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From the Departments of Medicine of the Toronto General Hospital and the Centre for Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada.
Dr. Hall (deceased) was a recipient of a Medical Research Council of Canada/Canadian Lung Association Fellowship. Dr. Ando was a recipient of a Canadian Hypertension Society/Merck Frosst Canada Fellowship and of support from the George R. Gardiner Foundation (Toronto, Canada). Dr. Floras is a Career Scientist of the Heart and Stroke Foundation of Ontario, and Dr. Bradley holds a Senior Scientist Award from the Canadian Institutes of Health Research.
Correspondence to: T. Douglas Bradley, MD, NU 9–112, The Toronto General Hospital, University Health Network, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada; e-mail: douglas.bradley{at}utoronto.ca
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Abstract |
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Design: Physiologic intervention study.
Setting: Cardiorespiratory physiology laboratory.
Participants: Nine patients with CHF and nine healthy control subjects matched for age and sex.
Interventions: Patients with CHF and healthy subjects generated - 30 cm H2O of intrathoracic pressure during 15-s Mueller maneuvers (MMs) to simulate the acute hemodynamic effects and aftereffects of obstructive apneas.
Results: In both groups, MMs caused an immediate rise in left ventricular transmural pressure during systole (LVPtmsys) [p < 0.05], but in CHF patients, this immediate increase was followed by a significant drop in LVPtmsys (p < 0.05), associated with significantly greater reductions in systolic BP and cardiac index than in healthy subjects (- 25 ± 3 mm Hg vs - 11 ± 2 mm Hg [p < 0.05] and - 0.53 ± 0.11 L/min/m2 vs - 0.15 ± 0.11 L/min/m2 [p < 0.05], respectively). Healthy subjects recovered promptly, but in CHF patients, these adverse hemodynamic effects were sustained following release of the MM.
Conclusions: CHF patients experience more pronounced and sustained reductions in BP and cardiac output both during and following the MM than do healthy subjects. These findings suggest the potential for adverse hemodynamic effects and aftereffects of negative intrathoracic pressure generation during obstructive sleep apnea in patients with CHF.
Key Words: cardiopulmonary interactions • heart failure • obstructive sleep apnea
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Increases in LV afterload cause greater reductions in cardiac output in subjects with impaired LF function than in those with normal LV function.13 Data14 also suggest that patients with CHF are more prone to reduced LV diastolic filling in the presence of right ventricular distension, as might occur during OSA.5 15 Therefore, negative intrathoracic pressure should cause greater decreases in cardiac output during obstructive apneas in patients with CHF than in subjects with normal cardiac function. We have previously shown, in patients with CHF, that the MM causes an abrupt increase in LV afterload and a fall in cardiac output proportional to the negative intrathoracic pressure generated.16 However, hemodynamic responses in patients with CHF were neither compared to those in healthy subjects, nor examined following release of the MM.
In a small study2 in CHF patients with OSA, nocturnal continuous positive airway pressure abolished apneas and caused marked improvement in LV ejection fraction measured in the daytime. These results suggest that deleterious effects of OSA on the failing heart are sustained well into the postapneic period. Since there is a high prevalence of OSA among patients with CHF,17 18 it is important to establish whether these mechanical events can have adverse cardiovascular consequences during and after the apneic period. We therefore hypothesized that CHF patients would experience greater reductions in cardiac output in response to generation of negative intrathoracic pressure during apnea, and that these would persist longer following its release than in healthy subjects. Because differences between patients in variables that we could not control, such as the magnitude and duration of negative intrathoracic pressure, hypoxia, and arousals,3 16 19 20 21 22 23 24 precluded the testing of this hypothesis in OSA patients during sleep, we simulated the effects of negative intrathoracic pressure during obstructive apneas by having subjects perform the MM to a target negative pressure over a fixed time period while awake.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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45% as measured by 99Tc equilibrium
radionuclide angiography; (3) chronic exertional dyspnea despite
medical therapy; and (4) sinus rhythm. Patients suffering from angina
or a myocardial infarction within 3 months of the study and patients
with primary valvular heart disease were excluded. Nine healthy men who
were not receiving any medications and who were free of cardiovascular
and respiratory disease were also studied. The protocol was approved by
the local institutional ethics committee, and participants provided
written informed consent beforehand.
