(Circulation. 1997;96:4273-4279.)
© 1997 American Heart Association, Inc.
Articles |
Diastolic Ventricular Interaction
A Possible Mechanism for Abnormal Vascular Responses During Volume Unloading in Heart Failure
From the Department of Cardiology, University of Wales College of Medicine (J.J.A., T.D.M., K.N.W., G.W.F.M., M.P.F.) and Heart Failure Research Unit, Department of Medicine, University of Queensland, Australia (H.L.T., L.E.F.).
Correspondence to Prof Michael Frenneaux, Cardiology Department, University of Wales College of Medicine, Heath Park, Cardiff, CF4 4XN, Wales, UK.
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Abstract |
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Background Baroreflex dysfunction is common in chronic heart failure and contributes to the associated sympathoexcitation. Baroreceptor activity normally decreases during volume unloading, causing an increase in sympathetic outflow and resulting in forearm vasoconstriction. Some heart failure patients develop attenuated vasoconstriction or paradoxical vasodilation. The mechanism for this is unknown. We have recently demonstrated diastolic ventricular interaction in some patients with chronic heart failure as evidenced by increases in left ventricular (LV) end-diastolic volume in association with decreases in right ventricular (RV) volume during volume unloading. We reasoned that such an increase in LV volume, by increasing LV mechanoreceptor activity, would decrease sympathetic outflow and could therefore explain the abnormal vascular responses seen in such patients.
Methods and Results We assessed changes in forearm vascular resistance (FVR) during application of -20 and -30 mm Hg lower-body negative pressure (LBNP) in 24 patients with chronic heart failure and 16 control subjects. Changes in LV and RV end-diastolic volumes were assessed during -30 mm Hg LBNP in all heart failure patients. Diastolic ventricular interaction was demonstrated in 12 patients as evidenced by increases in LV end-diastolic volume in association with decreases in RV end-diastolic volume during LBNP. Changes in FVR during LBNP (-20 and -30 mm Hg) were markedly attenuated in these 12 patients (-1.6±11.2 and -0.9±12.5 U) compared with both the remaining patients (11.9±10.0 and 17.0±12.3 U) and the control subjects (16.5±9.5 and 23.1±13.9 U) (P<.01 for both comparisons at each level of LBNP). FVR decreased in 5 of these 12 patients during -30 mm Hg LBNP, a response seen in none of the remaining patients (P=.01).
Conclusions Diastolic ventricular interaction in patients with chronic heart failure is associated with attenuated forearm vasoconstriction or paradoxical vasodilation during LBNP. This may explain the apparent derangement in baroreflex control of sympathetic outflow during acute volume unloading in heart failure.
Key Words: heart failure • baroreceptors
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Introduction |
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Autonomic control of the heart and peripheral circulation is regulated by mechanosensitive receptors (baroreceptors) located in the walls of the heart, coronary arteries, pulmonary veins, aorta, and carotid arteries.1,2 These receptors respond to changes in pressure and, in the case of cardiac receptors, also to changes in inotropic status of the heart. By regulating sympathetic and vagal outflow from the brain stem, baroreceptors provide an important cardiovascular control mechanism. Acute volume unloading, by decreasing arterial and cardiac filling pressures, normally decreases baroreceptor activity, causing an increase in sympathetic outflow (resulting in peripheral vasoconstriction) and a reduction in vagal outflow (resulting in an increase in heart rate), thus returning arterial and cardiac filling pressures toward normal.
Cardiac baroreceptors, particularly LV mechanoreceptors, appear to play an important role in determining changes in FVR during acute volume unloading in humans.3,4 Some heart failure patients exhibit attenuated forearm vasoconstriction or paradoxical vasodilation during volume unloading, suggesting impaired cardiac baroreflex control of vascular tone.5–11 These patients also develop attenuated increases or paradoxical decreases in muscle sympathetic nerve activity and norepinephrine spillover.12,13 Taken together, these observations suggest that the increase in sympathetic outflow that normally occurs during acute volume unloading is attenuated or, in some cases, reversed in patients with chronic heart failure. Abboud et al14 have previously suggested that this may represent reduced inactivation or paradoxical activation of LV mechanoreceptors during volume unloading. The reason that LV receptors might behave in such a paradoxical fashion in the setting of heart failure has not been determined. Given that mortality is increased in such patients15 and that it is likely that baroreflex dysfunction contributes to neurohumoral activation in heart failure,14,16 an understanding of the mechanisms underlying such derangements in baroreflex control is important.
