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European Journal of Heart Failure 2002 4(5):605-611; doi:10.1016/S1388-9842(02)00037-5
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© 2002 European Society of Cardiology

Autonomic function in elderly patients with chronic heart failure

M. Zia,*, N. Wisniackia, J. Delaneyb, C. Donnellana and M. Lyea

a Department of Geriatric Medicine, University of Liverpool The Duncan Building, Daulby Street, Liverpool L69 3GA, UK
b Department of Medicine, University of Liverpool Liverpool L69 3GA, UK

* Corresponding author. Tel.: +44-151-7064062; fax: +44-151-7064064. E-mail address: m.zi{at}liv.ac.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Aims: Autonomic function (AF) is attenuated by heart failure (HF). Reports have been based on studies of young patients with systolic heart failure (SHF). However, HF is a disease of older patients who are more likely to have diastolic heart failure (DHF). We investigated whether age alters AF in elderly HF patients and whether the haemodynamic type of HF influences AF.

Method and results: Thirty-six elderly HF (Framingham criteria) patients (11 with SHF, 25 with DHF) and 21 matched healthy subjects underwent simple bedside AF tests. Compared with the reference values for healthy adults, the mean E:I ratios and the median 30:15 ratios standing were all essentially normal. The median 30:15 ratios tilt and the mean Valsalva ratios were all significantly below the reference value (P for all cases <<0.050). Comparing three groups, there were no significant differences for mean E:I ratio (P=0.111), 30:15 tilt (P=0.619) and 30:15 standing (P=0.167), whereas there were significant differences for the mean Valsalva ratios (P=0.001). The mean Valsalva ratio of the SHF patients was significantly lower than that for the DHF patients (P<0.001) which in turn was significantly lower than the result of the healthy subjects (P<0.001).

Conclusion: There is an age-related impairment in AF with further impairment occurring in patients with HF. However, the severity of autonomic dysfunction is less in patients with DHF compared with patients with SHF.

Key Words: Ageing • Autonomic function • Diastolic dysfunction • Heart failure • Systolic dysfunction

Received August 13, 2001; Revised October 30, 2001; Accepted January 17, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Chronic heart failure (HF) is associated with impairment of autonomic reflexes controlling cardiovascular responses to perturbation [1–3]. Classically HF gives rise to a ‘square-wave’ blood pressure (BP) response to the Valsalva manoeuvre [4–6]. Additionally, there is an attenuation of sympathetic and parasympathetic induced heart rate changes during the Valsalva manoeuvre, to deep breathing and to head-up tilt [7–11].

Most autonomic function (AF) studies have been restricted to relatively young HF patients or have included very few patients over the age of 70 years. This is surprising as chronic HF is a disease of old age. More than 80% of patients with chronic HF are over the age of 65 years and the median age of HF patients is 76 years [12]. Increasing age itself is associated with autonomic changes [13–15] and it is therefore inappropriate to extrapolate the results from studies of AF obtained in relatively young HF patients to the majority of HF patients who are much older. In addition, young HF patients are usually characterised haemodynamically by having systolic dysfunction whereas older patients tend to have preserved systolic function—so-called ‘diastolic’ HF [16,17]. Thus, up to 60% of older (>=70 years of age) HF patients are likely to have preserved systolic function (‘diastolic’ HF) and it is a minority of older patients who manifest classic systolic heart failure (SHF) [18]. Most studies of AF have been confined to chronic HF patients with systolic dysfunction but AF in the majority of HF patients, i.e. elderly with diastolic heart failure (DHF), has not been characterised.

We decided, therefore, to assess AF in a group of stable HF patients over the age of 65 years and to compare their results with a healthy age-matched group. Furthermore, patients were assessed for haemodynamic status and the AF results obtained were compared between patients with and without preserved systolic function.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Patient selection
All patients aged over 65 years and admitted to the Royal Liverpool and Broadgreen University hospitals with a primary diagnosis of chronic HF during a period from 1997 to 1999 were screened. All patients fulfilled the Framingham criteria for the diagnosis of HF [19]. Exclusion criteria included a history of diabetes mellitus, systemic hypertension, arrhythmia or pacemaker, myocardial infarction or unstable angina within 3 months, significant valvular or pulmonary disease, renal failure, alcohol abuse, and current smoking. Patients prescribed digoxin or amiodarone were also excluded. Forty patients with stable chronic HF were recruited. All underwent a detailed medical history, physical and echocardiographic examination (SONOS 100CF, Hewlett Packard). Four patients were excluded because of high BP and/or recurrent frequent ectopics. Thirty-six patients were available for entry into the study. The patients with a left ventricular ejection fraction (LVEF) less than 40% were classified as having SHF. The patients with LVEF equal to or more than 40% and fulfilling the appropriate criteria for diagnosis of DHF according to European Guidelines [20], were classified as having DHF. All patients were ambulant. A further group of 21 elderly volunteers was recruited from a register of healthy elderly people living in a local community. They formed the healthy control group. None of these subjects had a history of cardiovascular or pulmonary disease, diabetes mellitus, neurological disease or cancer. The local Research Ethics Committee approved the study and fully informed consent was obtained from all participants.

