intramyocardial pressure on coronary arterioles (i.e., reduced arteriolar diameter) resulting in arteriolar retrograde flow that is transmitted upstream (1, 2, 24). Previous work has demonstrated that the extent of systolic retrograde flow can be modulated by three primary factors. First, elevations in myocardial contractility enhance early-systolic flow reversal (1, 15). A second mechanism relates to coronary vasomotor tone and intravascular blood volume. Morita et al. (19) demonstrated that systolic retrograde coronary flow was reduced by α-adrenergic-mediated vasoconstriction in the dog heart. Conversely, systolic flow reversal was enhanced by reductions in coronary tone with adenosine in the dog heart (2). Thus changes in arteriolar diameter modulate vascular compliance and intravascular blood volume (i.e., the volume that can effectively be displaced by extravascular compression). Third, alterations in coronary perfusion pressure are able to modify this systolic flow impediment (13). Chilian and Marcus (1) demonstrated that the systolic flow reversal was attenuated with increasing aortic pressure. Thus evidence demonstrates that each of these influences has the capacity to modulate the systolic component of CBF. A recent study has demonstrated that concurrent changes in these factors can additively modulate the systolic reversal of coronary flow. Using wave-intensity analysis (WIA), Sun et al. (25) demonstrated that the coronary “backward compression wave” responsible for systolic flow reversal is greatest when cardiac contractility is elevated while coronary vascular resistance is reduced. To date, however, our understanding of the integrated effect of these three factors on phasic CBF during complex physiological conditions like dynamic exercise is lacking. Exercise is an important physiological stimulus that is part of normal life but is also a stimulus during which these determinants of phasic coronary flow rarely change individually.

Whole body exercise places a tremendous burden on the heart to provide adequate blood flow to active tissues. Myocardial oxygen demand increases as a result of elevated heart rate, contractility, and ventricular work and is met by elevated CBF (i.e., oxygen supply) as coronary resistance falls via exercise-induced coronary vasodilation (5). The exercise-induced elevation in mean arterial pressure, the driving pressure for coronary flow, also contributes to the increase in CBF (5). Thus, during dynamic exercise, cardiac contractility, coronary resistance and blood volume, and coronary perfusion pressure are concurrently altered. The net effect of these changes on the phasic nature of CBF especially during systole, however, has not been examined. The relative amounts of antegrade and retrograde blood flow may be important to vascular health due to accumulating evidence that retrograde flow promotes a proatherogenic endothelial cell phenotype (16). Therefore, we explored, in a quantitative manner, the effects of exercise on the phasic characteristics of systolic CBF. For this purpose we employed results obtained from chronically instrumented swine exposed to a graded treadmill exercise test.

METHODS

Animal preparation.

All animal protocols were approved by an Institutional Animal Care and Use Committee at the University of Missouri. Daily adaptation of animals to laboratory conditions and treadmill running started 1 wk before surgery. Adult (1–2 yr) female miniature Yucatan swine (n = 7; 35–55 kg) were sedated with ketamine (20–30 mg/kg im) and rompun (2.25 mg/kg im), intubated, and ventilated with 0.2–1% (vol/vol) isoflurane in air. Body temperature was maintained between 36.5 and 37.5°C using a warming blanket, and ECGs were monitored from standard limb leads. Under sterile conditions, the chest was opened via the third intercostal space, and a fluid-filled polyvinylchloride catheter was inserted into the aortic arch for aortic blood pressure measurement and blood sampling for determination of Po₂, Pco₂, pH, O₂ saturation and hemoglobin concentration (Radiometer, Copenhagen), and computation of O₂ content, O₂ supply, and O₂ consumption (7, 18). A high-fidelity Konigsberg pressure transducer was inserted into the left ventricle via the apex for measurement of left ventricular pressure and dP/dt and for determination of heart rate. A fluid-filled catheter was inserted into the left atrium for pressure measurement and calibration of the Konigsberg signal. A small angiocatheter was inserted into the anterior interventricular vein for coronary venous blood sampling. Finally, bidirectional transit-time ultrasound flow probes (Transonic Systems) were placed around the ascending aorta and left anterior descending (LAD) coronary artery for measurement of cardiac output and CBF, respectively.