We recently demonstrated diastolic ventricular
interaction in 
50% of a cohort of patients with chronic heart
failure.17 In these patients, LV
end-diastolic volume increased during acute volume
unloading caused by the application of -30 mm Hg LBNP,
despite associated reductions in RV volume and right atrial pressure.
The reduction in RV volume caused by volume unloading allowed for
augmented LV filling and therefore an increase in LV
end-diastolic volume. Wang et al18
have previously demonstrated a close correlation between changes in LV
mechanoreceptor activity and changes in LV end-diastolic
volume. We therefore reasoned that such an increase in LV volume would
increase LV mechanoreceptor activity and thus reduce sympathetic
outflow and explain the paradoxical responses observed in some heart
failure patients during acute volume unloading. This study was designed
to test the hypothesis that attenuated forearm vasoconstriction or
vasodilation during acute volume unloading in chronic heart failure is
associated with diastolic ventricular
interaction as evidenced by increases in LV end-diastolic
volume.
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Methods |
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Subjects
We studied 24 heart failure patients referred to the Heart Failure Research Unit, University of Queensland, with a history of symptomatic heart failure and documented LV systolic dysfunction (LV ejection fraction <35%) of at least 3 months' duration. Exclusion criteria were rhythm other than sinus, myocardial infarction within 6 months, current unstable angina, valvular heart disease, previous cardiac surgery, hypertension, diabetes mellitus, chronic renal impairment, vasovagal syncope, or excessive alcohol intake. Patient symptom status and medical therapy had remained unchanged in the 2 weeks before the study. Sixteen approximately age- and sex-matched normal subjects with no history of heart disease, hypertension, diabetes mellitus, chronic renal impairment, vasovagal syncope, or excessive alcohol intake; no cardioactive medications; normal cardiovascular and neurological examinations; and a normal ECG and echocardiogram were recruited from the gastroenterology department endoscopy database and enrolled as control subjects.
Study Protocol
The investigations were performed at the Royal Brisbane Hospital
with the approval of the hospital ethics committee. Informed consent
was obtained from all patients and control subjects. Diuretics
were withheld on the morning of the study, but other drugs were
continued throughout the study. Forearm vascular responses during LBNP
were studied in the morning, 2 hours postprandial, in patients and
control subjects. Radionuclide ventriculography during LBNP was
performed in the afternoon, 2 hours postprandial, on the same day as
the plethysmography studies in all patients.
Vascular Responses During LBNP
Subjects were studied in a quiet environment at a constant room
temperature of between 22°C and 24°C. They lay supine in a LBNP bed
encased from below the iliac crests in an airtight seal and were
monitored by ECG. Arterial blood pressure was measured with
a Finapres recorder. Forearm blood flow was measured with a
standard mercury-in-Silastic strain-gauge plethysmography technique
(Hokanson).19 Forearm blood flow was calculated
from three slopes, and the results were averaged. A subset of 13 heart
failure patients had a 5F catheter inserted via the brachial vein to
measure central venous pressure with a Baxter transducer (Baxter Health
Care Corp).
Measurements were obtained during baseline after the subjects had been lying supine for 20 minutes and were repeated during -20 and -30 mm Hg LBNP (allowing 2 minutes for equilibration at each level). The pressure within the lower-body box was measured by a transducer (Dwyer series 602 differential pressure transmitter integrated with Innotech current sensing controller and display). All data were acquired by use of an Acq Knowledge multichannel data-acquisition system and fed to an Apple Macintosh II CI computer. FVR, expressed as resistance units, was calculated as the quotient of mean arterial pressure (millimeters of mercury) and forearm blood flow (milliliter per minute per 100 mL).