2.2. Study protocol
Patients were asked to discontinue diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor antagonists, calcium channel blockers and any other vasodilators, sympathomimetic, parasympathomimetic and anti-cholinergic drugs for 24 h before investigation. It would be difficult, and perhaps unethical, for elderly HF patients to be without these drugs for more than 24 h. It is unlikely that the cardiovascular effects of these drugs would last for more than 24 h. Patients and healthy subjects were not allowed to eat any food for 4 h or drink coffee or tea for at least 12 h before the tests. The tests were performed in a quiet room in the Clinical Investigation Unit in the Royal Liverpool University Hospital.

A profile of AF tests (the Valsalva manoeuvre, deep breathing, head-up tilt and standing tests) was performed [21,22]. From a body worn sensor belt cardiac rate was identified as R–R interval by an edge electronic circuit and downloaded telemetrically in real time to a personal computer. Software (Varia Pulse TF4, MIE Medical Research Ltd, Leeds, UK) captured and displayed heart rate and/or R–R interval and their responses during each test (Fig. 1). All data were recorded and analysed automatically by the software programme, which was calibrated before each test.


Figure 1
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  		Fig. 1 Screen capture of typical response of heart rate to Valsalva manoeuvre x-axis time (s), y-axis heart rate (beats/min). Pr: Phase I, the period during which the patient starts to blow achieving an airway pressure of 20 mmHg. Test: Phase II, 15 s maintaining airway pressure at 20 mmHg. 10S: Phase III, strain release. Rest: Phase IV, reflex bradycardia.

 
The order of the tests was fixed and the first test was started after at least 15 min rest in the supine position. Subsequent tests were performed only after the heart rate returned to baseline from the preceding test (the minimum period of rest was about 5 min). AF tests were:

Controlled deep breathing. After resting, the subject was asked to perform deep rhythm-controlled breathing for 1 min. Each respiration cycle was 5 s inspiration and 5 s expiration. The test was repeated three times. The mean of E:I ratios (longest R–R interval in expiration/shortest R–R interval in inspiration) was calculated.

Tilt test. The subject was passively tilted to 70° head-up position (within 20 s) and then maintained upright for 5 min. During this period the patient breathed normally. The 30:15 ratio (the 30th R–R interval/the 15th R–R interval) was determined. In addition, BP at baseline, 1st, 3rd, and 5th minute after tilting was recorded.

Orthostatic standing test. The subject was asked to stand unaided and remained standing for 5 min. The 30:15 ratio was obtained. BP at baseline, 1st, 3rd, and 5th minute after standing was recorded. A fall of at least 20 mmHg in systolic BP and/or 10 mmHg in diastolic BP after tilting or standing was defined as orthostatic hypotension (OHT) [23,24].

Valsalva manoeuvre. In a sitting position the subject was asked to blow into a mouthpiece attached to a manometer, to hold the airway pressure at 20 mmHg for 15 s, and then release. The heart rate was recorded until it returned to baseline. As shown in Fig. 1, changes in heart rate are displayed in four phases. Valsalva ratio (the longest R–R interval after strain released/the shortest R–R interval in phases two or three) was calculated. The procedure was repeated three times. BP was recorded immediately and at the first minute after pressure was released.