Electrical wires and catheters were tunneled subcutaneously to the back, the chest was closed, and animals were allowed to recover. Animals received analgesia [buprenorphine (0.3 mg im) for 2 days] and antibiotic prophylaxis [amoxicillin (25 mg/kg iv) and gentamycin (5 mg/kg iv) for 5 days]. Catheters were flushed daily with physiological saline containing 2,000 IU/ml heparin (5,000 IU/ml heparin for coronary venous catheters).

Exercise protocol.

Studies were performed 1 wk after surgery. After resting hemodynamic measurements, blood samples, and rectal temperature had been obtained, swine were subjected to a four-stage treadmill exercise protocol on a motor-driven treadmill [2–5 miles/h (mph) at 0% inclination]. Hemodynamic variables were continuously recorded on a Codas workstation, and blood samples were collected during the last 30 s of each 3-min exercise stage, at a time when hemodynamics had reached a steady state.

Data acquisition and analysis.

All signals were recorded at a sampling rate of 225 Hz, digitized on-line using an eight-channel data-acquisition program (ATCODAS, Dataq Instruments, Akron, OH), and stored on a computer for later postacquisition off-line analysis with a program written in MatLab (Mathworks, Natick, MA). Mean values for LV peak systolic pressure, aortic blood pressure, left atrial pressure, ascending aortic blood flow, and CBF were determined across 10 s at rest and at the end of each exercise level during steady-state hemodynamics. Cardiac output was computed as the sum of ascending aorta blood flow and total CBF computed as 2.5 times LAD coronary artery flow since this vessel supplies ∼40% of the LV. Systemic and coronary vascular conductances were calculated as the ratios of cardiac output and LAD coronary artery blood flow to mean aortic pressure, respectively. Blood O₂ content (μmol/ml) was calculated as (0.621·Hb_a·So₂) + (0.00131·Po₂), where Hb_a is arterial Hb and So₂ is oxygen saturation. Myocardial oxygen consumption (MV̇o₂) in the region perfused by the LAD coronary artery was calculated as the product of CBF and the difference in O₂ content between arterial and coronary venous blood.

The area under the blood flow curve per cardiac cycle was divided into systolic and diastolic portions. Area under the blood flow curve during each segment of the cardiac cycle was quantified using Prism (GraphPad, La Jolla, CA) and expressed as a percentage of the total area under the CBF curve (total antegrade CBF minus total retrograde CBF) for the entire cardiac cycle (CBF_CYCLE). Thus the mean diastolic CBF (CBF_DIAS), mean systolic CBF (CBF_SYS), antegrade systolic CBF (CBF_SYS-ANTE), and early and late retrograde systolic CBF (CBF_SYS-RETRO) were determined and expressed in absolute flow rates (ml/min) during each phase and as a percentage of mean CBF_CYCLE (Fig. 1).

Fig. 1.

Schematic drawing of left ventricular (LV) pressure, aortic (Ao) pressure. and coronary blood flow (CBF) delineating the various segments of phasic CBF used for data analysis. See methodsfor terms as defined in the text.

Each portion of the cardiac cycle was determined from the left ventricular pressure and aortic blood flow recordings shown in Fig. 2. The onset of ventricular systole was defined as the “notch” in the left ventricular pressure recording between the increase in LV pressure due to atrial ejection and the increase in LV pressure due to isovolumic ventricular systole. Diastole was measured beginning at the zero intercept of the aortic flow recording following the systolic increase in aortic flow. This point corresponds with the dicrotic notch in the aortic pressure trace and thus aortic valve closure at rest (Fig. 2). Determination of the duration of each segment of the cardiac cycle was performed directly in the Codas acquisition system. Each phasic blood flow data point was averaged across six consecutive cardiac cycles at rest and each exercise level during steady-state hemodynamics for each animal.

Fig. 2.

