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University of Wisconsin-Madison, John Rankin Laboratory of Pulmonary Medicine, Madison, Wisconsin
Submitted 17 July 2005 ; accepted in final form 10 March 2006
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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cardiac output; blood flow distribution; exercise; expiratory flow limitation; heart failure
Regardless of etiology, EFL ultimately limits further increases in alveolar ventilation and results in increases in both expiratory muscle pressure production and work (25). However, our understanding of the cardiovascular consequences of increases in PITP during exercise remains meager. Early investigations used high levels (15–30 cmH2O) of continuous positive airway pressure to increase PITP during submaximal exercise in healthy humans, which resulted in significant reductions in stroke volume and cardiac output ranging from 15 to 25% (4). However, the application of continuous positive airway pressure does not mimic the breathing mechanics present during physiological EFL, and more recent investigations using mild levels of expiratory threshold loading (10 cmH2O) have suggested a smaller effect of expiratory loading alone on stroke volume and cardiac output in healthy humans (34).
Whether augmented respiratory muscle pressure production contributes to the blunted cardiac output and locomotor limb blood flow responses to exercise (18, 35, 36) in CHF is unclear. Direct measurements of respiratory muscle blood flow in animal models of CHF have shown markedly elevated levels of respiratory muscle blood flow (24). That both the inspiratory and expiratory muscles can "steal" blood flow from the locomotor limb is supported by the observation that the activation of the respiratory muscle metaboreflex via the injection of lactic acid into these vascular beds elicits a reflex vasoconstriction in the exercising locomotor limb in healthy dogs (32). However, whether a more physiological stimulus such as increases in expiratory muscle work can elicit further reductions in cardiac output and/or locomotor limb blood flow in CHF is unknown.
We used varying levels of expiratory threshold loading to mimic EFL in chronically instrumented dogs during submaximal exercise to the to test the following hypotheses: 1) Augmenting the expiratory PITP excursion is detrimental to the cardiac response to exercise and will result in rapid (onset < 10 s) reductions in cardiac output and stroke volume during exercise in both healthy dogs and dogs with pacing-induced CHF. 2) Augmenting the expiratory PITP excursion is detrimental to the locomotor limb hyperemic response to exercise and will result in time-dependent reductions in both absolute locomotor limb blood flow and the fraction of cardiac output delivered to the locomotor limb during exercise in healthy dogs and dogs with pacing-induced CHF.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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All surgical and experimental procedures were approved by the Institutional Animal Care and Use Committee at the University of Wisconsin-Madison Medical School and conducted in accordance with the American Physiological Society's "Guiding Principles in the Care and Use of Animals." Five female mixed-breed hound dogs weighing between 19 and 23 kg were trained to run on a motorized treadmill. After training, two surgical procedures separated by at least 3 wk were required to instrument the dogs for study. General anesthesia and strict sterile techniques were used during all surgical procedures, and appropriate antibiotics and analgesics were used postoperatively. A chronic tracheostomy was created in all of the dogs via a midline incision caudal to the larynx and the subsequent removal of the ventral aspect of four or five cartilaginous rings. Ultrasonic, transit-time flow probes (Transonics, Ithaca, NY) were placed around the ascending aorta (n = 5 dogs) and terminal aorta (n = 4 dogs) for the measurement of cardiac output and hindlimb blood flow, respectively. A catheter was placed in the abdominal aorta via the cannulation of a small side branch of the femoral artery for the measurement of arterial blood pressure. A 7.5-mm-diameter flat-headed pressure transducer (Konigsberg Instruments, Pasadena, CA) was implanted in the intrathoracic space between the 9th and 10th ribs for the direct measurement of PITP. A bipolar pacing lead was sutured to the epicardium of the right ventricle and connected to a pacemaker (Medtronic, Minneapolis, MN) implanted in a subcutaneous tissue pocket for the induction of tachycardia-induced CHF. All cables, catheters, and electrode wires were exteriorized 3–5 cm lateral to the caudal thoracic spine.
All signals were digitized and stored on the hard drive of a personal computer for subsequent analysis and on a polygraph (AstroMed K2G, West Warwick, RI). All ventilatory, blood flow, and blood pressure data were analyzed on a beat-by-beat basis, on a breath-by-breath basis, or by signal-averaging each variable over the course of a breath by use of custom analysis software developed in our laboratory.
