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European Journal of Heart Failure 2000 2(1):41-45; doi:10.1016/S1388-9842(99)00062-8
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© 2000 European Society of Cardiology

Prognostic value of baroreflex sensitivity assessed by phase IV of Valsalva manoeuvre in patients with mild-to-moderate heart failure

Carlo Rostagnoa,*, Giorgio Galantia, Massimo Felicia, Massimo Maccherinib, Guido Sanib, Sabina Caciollia and Gian Franco Gensinia

a Istituto di Clinica Medica e Cardiologia, Università' di Firenze Viale GB Morgagni 85, 50134 Firenze, Italy
b Istituto di Cardiochirurgia, Università' di Siena Policlinico Le Scotte, Siena, Italy

* Corresponding author. Tel.: +39-55-427-7549; fax: +39-55-427-7608. E-mail address: g.gensini{at}dfc.unifi.it


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: In patients with heart failure, impairment of baroreflex function occurs early and contributes to sympathetic activation, however, at present its prognostic role has not been definitively established.

Aims: To evaluate the prognostic significance of baroceptor impairment in patients with different degrees of heart failure.

Methods: We enrolled 52 consecutive patients with heart failure, referred to our institution for functional evaluation. Twenty-eight suffered from ischemic cardiomyopathy and 26 from dilated cardiomyopathy. Thirteen patients were in NYHA class I, 20 in NYHA class II and 19 in class III. All patients underwent baroreflex assessment by phase IV Valsalva manoeuvre using Finapres finger monitoring of arterial blood pressure, echocardiography [with evaluation of left ventricular ejection fraction (LVEF), fractional shortening (LVFS), left ventricular end diastolic diameter (LVEDD) and mean pulmonary artery pressure] and functional evaluation by cardiopulmonary exercise test and 6-min walk corridor test within 2 days of hospital admission.

Results: Mean duration of follow-up was 26 months (range 6–35 months). At baseline, evaluation in 13 patients BRS was normal (>5 ms/mmHg), in 17 moderately impaired (1.5–5 ms/mmHg) and in 22 severely depressed (<1.5 ms/mmHg). Baroreflex function was relatively preserved in patients in NYHA class I (5.1±2.5) in comparison to patients in NYHA class II and III (2.1±2.3 and 2.08±1.9 ms/mmHg, respectively). Of the 52 patients who entered the study at the end of follow-up 15 died of cardiac cause and 5 underwent heart transplantation. Survival free from heart transplantation was 62% in patients with normal baroreflex function, 62% in patients with moderate impairment of baroreflex and 66% in patients with major derangement. NYHA class, LVEF, LVFS and LVEDD were significantly associated with event free survival while baroreflex function was not.

Conclusions: Our results suggest that evaluation of BRS impairment by phase IV Valsalva manoeuvre has limited prognostic value in patients with heart failure.

Key Words: Heart failure • Baroreceptors • Risk stratification

Accepted October 26, 1999


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Baroreflex functional impairment has been demonstrated to occur early in patients with heart failure [1,2] and is supposed to significantly contribute to sympathetic activation [3–5]. Several investigations have clearly shown an inverse relation between plasma NE levels, an index of sympathetic activation, and both extent of left ventricular impairment and survival in patients with heart failure [6,7]. Few data have been reported on prognostic value of arterial baroreceptor impairment [8,9]. Recently, Mortara et al. [10], in a large prospective trial, reported a threefold increased risk of mortality in patients with major depression of baroreceptor sensitivity evaluated by the phenilephrine method.

The aim of the present investigation was to prospectively investigate the prognostic value of baroreflex sensitivity, evaluated by heart rate response to increase of arterial pressure in phase IV of the Valsalva manoeuvre, in patients with mild-to-moderate heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients
Fifty-two consecutive patients with heart failure (mean age 56 years, range 31–72), referred to our department for clinical evaluation, entered the study. Of these, 28 suffered from coronary artery disease and 24 from idiopathic dilated cardiomyopathy. Diagnosis of dilated cardiomyopathy was confirmed in all patients by coronary angiography. Thirteen patients were in NYHA class I, 20 in NYHA class II and 19 in class III. All patients were in sinus rhythm and their clinical conditions had been steady in the 2 weeks preceding the study. Patients with ischemic heart disease did not suffer from acute myocardial infarction in the 3 months preceding the inclusion in the study. Ninety-five percent of patients were treated with ACE-I, and 74% with digoxin. Diuretics were not administered in the 48 h preceding the study. No patient was under treatment with beta-blockers at the time of inclusion in the study.

