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Am J Physiol Heart Circ Physiol 292: H580-H592, 2007. First published September 22, 2006; doi:10.1152/ajpheart.00211.2006
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The effects of inspiratory intrathoracic pressure production on the cardiovascular response to submaximal exercise in health and chronic heart failure

Jordan D. Miller, Curtis A. Smith, Sarah J. Hemauer, and Jerome A. Dempsey

John Rankin Laboratory of Pulmonary Medicine, University of Wisconsin-Madison, Madison, Wisconsin

Submitted 27 February 2006 ; accepted in final form 22 August 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
We sought to determine whether the normal inspiratory intrathoracic pressures (PITP) produced during exercise contribute to the blunted cardiac output and locomotor limb blood flow responses observed in chronic heart failure (CHF). Five chronically instrumented dogs exercised on a treadmill at 2.5 mile/h at 5% grade while healthy or after the induction of tachycardia-induced CHF. We observed several key differences in the cardiovascular responses to changes in the inspiratory PITP excursion between health and CHF; namely, 1) removing ~70% of the normally produced inspiratory PITP excursion during exercise (with 15 cmH2O inspiratory positive pressure ventilation) significantly reduced stroke volume (SV) in healthy animals by 5 ± 2% (P < 0.05) but significantly increased SV and cardiac output (QTOT) in animals with CHF by 5 ± 1% (P < 0.05); 2) doubling the magnitude of the inspiratory PITP excursion had no effect on SV or QTOT in healthy animals but significantly reduced steady-state QTOT and SV in animals with CHF by –4 ± 3% and –10 ± 3%, respectively; 3) removing the majority of the normally produced inspiratory PITP excursion had no effect on blood flow distribution in healthy animals but increased hindlimb blood flow (9 ± 3%, P < 0.05) out of proportion to the increases in QTOT; and 4) the only similarity between healthy and CHF animals was that increasing the inspiratory PITP excursion significantly reduced steady-state locomotor limb blood flow by 5 ± 2% and 6 ± 3%, respectively (P < 0.05 for both). We conclude that 1) the normally produced inspiratory PITP excursions are required for a maximal SV response to submaximal exercise in healthy animals but detrimental to the SV and QTOT responses to submaximal exercise in CHF, 2) the respiratory muscle ergoreflex tonically restrains locomotor limb blood flow during submaximal exercise in CHF, and 3) excessive inspiratory muscle work further compromises cardiac function and blood flow distribution in both health and CHF.

muscle metaboreflex; respiratory muscle pump; cardiopulmonary interactions

MUCH OF OUR UNDERSTANDING of the interactions between the cardiovascular and pulmonary systems has been derived from observations in anesthetized, mechanically ventilated animals. A near universal finding is that relatively small increases in mean intrathoracic pressure (PITP, <5 cmH2O) cause marked reductions in cardiac output, stroke volume, and systemic oxygen delivery in anesthetized preparations (10, 21, 26, 43, 44). However, the depressant effects of anesthesia on autonomic reflexes make the extrapolation of these data to an awake animal difficult at best (1, 10).

Few observations on the interactions between the cardiovascular and respiratory systems have been made in the exercising animal or human. The earliest observations were made by Guntheroth and colleagues (28, 42), who reported that changes in venous return and stroke volume were frequently phasic with spontaneous respiration in the healthy, exercising dog. However, Harms et al. (14) conducted the first experiments to experimentally reduce the inspiratory PITP excursion and found significant reductions in both cardiac output and stroke volume, which suggested the normally produced inspiratory PITP excursion was required for preload recruitment and a normal stroke volume response to maximal exercise. Conversely, blood flow to the locomotor limb was increased with inspiratory muscle unloading, suggesting that the blood flow demands of the respiratory muscles during maximal exercise could result in a sympathetically mediated "stealing" of blood flow from the locomotor limb (13).

A growing body of literature suggests that patients with chronic heart failure (CHF) may have a cardiac response to positive pressure ventilation that is opposite to that observed in normal, healthy subjects. More specifically, several groups have reported that patients and animals with severe chronic heart failure exhibited increases in cardiac output and stroke volume in response to acutely applied continuous positive airway pressure at rest (7, 9, 10) that may be a result of reductions in left ventricular transmmural pressure at end systole (10). If this is in fact true, one would expect that the more negative inspiratory PITP excursions associated with whole-body exercise would contribute to the blunted cardiac output and stroke volume responses to exercise in these patients. This may be especially true in patients with more severe CHF, where more negative inspiratory PITP excursions due to reductions in lung compliance (2) and an augmented hyperventilatory response to exercise (36) result in disproportionate increases in transmural pressure at a given metabolic rate.