Representative recording of left ventricular pressure (LVP), CBF, and aortic blood flow (ABF) at rest and during graded treadmill exercise. Aortic pressure (AoP) is presented at rest to illustrate the position of the dicrotic notch in relation to aortic flow. Vertical lines represent the borders of systole (S) and diastole (D). mph, miles/h.

WIA.

WIA was utilized to examine aortic hemodynamics in late systole before closure of the aortic valve as an indicator of ventricular effects on aortic and, by inference, CBF at this point in the cardiac cycle. By utilizing simultaneous measurements of pressure and flow at the same location in a vessel, WIA allows determination of the direction and intensity of the instantaneous wavefronts present at any given moment in a blood vessel (21, 22).

Wave intensity is defined as the product of simultaneous changes in pressure (P) and velocity (U) during a small time interval (21) and was computed using MatLab software. Aortic flow was converted to velocity by dividing flow by the inner square surface area of the flow probe (11, 23). With our instrumentation, aortic pressure was measured downstream with respect to the aortic flow probe. Thus aortic pressure was aligned with aortic velocity to ensure temporal fidelity between these measurements using the PU-loop method previously described by Khir et al. (11). This method relies on the linear relationship of aortic pressure and velocity in early systole when only forward-traveling waves are present. Therefore, the aortic pressure and velocity signals were shifted in time to achieve P-U linearity in early systole (11). Additionally, the slope of this linear relationship is proportional to the instantaneous wave speed (21). Instantaneous wave speed was determined on 12–20 pairs of waves at rest and postexercise for each animal. Frequency analysis of pressure and flow signals measured with this equipment demonstrated no significant components above 40 Hz (i.e., much lower than the bandwidths of the measurement equipment). Thus there is negligible influence of any differences in frequency response of the equipment. No additional offline filtering was employed during the analysis of pressure or flow data.

After aligning aortic pressure with aortic velocity, WIA was used to determine the wave intensity of the wave in the ascending aorta in late systole for 20 cardiac cycles at rest and within the first 20 s after stoppage of the treadmill following exercise at 5 mph. Analysis of wave intensities during exercise proved impossible due to movement artifacts in the aortic pressure recording from the fluid-filled transducer. Therefore, wave intensity was determined immediately after exercise at 5 mph while systemic hemodynamics remained elevated (based on heart rate and blood pressure) but movement artifacts were absent.

Statistical analysis.

Statistical analysis of hemodynamic, mean CBF, and area under the curve data was performed in Prism using one-way ANOVA for repeated measures (when appropriate) with a Bonferroni multiple comparisons post hoc test, when appropriate. Peak wave intensities at rest and immediately postexercise were compared using paired Student's t-test. Linear regression analysis was performed to determine the interaction among different variables. A P value < 0.05 was considered significant. Data are expressed as means ± SE.

RESULTS

Hemodynamics.

Compared with resting conditions, graded treadmill exercise induced intensity-dependent increases in cardiac output, heart rate, maximum LV dP/dt, systemic and coronary vascular conductances, mean CBF_CYCLE, and MV̇o₂ (Table 1). Mean arterial pressure was significantly increased only at the highest exercise intensities. Conversely, minimum LV dP/dt and the time constant for left ventricular relaxation (τ) were significantly reduced by exercise. Coronary venous So₂ and Po₂ were unchanged by exercise (Table 1). The relative durations of systole and diastole were also significantly increased and decreased, respectively, by exercise (Table 2).

Table 1.

Systemic and coronary hemodynamic responses to graded treadmill exercise in Yucatan miniature swine

