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(Circulation. 1997;96:3450-3458.)
© 1997 American Heart Association, Inc.
Articles |
Arterial Baroreflex Modulation of Heart Rate in Chronic Heart Failure
Clinical and Hemodynamic Correlates and Prognostic Implications
From the Division of Cardiology, Centro Medico di Montescano, "S Maugeri" Foundation, IRCCS, Pavia, Italy.
Correspondence to Andrea Mortara, Division of Cardiology, Centro Medico di Montescano, "S Maugeri" Foundation, IRCCS, Montescano, Pavia, Italy.
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Abstract |
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Background In chronic heart failure (CHF), arterial baroreflex regulation of cardiac function is impaired, leading to a reduction in the tonic restraining influence on the sympathetic nervous system. Because baroreflex sensitivity (BRS), as assessed by the phenylephrine technique, significantly contributes to postinfarction risk stratification, the aim of the present study was to evaluate whether in CHF patients a depressed BRS is associated with a worse clinical hemodynamic status and unfavorable outcome.
Methods and Results BRS was assessed in 282 CHF patients in sinus rhythm receiving stable medical therapy (age, 52±9 years; New York Heart Association [NYHA] class, 2.4±0.6; left ventricular ejection fraction [LVEF], 23±6%). The BRS of the entire population averaged 3.9±4.0 ms/mm Hg (mean±SD) and was significantly related to LVEF and hemodynamic parameters (LVEF, P<.005; cardiac index and pulmonary wedge pressure, P<.001 by regression analysis). Patients in NYHA classes III or IV and those with severe mitral regurgitation had markedly depressed vagal reflexes. The association of BRS with survival was described after its categorization in three groups: below the lowest quartile (<1.3 ms/mm Hg), between the lowest quartile and the median (1.3 to 3 ms/mm Hg), and above the median (>3 ms/mm Hg). During a mean follow-up of 15±12 months, 78 primary events (cardiac death, nonfatal cardiac arrest, and status 1 priority transplantation) occurred (27.6%). BRS was significantly related to outcome (log rank, 9.1; P<.01), with a relative risk of 2.7 (95% confidence interval, 1.6 to 4.7) for patients with the major derangement in BRS (<1.3 ms/mm Hg). At multivariate analysis, BRS was an independent predictor of death after adjustment for noninvasive known risk factors but not when hemodynamic indexes were also considered. In CHF patients with severe mitral regurgitation, however, BRS remained a strong prognostic marker independent of hemodynamic function.
Conclusions In moderate to severe CHF, a depressed sensitivity of vagal reflexes parallels the deterioration of clinical and hemodynamic status and is significantly associated with poor survival. Particularly in patients with severe mitral regurgitation the baroreceptor modulation of heart rate provides prognostic information of incremental value to hemodynamic parameters.
Key Words: heart failure • baroreceptors • nervous system, autonomic • prognosis • hemodynamics
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Introduction |
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Sinoaortic and cardiopulmonary baroreceptors normally exercise a restraining influence on resting central sympathetic activity. In CHF patients, these normal tonic inhibitory reflexes are depressed, contributing to sympathetic excitation.1–3 Baroreflex abnormalities in CHF have been reported both in experimental and human studies4–8 in association with a prolonged exposure to low cardiac output and reduced blood pressure. The exact mechanism of this baroreceptor dysfunction is still uncertain,1–3,9–11 but independent of the causal mechanisms, it has been shown to be reversible after optimization of medical treatment or after cardiac transplantation.7,8
BRS may be safely quantified by the phenylephrine method in normal subjects and in patients with cardiac diseases,12 and it has been proposed as a valid index of the capability to reflexly increase parasympathetic activity.13 In patients with a recent MI, a decreased BRS has been regarded as a powerful marker of poor prognosis.14–16 No prognostic data have been reported in CHF patients by this technique, and only limited experience with the neck suction method has been described.17
The purpose of the present study was to evaluate in a large population of CHF patients whether clinical and hemodynamic parameters correlate with BRS and whether baroreceptor function is significantly associated with poor survival.
