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European Journal of Heart Failure 2007 9(4):364-369; doi:10.1016/j.ejheart.2006.09.013
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© 2007 European Society of Cardiology

Diastolic dysfunction and autonomic abnormalities in patients with systolic heart failure

Phyllis K. Steina,*, Larisa Tereshchenkoa, Peter P. Domitrovicha, Robert E. Kleigera, Alfonso Perezb and Prakash Deedwaniac

a Washington University School of Medicine St. Louis, MO, USA
b Takeda Pharmaceuticals North America Lincolnshire, IL, USA
c UCSF Fresno/VACCHS Fresno, CA, USA

* Corresponding author. Washington University School of Medicine HRV Lab, 4625 Lindell Blvd, Suite 402, St. Louis, MO 63108, USA. Tel.: +1 314 286 1350; fax: +1 314 286 1394. E-mail address: pstein{at}im.wustl.edu


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Summary
 References
 
Background: Patients with systolic heart failure (SHF) often have concomitant diastolic dysfunction (DD). SHF is associated with decreased heart rate variability (HRV), but the impact of degree of DD on HRV in SHF is unclear.

Methods and results: HRV was measured in 139 patients, aged 64±12 years, 74% male, LVEF 30±8%. Patients had stable NYHA class II–III CHF on ACE inhibitors or ATII receptor blockers, with LVEF≤40% and BNP≥200 pg/ml. Subjects underwent 2-D echocardiography with Doppler assessment and 24-h Holters. Patients were categorized as having impaired relaxation (E-deceleration time>2 SD above age-adjusted normal values (AANV), E/A≤1, systolic/diastolic pulmonary vein flow≥1; N=30), pseudonormal (E-deceleration time within 2 SD of AANV, E/A=1–2, systolic/diastolic pulmonary vein flow <1 N=25) or restrictive filling patterns (E-deceleration time>2 SD below AANV or/and E/A ratio≥2; N=84) Differences were adjusted for clinical covariates using UNIANOVA, p<0.05. HRV was reduced and BNP higher in pseudonormal patients compared to impaired relaxation, but this difference was only significant for restrictive vs. impaired filling. Differences remained significant after adjustment for covariates.

Conclusion: Significantly more abnormal HRV, reflecting greater cardiac autonomic dysfunction, is associated with restrictive DD compared to impaired relaxation.

Key Words: Heart rate variability • Diastolic dysfunction • Congestive heart failure

Received January 6, 2006; Revised June 28, 2006; Accepted September 28, 2006


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Summary
 References
 
Depressed HRV is common in patients with heart failure (HF).[1-9] Diastolic dysfunction is present in most patients with LV systolic dysfunction and precedes systolic dysfunction in most, but not all, disease processes. Diastolic function may be an important determinant of symptom class in patients with systolic dysfunction.

Little is known about the association of left ventricular diastolic abnormalities and HRV. Arora et al [10] compared HRV in patients with systolic heart failure and patients with diastolic heart failure and preserved ejection fraction. HRV indices reflecting circadian variation in heart rate were found to be significantly lower in patients with systolic dysfunction, compared to those with diastolic dysfunction. Poulsen and co-authors [11] found that patients with a restrictive LV filling pattern, defined as deceleration time<140 ms in patients aged 40-75 years, had significantly reduced HRV compared with patients with a non-restrictive LV filling pattern. In this dataset HRV indices correlated weakly, but significantly, with parameters of LV diastolic function. Also, in an experimental study in dogs, impairment of LV diastolic function was followed by a parallel deterioration of autonomic regulation [12].

Clarification of the association between HRV parameters and restrictive diastolic filling patterns in patients with systolic CHF might help in prediction of outcomes in this group of patients and provide insights into the pathophysiology of diastolic dysfunction.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Summary
 References
 
2.1. Patients
The study population was recruited from a Holter-based heart failure drug treatment evaluation study. Data were obtained before randomization and prior to administration of the study drug. Eligible patients were >30 years old, New York Heart Association (NYHA) class II or III heart failure, left ventricular ejection fraction (LVEF)≤40%, B-type natriuretic peptide (BNP) level≥200 pg/ml, in predominantly normal sinus rhythm with well-defined QRS complexes suitable for Holter analysis. Of the 198 patients screened, 139 had recordings adequate for HRV analysis. No patient had a CRT device or pacemaker. All patients gave IRB-approved informed consent before participating in the trial.