However, evaluation of the direct mechanical effects of PITP on the heart are complicated by reductions in cardiac norepinephrine spillover (17), reductions in peripheral muscle sympathetic nerve activity (15), and systemic vascular resistance in response to continuous positive airway pressure (CPAP) in patients with CHF. Although it would appear that spontaneous respiratory muscle work contributes to sympathetic outflow only during high-intensity exercise in healthy humans (46), the blunted cardiac output response and exaggerated ventilatory response to exercise in both patients and animals with CHF may cause a competition for blood flow between the respiratory muscle and locomotor limb muscles at much lower workloads.

Thus, in the present study, we used chronically implanted ultrasonic flow probes to measure beat-by-beat changes in cardiac output and its distribution in a canine model of tachycardia-induced CHF, which allowed us to measure relatively rapid (e.g., onset of <10 s) changes in stroke volume following alterations in the inspiratory PITP excursion, which would exclude the possibility of cardiac output or stroke volume merely changing in parallel with oxygen consumption (14). We tested the following hypotheses: 1) normally produced inspiratory PITP excursions are required for a normal stroke volume response to submaximal exercise in the healthy dog, 2) normally produced PITP excursions do not compromise locomotor limb blood flow during submaximal exercise due to the presence of a considerable cardiac output reserve, 3) the normally produced inspiratory PITP excursion is detrimental to the stroke volume response to submaximal exercise in the dog with pacing-induced CHF, and 4) reducing the magnitude of the inspiratory PITP excursion will preferentially redistribute blood flow toward the locomotor limbs during submaximal exercise in the dog with pacing-induced CHF.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Chronic Instrumentation

All surgical and experimental procedures were approved by the Institutional Animal Care and Use Committee at the University of Wisconsin-Madison 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 lie quietly on a bed and to run on a motorized treadmill. After the training, two surgical procedures separated by at least 2 wk were required to instrument the dogs for study. The animals were induced using pentothal sodium (20 mg/kg), and a surgical plane of anesthesia was maintained using halothane gas (1%). 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 or by signal averaging each variable over the course of a breath using custom analysis software developed in our laboratory.

Protocols

Time line 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. Each animal performed the protocols described below over the course of 2 to 3 wk while healthy. Chronic heart failure was then induced by rapid ventricular pacing at 210 beats/min for 3–6 wk. The animals were routinely exercised and underwent each experimental protocol 2 to 3 times/wk during this pacing period to maintain a constant level of training and familiarity with the protocol. The pacemaker was turned off for 15–20 min, 2 to 3 times/wk to track changes in cardiac function using echocardiography. Briefly, animals were placed in the right lateral decubitus position on an examination table, and images were acquired in the short axis using standard echocardiographic landmarks (6). The area of the left ventricular cavity was measured using a computerized planimeter, and end-diastolic area (maximal area), end-systolic area (minimal area), and area ejection fraction [(end-diastolic volume – end-systolic volume)/end-diastolic volume] were calculated. 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 mile/h at 5% grade). The protocols were then repeated while the animal was in heart failure over the course of 1 to 2 wk. The baseline hemodynamic consequences of the pacing-induced heart failure are reported in Table 1.


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  		Table 1. Echocardiographic measurements before and after tachycardia-induced CHF

 
Animal preparation for exercise studies. The animal was guided onto a motorized treadmill and stood quietly while all hardwired instrumentation was connected. The tracheostomy was cannulated with a cuffed endotracheal tube (4.0–6.0 mm ID). Airflow was measured by a heated pneumotachograph that was connected to the endotracheal tube. The treadmill was then started, and the animal exercised at 2.5 mile/h at 5% grade for a minimum of 4 min or until cardiac output, hindlimb blood flow, blood pressure, and minute ventilation reached a steady state. At this point, one of the following two protocols was initiated. If the animal exhibited any signs of distress or discomfort during the intervention or exercise bout (excessive head movement, unwillingness to continue exercise despite encouragement, etc.), the intervention and/or exercise bout was immediately stopped.


INSPIRATORY UNLOADING: HOW DO THE NORMALLY PRODUCED INSPIRATORY PITP EXCURSIONS AFFECT CARDIOVASCULAR FUNCTION DURING EXERCISE IN HEALTH AND CHF? A customized non-rebreathing valve was then connected to the pnemotachograph that allowed for the connection of a two-arm, piston-operated, prototype ventilator. Inspiratory positive pressure ventilation was then applied in random order at levels of 5, 10, and 15 cmH2O for a minimum of 1 min (see representative raw data trace in Fig. 1).