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Methods |
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Population
Of 434 consecutive patients with dilated cardiomyopathy and moderate to severe heart failure admitted from November 1992 to March 1996 to the Heart Failure Unit of Montescano Medical Center for evaluation of possible heart transplantation, 354 were in sinus rhythm and were considered for BRS assessment. All patients had to have LVEF <40% and to have had at least one episode of severe cardiac decompensation in the preceding 6 months. Fourteen patients were excluded because of refractory decompensation, and 24 others were excluded because of frequent arrhythmias or pacemaker rhythm. Thirteen patients were also excluded because their cardiomyopathy was not idiopathic, ischemic, or valvular (restrictive, n=6; hypertrophic, n=4; congenital, n=3). Patients were studied in a stable condition with no changes in signs or symptoms in the 2 weeks preceding the study. The final study population consisted of 303 patients. They all gave informed consent to participate in the study, which had been approved by the local Ethical Committee.
Study Protocol and Follow-up Data
Instrumental assessments were performed on hospitalized stable
patients at the time of the entry visit and every 6 months, whereas
clinical data were obtained every 3 months during visits to our
outpatient heart failure clinic.
The prespecified end point was cardiac death, nonfatal cardiac arrest resulting from documented ventricular fibrillation, or status 1 transplant priority. Status 1 patients were defined as those requiring an intensive care unit admission and prolonged inotropic or mechanical cardiovascular support for irreversible pump failure, fatal unless heart transplant is performed. Arrhythmic deaths were not considered separately because in most cases they were not documented arrhythmic deaths, and the available data do not allow us to distinguish between tachyarrhythmic and bradyarrhythmic events. Only one event was considered for each patient, and any event occurring after the initial event was not considered. Patients who underwent elective heart transplantation were considered censored at the date of the transplantation; data on surviving patients were censored at the last day they were known to be alive, and data on deaths from other causes were censored on the date of death.
BRS Assessment
Arterial baroreceptor function was evaluated by
administration of the vasoactive drug phenylephrine as
previously described.14,18 BRS studies were
analyzed by two independent and experienced observers (A.M. and
M.T.L.R.). Heart rate and SAP obtained either directly from the
radial/brachial artery or noninvasively by Finapres (Ohmeda)
were continuously recorded. The invasive and noninvasive methods
provide highly correlated BRS values.19,20
Phenylephrine (3 to 4 µg/kg IV) was given to raise
the SAP by 15 to 30 mm Hg by at least three bolus injection. If
blood pressure did not increase as desired, additional injections were
made, with the dose of phenylephrine increased by 50 µg.
The RR intervals were plotted against the preceding
arterial systolic peak, and a linear regression
analysis was performed for those points included between the
beginning and the end of the first significant increase in SAP.
Regression lines with a statistically significant correlation
coefficient (P<.05) were accepted for analysis;
only for BRS near zero (± 0.5 ms/mm Hg), if the increase of SAP was
adequate (above 15 mm Hg), were the coefficients of regression
accepted independent of the probability value. Indeed, if SAP increase
causes no reflex changes (or little erratic changes) of RR interval,
the correlation between 
values of SAP and RR is obviously poor, with
a regression line running along the horizontal axis. The final slope
obtained by calculating the mean value of the injections performed at
the optimal phenylephrine dose was considered as
representing BRS (millisecond of RR change per 1
mm Hg of SAP increase). Examples of poor and sensitive BRS are
reported in Fig 1A
and 1B.
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Hemodynamic and Doppler Echocardiographic
Evaluation
Catheterization of the right –side of the heart
was performed by use of a 7F Swan-Gantz balloon-tipped catheter
inserted into the right internal jugular vein and advanced through the
right heart into the pulmonary artery. Baseline standard
hemodynamic measurements, including pulmonary
artery pressure, PWP, and right atrial pressure, were made with the
patients in the supine position by use of a Hewlett Packard transducer
connected with a 7005 Marquette polygraph and recorded on a
polygraph at a speed of 50 mm/sec on a scale calibrated from 0 to
80 mm Hg. Cardiac output was measured by the thermodilution
method as the mean of three consecutive measurements not varying by
>10%.