Arterial and Esophageal Pressures and Respiratory Measurements
Finger BP was measured beat by beat using the digital volume
clamp method (Finapres; Ohmeda 2300; Englewood, CO) with the arm and
hand resting horizontally at heart level throughout the study. As an
index of intrathoracic pressure, esophageal pressure was
measured using a balloon catheter system attached to a pressure
transducer (Validyne Engineering, MP 45 ± 50 cm
H2O; Northridge, CA).25
26
Thoracoabdominal movements and tidal volume were quantitated by a
respiratory inductance plethysmograph (Respitrace; Ambulatory
Monitoring; White Plains, NY) calibrated in the direct-current
mode against a spirometer.27
28
29
Oxyhemoglobin
saturation was monitored continuously with an ear pulse oximeter
(Oxyshuttle; Sensormedics; Anaheim, CA). The R-R interval was
determined from a precordial ECG lead. Signals were recorded
continuously onto a strip chart recorder (Model 2800S; Gould;
Cleveland, OH).
Stroke Volume and Cardiac Output
Maximum instantaneous flow velocity in the ascending aorta was
measured from the suprasternal notch with subjects in the supine
position, using continuous-wave echocardiographic Doppler technique
(Ultramark 8; Advanced Technology Laboratories; Bothell, WA) as
previously described.26
Stroke volume was calculated as
the product of the mean time-velocity integral (stroke distance) and
the cross-sectional area of the aortic annulus (A) calculated as
A = 
(D/2)2, where D is the diameter of the
aortic annulus obtained from a prior parasternal long-axis view at
baseline. Echocardiographic Doppler estimates of stroke volume have
been validated under experimental conditions similar to those described
herein, and have been shown to accurately reflect changes in stroke
volume.21
30
Cardiac output was calculated from the
product of heart rate and stroke volume from which stroke volume index
(SVI) and cardiac index (CI) were calculated. Because alterations in
thoracic configuration during the MM might affect measures of flow
velocity from the suprasternal notch, we performed initial validation
experiments in seven healthy subjects and three CHF patients.
Time-velocity integrals were acquired by Doppler echocardiography from
the suprasternal notch and the right carotid artery, an extrathoracic
site that would not be affected by alterations in thoracic
configuration during the MM. Measurements were made from each site
during tidal breathing and two 15-s MMs (see below). In these 10
subjects, there were no significant differences in relative reductions
in time-velocity integrals from baseline, between the suprasternal
window and the carotid artery whether averaged over the first 5 s
(mean ± SE, - 23 ± 3% vs - 17 ± 3%) or the last 5 s
of the MM (- 25 ± 5% vs - 15 ± 5%). Thus, the magnitude of
changes in time-velocity integrals measured from the suprasternal notch
parallel those measured from the right carotid artery.16
Protocol
Diuretic treatments were withheld the morning of each study.
Baseline measurements were recorded during quiet breathing while in the
supine position prior to each MM. Subjects wore a nose clip and a
mouthpiece with a small air leak through a 21-gauge needle to prevent
closure of the glottis during the MM. Mouth pressure was visually
monitored by each subject to maintain the target intrathoracic pressure
of - 30 cm H2O. All healthy subjects and CHF
patients performed several practice MMs before data collection began.
In preliminary studies, we found that 15 s was the longest period
CHF patients could sustain an MM without discomfort or oxyhemoglobin
desaturation. Subjects performed two 15-s MMs separated by a 3-min rest
period.