Figure 1
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  		Fig. 1. Raw data traces showing the cardiovascular consequences of 15 cmH2O inspiratory positive pressure ventilation (IPPV) in 1 representative dog while healthy (left) and after the induction of chronic heart failure (CHF; right). The x-axes are aligned to the mean value of the control conditions. Note that 15 cmH2O IPPV elicited relatively rapid reductions in stroke volume (onset < 10 s), whereas cardiac output was unaffected due to a compensatory tachycardia. After the induction of CHF, however, stroke volume is rapidly increased at the onset of IPPV, and these increases in stroke volume are maintained for the duration of IPPV administration.

 

INSPIRATORY LOADING: HOW DO AUGMENTED INSPIRATORY PITP EXCURSIONS AFFECT CARDIOVASCULAR FUNCTION DURING EXERCISE IN HEALTH AND CHF? A fixed resistance (~40 cmH2O·l–1·s–1) was placed on the inspiratory arm of the breathing circuit for a minimum of 30 s (see representative raw data trace in Fig. 4).


Figure 4
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  		Fig. 4. Raw data traces showing the cardiovascular consequences of inspiratory loading in 1 representative dog while healthy (left) and after the induction of CHF (right). The x-axes are aligned to the mean value of the control conditions. Note that augmenting the inspiratory PITP excursion had no effect on stroke volume in healthy dogs but rapidly decreased stroke volume in the animals with CHF.

 
Animal preparation for resting studies. At the beginning of each study, the dog was placed on a padded bed in a sound-attenuated room, at which point all hardwired instrumentation was connected. The tracheostomy was cannulated with a cuffed endotracheal tube (4.0–6.0 mm ID). Airflow was measured by a heated pneumotachograph connected to the endotracheal tube.

Once the animal entered non-rapid eye movement (REM) sleep, one of the following two interventions was performed: 1) the magnitude of the inspiratory PITP excursion was reduced by the application of 5 cmH2O inspiratory positive pressure ventilation (IPPV) using a mechanical ventilator (Veolar, Hamilton), or 2) the magnitude of the inspiratory PITP excursion was increased by applying a fixed inspiratory resistance (~40 cmH2O·l–1·s–1).

Data Analysis

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, mean arterial pressure, and hindlimb blood flow. Data averaged in 5-s intervals were used to derive systemic and hindlimb vascular conductances, which were calculated as the ratio cardiac output or hindlimb blood flow to mean arterial pressure, respectively.

For each individual variable, 5-s averages were obtained during the control period and for 1 min after the onset of each intervention. Each 5-s block during inspiratory unloading or inspiratory loading was compared with its preceding control condition using a two-way ANOVA with repeated measures and Dunnett's post hoc testing. Statistical significance was considered to be present when P < 0.05.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Effects of Reducing the Magnitude of the Inspiratory PITP Excursion on Cardiovascular Function

Healthy conditions. The inspiratory PITP excursion averaged –13 ± 2 cmH2O in healthy dogs under control conditions. The cardiovascular responses to 15 cmH2O IPPV in health are shown in raw data traces in Fig. 1, left, with the mean cardiac responses of all five dogs shown in Fig. 2. The application of 15 cmH2O IPPV reduced the magnitude of the negative inspiratory PITP excursion by 69 ± 9% (P < 0.05, see Fig. 2) and significantly reduced stroke volume within 10 s of the onset of IPPV (P < 0.05, see Figs. 1, left, and 2). Cardiac output was not significantly affected due to the presence of a compensatory tachycardia (see Table 2). Systemic vascular conductance, hindlimb conductance, hindlimb blood flow, and mean arterial pressure were not significantly changed with 15 cmH2O IPPV (see Fig. 3).


Figure 2
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  		Fig. 2. Effects of 15 cmH2O IPPV on cardiac function over time (n = 5 dogs, average of 3 ± 1 trials/dog) in healthy dogs ({circ}) and dogs with CHF (bullet). Note that the effect of reducing the intrathoracic pressure (PITP) excursion with 15 cmH2O IPPV on stroke volume is directionally opposite between healthy dogs and dogs with CHF. *P < 0.05 for each time point vs. control conditions.