A Hewlett Packard 1500 ultrasound system with 2.5- and 3.5-MHz probes was used to perform Doppler and two-dimensional echocardiographic examinations, which were obtained with the patients lying in a supine or slightly left lateral decubitus position. Examinations were recorded on a super-VHS videotape and analyzed by an experienced cardiologist. Left ventricular volumes and LVEF were assessed by two-dimensional apical two- and four-chamber views by use of the modified Simpson's rule. Mitral regurgitation was diagnosed and semiquantitatively graded by color-flow Doppler from the apical view.21
Statistical Analysis
Results are given as mean±SD. ANOVA with post hoc comparison
with Scheffé's procedure for continuous variables and
2 test for categorical variables were
applied. Because of the skewed distribution of BRS, Wilcoxon
signed-rank test and Kruskal-Wallis ANOVA were used when appropriate;
Spearman's rank correlation procedure was used to determine the
correlation of BRS with continuous clinical variables. Statistical
significance was defined at the P<.05 level.
The association of BRS with mortality was described after its categorization according to the following cutoff values: below the lowest quartile (<1.3 ms/mm Hg), between the lowest quartile and the median value (1.3 to 3 ms/mm Hg), and above the median (>3 ms/mm Hg). Tricotomization of the variables used to predict risk is an established procedure, especially when dealing with continuous variables of still-undefined prognostic value.
Kaplan-Meier survival curves were used to describe the survival of patients stratified according to the levels of the categorical variable, and the log-rank test was used for statistical comparison. BRS as a categorical variable and other clinical hemodynamic parameters were tested with the Cox proportional hazards analyses to identify correlates of out-of-hospital outcome, and the association between BRS and mortality was expressed as relative risk with 95% confidence intervals. The Cox proportional hazards model was used to estimate the independent effects of BRS on survival after adjustment for the variables significantly associated with mortality in our CHF patients. These covariates were all continuous variables except for NYHA functional class, which was dichotomized into class I or II and class III or IV, and mitral regurgitation, which was tricotomized as absent or moderate (1 to 2+) and severe (3 to 4+). Multivariate analysis was applied in two steps: first, the association between BRS and survival was assessed after adjustment for those parameters that are easily detectable in clinical practice; then, that association was assessed for the same variables plus the hemodynamic parameters. Similar sets of analyses (ie, BRS in univariate analysis and after adjustment for significant covariates) were performed for prespecified subgroups of patients according to cause of heart failure (ischemic versus idiopathic), NYHA class (I or II versus class III or IV), and mitral regurgitation (absent/moderate versus severe). The analyses were performed by use of SAS statistical software.
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Results |
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The clinical characteristics of the population are reported in Table 1
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BRS and Clinical and Hemodynamic Correlates
BRS was determinable in 282 of 303 CHF patients (93%), and the
mean value was 3.9±4.0 ms/mm Hg (median, 3; range, -7 to 21
ms/mm Hg). No adverse effects were observed during or after the
phenylephrine injections. In 11 patients, SAP did not
increase adequately (<15 mm Hg) despite a high dose of
phenylephrine (>10 µg/kg), whereas in 10
subjects, an erratic behavior of SAP and heart rate was observed.
No difference was found in heart rate response to
phenylephrine between ischemic (n=142) and
idiopathic (n=128) cardiomyopathy (3.9±3.6 versus
4.0±4.5 ms/mm Hg); BRS was significantly associated with symptoms
of heart failure (Fig 2), and as a
continuous variable, it was weakly related to LVEF
(r=.20, P<.005; Fig 3A), cardiac index (r=.30,
P<.001), and PWP (r=-.29, P<.001;
Fig 3B). BRS was also significantly more depressed in patients with
severe mitral regurgitation (Fig 4).
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Table 2 compares clinical and
hemodynamic characteristics of the patients according
to BRS categorization. A significant trend is present for all
variables when moving from a relatively preserved to a more
depressed BRS, suggesting an association between severity of heart
failure and baroreflex function. BRS was also related to age, when
considered as both a continuous (r=-.33,
P<.0001) or a categorized variable (see Table 2).