Protocols
Timeline of data collection.
The animals underwent both surgical procedures to complete their chronic instrumentation and were allowed to recover for 
2 wk after the second surgery. Experimental testing sessions were separated by at least 24 h with no more than eight trials performed per session. Each animal performed the protocol described below over the course of 2–3 wk while healthy. CHF was then induced by rapid ventricular pacing at 210 beats/min for 3–6 wk. CHF was defined as an ejection fraction < 45% with a considerably blunted cardiac output and stroke volume response to a fixed exercise workload (2.5 mph/5% grade). The protocols were then repeated while the animal was in heart failure over the course of 1–2 wk. The baseline hemodynamic consequences of the pacing-induced heart failure are reported in Table 1.
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EXPIRATORY THRESHOLD LOADING PROTOCOL: HOW DO AUGMENTED EXPIRATORY PRESSURES AFFECT CARDIAC OUTPUT AND ITS DISTRIBUTION? The tubing connected to the nonrebreathing valving was attached to posts on a cart placed immediately next to the treadmill. Once steady-state conditions were reached, expiratory threshold loads of 5, 10, or 15 cmH2O were placed on the expiratory arm of the breathing circuit for a minimum of 30 s (see Fig. 1).
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40 cmH2O·l–1·s–1) was placed on the inspiratory arm of the breathing circuit in addition to a 15 cmH2O expiratory threshold valve placed on the expiratory side of the breathing apparatus (see Fig. 2). This expiratory load was sufficient enough to cause a positive shift in mean PITP of at least 50% of that elicited by inspiratory loading alone, while leaving the magnitude of the inspiratory pressure excursion relatively unaffected (see Fig. 1).
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The transient cardiovascular responses to alterations in PITP were analyzed with custom-made computer software on a beat-by-beat basis for cardiac output, heart rate, stroke volume, mean arterial pressure, terminal aortic blood flow, and regional and systemic vascular conductances. Transpulmonary pressure was calculated as mouth pressure minus PITP. For each individual variable, 5-s averages were obtained during the control period and for 1–2 min after the onset of each intervention. The change from baseline for each 5-s block during expiratory loading or combined inspiratory and expiratory loading was compared with the 5-s blocks from the preceding control condition by a two-way ANOVA with repeated measures and Dunnett's post hoc test. Statistical significance was considered to be present when P < 0.05. Data are presented as means ± SE in all figures, tables, and text.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Changes in cardiovascular function over time in response to expiratory loading. During control conditions, the inspiratory and expiratory PITP excursions averaged –14 ± 3 and 7 ± 2 cmH2O, respectively. The addition of a 5, 10, or 15 cmH2O expiratory threshold load resulted in increases in the expiratory PITP excursion of 47 ± 23% (P < 0.05), 67 ± 32% (P < 0.05), and 118 ± 18% (P < 0.05), respectively. The magnitude of the inspiratory PITP excursion was not significantly affected by the addition of an expiratory load.
The raw data traces from one representative trial in a healthy animal are shown in Fig. 1, with the mean cardiac responses to increases in the expiratory PITP excursion over time in five dogs shown in Fig. 2. Steady-state cardiac output was significantly reduced by all three levels of expiratory loading owing to significant reductions in stroke volume (–2 ± 1, –2 ± 1, and –4 ± 1%, respectively, P < 0.05 for all) (see Figs. 1–2 and Table 1). A compensatory tachycardia was only evident during 15 cmH2O expiratory threshold loading (2 ± 1%, P < 0.05; see Fig. 2).
As reported in Table 1 and Fig. 2, mean arterial pressure was significantly elevated only during 15 cmH2O expiratory threshold loading (2 ± 1%, P < 0.05) owing to significant reductions in systemic vascular conductance (–4 ± 1%, P < 0.05, Fig. 3). Hindlimb blood flow and vascular conductance were also significantly reduced by –5 ± 2 and –7 ± 2%, respectively (P < 0.05 for both, see Fig. 3 and Table 1).