 

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  		Table 2. Summary of cardiovascular consequences of inspiratory unloading and loading

 

Figure 3
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  		Fig. 3. Effects of 15 cmH2O IPPV on systemic and hindlimb vascular conductances over time (n = 4 dogs, average of 3 ± 1 trials/dog) in healthy dogs ({circ}) and dogs with CHF (bullet). Whereas reducing the magnitude of the inspiratory pressure excursion with 15 cmH2O IPPV had no effect on limb blood flow in healthy dogs, 15 cmH2O IPPV significantly increased systemic vascular conductance, hindlimb vascular conductance, and hindlimb blood flow in dogs with CHF. *P < 0.05 for each intervention vs. its own respective control.

 
CHF conditions. Following 3–6 wk of rapid cardiac pacing, the animals exhibited significant increases in end-diastolic and end-systolic cardiac left ventricular areas at rest, as well as significant reductions in left ventricular area ejection fraction at rest (P < 0.05 for all, see Table 1). Cardiac output, stroke volume, and mean arterial pressure were all reduced at a constant, submaximal exercise workload, and heart rate was significantly increased (P < 0.05 for all, see Table 2).

After the induction of CHF, the inspiratory PITP excursion averaged –12 ± 1 cmH2O (P = not significant vs. healthy), and the application of 5, 10, or 15 cmH2O IPPV elicited similar, significant reductions in the magnitude of the negative inspiratory PITP excursion of 22 ± 3%, 52 ± 13%, or 72 ± 16% (P < 0.05 for all vs. control), respectively, compared with control conditions.

In contrast to the effects of IPPV under healthy conditions, all three levels of IPPV significantly increased left ventricular stroke volume within the first 15 s of IPPV (see Fig. 2), with this effect being sustained for the duration of the application of IPPV (see steady-state responses reported in Table 2). Furthermore, 15 cmH2O IPPV significantly increased cardiac output (P < 0.05) following the induction of CHF (see Fig. 2).

Systemic vascular conductance was increased by 1.5 ± 1.0 (P < 0.05), 1.6 ± 1.5 (P < 0.05), and 3.4 ± 1.1 ml·min–1·mmHg–1 (P < 0.05) during the first minute of 5, 10, and 15 cmH2O IPPV (see Fig. 3 and Table 2) in animals with CHF. Hindlimb vascular conductance and blood flow were also significantly increased by all three levels of IPPV (see Fig. 3 and Table 2) in animals with CHF. That there was a preferential vasodilation in the exercising hindlimb with 15 cmH2O IPPV is supported by the observation that the percent increase in hindlimb vascular conductance was more than double that observed in systemic vascular conductance (hindlimb vascular conductance, 10.1 ± 2.5%; and systemic vascular conductance, 2.9 ± 1.6%). Mean arterial pressure was not significantly affected by any level of IPPV in animals with CHF.

Changes in minute ventilation, breathing pattern, and arterial blood-gas parameters are reported in Table 3. In general, 5, 10, and 15 cmH2O IPPV resulted in significant increases in minute ventilation that were mediated exclusively by increases in tidal volume. Consequently, arterial PO2 was slightly (but significantly) increased and PCO2 was significantly decreased with both 10 and 15 cmH2O IPPV.


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  		Table 3. Ventilatory and blood-gas responses from rest to exercise and to inspiratory pressure support ventilation or inspiratory loading

 
Effects of a More Negative Inspiratory PITP Excursion on Cardiovascular Function

Healthy conditions. Raw data traces showing the cardiovascular responses to 1 min of inspiratory loading in one dog are shown in Fig. 4, with the mean cardiac responses of the four dogs with terminal aortic flow probes shown in Fig. 5. The addition of a fixed inspiratory resistance increased the magnitude of the inspiratory PITP excursion to 192 ± 39% of control conditions (P < 0.05). Unlike 15 cmH2O IPPV, inspiratory loading had no significant effect on left ventricular stroke volume, cardiac output, systemic vascular conductance, and heart rate (see Figs. 2, 4, and 5). However, mean arterial pressure was significantly elevated during the first minute of inspiratory loaded conditions as a result of a combined effect of slight increases in cardiac output and slight decreases in systemic vascular conductance (see Fig. 6).


Figure 5
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  		Fig. 5. Effects of inspiratory loading on cardiac function over time (n = 5 dogs, average of at least 2 trials per dog per condition) in healthy dogs ({circ}) and dogs with CHF (bullet). Note that in the healthy dog, increasing the magnitude of the inspiratory PITP excursion had negligible effects on cardiac function. However, after the induction of CHF, inspiratory loading resulted in significant reductions in cardiac output and stroke volume and increases in heart rate. Significant main effects and absolute values during control conditions are reported in Table 2. *P < 0.05 vs. control conditions.