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In 22 patients, a paradoxical tachycardia to
baroreceptor stimulation occurred, and consequently a negative estimate
of BRS was obtained (mean, -1.8±1.7 ms/mm Hg; range, -7 to -0.1
ms/mm Hg). Compared with patients with positive BRS, these patients
exhibited a worse clinical status, higher PWP, and a higher incidence
of severe mitral regurgitation (Table 3). Baseline RR interval and SAP before
BRS assessment were also reduced in patients with negative BRS (Table 3). In Fig 5, an example of negative BRS
is reported before and after optimization of medical therapy when a
significant reduction of PWP and mitral regurgitation
is associated with a less tachycardic response to blood pressure
increase.
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Mortality Data and Survival Analysis
Mean duration of follow-up was 15±12 months (median, 12 months).
Of the 282 patients with assessed BRS, 53 died of cardiac causes
(20.5%), 5 had nonfatal cardiac arrest, and 20 were transplanted in
status 1 priority. Of the 53 deaths, 15 were sudden and 38 were due to
progressive pump failure. The end-point cardiac death, nonfatal cardiac
arrest, and status 1 priority occurred in 78 patients (27.6%).
Thirty-six patients (12.7%) underwent elective cardiac transplantation
without status 1 priority.
Fig 6 shows the 2-year survival curves
according to BRS values. Mortality was higher among patients with BRS
<1.3 ms/mm Hg than in patients with more preserved BRS (58% versus
27%, P<.002), thus establishing the prognostic value of
this autonomic marker. Table 4 summarizes
the univariate relative risk for depressed BRS and the
multivariate results of Cox analysis after
adjustment for the covariates that are significantly associated with
mortality in this CHF population (Table 5). BRS remained statistically
significant after adjustment for NYHA, LVEF, baseline RR interval and
maximum VO2 but not when
hemodynamic data were also entered into the model
(Table 4).
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Univariate and multivariate relations with
mortality (ie, BRS alone and after adjustment for significant
covariates) were performed for subgroups of patients according to cause
of heart failure (ischemic versus idiopathic, valvular
excluded), NYHA class I or II versus class III or IV, and
absent/moderate versus severe mitral regurgitation
(Table 6). Although secondary
analyses should be considered with caution because the number
of events decreases in each subgroup of patients, we found that BRS
seems to perform better as a prognostic marker in ischemic
rather than in idiopathic cardiomyopathy (adjusted
RR, 2.0 versus 0.6); nevertheless, it was not independently related to
better survival in any subset of patients with the exclusion of severe
mitral regurgitation (3 to 4+). In these subjects, a
reduced heart rate response to phenylephrine-induced
increase of blood pressure emerged as an important determinant of
survival.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our study in a large group of patients with stable CHF shows that arterial BRS is markedly depressed in CHF, and although it clearly parallels the deterioration of clinical and hemodynamic status, the relation with all indexes of ventricular function is weak, suggesting that other factors are important in its determination.
As in post-MI patients, it was found that a depressed BRS, assessed by the phenylephrine technique, is significantly associated with poor survival, and its quantification adds prognostic information to the predictive accuracy of the other established risk factors such as age, LVEF, and maximum O2 consumption during exercise. When hemodynamic variables are considered, however, only in those patients with depressed ventricular function and severe mitral regurgitation, a blunted reflex heart rate response, or even a paradoxical tachycardia to blood pressure increase did it appear as a powerful and independent marker of cardiac mortality.
Arterial Baroreflex Assessment in Heart
Failure
BRS as measured by reflex heart rate response to pharmacologically
induced elevation of arterial pressure has been reported to
be reduced in different cardiac
diseases,6,22,23 including heart
failure,6,7 and our results are concordant
with these data. Because the bradycardia that occurs in response to the
hypertensive stimulus is mediated largely by increased parasympathetic
tone,24 the phenylephrine test
is considered a safe and valid technique to quantify the ability of
cardiovascular regulatory system to increase vagal
activity.12 However, it has been shown that
changes in sympathetic activity may interfere with the ability to
increase vagal activity1,12,25; as a
consequence, a depressed BRS is likely to be secondary to either a
decrease in parasympathetic activity or an increase in sympathetic
activity.