2.2. Assessment of HRV
Twenty-four hour, 3-channel Holter recordings were obtained using Del Mar 438 Digicorder recorders. ECG signals from these recordings were converted to a format that permitted them to be scanned onto a MARS 8000 Holter Analyzer (GE Medical Systems, Milwaukee, WI). Scanning was performed by research technicians at the Washington University School of Medicine Heart Rate Variability Laboratory. After the scanner automatically detected and labeled all QRS complexes, data were reviewed and edited by the technicians using standard Holter analysis procedures. All Holter analyses were reviewed in detail by one of us (PKS) with special attention paid to ensuring that only normal-to-normal (N-N) beats with uniformly detected onsets, within each recording, were included in the HRV analysis. The longest and shortest true N-N intervals were identified for each recording, and intervals outside of these limits, as well as all ectopic beats, excluded from all calculations. All intervals that resulted from blocked atrial premature beats were excluded.

After editing, the labeled QRS data stream was transferred to a Sun Enterprise 450 server (Sun Microsystems, Palo Alto, CA) for HRV analyses. Calculations of time and frequency domain HRV were performed according to standard methods. Recordings were eligible for time domain analyses if ≥18 h of data with 50% N-N interbeat intervals were present on the recording. Eighty percent N-N interbeat intervals were required for frequency domain and non-linear analyses. Patients not in normal sinus rhythm were excluded. Using these criteria, N=139 recordings were adequate for time domain and N=115 for frequency domain and non-linear analyses.

HRV indices are grouped as longer-term, i.e., quantifying variations in heart rate over >5 min period (primarily circadian rhythms), intermediate-term, i.e., quantifying variations in heart rate over <5 min periods (reflecting combined sympathetic and parasympathetic modulation of heart rate) and short-term, i.e., quantifying beat-to-beat (parasympathetically-modulated) changes in heart rate [13]. Longer-term indices include SDNN, the standard deviation of all normal-to-normal (NN) intervals, and SDANN, the standard deviation of the5-min averages of NN intervals, in the time domain. Total power, the total amount of variance in NN intervals, and ultra low frequency power, the total variance in NN intervals between once in 5 min and once in 24 h are longer-term indices in the frequency domain. SDNNIDX, the average standard deviation of NN intervals over 5 min, is an intermediate-term index in the time domain. Both very low frequency power (the variance in NN intervals at frequencies between every 20 s and every 5 min) and low frequency power (the variance in NN intervals at frequencies between 3 and 9 times/min) are intermediate-term indices in the frequency domain. Short-term indices in the time domain include rMSSD (the root mean square of successive differences in NN interbeat intervals) and pNN50 (the percent of differences between successive NN interval that is >50 ms) and in the frequency domain, high frequency power (the amount of variance in NN intervals at respiratory frequencies, i.e., 9-24/min).

2.3. Echocardiography
Standard two dimensional and pulsed Doppler echocardiographic examinations were performed at the study sites and read in a central laboratory. LV dimensions and chamber sizes were obtained according to the recommendations of the American Society of Echocardiography [14]. Pulsed-wave Doppler tracing of mitral valve inflow was recorded at the leaflet tips, pulmonary venous return was measured and diastolic filling pattern was estimated [14-18].

Patients were divided into three groups: impaired relaxation, pseudonormal and restrictive filling patterns based on Doppler echocardiography [19]. An impaired relaxation filling pattern (E-deceleration time above 2 SD of age-adjusted normal values, E/A≤1, systolic/diastolic pulmonary vein flow≥1) was observed in 30 patients. A pseudonormal filling pattern (E-deceleration time within 2 SD of age-adjusted normal values, E/A=1-2, systolic/diastolic pulmonary vein flow<1) was observed in 25 patients. Patients (N=84) with E-deceleration time greater than 2 SD below age-adjusted normal values or/and E/A ratio ≥2 were considered, to have restrictive filling patterns.

2.4. Statistical analysis
Data are expressed as mean±S.D. Patient groups were compared using univariate analysis of variance for continuous variables and chi-square test for categorical variables. Univariate linear regression analysis was used to determine independent predictors of HRV parameters. The UNIANOVA procedure was used to determine the independent relationship between HRV and diastolic filling patterns by significant clinical covariates. Differences were considered significant at the p<0.05 level. All statistical analyses were performed using SPSS 11.0 (SPSS, Chicago, IL).


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Summary
 References
 
Table 1 describes the clinical characteristics of the patients with systolic HF according to the degree of diastolic dysfunction. Patients with an impaired relaxation filling pattern were significantly older than patients with restrictive filling pattern, although there were no differences in age between patients with pseudonormal and impaired relaxation filling patterns. Among those with a restrictive diastolic filling pattern mean BNP levels were twice as high (p<0.0001) as in patients with impaired relaxation or pseudonormal filling. The only significant between-groups difference in medical history or medications was that patients with restrictive diastolic dysfunction were more likely to be diabetic (56%), whereas patients with delayed relaxation were less likely to be diabetic (30%). History of hypertension was not different between groups, but diastolic blood pressure was significantly higher in patients with a restrictive diastolic filling pattern compared to impaired relaxation. All patients were on diuretics and there were no differences in beta-blocker use between groups. The range of E-deceleration times for each category of diastolic function by age group is shown in Table 3.