2.2. Study protocol and follow-up data
All patients underwent baroreflex assessment, echocardiography and functional evaluation by cardiopulmonary exercise test and 6-min walk corridor test within 2 days of hospital admission. Clinical follow-up was performed as outpatient evaluation every 6 months.

Prespecified end points were cardiac death or cardiac transplantation for UNOS-1 status.

2.3. Baroreflex evaluation
Baroreflex sensitivity was evaluated by assessing beat-to-beat changes of arterial pressure and heart cycle length during standardized Valsalva manoeuvre. A mouthpiece was connected to a mercury manometer and patients blew to maintain an expiratory strain of 40 mmHg for 15 s. Arterial pressure and heart rate were non-invasively monitored by Finapress (Ohmeda), digitally converted and acquired by a PC (IBM, Intel 486). Arterial baroreflex sensitivity (BRS) was evaluated from the slope of the regression line between RR intervals (measured in ms) against the preceding systolic peak (measured in mmHg), during phase IV (overshoot) of Valsalva manoeuvre, selected from the first beat when systolic arterial pressure exceeded the mean pre-test value. Only regression lines with a coefficient higher than 0.8 were considered for statistical analysis. The average value of two measurements, taken 5 min apart, was considered for statistical analysis. For survival analysis, patients were subdivided into three groups in relation to BRS: below the lowest quartile (<1.5 ms/mmHg), between the lowest quartile and the median (1.5–5 ms/mmHg) and above the median (>5 ms/mmHg).

2.4. Doppler echocardiography
Patients underwent M-mode and 2D-echocardiography using an ESAOTE Biomedica SIM 5000 instrument with monoplane probe 2.5 MHz, according to the recommendations of the American Society of Echocardiography [11]. Left ventricular end-diastolic diameter and fractional shortening were measured. Ejection fraction was calculated from apical four chambers position by the area–length method. Mean pulmonary artery pressure was calculated by Doppler evaluation using the acceleration method.

2.5. Six-minute walk corridor test
The walk test was performed in a 25-m long indoor corridor. Patients were educated to walk the corridor from one extremity to the other, as many times as possible in the established time, at the maximum possible rate. The test was performed under the control of a physician who encouraged the patients. At the end of the 6 min the distance walked by the patient was measured.

2.6. Cardiopulmonary exercise test
Cardiovascular functional capacity was measured by incremental stress testing, according to the modified Bruce’s protocol. Anaerobic threshold and peak oxygen consumption were measured by continuous expired gas analysis (OXYCON alfa, JAEGER, Wurzburg, Germany). Anaerobic threshold was measured according to Wasserman et al. [12].

2.7. Statistical analysis
Results are expressed as mean±S.D. Difference among groups were evaluated using ANOVA test. The association of different variables with prognosis was studied by multivariate regression analysis. Kaplan Maier survival curves were used to describe the survival of patients, stratified according to different levels of categorical variables. Log rank test was used for statistical comparison.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Clinical characteristics of patients are shown in Table 1.


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  		Table 1 Clinical characteristics of patientsa

 
Mean duration of follow-up was 26 months (range 6–35 months). At baseline evaluation in 13 patients BRS was normal (>5 ms/mmHg), in 17 moderately impaired (1.5–5 ms/mmHg) and in 22 severely depressed (<1.5 ms/mmHg). Baroreflex function was relatively preserved in patients in NYHA class I (5.1±2.5) in comparison to patients in NYHA class II and III (2.1±2.3 and 2.08±1.9 ms/mmHg, respectively). No significant difference was found between these two latter groups (Fig. 1).


Figure 1
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  		Fig. 1 Baroreflex sensitivity in relation to NYHA functional class.

 
Of the 52 patients who entered the study, at the end of follow-up 15 died of cardiac causes and 5 underwent heart transplantations. Survival free from heart transplantation was 62% in patients with normal baroreflex function, 62% in patients with moderate impairment of baroreflex and 66% in patients with major derangement. Actuarial survival curves are shown in Fig. 2.


Figure 2
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  		Fig. 2 Actuarial survival curves in relation to baroreflex sensitivity, NYHA functional class and left ventricular ejection fraction.

 
Univariate relation with mortality for other common indexes of cardiac function is shown in Table 2. NYHA class, left ventricular ejection fraction and fractional shortening and left ventricular end diastolic diameter, were significantly associated with event-free survival, while tests of cardiopulmonary function were not. At multivariate analysis (Table 2), left ventricular ejection fraction and NYHA class were the strongest predictors of survival.