	Rest	Exercise Level, mph
		2	3	4	5
Systemic hemodynamics
CO, l/min	4.5 ± 0.2	7.8 ± 0.3*	9.5 ± 0.2*†	11.4 ± 0.3*†‡	12.1 ± 0.4*†‡
HR, beats/min	98 ± 4	172 ± 6*	210 ± 8*†	243 ± 6*†‡	256 ± 6*†‡
SV, ml	46 ± 2	45 ± 2	46 ± 1	47 ± 1	47 ± 1
LVdP/dt max, mmHg/s	2,325 ± 149	3,793 ± 180*	4,519 ± 302*	5,783 ± 246*†‡	5,971 ± 267*†‡
LVdP/dt min, mmHg/s	−2,094 ± 67	−2,536 ± 189	−3,357 ± 207*	−4,552 ± 399*†‡	−5,084 ± 467*†‡
τ, ms	34 ± 2	29 ± 3	30 ± 3	22 ± 3*	20 ± 3*
MAP, mmHg	95 ± 4	103 ± 4	106 ± 4	110 ± 5*	114 ± 6*
SVC, ml·min−1·mmHg−1	48 ± 3	76 ± 4*	91 ± 4*	105 ± 5*†	109 ± 7*†‡
Coronary hemodynamics
CBF, ml/min	62 ± 5	99 ± 8*	127 ± 11*†	170 ± 6*†‡	180 ± 7*†‡
CVC, ml·min−1·mmHg−1	0.7 ± 0.1	1.0 ± 0.1*	1.2 ± 0.1*	1.6 ± 0.1*†‡	1.6 ± 0.1*†‡
ScvO2, %	15.4 ± 0.8	16.1 ± 1.2	16.4 ± 1.0	19.4 ± 3.0	18.6 ± 2.5
PcvO2, mmHg	19.0 ± 0.6	19.3 ± 0.7	19.7 ± 0.9	21.3 ± 1.6	21.5 ± 1.6
MV̇o2, μmol/min	240 ± 11	477 ± 29	732 ± 80*†	883 ± 112*†	1,056 ± 43*†‡

Values are means ± SE. CO, cardiac output; HR, heart rate; SV, stroke volume; LV dP/dt_max, maximum rate of rise in left ventricular pressure; LV dP/dt_min, maximum rate of fall in left ventricular pressure; τ, time constant of left ventricular relaxation; MAP, mean arterial pressure; SVC, systemic vascular conductance; CBF, coronary blood flow; CVC, coronary vascular conductance; ScvO₂, coronary venous oxygen saturation; PcvO₂, coronary venous Po₂; MV̇o₂, myocardial oxygen consumption.

^*P < 0.05 vs. at rest.

^†P < 0.05 vs. 2 miles/h (mph).

^‡P < 0.05 vs. 3 mph.

Table 2.

Effect of exercise on the durations of antegrade and retrograde flow phases of the cardiac cycle

	Rest	Exercise Level, mph
		2	3	4	5
Diastole, ms	318 ± 23	136 ± 13*	100 ± 6*	89 ± 4*	89 ± 4*
(% of cardiac cycle)	(50 ± 2)	(37 ± 2)*	(34 ± 1)*	(36 ± 1)*	(37 ± 1)*
Systole, ms	308 ± 4	228 ± 5*	190 ± 7*†	157 ± 3*†‡	152 ± 4*†‡
(% of cardiac cycle)	(50 ± 2)	(63 ± 2)*	(66 ± 1)*	(64 ± 1)*	(63 ± 1)*
Early-systolic retrograde flow, ms	15.7 ± 1.1	9.9 ± 1.0*	10.7 ± 0.9*	9.4 ± 0.9*	8.9 ± 0.6*
(% of cardiac cycle)	(2.6 ± 0.3)	(2.7 ± 0.2)	(3.7 ± 0.3)	(3.8 ± 0.4)	(3.7 ± 0.3)
Late-systolic retrograde flow, ms			15.5 ± 3.3*	24.2 ± 2.5*†	27.0 ± 1.0*†
(% of cardiac cycle)			(3.1 ± 1.2)*	(9.8 ± 0.9)*†	(11.1 ± 0.3)*†

Values are means ± SE.

^*P < 0.05 vs. at rest.

^†P < 0.05 vs. 2 mph.

^‡P < 0.05 vs. 3 mph.

Effect of exercise on phasic blood flow in the left anterior descending artery.