2.3. Statistics
Data are presented as mean±S.D. or median and 95% CIs as appropriate. Chi-squared and Fisher's exact test were employed to compare proportions (aetiology and medications). The skewness and kurtosis parameters were used to confirm normal distribution and parametric tests were employed with these data. The Kruskal–Wallis test was used to analyse the differences between groups for non-normally distributed variables (30:15 ratio during tilt and standing tests). ANOVA was used to explore differences between the three groups (healthy, diastolic and SHF). ANOVA with repeated measures was used to explore the differences between three measures within individuals and between the three groups (healthy, diastolic and SHF) in both the deep breathing test and Valsalva manoeuvre. A value of P<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Baseline characteristics
Table 1 and Table 2 show baseline characteristics of the study subjects. The HF patients were older than the healthy subjects were (71.4±4.8 vs. 74.7±6.5 years, P=0.048). Compared with the healthy group, the baseline mean heart rates were slightly increased and mean systolic and diastolic BPs were slightly decreased in HF patients but the differences were not statistically significant (P=0.147; P=0.528; P=0.513, respectively). There were no significant differences in NYHA class, prevalence of coronary heart disease, or prior history of myocardial infarction or angina between the two HF groups. Three patients in the SHF group had dilated cardiomyopathy whilst there was none in the DHF group (P=0.023). A higher (though not statistically significant) proportion of patients in SHF group were prescribed angiotensin-converting enzyme inhibitors (73%) than those in DHF group (44%) (P=0.156). No differences between the two HF groups were found in the use of other medications.


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  		Table 1 Baseline characteristics of healthy subjects and HF patients mean±1 S.D.

 


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  		Table 2 Clinical characteristics of HF patients

 
3.2. Echocardiography
All results were within the predicted ranges apart from the mean values for ejection fraction and fractional shortening of the patients with SHF, which were significantly lower than predicted (Table 3). Mean ejection fraction and fractional shortening were significantly lower in the SHF group when compared with healthy subjects and diastolic failure patients (P in all cases <<0.001). The ratios of early to late left ventricular inflow velocity of all three groups were within the predicted range and there were no significant differences between the groups (P=0.517). The mean deceleration times for all three groups were within the normal range though there were significant differences between the groups (P<0.001). The mean deceleration times were significantly higher in the DHF group compared with the healthy group (P=0.002) and with the SHF group (P<0.001). The mean isovolumic relaxation time of the two HF groups were outside the predicted limits but not significantly so (P=0.060 for diastolic and P=0.844 for SHF groups).


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  		Table 3 Echocardiographic results (mean±1 S.D.) of healthy subjects and HF patients compared with predicted values

 
3.3. Autonomic function tests
The mean E:I ratios of the three groups were all within the reference value (P for all >>0.050). The median 30:15 tilt results were all below the reference value (P for all cases <0.050). The median results for 30:15 standing were all essentially normal (P for all cases >>0.050). The mean results for the Valsalva ratio were all significantly below the reference value (P for all cases <0.001) (Table 4).


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  		Table 4 AF results (mean±1 S.D. or median and 95% CI)

 
There were no significant differences between the results of the three groups for mean E:I ratio (P=0.111), for median 30:15 tilt (P=0.619) and median 30:15 standing (P=0.167). There were significant differences between the three groups for the mean results of the Valsalva ratio (P=0.001). The mean Valsalva ratio of the systolic group was significantly lower than that for the diastolic group (P<0.001) which in turn was significantly lower than the mean result of the healthy subjects (P<0.001) (Fig. 2).


Figure 2
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  		Fig. 2 Valsalva ratios in healthy subjects, DHF and SHF patients (P<0.001 comparing three groups).

 
There were no significant gender differences overall in the four AF tests (P>0.370 in all cases). Again no differences of AF tests were found between those HF patients taking and not taking ACE inhibitors (P>0.060).

3.4. Safety of the tests
OHT occurred in some patients during the tilt and standing tests (Table 5). Only one patient with OHT manifested symptoms of dizziness during the procedure. During head-up tilt, the rate of OHT was increased from 10% in the healthy elderly to 32% in DHF group and 21% in SHF group, but there was no significant difference between the three groups (P=0.171). In the standing test, the rate of OHT was also increased from 10% in healthy elderly to 20% in DHF group but none in SHF group. Again there was no significant difference between the three groups (P=0.215).


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  		Table 5 Proportion of subjects and patients with OHT during and standing tests

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
To the best of our knowledge this is the first study to comprehensively investigate AF in elderly patients with chronic HF, especially with DHF. The mechanism of autonomic dysfunction in HF is not well established. Impairment of baroreceptor and cardiopulmonary reflexes in congestive HF (LVEF<40%) has been demonstrated in previous studies [3,25–29]. The reduced activity appears to be due to functional changes in the reflex arc because the abnormalities appear to be restored when the clinical conditions are improved by the treatment with ACE inhibitors [30,31], beta-blockers [32], digoxin [33], or following heart transplantation [34]. Limited information on AF is available in HF patients with preserved systolic function. Few studies involved in patients with LVEF between 40 and 49% but not exceeding 50 [25,35]. The plasma norepinephrine in these patients did not significantly increase from the normal level [25]. The impairment of baroreflex has been found in patients with mild impaired LV function and NYHA class I or II but it is not as serious as in those with LVEF<40% and NYHA class III or IV [35]. The patients with preserved systolic function and NYHA class III and IV were excluded. Therefore, the mild impaired LV function means less haemodynamic and neurohormonal changes in these studies. As a result, one could assume that the varying autonomic control is related to the severity of LV function. Such a relationship has, however, not been corroborated [35–37].