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During control conditions, cardiac output, stroke volume, heart rate, and mean arterial pressure did not vary significantly over the course of a breath (see Fig. 4). The addition of a 15 cmH2O expiratory threshold load significantly increased cardiac output and heart rate during the loaded, expiratory phase of the breath (P < 0.05 vs. end-expiratory levels, see Fig. 4). In contrast, stroke volume and mean arterial pressure were significantly decreased from end-expiratory levels during the inspiratory phase of the breath (P < 0.05 vs. end-expiratory levels).
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CHF Dogs
Changes in cardiovascular function over time. During control conditions, the inspiratory and expiratory PITP excursions averaged –13 ± 2 and 8 ± 2 cmH2O, respectively. The addition of 5, 10, or 15 cmH2O expiratory threshold loads resulted in increases in the peak expiratory PITP excursion of 15 ± 7% (P < 0.05.), 23 ± 7% (P < 0.05.), and 31 ± 7% (P < 0.05), respectively, and resulted in increases in mean PITP over the course of the entire breath of 1.2 ± 0.3 (P < 0.05), 2.1 ± 1.6 (P < 0.05), and 2.6 ± 0.2 cmH2O (P < 0.05). The magnitude of the inspiratory PITP excursion was not significantly affected across any of the expiratory loaded conditions relative to nonloaded breathing conditions.
The raw data traces from one representative trial in an animal after the induction of CHF are shown in Fig. 5, with the mean cardiac responses to increases in the expiratory PITP excursion over time in five dogs shown in Fig. 6. Steady-state cardiac output was significantly reduced by both 10 and 15 cmH2O expiratory threshold loads owing to significant reductions in stroke volume of 3 ± 1 and 5 ± 1%, respectively (see Figs. 5 and 6 and Table 3, P < 0.05 for all). A compensatory tachycardia was only evident during 15 cmH2O expiratory threshold loading (see Fig. 6, P < 0.05).
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Effects of expiratory loading on cardiovascular function at rest. Only a 5 cmH2O expiratory threshold load was tolerated by all of the animals at rest, which elicited an increase in the expiratory PITP excursion of 1.6 ± 0.8 cmH2O while the animals were healthy and 4.0 ± 1.5 cmH2O after the induction of CHF (P < 0.05 for both). None of the steady-state cardiovascular parameters measured were significantly affected by the application of a 5 cmH2O expiratory threshold load while the animals were healthy or after the induction of CHF.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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5%) and vascular conductance (7%). 2) Augmenting the inspiratory PITP excursion during 15 cmH2O expiratory threshold loading restored cardiac output and stroke volume to control levels, although hindlimb blood flow and vascular conductance remained depressed. 3) In the submaximally exercising dog with heart failure, the application of 10 and 15 cmH2O expiratory threshold loading significantly reduced cardiac output (2–3%) and stroke volume (3–4%), although only 15 cmH2O significantly reduced hindlimb blood flow (4%) and vascular conductance (5%). 4) In contrast to the healthy dog, augmenting the inspiratory PITP excursion during 15 cmH2O expiratory threshold loading in the CHF dog resulted in further reductions in cardiac output, stroke volume, hindlimb blood flow, and vascular conductance. Collectively, these data strongly suggest that augmented expiratory pressure has deleterious effects on cardiovascular function during exercise in both health and CHF. Expiratory threshold loading impairs cardiac function in healthy dogs during exercise by reducing cardiac preload.
In the present investigation, relatively small increases in expiratory PITP production (+3 cmH2O) significantly reduced cardiac output and stroke volume in healthy dogs during submaximal exercise, with greater increases in expiratory PITP resulting in reductions in stroke volume as large as –10% (see Fig. 9). Our observations that these reductions in stroke volume occur rapidly (onset < 10 s) and are directionally opposite to changes in systemic oxygen demand suggest that increases in the magnitude of the expiratory PITP excursion may mechanically constrain cardiac filling by reducing the transmural pressure gradient across the ventricles during diastole.