CBF presented as absolute flow rates and percent of mean CBF_CYCLE is presented for total antegrade and retrograde CBF in Fig. 3 and early- and late-systolic retrograde CBF in Fig. 4. Treadmill exercise induced graded increases in both systolic and diastolic antegrade coronary blood flow (Fig. 3A) while the percent of net flow occurring during each phase was largely unaffected (Fig. 3B). One notable exception is that the percent of net antegrade flow occurring during systole increased at 2 mph compared with at rest (33 ± 1 vs. 27 ± 1%, P < 0.05). The percent of net flow during diastole was correspondingly decreased at 2 mph (67 ± 1 vs. 73 ± 1%, P < 0.05).

Fig. 3.

Total antegrade and retrograde coronary blood flow during systole and diastole expressed as mean flow rates (A) and as a percent of net flow across the cardiac cycle (B) at rest (R) and during graded treadmill exercise (2–5 mph). Total retrograde flow values include early- and late-systolic flow reversals. Values are means ± SE. *P < 0.05 vs. all other speeds. **P < 0.05 vs. at rest and 2 mph. †P < 0.05 vs. at rest and 2 and 3 mph.

Fig. 4.

Early (E)- and late (L)-systolic retrograde coronary flows expressed as mean flow rates (A) and as a percent of net flow across the cardiac cycle (B) at rest (R) and during graded treadmill exercise (2–5 mph). Values are means ± SE. *P < 0.05 vs. at rest. **P < 0.05 vs. zero. †P < 0.05 vs. 5 mph., ‡P < 0.05 vs. 3 mph.

Whole body exercise significantly increased systolic coronary retrograde flow in the left anterior descending artery (Fig. 3). At rest, a minor but statistically nonsignificant coronary flow reversal was noted in early systole (i.e., isovolumic ventricular systole) in ∼50% of cardiac cycles analyzed (Fig. 4 and Table 3). Early-systolic retrograde flow was elevated by treadmill exercise with increases becoming statistically significant both in magnitude (−17 ± 2 ml/min; Fig. 4A) and as a percent of net coronary flow (−0.5 ± 0.1%, Fig. 4B) at 3 mph. Higher exercise intensities further enhanced mean retrograde flow in early systole reaching −33 ± 4 ml/min at 5 mph (Fig. 4A) with no additional change as a percent of net antegrade flow (−0.6 ± 0.1%; Fig. 4B). The early-systolic flow reversal lasted only briefly at rest and was even shorter during exercise but comprised a similar percentage of total cardiac cycle duration (Table 2).

Table 3.

Effect of exercise on the frequency (% of cardiac cycles) of systolic coronary retrograde flows

	Rest	Exercise Level, mph
		2	3	4	5
Early-systolic retrograde flow	50 ± 18	86 ± 6	88 ± 6*	76 ± 8	74 ± 9
Late-systolic retrograde flow			33 ± 10*	76 ± 10*†	95 ± 3*†

Values are means ± SE.

^*P < 0.05 vs. at rest.

^†P < 0.05 vs. 3 mph.

Our results also reveal that moderate intensity (i.e., 4 and 5 mph) whole body exercise causes retrograde coronary flow during late systole before aortic valve closure (Fig. 2). The duration of the late-systolic flow reversal was very short (15–30 ms) and unlike the early-systolic flow reversal increased with exercise intensity comprising ∼11% of total cardiac cycle duration at 5 mph (Table 2). This late-systolic flow reversal was first noted at 3 mph in ∼33% of cardiac cycles albeit nonsignificant (Fig. 4 and Table 2) and became statistically significant at 4 and 5 mph, reaching a mean magnitude of −53 ± 1 ml/min (Fig. 4A) and percent of net antegrade flow of −3.4 ± 0.8% (Fig. 4B). In addition, at 5 mph ∼95% of cardiac cycles analyzed exhibited late-systolic flow reversal (Table 3).

WIA of aortic hemodynamics in late systole.