Radionuclide Ventriculography
We used a technique we have previously described to demonstrate
diastolic ventricular interaction in the heart
failure patients.17 Radionuclide ventriculography
was performed before and during -30 mm Hg LBNP by use of a
modified in vivo technique to label red blood cells with Tc-99m
pertechnetate. Following 20 minutes of rest, a 4-minute cardiac
scintigram was performed in the left anterior oblique view by use of a
small field-of-view gamma camera (GE 300A, GE Medical Systems) fitted
with a low-energy, general-purpose, parallel-hole collimator and
interfaced to a dedicated computer system (Max Delta, Siemens). LBNP of
-30 mm Hg was applied for 5 minutes, during the final 4
minutes of which the scintigram was repeated. Venous blood samples (10
mL) were obtained to determine blood activity during each acquisition.
The radionuclide ventriculograms were analyzed off-line by an
investigator blinded to the patient's clinical status or results of
other investigations. Background-corrected LV end-diastolic
counts were determined by use of a semiautomated edge-detection
algorithm and corrected for decay, blood activity, and tissue
attenuation to allow determination of LV end-diastolic
volume.20 Background-corrected RV
end-diastolic counts were determined manually with the aid
of stroke volume, ejection fraction, and paradox images. Corrections
were made for decay and blood activity to allow determination of the
change in RV end-diastolic volume during LBNP.
Diastolic ventricular interaction was implied
if there was an increase in LV end-diastolic volume during
LBNP greater than the coefficient of variation for replicate
measurements (ie, >3.1%).17
Statistical Analysis
Data are presented as mean±SD. One-way ANOVA and
Bonferroni's t tests were used to compare changes during
LBNP. Fisher's exact test was used to compare the proportion of
patients who decreased FVR divided according to whether or not they
increased LV volume. Linear regression analysis was used to
assess correlations between the change in FVR during LBNP and other
parameters. A value of P<.05 was considered
statistically significant.
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Results |
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Subject Characteristics
The heart failure patients were 53±12 years (20 men, 4 women), and control subjects were 53±10 years (13 men, 3 women). Fifteen patients had dilated cardiomyopathy and 9 had ischemic heart disease. Six patients were in New York Heart Association functional class I, 11 were in class II, and 7 were in class III. The patients were taking the following cardioactive medications: ACE inhibitors (n=21), diuretics (n=16), digoxin (n=12), hydralazine (n=8), nitrates (n=8), ß-blockers (n=2), and amiodarone (n=3). Mean LV ejection fraction in the patients was 21±8%. None of the patients or control subjects participated in competitive athletics. The heart failure patients at baseline had a higher heart rate (79±17 versus 63±6 bpm, P<.01), lower mean arterial pressure (79±10 versus 87±13 mm Hg, P=.04), and similar FVR (41.6±28.5 versus 38.4±13.6 U, P=NS) compared with the control subjects.
Changes During LBNP
The changes occurring during LBNP are described in Table 1
. One patient was not studied at
-30 mm Hg LBNP because he developed lower back discomfort.
Changes in heart rate and FVR were different between heart failure
patients and control subjects (Table 1, Fig 1). A reduction in FVR was observed in 6
patients during -20 mm Hg and in 5 patients during -30
mm Hg LBNP, a response seen in none of the control subjects.
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RV end-diastolic volume decreased in all heart failure
patients during -30 mm Hg LBNP. Diastolic
ventricular interaction was demonstrated in 12 patients as
evidenced by an increase in LV end-diastolic volume during
LBNP in association with a decrease in RV volume. Compared with the
remaining heart failure patients, these patients were of similar age
(57±14 versus 50±8 years, P=NS) with a similar baseline
heart rate (82±17 versus 75±17 bpm, P=NS), mean
arterial pressure (81±11 versus 77±9 mm Hg,
P=NS), FVR (48.1±36.1 versus 35.2±17.2 U,
P=NS), and LV ejection fraction (19±8% versus 23±7%,
P=NS), but central venous pressure was higher (11.8±3.5
[n=8] versus 7.0±2.3 [n=5] mm Hg, P=.02).