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During control, nonloaded breathing conditions in the healthy dog, we did not observe any significant within-breath changes in cardiac output or stroke volume in response to the normally produced inspiratory and expiratory PITP excursions. However, increasing the expiratory PITP excursion resulted in significant reductions in stroke volume during inspiration, whereas cardiac output was significantly increased during expiration owing solely to increases in heart rate. That these inspiratory reductions in stroke volume are not the primary cause for the reductions in steady-state stroke volume and cardiac output is supported by the observation that combined inspiratory and expiratory loading conditions do not have an effect on stroke volume or cardiac output. Instead, our data support the postulate that the increases in cardiac output during the expiratory phase of the breath result in a loss of central blood volume (5, 10) that is not regained during the ensuing inspiratory phase of the breath because of the relative prolongation of the expiratory phase of the breath. This notion is supported by the recent work of Stark-Leyva et al. (34) in healthy, exercising humans, which demonstrated that progressive hyperinflation during expiratory loaded conditions, which increases the negativity of the inspiratory PITP excursion, reduces the detrimental effect of increases in the expiratory PITP excursion on steady-state stroke volume and cardiac output.
Expiratory threshold loading impairs cardiac function in CHF dogs during exercise by increasing cardiac afterload.
After the induction of CHF in our animals, similar increases in expiratory PITP (4 cmH2O) significantly reduced stroke volume and cardiac output. However, the onset of the reductions in stroke volume was considerably delayed (onset of 30 s), despite the fact that the increases in mouth pressure and PITP in response to expiratory loading were very similar between health and CHF. A possible explanation for the reductions in stroke volume observed during expiratory loading is that the end-diastolic volume is modestly reduced by increases in expiratory PITP, which makes the ventricle more sensitive to the inspiratory PITP excursion during systole (8). This postulate is supported by our findings that, over the course of a breath, both cardiac output and stroke volume are significantly reduced during the inspiratory phase of the breath and return to end-expiratory levels only during the latter portion of expiration. Additionally, combined inspiratory and expiratory loading does not normalize stroke volume in animals with CHF but instead worsens cardiac function further.
Expiratory threshold loading reduces locomotor limb blood flow in both healthy dogs and dogs with CHF.
The addition of the highest expiratory load (15 cmH2O) significantly reduced hindlimb blood flow due to significant reductions in vascular conductance in these animals both while healthy and after the induction of CHF. The reductions in hindlimb vascular conductance appear to be due in part to a systemic sympathoexcitatory response to increases in expiratory PITP and expiratory muscle work in our animals both while healthy and after the induction of CHF. Furthermore, the percent changes in hindlimb vascular conductance were approximately double those observed in systemic vascular conductance (3% reduction in systemic conductance vs. a 6% reduction in hindlimb vascular conductance).
It is possible that the reductions in hindlimb vascular conductance with increases in expiratory PITP production are the result of reflex-mediated increases in sympathetic outflow originating from the activation of type III and IV thin-fiber afferents in the expiratory muscles (22), as the injection of lactic acid into the expiratory muscle vascular bed results in sympathetically-mediated reductions in locomotor limb blood flow in the resting and exercising healthy dog (32). However, we cannot exclude the possibility that increases in expiratory PITP activated the cardiopulmonary and aortic baroreflexes (2), both of which would send the sympathoexcitatory signal of an apparent hypotension to the cardiovascular control centers in the brain stem.
Expiratory threshold loading in the dog as a model of expiratory flow limitation.
The application of an expiratory threshold load to submaximally exercising dogs in this investigation successfully mimicked several key changes in ventilatory mechanics associated with chronic expiratory flow limitation, including increases in expiratory pressure production (12, 25, 26), a relative prolongation of expiratory time (25), progressive dynamic hyperinflation (29), reductions in peak expiratory flow rate (12, 25), and a progressive alveolar hypoventilation with increasing severities of airflow limitation (27). These changes occurred despite the fact that our expiratory threshold loading device did not constrain expiratory airflow. Thus humans or animals may choose to defend their end-expiratory lung volume and alveolar ventilation if an expiratory threshold load is added under conditions in which background ventilatory drive is considerably higher (e.g., exercise at higher intensities). However, under the present conditions we feel that our expiratory threshold loading intervention effectively replicates the pulmonary mechanics observed in patients with severe expiratory flow limitation.
Limitations
In the present investigation, the application of an expiratory load resulted in progressive dynamic hyperinflation, as evidenced by increases in the transpulmonary pressure at end expiration (i.e., zero airflow conditions) (14). Thus we cannot rule out the possibility that these increases in lung volume impaired cardiac filling because of reductions in the size and compliance of the cardiac fossa (17). However, two observations would speak against this phenomenon being a primary determinant of the cardiovascular responses to expiratory loading. First, the shear modulus of the lung is relatively low over most operating lung volumes, thus making it more likely to be deformed rather than compressing or deforming another object (15). Second, the investigation of Stark-Levya et al. (34) demonstrated that the reductions in cardiac output and stroke volume in response to expiratory threshold loading were actually smaller when the subjects were allowed to hyperinflate, which strongly suggests that the central cardiovascular responses to expiratory loading are mediated primarily by increases in PITP.