In a subset of five animals, WIA was performed using blood pressure and flow measurements in the ascending aorta during late systole at rest and immediately following exercise at 5 mph (Fig. 5, A and B). Instantaneous wave speeds in the aorta were not significantly different immediately postexercise compared with resting values (4.7 ± 0.7 vs. 4.2 ± 0.9 m/s). Our results confirm previous reports of a forward-going decompression wave in the aorta at rest during late systole (24 ± 3 W/m²), since aortic pressure and flow are both decreasing at this point in the cardiac cycle (8, 21, 28). This decompression wave results from left ventricular relaxation and acts to slow aortic outflow and contributes to closure of the aortic valve (8, 21, 28). Further, our data reveal the novel finding that peak wave intensity is elevated immediately following exercise at 5 mph to 215 ± 62 W/m² (Fig. 5C). In addition, peak aortic wave intensity of the forward-going decompression wave coincided with the peak retrograde flow in late systole (Fig. 5B). First-order linear regression analysis revealed that peak wave intensity correlated significantly with minimum dP/dt (r² = 0.94; Fig. 5D) and τ (r² = 0.32).

Fig. 5.

Representative results of aortic wave-intensity analysis in systole at rest (A) and within 20 s after exercise at 5 mph (B). Net, forward-going and backward-going wave intensities (WI) are shown in relation to CBF. Wave intensity units: W/m²; CBF units: ml/min. Vertical lines represent aortic valve opening (AO) and closure (AC). Black bars in upper right of each panel equal 5 ms. C: peak wave intensities in late systole prior to aortic valve closure at rest and immediately following exercise at 5 mph. D: peak wave intensity plotted against maximum rate of fall in LV pressure (dP/dt_min). Data were fitted to a first-order linear regression equation. Results for individual animals (C and D) along with group means ± SE (C) are presented. *P < 0.05 vs. at rest.

DISCUSSION

The present study illustrates and quantifies a unique effect of dynamic exercise on the pattern of coronary blood flow, particularly in systole. Relative to resting conditions, exercise augmented the early-systolic reversal of coronary flow. Additionally, our results demonstrate that moderate intensity exercise (>3 mph) induces a late-systolic reversal of coronary flow that coincides with an enhanced forward-going decompression wave originating within the left ventricle (vs. at rest). While the enhancement of early-systolic retrograde flow is largely predictable via existing models of phasic CBF, the finding of flow reversal in late systole is not. Thus dynamic exercise in conscious, instrumented swine induces a unique pattern of phasic CBF worthy of further examination.

Early-systolic flow reversal and exercise.

The systolic reduction and transient reversal of CBF occurs due to the mechanical effect of cardiac contraction and increased intramyocardial pressure on intramyocardial blood vessels (1, 13, 15, 24). Indeed, the “vascular waterfall,” “intramyocardial pump,” and “time-varying elastance” models have been proposed to explain how increasing intramyocardial pressure and/or extravascular stiffness impede systolic coronary flow (4, 14, 24). No single model, however, is currently able to completely describe the effect of cardiac contraction on the coronary vasculature (see Ref. 29 for review). Regardless, numerous elegant studies have directly demonstrated that the level of cardiac contractility, coronary vascular tone and perfusion pressure (i.e., aortic pressure) can individually modulate the coronary systolic flow reduction/reversal in large part by effecting early-systolic retrograde flow (2, 13, 19, 25). Little is currently known, however, concerning the integrated effect of changes in two or more of these factors on systolic coronary flow. Our data expand on previous findings by demonstrating that the elevations in contractility and aortic pressure and reduction in coronary tone during dynamic exercise result in a net increase in early-systolic retrograde flow. This is consistent with recent data from Sun et al. (25) who demonstrated, using WIA, that the “backward compression wave” in the coronary arterial tree responsible for its systolic flow reversal is greatest when contractility is elevated while coronary tone is reduced. To our knowledge, this is the first study to examine the integrated effect of multiple factors in modulating systolic coronary flow patterns during exercise, a relevant physiological stressor.