Data Analysis
Baseline data in the two groups were compared by unpaired
t tests. LV systolic transmural pressure (LVPtmsys), an
index of LV afterload, was calculated as the differences between
esophageal pressure measured synchronously with systolic
BP.7
24
Data collection began during the baseline control
period prior to each MM, and continued throughout and for 25 s
after the release of each MM. Beat-by-beat measurements were obtained
for these variables for each individual. Baseline values were averaged
over the 5 s immediately before the onset of the MM. Mean values
for the first and last 5 s of each MM and for 5-s periods
immediately, 10 s, and 20 s after release of the MM were also
obtained and were averaged for the two MMs performed by each subject.
Mean changes from baseline at each of these points for each variable
were calculated and compared within and between the two groups by
two-way analysis of variance for repeated measures, corrected for
multiple comparisons by Student-Newman-Kuels test. A p value of
< 0.05 was considered statistically significant. All data are
expressed as mean ± SE.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LVPtmsys increased initially and remained significantly above baseline over the course of the MM in healthy subjects (Fig 3 ). Patients with CHF also experienced an immediate increase in LVPtmsys over the first 5 s. However, by the last 5 s, LVPtmsys decreased significantly more than in healthy subjects (- 5 ± 3 mm Hg vs 11 ± 1 mm Hg; p < 0.05) and fell significantly below the baseline level due to the progressive fall in systolic BP.
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The pattern of the chronotropic response to the MM was similar in the two groups (Fig 4 ). In the healthy subjects, R-R intervals tended to fall during the first and final 5 s of the MM, but these reductions were not significant. In the CHF patients, R-R intervals fell significantly below baseline in the first and final 5 s of the MM.
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Responses Following Release of the MM
Following release of the MM, systolic esophageal pressure rose
above the baseline value in both groups (Fig 1
, 2)
. This increase
occurred immediately in the CHF patients but was delayed in the healthy
subjects. Systolic BP recovered to baseline immediately following
release of the MM in healthy subjects (Fig 2)
, but remained
significantly below baseline among CHF patients. This reduction in
systolic BP was greater than in the healthy subjects (- 15 ± 4 mm
Hg vs - 4 ± 3 mm Hg; p < 0.05). Immediately following release
of the MM, diastolic BP remained at the baseline level in healthy
subjects and recovered to the baseline level in the CHF patients.
In the immediate period following the MM, LVPtmsys, the index of afterload, returned abruptly to its baseline level in the healthy subjects (Fig 3) . In contrast, LVPtmsys remained significantly below baseline in the immediate and 10-s post-MM periods in the CHF patients. The LVPtmsys in the immediate post-MM period was significantly lower in the CHF than in the healthy subjects (- 19 ± 4 mm Hg vs - 3.9 ± 3 mm Hg; p < 0.05).
SVI remained at the baseline level throughout the post-MM period in healthy subjects (Fig 3) . In contrast, in CHF patients, the decrease in SVI that occurred during the MM was sustained into the immediate post-MM interval, even though LVPtmsys, or afterload, was significantly reduced from baseline values at this time. SVI then recovered to baseline by the 10-s post-MM interval. R-R intervals were significantly reduced only immediately following release of the MM in the healthy subjects and then returned to baseline at the 10-s post-MM interval (Fig 4) . In patients with CHF, significant reductions in R-R intervals were also present immediately following release of the MM, but were sustained throughout the post-MM period. Whereas CI was maintained at the baseline level throughout the post-MM period in healthy subjects (Fig 4) , in patients with CHF, reductions in CI were sustained into the immediate post-MM period. At this time, the reduction in CI was significantly greater than in healthy subjects (- 0.31 ± 0.11 L/min/m2 vs 0.05 ± 0.09 L/min/m2; p < 0.05.).