 

Figure 6
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  		Fig. 6. Effects of inspiratory loading on systemic and hindlimb vascular conductances over time (n = 4 dogs, average of 3 ± 1 trials/dog) in healthy dogs ({circ}) and dogs with CHF (bullet). Increasing the magnitude of the inspiratory pressure excursion did not have a significant effect on systemic vascular conductance in healthy or CHF animals but did significantly reduced hindlimb vascular conductance and hindlimb blood flow in both groups. *P < 0.05 for each intervention vs. its own respective control. #P < 0.05 for each mean value vs. its respective control value for each time period denoted.

 
Hindlimb vascular conductance and blood flow progressively declined during the application of the inspiratory load and were significantly lower than control conditions during the second minute of inspiratory loading (see Fig. 6). Subsequently, the fraction of the total cardiac output going to the hindlimb was slightly but significantly reduced during inspiratory loaded conditions (20 ± 1% during control and 19 ± 1% during inspiratory loading, P < 0.05; range from 82% to 98% of control).

CHF conditions. Raw data traces showing the cardiovascular responses to 1 min of inspiratory loading in one dog are shown in Fig. 4, with the mean cardiac responses of the four dogs with terminal aortic/hindlimb blood flow probes shown in Fig. 5. The addition of a fixed inspiratory resistance increased the magnitude of the inspiratory PITP excursion by 11 ± 1 cmH2O (P < 0.05). Significant decreases in left ventricular stroke volume occurred within 15 s of the onset of inspiratory loading (see Figs. 4 and 5). Cardiac output was significantly decreased despite the presence of a significant increase in heart rate (P < 0.05 for both; see Fig. 5).

Mean arterial pressure was significantly reduced during the first minute of inspiratory loaded conditions as a result of the significant reductions in cardiac output (see Figs. 4 and 6). Though inspiratory loading did not significantly affect systemic vascular conductance, hindlimb vascular conductance and blood flow were significantly reduced by 5 ± 3% and 6 ± 3%, respectively (see Fig. 6). The fraction of the total cardiac output going to the hindlimb was not significantly altered by inspiratory loading (21 ± 2% during control and 20 ± 2% during inspiratory loading, P = not significant).

The addition of a fixed inspiratory load significantly reduced minute ventilation primarily due to reductions in tidal volume (see Table 3), although arterial PO2 and PCO2 were not significantly altered with inspiratory loading (see Table 3). Maintaining the arterial PO2 at control levels by increasing the inspired PO2 in four of the dogs did not alter the qualitative or quantitative cardiovascular responses to inspiratory loading.

Stimulus-Response Relationship Between Stroke Volume and PITP

The 5-s averages of stroke volume are plotted versus the 5-s averages of integrated mouth pressure per breath for each dog while healthy and after the induction of CHF are shown in Figs. 7, A and B, respectively. Note that the effects of changing PITP are directionally opposite under healthy and CHF conditions. Note that during healthy conditions, interventions that reduced the magnitude of the inspiratory PITP excursion (i.e., inspiratory unloading) significantly reduced stroke volume. The largest reductions in stroke volume (>10%) were achieved when the inspiratory pressure excursion was reduced by 75–85% in two dogs using 20 cmH2O IPPV. However, after the induction of CHF, interventions that reduced the negativity of the inspiratory PITP excursion increased stroke volume, whereas interventions that made the inspiratory PITP excursion more negative decreased stroke volume.


Figure 7
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  		Fig. 7. Stimulus-response relationship between stroke volume and integrated mouth pressure (PM dt, an estimate of the change in mean PITP) for all animals studied. A: a more positive PM dt, which results in a positive shift in PITP, elicited significant reductions in stroke volume in the healthy dog. B: in contrast to the responses observed in the animals while healthy, a more positive PM dt elicited significant increases in stroke volume after the induction of CHF. Additionally, a more negative PM dt elicited significantly reduced stroke volume in animals with CHF.

 
Effects of IPPV and Inspiratory Loading on Cardiovascular Function at Rest

Healthy conditions. Neither reducing the inspiratory PITP excursion from –4 ± 1 to 2 ± 1 cmH2O using 5 cmH2O IPPV nor augmenting the inspiratory PITP excursion to –19 ± 12 cmH2O with a fixed inspiratory load significantly changed any of our measured cardiovascular parameters under resting conditions in healthy dogs (data not shown).