The mechanics underlying the early-systolic flow reversal are complex, and our data clearly demonstrate concomitant changes in various factors during exercise that augment this phenomenon. Overall, the mean values (i.e., magnitude) of early-systolic retrograde flow were increased in an exercise intensity-dependent fashion in this study. This reversal is also augmented when viewed as a percentage of net coronary flow; however, this value is likely tempered by the capacitive nature of the epicardial vessel where flow was measured (1, 2). It is then likely that the latter measure underestimates the percent of net epicardial flow actually attributable to early-systolic retrograde flow. Nevertheless, the phasic nature of coronary blood flow as measured in epicardial coronary arteries reflects the summed effect of cardiac contraction on flow in downstream coronary arteries and arterioles (9). Indeed, systolic retrograde flow has been observed in endocardial and epicardial arterioles, and this is sensitive to changes in vascular tone (19, 25, 27). For instance, α-adrenergic-mediated vasoconstriction and adenosine-mediated vasodilation reduced and enhanced early-systolic retrograde flow, respectively (2, 19). Thus augmentation of early-systolic retrograde flow during exercise is partly attributable to the effect of increased contractility on intramyocardial coronary vessels with reduced tone that are more susceptible to compression and displace a larger blood volume in response to elevated extravascular pressure.

Late-systolic flow reversal and exercise.

Our data demonstrate that dynamic exercise causes a second coronary flow reversal during late systole before closure of the aortic valve, a phenomenon not predictable using available models of phasic CBF (29). This second reversal was observed in Yucatan swine at treadmill speeds consistent with moderate intensity exercise (i.e., 4–5 mph) via previous maximal oxygen consumption (V̇o_{2 max}) measurements (17). A second reversal of coronary flow during late systole was previously noted by Khouri et al. (12) in the exercising dog heart. Gorman et al. (10) also demonstrated late-systolic retrograde flow in the dog heart during exercise only after α-adrenoceptor blockade with phentolamine. Thus the lack of α-adrenergic constriction in the pig heart (6) may be one underlying factor predisposing the swine coronary circulation to this phenomenon during exercise. To our knowledge this is the first quantitative characterization of exercise-induced coronary flow reversal during late systole.

Wiggers (30) previously implied that an “aspirating force” is generated by the left ventricle during relaxation due to the rapid decline in left ventricular pressure. Recent evidence demonstrates that the left ventricle creates such an “aspirating force” at the onset of ventricular relaxation before aortic valve closure. Using WIA, our data and that of other groups confirm that a forward-going (i.e., in the direction of antegrade blood flow) decompression wave is created by the left ventricle at the onset of ventricular relaxation at rest (3, 26, 28). By definition this wave acts to decelerate stroke volume moving through the aorta during early ventricular relaxation and as demonstrated by Wang et al. (28) reaches peak effect when dP/dt reaches its minimum value immediately preceding aortic valve closure in dogs. Two additional studies in dog and human hearts at rest further demonstrate that this wave acts to decelerate coronary blood flow in late systole even as downstream coronary impedance falls during early ventricular relaxation (3, 26). Therefore, the left ventricle does generate an “aspirating force” that acts to reduce (i.e., decelerate) aortic and coronary blood flow in late systole at rest. We should emphasize that our analysis of wave intensity was focused on aortic hemodynamics before aortic valve closure and is therefore not an examination of classic “diastolic suction” but rather the immediate effect of ventricular relaxation on aortic and, by inference, coronary hemodynamics.

Our data expand previous findings by clearly demonstrating for the first time that the peak wave intensity of the forward-going decompression wave in the ascending aorta is increased immediately following exercise at 5 mph. This observation is consistent with data from Wang et al. (28) demonstrating an inverse relationship between the energy of the forward-going decompression wave and the time constant of left ventricular relaxation (τ), which was significantly reduced only at 4 and 5 mph in this study. Our data demonstrate similar strong correlations between peak intensity of this wave and measures of ventricular relaxation at rest and during exercise (i.e., dP/dt_min and τ). With regard to the pattern of coronary flow, peak wave intensity coincided temporally with the minimum peak of the coronary flow reversal in late systole which would be expected if this ventricular “suction” is causative, at least in part, for this phenomenon. This reversal is likely also aided by the more rapid decline of aortic pressure in late systole owing to pronounced systemic vasodilation during exercise (i.e., a late-systolic capacitance effect).