Implications for Humans During Exercise
When extrapolating findings from quadrupeds to upright humans, it is important to consider the fact that the directionality of the hydrostatic column is reversed; that is, during exercise 70% of the circulating blood volume is below the heart in humans, whereas 70% of the circulating blood volume is above the heart in the exercising dog (33). However, it is likely that this change in the directionality of the hydrostatic pressure would favor even larger decreases in stroke volume and cardiac output with expiratory loading in healthy humans, because a given increase in expiratory PITP would only have to overcome the increases in intravascular pressure due to the peripheral skeletal muscle pump.
Patients with CHF exhibit augmented inspiratory and expiratory PITP excursions during submaximal exercise. Thus it may be possible that the normally produced respiratory muscle pressures compromise cardiac function during exercise in CHF and may further compromise cardiac function during an episode of acute decompensation or if the patient also suffers from COPD. Support for such a postulate comes from the observation that both inspiratory muscle (28) and combined inspiratory and expiratory muscle unloading (19) improve exercise performance in patients with CHF. Furthermore, our data support a role for inspiratory pressure production as a major contributor to increases in ventricular afterload with expiratory loading (which makes the confounding influence of the differences in the directionality of the hydrostatic column negligible); we believe that cardiovascular consequences of expiratory flow limitation in humans with CHF would be very similar to those observed in the present investigation.
Finally, we do acknowledge that the magnitude of the changes in blood flow we observed in the present investigation is rather small and may have a relatively modest impact on locomotor limb fatigue at the workloads examined. However, we expect that the cardiovascular effects of expiratory loading would persist during higher intensities of exercise. During maximal exercise, whole body maximal oxygen uptake is reduced directly in proportion to reductions in maximal oxygen delivery (9, 31), and reductions in blood flow, per se, can significantly increase locomotor limb fatigue (3). Consequently, it is plausible to suggest that both maximal oxygen uptake and exercise performance would be significantly reduced in the presence of lowered locomotor limb blood flow and oxygen delivery due to expiratory loading (or expiratory flow limitation) during high-intensity exercise.
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GRANTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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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.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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O2 max in women. Med Sci Sports Exerc 32: 1101–1108, 2000.[ISI][Medline]O2 max in the exercise-trained human quadriceps. J Appl Physiol 86: 1048–1053, 1999.This article has been cited by other articles:
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  B. J. Taylor and L. M. Romer Effect of expiratory muscle fatigue on exercise tolerance and locomotor muscle fatigue in healthy humans J Appl Physiol, May 1, 2008; 104(5): 1442 - 1451. [Abstract] [Full Text] [PDF]
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L. M. Romer and M. I. Polkey Exercise-induced respiratory muscle fatigue: implications for performance J Appl Physiol, March 1, 2008; 104(3): 879 - 888. [Abstract] [Full Text] [PDF]
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 M. K. Stickland, A. T. Lovering, and M. W. Eldridge Exercise-induced Arteriovenous Intrapulmonary Shunting in Dogs Am. J. Respir. Crit. Care Med., August 1, 2007; 176(3): 300 - 305. [Abstract] [Full Text] [PDF]
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) and during the application of 15 cmH2O expiratory threshold loading (
) in all 5 dogs while healthy. Although there is no significant within-breath modulation of any cardiac parameter during control conditions, the addition of a 15 cmH2O expiratory load resulted in significant reductions in stroke volume and mean arterial pressure over the course of the breath, whereas cardiac output was significantly increased during expiration. QTOT, cardiac output; SV, stroke volume; MAP, mean arterial blood pressure; EELV-C and EELV-EL, end-expiratory lung volume during control conditions and expiratory loading, respectively. *P < 0.05 for peak or nadir values vs. end-expiratory levels; 
P < 0.05 for peak or nadir values vs. control conditions.
PM dt, an estimate of the change in mean PITP). Healthy dogs: a more positive