In CHF, the mechanism of arterial baroreflex dysfunction is probably multifactorial and may be located in all components of the reflex arc.1,5,9,26,27 Moreover, activation of the renin-angiotensin system in heart failure by increased plasma levels of angiotensin II may act on baroreflex control of sympathetic activity and heart rate both directly in the vasomotor and cardiac centers in the brain and in the peripheral nerve terminals, facilitating norepinephrine release and inhibiting acetylcholine release.11 CHF patients may also have abnormalities of sinus node responsiveness to changes in efferent traffic to the heart.4
This study was not designed to confirm or reject any of the possible mechanisms involved in baroreceptor dysfunction of CHF patients, but it highlights in a large CHF population that the depression of the capability to reflexly decrease heart rate follows the severity of ventricular dysfunction as expressed by both clinical symptoms and hemodynamic parameters. However, the association between BRS and LVEF or hemodynamic parameters, although evident and statistically significant, is rather weak, suggesting that BRS is not merely dependent on the hemodynamic status and that other mechanisms, as reported above, are probably involved.
Admittedly, in patients with more severe CHF and in those with severe
mitral regurgitation, the modest increase in blood
pressure induced by phenylephrine is often accompanied by a
paradoxical tachycardia (negative BRS). Although
sympathostimulatory reflexes by stretch of cardiac chambers after the
phenylephrine-induced increase of afterload or a direct
ß-adrenergic stimulation at sinus node level by high doses of the
drug28 can play a role, it is likely that
the observed paradoxical tachycardia is caused by a further
hemodynamic impairment accompanied by an uncompensated
increase in mitral regurgitation. This is supported by
the observation that BRS may be restored by hemodynamic
improvement and reduction of severity of mitral
regurgitation (see the example in Fig 4
). The net
effect of this mechanism is a reduction in amplitude and rate of
increase in stroke volume despite a drug-related increase in
peripheral resistances. These new findings open up the
possibility of reconsidering the phenylephrine test in CHF;
it is suggested that this method, particularly in patients with severe
ventricular dysfunction and mitral
regurgitation, should be regarded not as a probe to
evaluate the "pure" baroreceptors function but as a test to assess
the capability of baroreceptors to evoke an increase in parasympathetic
drive in the context of the patient's actual
hemodynamic status. This may represent an
advantage of the phenylephrine method because any measure
of "pure" arterial baroreceptor function (such as that
obtained by mechanical stimulation of the carotid baroreceptors) may
not have any clinical usefulness and prognostic implication if in real
life the vagal stimulation of baroreflexes by an increase in blood
pressure (ie, during emotional stress, or transient ischemia)
is limited by the hemodynamic impairment and by the
increase of mitral regurgitation that ultimately
prevails, causing tachycardia and further sympathetic
activation.
BRS and Cardiac Mortality in Heart Failure
The possibility of using BRS as a prognostic indicator in patients
with CHF stems directly from the compelling experimental and clinical
evidence that has accumulated over the last 20 years about the
importance of autonomic markers in risk stratification after MI. In a
well-known animal model combining previous MI, acute ischemia,
and sympathetic hyperactivity, the quantitative estimation of
baroreflex function was inversely related to the risk of developing
ventricular fibrillation, and the animals at risk could be
identified in advance by the presence of depressed
BRS.29 These observations were confirmed by
small studies in post-MI patients14,15 and
more recently by the multicenter study
ATRAMI.16,30 The results of this study and
particularly the finding that when a depressed BRS (<3 ms/mm Hg) was
associated with an LVEF <35%, the relative risk increased markedly
for both cardiac deaths16 and arrhythmic
events30 support the rationale of testing
the same hypothesis even in stable CHF patients. Moreover, in post-MI
patients, BRS appeared to predict not only sudden death but also total
cardiac mortality.12,14,16 These data
suggest that at a clinical level, the impairment in vagal reflexes, as
a measure of both a decrease in parasympathetic activity and an
increase in sympathetic activity, may act not only to facilitate the
substrate for life-threatening arrhythmias (as in animals
model) but also to facilitate other pathological substrates leading to
cardiac events (ventricular remodeling, platelet
aggregability, and coronary vasoconstriction).