It should be pointed out that we are not proposing a single predictor or cause of late-systolic coronary flow reversal. In fact, it is likely that this flow reversal involves a complex interaction of numerous factors including stroke volume inertia, τ, dP/dt, left ventricular end-systolic volume/pressure, coronary tone, intramyocardial pressure, and respiratory effects, among others. It should be emphasized, however, that no currently described model of phasic CBF would predict a reversal of CBF in late systole (29). The utilization of WIA in the present study indicates for the first time that during exercise an enhanced forward-going decompression wave in the aorta, likely due to the increased rate of ventricular relaxation, could provide an explanation for exercise-induced late-systolic flow reversal.

The late-systolic flow reversal comprised an impressive portion of nearly every cardiac cycle at 5 mph (11.1 ± 0.3%) and reached substantial reverse flow rates (−53 ± 1 ml/min). When combined with the early-systolic flow reversal, retrograde flow accounted for ∼15% of cardiac cycle duration at 5 mph. Total retrograde flow at 5 mph, however, equaled less than 5% of net coronary flow. Thus the tempting speculation that this retrograde flow might limit oxygen supply to the myocardium at this high work rate is unlikely. In fact, our data demonstrate that coronary venous oxygen saturation was not reduced from resting levels at either 4 or 5 mph. Thus these significant exercise-induced flow reversals do not appear to impact the tight coupling of CBF to myocardial metabolism in the normal swine heart.

Methodological considerations.

The instrumentation utilized in this study required that the aortic pressure trace be shifted backward in time to align with aortic flow for the calculation of aortic wave speed and wave intensity. Although this method of alignment was confirmed using the PU-loop method (11, 21) subtle temporal discrepancies may still exist between the aortic flow and pressure measurements, precluding definitive conclusions regarding a causative role for this decompression wave in late-systolic flow reversal. We remain confident in this methodology, however, especially given the strong correlation of wave intensity and dP/dt_min and τ, similar to another report (28). Since the aortic systolic pressure peak contains reflection waves, shifting a signal does not account for the phasic shift that is induced by a traveling pulse wave. Therefore this shift introduces an error in the WIA; however, it is expected that this error is negligible for the segment of the pressure and flow curve that are used in the analysis, as the gradient of both signals is steady just before the dicrotic notch (20). It was also necessary to convert aortic flow to velocity for this analysis. This was done by dividing aortic flow by the inner square surface area of the flow probe. This conversion was assumed to be reasonable since the flow probe used completely surrounds the aorta and was in place at least 1 wk before the study. Therefore no change in aortic diameter within the flow probe was expected due to pulsatile pressure changes (11, 23). This method will however introduce some gain error, as the inner diameter of the flow probe is larger than the lumen diameter of the aorta, leading to an underestimation of velocity gradient and wave intensity. However, this represents a systematic error that will not influence the relative changes from rest to exercise.

Clinical relevance and conclusions.

The impact of cardiovascular disease states on phasic coronary flow, particularly with regard to retrograde flow, remains to be examined. This seems to be an increasingly relevant area for research given the accumulating evidence that retrograde flow promotes a proatherogenic endothelial phenotype (16). It remains to be seen how the reported increase in retrograde flow during exercise may relate to the progression of coronary disease, especially since dynamic exercise has long been recognized as a beneficial stimulus for coronary vascular function (5).

In conclusion, this study is the first to show that coronary epicardial retrograde flow is significantly increased by dynamic exercise and the first to characterize a unique exercise-induced late-systolic flow reversal related to the hemodynamic effects of left ventricular relaxation. These findings are important because they expand on our understanding of the complex interaction between the coronary vasculature and cardiac muscle in dictating myocardial perfusion patterns during exercise, a complex physiological stimulus. The late-systolic flow reversal warrants further examination in future biophysical studies/models of cardiac-coronary-aortic interactions, especially during hyperkinetic states, since this flow reversal is not predictable using currently available models of phasic CBF (29).

GRANTS

This study was supported by National Institutes of Health Grants HL-52490, RR-018276, and AR-048523 to M. H. Laughlin and Dräger (M. J. van Houwelingen).

DISCLOSURES

No conflicts of interest are declared by the authors.