In this study, although there was no reduction in deep breathing and standing test results, the response of heart rate to tilt and the Valsalva manoeuvre were all slightly reduced in normal subjects when compared with the reference value for young adult [22]. These results further confirm the age-related changes in AF reported in previous studies [13–15,38,39]. In our elderly HF patients, the heart rate response to deep breathing, head-up tilt, and standing tests are reduced but not significantly different from the healthy elderly. Therefore, it is difficult to identify whether the reduction is due to HF or to the effect of increasing age or factors other than baroreceptor abnormality. However, the mean of the Valsalva ratios in both groups of HF patients decreased significantly compared with the healthy subjects. Change in the Valsalva ratio primarily depends on the increased sympathetic activity and parasympathetic withdrawal due to HF. Our study therefore confirms that the alteration of AF in elderly patients with HF is over and above age-related changes as demonstrated by the Valsalva Manoeuvre.

We compared the AF responses in patients with SHF (LVEF<40%, mean 32%) and with DHF (LVEF>=40%, mean 59%). NYHA classes in both groups were similar. A progressive reduction of heart rate response from DHF to SHF was found in the Valsalva manoeuvre (P<0.001). This implies that AF is also impaired in DHF but not to the same extent as in patients with SHF.

The mechanisms of autonomic dysfunction in HF remain unclear. There may be underlying changes other than LV function that affect the reflex arc and regulate the autonomic tone in diastolic and SHF, or even in ageing. Cardiac filling pressure has also been considered [36]. The autonomic dysfunction in HF has been attributed mainly to the parasympathetic component, i.e. reduced Valsalva ratio and/or reduced high frequency component of heart rate variability. Classically, reduced sympathetic activity is compensated by an increased release of norepinephrine and epinephrine from the adrenal medulla. High catecholamine levels may be harmful for HF patients. Reduced parasympathetic activity cannot be countered except by sympathetic withdrawal. This may explain why autonomic dysfunction is usually accompanied by increased plasma norepinephrine in SHF. Unfortunately, we did not measure norepinephrine or cardiac filling pressure in our study. It is not clear whether the difference in AF tests results from different mechanisms or from different degrees of the sympathetic and parasympathetic dysfunction in diastolic and systolic HF.

According to European Guidelines [20], HF due to diastolic dysfunction can be imputed when echocardiographic systolic function is preserved and there is either abnormal decrease of E:A ratio and increase of deceleration time or prolonged isovolumic relaxation time. The results of our study show that deceleration time significantly differs between the three groups. Deceleration times decrease significantly in patients with SHF and increase significantly in patients with diastolic dysfunction. However, isovolumic relaxation time and E:A ratio do not differ. Isovolumic relaxation time is the time instant between the aortic valve closure and mitral valve opening. It depends not only on myocardial relaxation but also on valvular conditions that may change with increasing ageing [13]. Thus, isolated isovolumic relaxation time may not be a good measure of diastolic dysfunction in older patients.

The recruitment of the older patients, especially those with SHF, was difficult because the exclusion criteria required to reduce any possible changes in autonomic tone. This limited the study sample size. Our healthy controls were slightly younger than HF patients were and there were fewer men. These differences, however, were not statistically significant. No adverse events were evident when the patients stopped the medication for 24 h prior to and during the tests. The rates of OHT during the tilt and standing tests in healthy subjects were 10 and 10%, respectively, 32 and 20% in DHF group and 21% and 0 in SHF group. The overall incidence is much lower than other studies [24] confirming the tolerability and safety of these assessments in elderly HF patients.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
The results of this study demonstrate that there is age-related impairment in AF with further reduction in AF occurring in patients with HF. However, the severity of autonomic dysfunction is less in patients with DHF compared with patients with SHF.


   Acknowledgements
 
We are grateful for the participation of the research volunteers and specifically acknowledge the help and support from Prof. David Brodie, Research Centre for Health Studies, Buckingham Chilterns University College, UK.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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