Although the changes in heart rate, mean arterial pressure,
and central venous pressure were similar, the changes in FVR during
LBNP (-20 and -30 mm Hg) were markedly different in the 12
heart failure patients who increased LV end-diastolic
volume during -30 mm Hg LBNP (-1.6±11.2 and -0.9±12.5 U)
compared with both the remaining patients (11.9±10.0 and 17.0±12.3 U)
(Table 2, Fig 2) and the control subjects (16.5±9.5
and 23.1±13.9 U) (P<.01 for both comparisons at each level
of LBNP). The changes in FVR observed in the heart failure patients who
did not increase LV end-diastolic volume during LBNP were
similar to those observed in the control subjects. Of the 12 patients
who increased LV end-diastolic volume, 5 developed a
reduction in FVR during -30 mm Hg LBNP, a response seen in
none of the remaining patients (P=.01).
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A comparison of patients in whom the change in FVR during -30 mm Hg LBNP was less (group 1, n=12) or more (group 2, n=11) than the mean for all heart failure patients showed that the change in LV end-diastolic volume was different (17±19 versus -3±10 mL, P<.005), but the changes in RV end-diastolic volume (-4.6±2.3 versus -6.5±3.7 volume equivalents, P=NS), central venous pressure (-3.2±0.9 versus -2.7±0.7 mm Hg, P=NS), and LV ejection fraction (-1±2% versus -2±4%, P=NS) were similar. The change in FVR during -30 mm Hg LBNP for the entire group of heart failure patients correlated with the change in LV end-diastolic volume (r=-.54, P<.01) but not with the change in RV end-diastolic volume (r=-.07, P=NS) or central venous pressure (r=.23, P=NS).
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Discussion |
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The important new finding of this study is that consistent with our hypothesis, there is an association between the presence of diastolic ventricular interaction and attenuated forearm vasoconstriction or vasodilation during application of LBNP in patients with chronic heart failure.
In normal subjects, central blood volume unloading evokes an increase in FVR, muscle sympathetic nerve activity, and norepinephrine spillover,13,21–24 reflecting withdrawal of baroreflex-mediated restraint on sympathetic outflow. Controversy exists regarding the relative contribution of cardiopulmonary and arterial baroreceptors in determining changes in autonomic outflow during volume unloading. It has been argued that because arterial pressure is not reduced by minor levels of LBNP, arterial baroreceptor influence is likely to be minimal.22,23 This is probably not the case. Hartikainen et al25 observed in anesthetized dogs subjected to slow hemorrhage that arterial baroreceptor firing was diminished in association with reductions in mean aortic diameter and tension, before a decrease in mean aortic pressure was detectable. Similarly, subhypotensive LBNP in humans reduces carotid arterial diastolic diameter and ascending aortic pulse area and therefore probably inhibits arterial baroreceptor firing.26,27 However, whereas arterial baroreceptors in cats and dogs exert the dominant effect on hind-limb vascular resistance,28,29 it appears that cardiopulmonary baroreceptors may be the principal receptor group involved in mediating changes in FVR during LBNP in humans.3,4,21 In an elegant study performed by Abboud et al,21 increases in both forearm and splanchnic vascular resistance were observed when central venous pressure and arterial blood pressure were lowered by -40 mm Hg LBNP. Simultaneous application of neck suction (to minimize the contribution of carotid baroreceptors to the changes occurring during LBNP) prevented most of the splanchnic vasoconstriction but did not attenuate the forearm vasoconstriction.21 This does not exclude the possibility that aortic baroreceptors contribute to changes in FVR during LBNP. However, in cardiac transplant recipients (with denervated ventricles but innervated atria and pulmonary veins), forearm vasoconstriction is markedly attenuated or absent during application of LBNP suggesting that LV mechanoreceptors are important in mediating changes in FVR in humans.4
There is some debate as to whether the actual stimulus for LV mechanoreceptor firing is diastolic wall strain or the rate of systolic fiber shortening.18,30,31 Providing that inotropic status remains unchanged, however, an increase in diastolic LV wall strain will result in an increase in the rate of fiber shortening, according to the Frank-Starling Law of the Heart. Therefore, an increase in LV end-diastolic volume, such as that which occurred during LBNP in some of our heart failure patients, will increase LV mechanoreceptor activity, regardless of the actual stimulus for receptor firing. Consistent with this are the observations of Wang et al18 during volume loading and unloading that the rate of firing of LV mechanoreceptors is directly related to changes in LV end-diastolic volume.