Data on prognostic implications of BRS are more scanty in CHF. Osterziel et al17 in a small number of stable patients (n=35) observed that BRS, as obtained by a modified neck-chamber technique, was lower in patients who died compared with survivors (1.3±0.2 versus 2.1±0.4 ms/mm Hg, P<.02); however, depressed BRS (<1.5 ms/mm Hg) was significantly associated with higher mortality only in univariate analysis but not in multivariate analysis.
When the same technique that was used in post-MI patients was used in a large group of stable sinus rhythm patients with moderate to severe heart failure, our study shows that BRS may contribute to identifying patients at higher risk of death. Indeed, it is noteworthy that in a noninvasive multivariate model including NYHA class, maximum oxygen consumption during exercise, LVEF, and baseline 24-hour mean heart period, BRS still has an independent prognostic content, which is no longer evident when PWP and cardiac index are also considered. This observation suggests that analysis of vagal reflexes may be a useful test to be added for stratification purposes in CHF, particularly when only a simple routine approach is available.
For certain subgroups of CHF patients, BRS analysis may give new and important information. We found that in patients with ischemic cardiomyopathy, the test is more informative that in idiopathic cardiomyopathy, and this is concordant with the previous experiences in post-MI ventricular dysfunction.14–16 However, the most relevant finding was observed in patients with severe mitral regurgitation in whom the possibility of reducing heart rate in response to blood pressure increase was significantly and independently associated with cardiac mortality even if hemodynamic parameters are considered. These last data confirm the considerations reported above on the possible role of the phenylephrine test in CHF patients, particularly when severe mitral regurgitation is present. Indeed, it is likely that this method, by quantifying the neural and hemodynamic capability to reflexly increase parasympathetic tone, provides in these patients a sensible indicator of the intrinsic neural and hemodynamic "reserve" of the system in response to a provocative stimulus. In agreement with this hypothesis, BRS may represent an important marker of poor survival independent of baseline hemodynamic data.
Study Limitations
A possible limitation of our study is that in our patients, we did
not study the whole heart rate response to deactivation and activation
of arterial baroreflexes by also assessing the reflex heart
period shortening induced by intravenous bolus injection of
nitroglycerin.31 This was
deliberately not performed for two important reasons: First, it has
been documented that the relation between arterial pressure
and heart rate is sigmoidal with linear and saturation regions and that
BRS is a measure of the slope in the linear portion of this
curve.32 However, CHF patients are likely to be
in a saturation and no-longer-linear portion of this curve
characterized by low arterial pressure and high sympathetic
drive.33 This implies a
physiological limit to evoking further sympathetic
activation and the calculation of an only apparently reduced BRS.
Second, the hemodynamic response to nitroprusside
infusion in CHF is an important confounder of BRS assessment because
the induced reduction of the drug of peripheral resistances
causes a beneficial increase in stroke volume and cardiac output that
deactivates arterial baroreflexes, leading to
bradycardia and not, as expected, to the shortening of heart
period.34
Drugs can also be included among factors that may have affected our data. In CHF patients, a pharmacological influence on sympathovagal balance cannot be excluded, specifically in patients treated with ACE inhibitors, ß-blockers, or digoxin.1,3 However, the clinical status of our patients would allow only changes in or withdrawal of drug therapy at the expense of losing the "steady condition" that may be considered the "natural" status of patients with severe heart failure, particularly when dealing with prognostic indicators.
In conclusion, this study shows that arterial baroreflex modulation of heart rate may be safely quantified by the phenylephrine technique, even in patients with mild to severe heart failure. It is suggested, however, that in CHF this method can be an indicator of both neural and hemodynamic capability to reflexly increase parasympathetic activity. Because it has been clearly demonstrated that these reflexes are protective, the hypothesis was that their quantification may provide clinical and prognostic implications. Indeed, we found that arterial baroreflex modulation of heart rate is clearly more depressed in the advanced stages of the disease and that this depression is significantly associated with higher incidence of cardiac death. The prognostic power of BRS appears relevant and independent of other known risk factors such as hemodynamic data, particularly in the subsets of patients with ventricular dysfunction and severe mitral regurgitation.
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Selected Abbreviations and Acronyms |
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Received March 31, 1997; revision received July 29, 1997; accepted August 5, 1997.
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