CHF conditions. Reducing the inspiratory PITP excursion from –6 ± 2 to 2 ± 2 cmH2O with 5 cmH2O IPPV significantly increased cardiac output and stroke volume by 7 ± 3% and 7 ± 2%, respectively (P < 0.05 for both) in dogs with CHF. In contrast, increasing the inspiratory PITP excursion to –20 ± 10 cmH2O significantly reduced stroke volume by 5 ± 2% (P < 0.05) in dogs with CHF, although cardiac output was maintained by a compensatory tachycardia.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
This study identifies several key differences in the cardiovascular responses to changes in the inspiratory PITP excursion between health and severe CHF during submaximal exercise; namely, 1) removing the majority of the normally produced inspiratory PITP excursion during exercise (with 15 cmH2O IPPV) significantly reduced stroke volume in healthy animals but resulted in significant increases in stroke volume and cardiac output in animals with CHF, 2) increasing the magnitude of the inspiratory PITP excursion had no effect on stroke volume or cardiac output in healthy animals but significantly reduced steady-state cardiac output and stroke volume in animals with CHF, 3) removing the majority of the normally produced inspiratory PITP excursion had no effect on blood flow distribution in healthy animals but significantly increased the fraction of cardiac output directed to the locomotor limb in animals with CHF, and 4) increasing the inspiratory PITP excursion (via the addition of a resistive load) significantly reduced steady-state locomotor limb blood flow and vascular conductance in both health and CHF.

Normally Produced Inspiratory PITP Excursions are Required for Normal Stroke Volume Response to Exercise in Health But Contribute to Blunted Cardiac Output Response to Exercise in CHF

In the present study, removing the majority of the normal inspiratory PITP excursion with 15 cmH2O IPPV in healthy animals elicited rapid (onset < 10 s) reductions in stroke volume during submaximal exercise. These reductions in stroke volume averaged ~5% when ~70% of the normal PITP excursion was removed but ranged from 10–15% when >75% of the normal inspiratory PITP excursion was removed with 20 cmH2O IPPV (see Fig. 7). These changes occurred despite the presence of the peripheral skeletal muscle pump forcing blood centrally. This suggests that the normally produced negative inspiratory PITP excursions participate in the maintenance of central blood volume and left ventricular preload by widening the transmural pressure gradient across the walls of the heart. Such a postulate is supported by observations in acutely instrumented anesthetized or sedated animals, where the application of relatively low levels of positive pressure ventilation (5–10 cmH2O) elicits significant reductions in end-diastolic volume and stroke volume (20, 25).

Our changes in stroke volume are considerably smaller than those observed in anesthetized preparations, with this discrepancy likely being attributable not only to the peripheral skeletal muscle pump forcing blood centrally in our exercising animals but also due to intact, nonobtunded reflexes. Evidence for the latter comes from the observation that our healthy animals maintained cardiac output during inspiratory unloading conditions by increasing heart rate, a compensatory mechanism that serves to lower right atrial pressure and widen the pressure gradient for venous return. Thus, when the heart rate reserve is exhausted [such as during maximal exercise (14)] or reduced by anesthesia (1), our findings suggest that the heart would become considerably more dependent on the preload recruiting effect of the inspiratory PITP excursion to maintain cardiac output.

In the present study, removing the majority of the normal inspiratory PITP excursion with 15 cmH2O IPPV in animals with CHF resulted in significant increases in stroke volume and cardiac output during submaximal exercise. These changes in stroke volume are directionally opposite to those observed in these animals while healthy and to healthy humans receiving IPPV during maximal exercise (14). This suggests that the normally produced negative inspiratory PITP excursions are detrimental to the stroke volume and cardiac output responses to exercise in CHF and are likely to impede left ventricular emptying by widening the left ventricular transmural pressure gradient. This hypothesis is supported by observations in acutely instrumented sedated pigs with pacing-induced CHF, where the application of continuous positive airway pressure (CPAP) elicits significant reductions in end-systolic volume while leaving end-diastolic volume relatively unchanged (9). However, CPAP unloads inspiration and loads expiration, thus precluding the determination of the specific effects of the normal inspiratory PITP excursions on cardiovascular function.

Can Increased Inspiratory PITP Excursions Augment Venous Return and Cardiac Output?

In contrast to the effects of reducing the magnitude of the normally occurring inspiratory PITP excursion, nearly doubling the magnitude of the normal inspiratory PITP excursion (via the addition of an inspiratory resistive load) did not have an effect on steady-state left ventricular stroke volume, cardiac output, or heart rate during submaximal exercise in our healthy animals. Our finding that steady-state stroke volume is unaffected by more negative inspiratory PITP excursions is consistent with observations made in healthy, anesthetized animals subjected to similar inspiratory loading protocols (35), although it remains unclear whether the healthy left ventricle is able to maintain stroke volume as a result of afterload insensitivity, preload recruitment, or increases in ventricular contractility under such conditions.