Some patients with chronic heart failure develop attenuated increases or apparently paradoxical decreases in muscle sympathetic nerve activity, norepinephrine spillover, and FVR during acute volume unloading,5–13 suggesting impaired cardiac baroreflex control of sympathetic outflow. We have observed similar responses in other conditions, including vasovagal syncope and hypertrophic cardiomyopathy.32,33 Acute intravenous administration of digoxin has been shown to normalize abnormal forearm vasoconstriction during LBNP in patients with chronic heart failure,7 implying that the baroreflex abnormalities responsible for abnormal vascular responses during volume unloading are reversible and therefore not due to structural changes.
Previous Explanations for Abnormal Baroreflex Control Mechanisms
During Volume Unloading
It has been suggested that LBNP or upright tilt may cause less
venous pooling in heart failure patients.34 This
would result in attenuated vasoconstriction but fails to explain
vasodilation during such maneuvers. In any case, it is not supported by
our observation in a previous study of a similar reduction in RV
end-diastolic volume in heart failure patients and control
subjects exposed to the same degree of LBNP.17
Furthermore, in the present study, there was no relationship
between the change in FVR during LBNP and the reduction in either RV
end-diastolic volume or central venous pressure.
Kassis and colleagues8,9 performed a series of
elegant studies aimed at determining the mechanisms controlling FVR
during upright tilt in heart failure patients. They observed that the
vasodilator response to upright tilt was converted to a vasoconstrictor
response by the prior local administration of
intra-arterial propranolol (suggesting a
ß-adrenergic mechanism).9 In another study,
Kassis8 observed that vasodilation during upright
tilt was associated with increased stroke volume and aortic pulsatile
stretch and proposed that in the setting of reduced baroreceptor
sensitivity, the reflex relaxation of the aorta may give rise to
secondary reflexes resulting in ß-adrenergic vasodilation (rather
than 
-adrenergic vasoconstriction). This fails to explain all the
apparently paradoxical responses that occur during acute volume
unloading in heart failure and is not supported by the observation that
muscle sympathetic nerve activity does not increase during
nitroprusside infusion in heart failure
patients.12 The exact reason why aortic pulsatile
stretch increased in these patients was not determined, but we would
speculate that abolition of diastolic
ventricular interaction by upright tilt may have been
important.
Abboud et al14 have suggested that the paradoxical changes observed in sympathetic outflow in patients with heart failure are due to LV mechanoreceptor activation. They proposed that a decrease in cardiac size would occur during volume unloading and that this would result in increased ventricular compliance in some heart failure patients. This would lead to a decrease in end-diastolic pressure and wall tension, thus reducing energy consumption and permitting a greater fractional shortening (and therefore increased LV mechanoreceptor firing) for the same contractile state. Although this certainly provides an explanation for baroreflex activation during central volume unloading, it is not entirely clear why volume unloading should increase intrinsic myocardial compliance in some patients with heart failure. Furthermore, our observations in this study that the patients with abnormal forearm vascular responses during LBNP increased LV end-diastolic volume and tended to decrease LV ejection fraction are in direct contrast to their proposed mechanism.
Diastolic Ventricular Interaction: An
Explanation for Abnormal Vascular Responses During Volume Unloading in
Heart Failure?