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our data demonstrate three important differences in the hemodynamic responses to an MM between subjects with normal and impaired ventricular function. First, for the same negative intrathoracic pressure generated, there were greater reductions in stroke volume and cardiac output in patients with CHF than in healthy subjects. Second, in contrast to healthy subjects, in CHF patients these reductions in stroke volume and cardiac output were sustained after cessation of the MM, despite a greater reduction in LV afterload below baseline at this time. Finally, the hemodynamic effects of the MM differed significantly over its course between healthy subjects and CHF patients. BP and LVPtmsys decreased significantly over the duration of the MM in CHF patients but not in healthy subjects. These findings indicate that negative intrathoracic pressure generated during apnea causes more pronounced and prolonged hemodynamic impairment in treated CHF patients than in healthy subjects.
Responses During MMs
We observed significant reductions in systolic BP during MMs in
both groups7
9
19
31
and in diastolic BP in the CHF
patients. By the end of the MM, systolic BP had fallen more than twice
as much, and cardiac output three times more in CHF patients than in
healthy subjects. As a measure of LV afterload, we used
LVPtmsys.16
26
Changes in intrathoracic pressure
accurately reflect changes in pericardial pressure for systolic events
during the MM in both humans and animals.3
32
In the
healthy subjects, LVPtmsys remained elevated throughout the
MM.33
In contrast, following an initial increase in
LVPtmsys in the patients with CHF, it decreased to below the baseline
value over the final 5 s of the MM, indicating a reduction in LV
afterload. This was in keeping with the decline in systolic BP. These
findings indicate that changes in LVPtmsys during MM in CHF patients
are time dependent and must be taken into account when interpreting
cardiac output responses to upper-airway occlusion.
A striking finding of our study was the divergence of the stroke volume and cardiac output responses between the two groups during the MM. In both the healthy and CHF subjects, SVI and CI decreased during the initial part of the MM. Therefore, the increase in LVPtmsys, due to the fall in intrathoracic pressure, observed at this point suggests that increased LV afterload is an important cause of initial reductions in SVI and CI in subjects with both normal and impaired LV function, just as in unanesthetized dogs with experimental OSA.6 In healthy subjects, SVI and CI returned to baseline by the end of the MM, despite the concomitant increase in LV afterload. In patients with CHF, however, SVI and CI fell more than twice as much at the end of the MM as in healthy subjects. This hemodynamic compromise occurred despite the simultaneous decrease in LV afterload, which should have allowed CI to increase, or at least prevented it from falling further. Taken together, these data indicate that CHF patients were less able to maintain cardiac output or defend against a fall in BP over the course of the MM than healthy subjects.
The mechanism(s) responsible for the progressive decrease in stroke volume during the final 5 s of the MM in the CHF patients cannot be determined from the present study. It cannot be attributed to increased LV afterload since LVPtmsys had fallen below baseline at this point. One possible mechanism is a reduction in LV preload. This could result from leftward interventricular septal shift due to increased venous return causing reduced LV filling.5 34 35 Atherton et al14 observed, in a subset of patients with severe CHF, that right ventricular distension was limiting LV filling. Generation of exaggerated negative intrathoracic pressure with consequent further distension of the right ventricle in similar patients could further restrict LV filling by further displacing the interventricular septum to the left.15 16 Patients with CHF might be particularly susceptible to such an effect.16 36 Our findings over the last 5 s of the MM in the CHF patients might be explained by this mechanism. However, recent data6 in unanesthetized, intact dogs with experimentally induced OSA indicated that as stroke volume fell during obstructive apneas, LV end-diastolic volume actually increased. Therefore, in that model, reductions in stroke volume could not be attributed to decreases in LV filling. Unfortunately, because chest wall distortion precluded reliable measurements of changes in LV end-diastolic dimensions from normal breathing to MMs by echocardiography in our experiments, we could not resolve this issue. Therefore, we cannot exclude a reduction in LV preload as a factor contributing to the reduced SVI observed during these MMs. Decreased LV filling by increased pooling of blood in the pulmonary circulation is not relevant to the MM because increased pooling occurs secondary to restriction to LV filling by high left atrial pressures, and cannot be its cause. Another possible explanation for reductions in stroke volume in the CHF patients, suggested by the progressive reductions in both systolic BP and LVPtmsys during MMs, is a reduction in myocardial contractility due to concurrent drops in diastolic BP and coronary artery perfusion with ischemia.7 37 38
Responses Following Release of the MM
Following release of the MM, esophageal pressure during
systole rose above baseline values in both groups (Fig 1
, 2)
. This
novel observation indicates that the respiratory system contributed to
unloading of the left ventricle in the post-MM period by increasing
esophageal pressure and reducing LVPtmsys through recruitment of
expiratory muscles, analogous to the effects of applying continuous
positive airway pressure.26
39
This response could assist
in the recovery of CI in the post-MM period, especially in the CHF
patients. The mechanism mediating this response is not known.