Several other investigations have reported that cardiac output and heart rate increase out of proportion to metabolic rate in response to a variety of inspiratory loading protocols in resting humans. Thus, these authors have concluded that exaggerated negative inspiratory PITP excursions are an independent contributor to increases in venous return and cardiac output (3). However, previous reports from our laboratory and others have provided both theoretical (27, 34) and empirical (11, 24) evidence that this is not likely to be the case. More specifically, large reductions in right atrial pressure have repeatedly been shown to result in the collapse of the inferior vena cava in both dogs (11, 16) and humans (45), especially when abdominal pressure is elevated [as is the case with diaphragmatic descent (21)]. Additionally, even if the abdominal vascular zone conditions were appropriate for the respiratory muscle pump to increase venous return from the limbs during the inspiratory phase of a breath (44), equal and opposite reductions in locomotor limb venous return during the expiratory phase of the breath are likely to render net flow in the steady state unchanged (24). Our present findings add further support to our working hypothesis that transient increases in venous return brought about by exaggerated negative inspiratory PITP excursions cannot alter steady-state blood flow (33).

In contrast to the effects in the healthy animal, in CHF, doubling the magnitude of the normal inspiratory PITP excursion significantly reduced steady-state left ventricular stroke volume and cardiac output despite significant increases in heart rate. This strongly suggests that, unlike the healthy heart, the ability of the autonomic nervous system to compensate for increases in the transmural pressure gradient across the left ventricular free wall was very limited in these animals after the induction of CHF. Such a notion is supported by recent findings from O'Leary et al. (32) demonstrating that the inotropic left ventricular response to metaboreflex activation from the locomotor limb is markedly impaired in dogs with CHF, with these animals relying heavily on peripheral vasoconstriction to increase arterial driving pressure in response to hindlimb ischemia (4, 12).

Does a Tonically Active Respiratory Muscle "Ergoreflex" Limit Locomotor Limb Blood Flow During Submaximal Exercise in Health and CHF?

In the present study, in healthy animals, even the highest level of inspiratory unloading did not increase locomotor limb arterial blood inflow or vascular conductance. This finding agrees with previous inspiratory unloading studies from our laboratory in submaximally exercising humans (46) and supports the notion that the normal blood flow demand of the respiratory muscles does not compromise locomotor limb blood flow when respiratory muscle work is moderate and a significant cardiac reserve is present.

In contrast, in animals with CHF, when the magnitude of the inspiratory PITP excursion was reduced by ~70% with 15 cmH2O IPPV, hindlimb vascular conductance increased out of proportion to the increases in systemic vascular conductance, such that ~45% of the increase in systemic conductance occurred in the exercising hindlimb. Our animals had a cardiopulmonary response to exercise very similar to that observed in patients with CHF, namely, an excessive hyperventilatory response to exercise (36), a tachypneic and inefficient breathing pattern (2), and a blunted cardiac output response to exercise (4) (see Tables 2 and 3). This combination of excessive respiratory muscle work combined with a limited oxygen delivery is likely to be sufficient to cause the respiratory muscle metaboreflex to be tonically active (and persistently "stealing" blood flow from the locomotor limb) in CHF. This hypothesis is supported by observations in the exercising rat with CHF, where respiratory muscle blood flow is significantly elevated (29) and locomotor limb blood flow is significantly reduced (30). That there is significant sympathetically mediated constraint of locomotor limb blood flow in human submaximal exercise is supported by the observation that the acute blockade of {alpha}-adrenergic receptors significantly increases leg blood flow during submaximal treadmill exercise (19), and peak locomotor limb perfusion is only attained when a single locomotor limb is exercised (22). Although this investigation is the first to demonstrate experimentally that the normal blood flow demands of the respiratory muscles are sufficient to reduce blood flow to the exercising locomotor limbs in CHF, the relative contributions of the respiratory muscle ergoreflex, peripheral muscle ergoreflex (37, 39), carotid chemoreceptor afferent input (40, 41), and peripheral vascular dysfunction (18) to the blunted locomotor limb blood flow response to exercise in CHF are only beginning to be understood (8).

On the other hand, inspiratory loading in the present study elicited similar reductions in locomotor limb blood flow in both healthy and CHF animals that were due in large part to reductions in limb vascular conductance. Thus, it would appear that substantial increases in inspiratory muscle work (i.e., >200% of control) are sufficient enough to elicit a preferential, sympathetically mediated vasoconstriction in the exercising hindlimb in both health and CHF.