Diastolic ventricular interaction refers
to the situation in which the volume of one ventricle is directly
influenced by the volume of the other
ventricle.17,35–38 Such interaction is normally
minimal but is accentuated in circumstances associated with
pulmonary hypertension and volume
overload.17,35,37,38 When this occurs, acute
volume unloading results in a reduction in RV end-diastolic
volume as expected, but LV end-diastolic volume increases
(because of decreased external constraint to LV filling). We recently
demonstrated such an interaction to be common in patients with chronic
heart failure and observed that the patients who increased LV
end-diastolic volume had higher pulmonary capillary
wedge, pulmonary arterial, and right atrial
pressures compared with patients who decreased LV volume during acute
volume unloading.17 We reasoned that in the
presence of diastolic ventricular interaction,
acute volume unloading will increase LV end-diastolic
volume and therefore increase LV mechanoreceptor firing. This would
result in a reduction in sympathetic outflow and could therefore
explain attenuated increases or apparently paradoxical reductions in
FVR and norepinephrine spillover. Consistent
with this proposed mechanism, we observed that the patients who
increased LV end-diastolic volume during -30 mm
Hg LBNP in this study had markedly attenuated vascular responses at
-20 and -30 mm Hg LBNP and, in some cases, exhibited
vasodilation. That the increase in LV end-diastolic volume
occurred in association with reductions in both central venous pressure
and RV end-diastolic volume is consistent with
diastolic ventricular interaction being the
mechanism. We suggest therefore that the paradoxical responses observed
during volume unloading in heart failure patients do not necessarily
imply abnormal cardiac baroreflex function, as has been previously
suggested. Indeed, we propose that the apparently paradoxical increase
in LV mechanoreceptor activity may reflect an appropriate response to
the abnormal increase in LV volume that occurs in the presence of
diastolic ventricular interaction.
We cannot exclude the possibility that changes in arterial baroreceptor activity may be responsible for the paradoxical changes in FVR observed during volume unloading in patients with chronic heart failure. Dornhorst et al36 originally proposed that a change in LV volume occurring as a result of diastolic ventricular interaction would cause a proportional change in stroke volume, as would be expected according to Frank-Starling mechanisms. Consistent with this, Belenkie et al35 observed in a volume-loaded model of acute pulmonary hypertension that volume unloading caused an increase in both LV end-diastolic volume and stroke work. An increase in stroke volume resulting in an increase in arterial baroreceptor activity could further contribute to a reduction in sympathetic outflow during volume unloading. However, vasoconstriction during volume unloading in the renal and splanchnic beds, which in humans is influenced predominantly by arterial baroreceptors,21,39 is preserved in heart failure patients.6
Study Limitations
Other factors may also be involved in determining changes in FVR
during volume unloading in heart failure. Cardiac (in particular,
atrial baroreceptor sensitivity) is reduced in experimental animal
heart failure models.40–44 Studies by Halliwill
et al45 and Smith et al46
suggest that the same is true in patients with LV systolic
dysfunction. Rapid ventricular pacing in healthy
anesthetized dogs caused a transient reduction in renal
sympathetic nerve activity. After cardiopulmonary baroreceptor
denervation (with sinoaortic baroreceptors left intact), rapid
ventricular pacing caused an abrupt and sustained increase
in renal sympathetic nerve activity, suggesting that
cardiopulmonary baroreceptors normally exert the dominant
influence on sympathetic nerve activity during ventricular
pacing in dogs.45 In contrast, rapid
ventricular pacing or ventricular
tachycardia caused an increase in muscle sympathetic nerve
activity in patients with LV systolic dysfunction, implying
that the reduction in arterial baroreceptor activity
(caused by decreased arterial pressure) dominated the
increase in cardiac baroreceptor activity (caused by increased cardiac
filling pressures).46 Halliwill et
al45 suggested a number of possible reasons for
the different responses observed during rapid ventricular
pacing in healthy dogs and unhealthy humans and concluded that the most
likely explanation was that cardiac baroreceptor sensitivity was
reduced in patients with LV systolic dysfunction. Another
explanation could be that diastolic ventricular
interaction may be prominent in the latter group. If that were the
case, one would expect left and right heart filling pressures to
increase in parallel during ventricular
tachycardia or rapid ventricular pacing.