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  		Table 2 Predictive value of different functional parameters at univariate and multivariate analysis

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Results from our study show that the impairment of arterial baroceptor function is more frequent in patients with more severe clinical heart failure, NYHA class II and class III patients, however, it is not an uncommon feature in the earlier phases of heart failure before overt left ventricular systolic dysfunction.

We failed to find significant differences in survival free from heart transplantation for UNOS 1 status in patients with depressed baroceptor function, in comparison to patients with normal baroceptor response.

Investigations on the prognostic role of baroceptorial dysfunction in patients with heart failure are limited. In patients after acute myocardial infarction, La Rovere et al. [13] did not find any significant relation between left ventricular ejection fraction and BRS, however, BRS depression was associated with a higher mortality even among patients with depressed left ventricular function. Similar results were reported by Farrel et al. [14], who again did not find any relation between left ventricular function and BRS even if impaired BRS showed the strongest association with inducibility of sustained ventricular monomorphic tachycardia. Recently, the Autonomic Tone and Reflex After Myocardial Infarction study (ATRAMI), clearly showed that impairment of parasympathetic response after acute myocardial infarction was associated with a near threefold increased risk of cardiac mortality [9]. The association of depressed BRS with low left ventricular ejection fraction (<35%) increased the relative risk to 8.7 in comparison with patients with normal BRS and LVEF>35%.

In patients with heart failure, Osterziel et al. [8], found a lower BRS to neck suction in patients who subsequently died in comparison to survivors, but BRS depression was not associated with higher mortality at multivariate analysis.

Recently, Mortara et al. [10], in a large study including 282 patients, reported that severe derangement in BRS (<1.3 ms/mmHg) was associated with an increased risk of mortality or cardiac transplantation for UNOS 1 status in patients with heart failure. In fact, 58% of the patients with severely depressed BRS reached the end-point of the study, in comparison with 27% of the patients with preserved BRS. Depressed BRS predicted mortality also at multivariate analysis.

Despite similar cut-off values for BRS response, overall results from our investigation did not confirm the data of Mortara et al. [10]. The two studies, however, differ in several respects and this may account at least in part for their different conclusions.

At variance with previous investigation we used a non-invasive method as Valsalva manoeuvre instead of the semi-invasive phenylephrine method to evaluate baroreflex function. The employment of Valsalva manoeuvre for BRS evaluation may be criticised for its low reproducibility and sensitivity, moreover, atypical response of blood pressure and heart rate (so called ‘square wave response’) may further limit the usefulness of Valsalva-based methods in congestive heart failure. Also, we cannot exclude that patients with heart failure may not be able to perform correctly the Valsalva manoeuvre, even if the close adherence to standardisation of the manoeuvre significantly decreased this risk. Nevertheless, several studies showed a close relationship between the two methods both in healthy subjects [15,16] and in patients with arterial hypertension or coronary artery disease [17]. At present there are no studies that directly compare the two methods in patients with heart failure. Data from a previous investigation from our institution [18] suggests that in patients with mild-to-moderate heart failure evaluation of BRS by Valsalva manoeuvre gives results quite similar to those obtained by phenylephrine infusion [1], thus suggesting that the two methods give at least qualitatively similar results in patients with heart failure.

As baroceptor dysfunction has been demonstrated to occur early in the course of natural history of heart failure, differently from Mortara et al. [10], who included in the study only patients with ejection fractions below 40%, we did not choose any cut-off value for left ventricular ejection fraction. Seven out of 13 patients with preserved systolic left ventricular function (EF>40%) and prevailing diastolic impairment had severely depressed BRS (<1.5 ms/mmHg), but all survived at follow-up. These figures agree with ATRAMI results, which showed a low 2-year mortality (<4%) in patients with depressed BRS and preserved EF.

Aetiology of heart failure may influence the prognostic value of BRS. In fact, in the study by Mortara et al. [10], BRS appeared to be a better prognostic marker in patients with ischemic rather than in those with dilated cardiomyopathy (RR 2.0 vs. 0.8). In our study, 12 of 20 events (60%) occurred in patients with dilated cardiomyopathy, perhaps in relation to a more severe degree of heart failure in comparison to patients with ischemic heart disease. The high incidence of events in dilated cardiomyopathy and conversely the small number of events in patients with main diastolic dysfunction, may contribute to the overall limited prognostic value of BRS impairment observed in our study.

However, the limited number of patients included in the present investigation and the small number of events, do not allow us to draw definitive conclusions about the prognostic value of BRS in patients with heart failure. Moreover, the assessment of BRS by Valsalva manoeuvre cannot be extrapolated to phenylephrine assessment and is conceivable that baroreflex impairment evaluated by Valsalva manoeuvre may have limited prognostic value rather than baroreflex sensitivity in general.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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