Implications for Humans

Perhaps the greatest difference between humans and quadrupeds is 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 (38). However, we feel the directionality of this difference would favor an even larger role of the respiratory muscle pump in maintaining central blood volume in the healthy, submaximally exercising human. In the exercising dog, increases in right atrial pressure as a result of increases in PITP (e.g., inspiratory unloading conditions) must overcome a driving pressure for venous return comprised of two primary forces: 1) a hydrostatic column forcing blood centrally, and 2) the peripheral skeletal muscle pump. Conversely, in the exercising human, an increase in right atrial pressure associated with inspiratory unloading must primarily overcome the driving pressure due to the peripheral skeletal muscle pump, which expends energy to force blood centrally against the hydrostatic column. Reciprocally, we believe that reductions in right atrial pressure under appropriately controlled conditions will not serve to increase venous return, since losses in peripheral venous recoil due to the central translocation of blood and increases in inferior vena caval resistance will serve to limit steady-state increases in stroke volume and cardiac output (11) [a postulate supported by observations in the maximally exercising human (14)].

As noted in the introduction, low levels of IPPV (5 cmH2O) elicit substantial increases in exercise performance in patients with CHF (31). Interestingly, reducing the work of breathing using either a helium-oxygen mixture or IPPV does reduce sensations of locomotor limb discomfort (23). Thus our data would suggest that these improvements in exercise performance and ratings of perceived exertion are at least in part a result of increases in locomotor limb blood flow and oxygen transport (14). It is also likely that a lower level of IPPV would be required to elicit such an effect in humans, due to the fact that humans are able to voluntarily reduce their respiratory motor output and allow a given level of IPPV to reduce the inspiratory PITP excursion to a greater extent. Consequently, IPPV may serve as a useful tool to facilitate the rehabilitation of patients with CHF under supervised conditions.

Limitations

In this investigation we did not have measurements of left ventricular volumes in our animals. Although we speculate that the improvements in cardiac function are the result of changes in PITP affecting left ventricular transmural pressure (and in turn, preload or afterload), we cannot exclude the possibility that at least part of the improvements in left ventricular function resulted from changes in left ventricular contractility or through altering the mechanical interaction between the right and left ventricles (e.g., ventricular interaction during diastole) (5) and/or pericardium.

As we did not control heart rate with a pacer during the inspiratory unloading conditions in the present study, we cannot experimentally exclude the possibility that the changes in stroke volume we observed were secondary to changes in cardiac filling times (which are roughly inversely proportional to heart rate). However, evidence against changes in filling time as a primary determinant of the changes in stroke volume can be gleaned from Fig. 2, where the changes in stroke volume with inspiratory unloading in both healthy and CHF conditions are frequently dissociated from changes in heart rate (with the increase in stroke volume clearly preceding the reductions in heart rate in the CHF conditions).

A final concern is that using IPPV to reduce the magnitude of the inspiratory PITP excursion does have the potential to increase pulmonary vascular resistance due to the compression of alveolar capillaries [as much as 17% in previous investigations (14)]. However, our observation in CHF animals that reducing the PITP excursion increases cardiac output and stroke volume suggests that this effect did not predominate during the present study, although removing the inspiratory PITP excursion without concomitant increases in pulmonary vascular resistance (e.g., with helium-oxygen gas mixtures) may have elicited even larger increases in cardiac output and stroke volume in our animals.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by a Grant-in-Aid from the American Heart Association, as well as National Heart, Lung, and Blood Institute (NHLBI) Grant RO1-HL-015469. J. D. Miller was supported as a predoctoral fellow by T32-HL-007654 from the NHLBI.


   ACKNOWLEDGMENTS
 
We are indebted to Dr. Magdy Younes, who developed the ventilator used in this investigation and loaned us one of his prototypes to conduct this study. Additionally, we extend our most sincere appreciation to Jerry Zarychta of Respironics, who repaired the ventilator on several occasions on very short notice. We would also like to recognize the assistance of Kathleen S. Henderson, Hans C. Haverkamp, Andrew T. Lovering, and Michael K. Stickland during these studies, the considerable effort put forth by Anthony J. Jacques in the design and continual modification of our data acquisition and processing software, and the technical assistance and surgical expertise provided by Larry F. Whitesell during several of these studies.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. D. Miller, Univ. of Iowa, 200 Hawkins Dr., 340B Eckstein Medical Research Bldg., Iowa City, IA 52242 (e-mail: jordan-miller{at}uiowa.edu)

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
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 RESULTS
 DISCUSSION
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