Cardiac transmural filling pressure and baroreceptor activity would
therefore remain unchanged, thereby explaining the reduced contribution
of cardiopulmonary baroreceptors to changes in sympathetic
outflow during ventricular pacing in patients with LV
systolic dysfunction.It is likely, however, that cardiac
baroreceptor sensitivity is reduced in human heart failure. This may
certainly contribute to attenuated vasoconstriction during volume
unloading but does not explain the vasodilation seen in some patients
and furthermore does not preclude the mechanism we are proposing to
explain the paradoxical vascular responses observed during volume
unloading in heart failure. We suggest that although cardiac
baroreceptor sensitivity is reduced in heart failure, the paradoxical
reduction in FVR that occurs during LBNP in some patients may
represent an appropriate cardiac baroreflex response to the
abnormal increase in LV end-diastolic volume. There may
also be inhomogeneity in changes in LV wall strain that may result in
differing mechanoreceptor responses in different parts of the
ventricle. We have previously proposed that this may explain abnormal
forearm vascular responses during application of LBNP in patients with
vasovagal syncope and hypertrophic
cardiomyopathy.32,33
We studied patients on their usual medical therapy. This could contribute to the variable vascular responses observed during LBNP and is a potential limitation of our study. Apart from the ethical implications, we decided that cessation of medical therapy would result in unstable hemodynamics at the time of study. Even if the patients could tolerate such an approach, we could not exclude a longer-acting tissue effect in the case of some medications. ACE inhibitors and digoxin have both been shown to improve baroreflex function.7,47,48 Although it is likely that part of their influence on baroreflex function is determined by their hemodynamic effect, there is evidence that digoxin may directly increase baroreflex activity.47 Vasodilation was observed, however, even in patients taking both these medications.
Our data do not provide a complete explanation for all the apparent derangements in baroreflex function in heart failure. Whereas arterial baroreflex control of vascular resistance appears to be preserved in patients with chronic heart failure,6,49 arterial baroreflex modulation of heart rate is abnormal.50 A number of mechanisms may contribute, including changes in cellular Na+-K+ ATPase activity, decreased arterial compliance (caused in part by endothelial dysfunction), and the effect of various neurohumoral substances and paracrine factors such as angiotensin II, endothelin, aldosterone, nitric oxide, and oxygen-derived free radicals on baroreflex gain.47,51–55 Diastolic ventricular interaction, by blunting changes in stroke volume (and hence arterial stretch) in response to changes in blood pressure, might also contribute to abnormal arterial baroreflex control of heart rate.
We have demonstrated an association between diastolic ventricular interaction and abnormal forearm vascular responses during acute volume unloading in heart failure patients. Although we infer a causal relationship, this will require further study, perhaps an examination of the effects of ventricular interaction on LV mechanoreceptor and arterial baroreceptor activity in an experimental heart failure model.
Clinical Implications
Baroreflex dysfunction is associated with an adverse prognosis in
patients and animal models with heart
failure.15,56 Mortality is markedly increased in
heart failure patients who exhibit abnormal baroreflex control of
autonomic outflow during nitroprusside
infusion.15 Cardiac baroreflex activity is
reduced in experimental heart failure
models.40–44 It is likely that this reduced
baroreceptor activity leads to increased sympathetic outflow,
contributing to neurohumoral activation in heart
failure,14,16 which is also known to be
associated with reduced life expectancy.57
Measures aimed at increasing cardiac and arterial
baroreceptor activity may therefore be beneficial in the setting of
heart failure. If our hypothesis is correct, these apparent
abnormalities could be corrected (at least in part) by abolition of
diastolic ventricular interaction. Venodilators
will be particularly useful in this respect. The reduction in RV volume
that occurs after administration of such agents will allow improved LV
filling. According to our data, this will be associated with a
reduction in sympathetic outflow and therefore decreased neurohumoral
activation.
We have previously demonstrated that filling pressures are increased in patients with diastolic ventricular interaction.17 A large proportion of patients in this study were on standard therapy, including ACE inhibitors, and despite this, they exhibited evidence of diastolic ventricular interaction and abnormal vascular responses during volume unloading. A more aggressive approach to tailoring therapy (eg, higher doses ACE inhibition, adjunctive nitrates, or angiotensin II receptor blockers) may abolish diastolic ventricular interaction and improve baroreflex control of sympathetic outflow in such patients.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Dr Atherton, Thomas Moore, Karen Wright, and Prof Frenneaux are supported by the British Heart Foundation. In addition, this work was supported in part by a National Heart Foundation of Australia Postgraduate Medical Research Scholarship (PM93B0172).
Received July 3, 1997; revision received September 9, 1997; accepted September 14, 1997.
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References |
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