In contrast to healthy subjects, in CHF patients, falls in systolic BP and LVPtmsys persisted into the post-MM period. Despite this reduction in LV afterload, stroke volume remained depressed. The potential mechanisms responsible for this depression of stroke volume in the immediate post-MM period include reductions in preload and/or myocardial contractility. However, since esophageal pressure became positive following release of the MM and should have reduced rather than increased adverse ventricular interactions, it appears less likely that reduced LV preload played as prominent a role in reducing stroke volume as it might during the MM.14 40 This suggests a significant role for reduced contractility, but one we could not directly assess.
In a previous study, MMs were shown to reduce LV ejection fraction more in patients with coronary artery disease than in healthy subjects.38 However, in contrast to the present study, most patients in that study did not have CHF, and the time courses of ejection fraction, BP, and LVPtmsys responses during and following the MMs were not characterized. Therefore, our study extends the findings of that previous study to heart failure patients and demonstrates that, in contrast to healthy subjects, reductions in stroke volume are progressive over the course of MMs, and are sustained after their release.
We are limited in extrapolating our findings to clinical OSA by several considerations. The MM applied in our protocol differs from obstructive apnea in that negative intrathoracic pressure was sustained rather than intermittent. Nevertheless, its immediate effects on afterload and cardiac output are similar to those of obstructive apneas in both animals and humans with normal LV function.6 8 35 41 Therefore, the hemodynamic effects and aftereffects of the MM we observed should be representative of those occurring in response to obstructive apneas. Second, our study did not examine the effects of other features of OSA, such as hypoxia and arousals from sleep. Therefore, further experiments should be performed during sleep in CHF patients to delineate the functional significance of each of these factors. Unlike control subjects, CHF patients were receiving medications with vasodilator properties. Nonetheless, our present findings are relevant to the clinical setting since CHF patients with OSA would be receiving similar medications. Moreover, similar reductions in BP have been described during obstructive apneas in patients with normal cardiac function, as well as in patients with CHF receiving similar vasodilating drugs.42 43
The most impressive finding of our study is that in patients with CHF, generation of - 30 cm H2O of intrathoracic pressure lasting only 15 s can precipitate marked reductions in BP and stroke volume that persist beyond the release of the obstruction. Although our experiments do not define the precise mechanism for this sustained hemodynamic impairment, this finding could well have important clinical implications. Since CHF patients with OSA typically experience hundreds of apneas per night accompanied by negative intrathoracic pressure swings,2 there may be a cumulative adverse effect on the failing myocardium. Our previous observation that abolition of OSA in CHF patients by nocturnal continuous positive airway pressure improves daytime LV function is consistent with this concept.2 We conclude that negative intrathoracic pressure causes more profound and sustained reductions in stroke volume and cardiac output during the MM and following its release in treated CHF patients than in healthy subjects.
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Acknowledgements |
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Footnotes |
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Supported by operating grant MOP-11607 from the Medical Research Council of Canada.
Received for publication September 7, 2000. Accepted for publication January 24, 2001.
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= p < 0.05 vs the same time interval in the
healthy subjects.