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  		Table 1 Clinical and demographic characteristics of patients with different diastolic filling patterns

 
3.1. Echocardiographic parameters
Table 2 compares echocardiographic variables for patients according to the different diastolic filling patterns. Within this systolic heart failure population (mean EF 30.3±8.5%), there were no patients with normal diastolic function. LVEF declined in association with worsening of diastolic function and was significantly lower in patients with restrictive diastolic dysfunction compared to patients with impaired relaxation (29% vs 34%, p=0.004). No between-group differences were found in relative wall thickness, LV mass, LV end systolic or end diastolic volumes indices. Left atrial systolic volume index increased in association with diastolic dysfunction abnormalities but this difference was not statistically significant.


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  		Table 2 Echocardiographic left ventricular function parameters

 
3.2. HRV
Time and frequency domain HRV parameters are listed in Table 3. A decrease in most long-term and short-term time domain HRV parameters was seen in association with increased degree of diastolic dysfunction, and this difference became significant among patients with restrictive diastolic filling patterns compared to patients with an impaired relaxation filling pattern. Results were similar in the frequency domain except for a lack of significant difference in very low frequency power.


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  		Table 3 Range of E-deceleration (ms) by age group and time and frequency domain HRV parameters, according to diastolic filling group

 
To verify the contribution of diastolic dysfunction patterns per se to HRV analysis, we adjusted HRV for factors that were significantly different between groups and potentially associated with HRV, i.e. diabetes mellitus, LVEF, NYHA class and diastolic blood pressure (Table 4). After adjustment for all of the clinical factors, significant differences persisted between patients with impaired and those with restrictive diastolic filling patterns. Notably, although diastolic dysfunction and NYHA class were significantly associated with HRV in most models, there was no relationship between LVEF and HRV for any HRV index.


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  		Table 4 Independent association of diastolic filling patterns, clinical covariates and time and frequency domain HRV (β, 95% CI, p-value shown for p<0.10)

 

   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Summary
 References
 
The reduction in HRV among patients with heart failure is well documented [3]. Previous studies of HRV in HF, like the present one, have involved heterogeneous groups of patients with varying degrees of concomitant diastolic dysfunction. Our results indicate that patients with severe systolic heart failure and restrictive diastolic filling patterns have significantly more abnormal HRV, despite being younger, than patients with impaired relaxation. Interestingly, SDNNIDX and its frequency domain very low frequency power were not significantly different between groups. This could reflect a higher prevalence of Cheyne-Stokes breathing, which might elevate very low frequency power, among patients with more severe diastolic dysfunction in whom these HRV indices would otherwise be lower [20,21] However, the presence of Cheyne-Stokes breathing was not assessed in this study.

Although patients with a restrictive filling pattern were more likely to be diabetic, the difference in HRV compared to patients with impaired relaxation persisted after adjustment for clinical covariates, including diabetes mellitus, LVEF and NYHA class. Importantly, LVEF had no relationship to HRV. These findings suggest that in this population with severe systolic dysfunction, more adverse diastolic filling patterns may have a stronger effect on cardiac autonomic functioning than further decrements in systolic function. Thus, there may be an additive effect of severe diastolic dysfunction and systolic dysfunction on cardiac autonomic function which is clearly evident in patients with restrictive filling patterns.

Mechanisms underlying the reduction in HRV for patients with a restrictive diastolic filling pattern compared to patients with impaired relaxation are unclear. Impaired sympathovagal balance, characterized by sympathetic overactivity and parasympathetic withdrawal, is an integral component of heart failure [5,22-24]. A relationship between increased plasma epinephrine level, a marker of neuroendocrine activation and disease progression in CHF, and decreased HRV was demonstrated by Yoshikawa et al [5]. Our results suggest that significantly increased compensatory neuroendocrine activation is present in patients with systolic dysfunction at the restrictive stage, resulting in decreased HRV due to pathologically saturated sympathetic tone [25], β-adrenoreceptor desensitization resulting in impairment of post-receptor signal transduction [26], noradrenergic nerve loss, end-organ unresponsiveness or primary central abnormalities in autonomic modulation [22].

However, the question of whether the observed loss of HRV is due to the increased compensation for the mechanical decrements associated with restrictive filling or whether the mechanical decrements are a consequence of loss of cardiac autonomic function is unanswered. Thus, the association between diastolic filling patterns and autonomic nervous system dysfunction described in this study may be the hemodynamic consequence of disturbed parasympathetic flow to the heart and/or an abnormal afferent parasympathetic inflow from carotid and aortic baroreflexes and atrial receptors. Efferent or afferent parasympathetic denervation may induce slowed ventricular relaxation, leading to a fall in the velocity of the passive, early diastolic transmitral flow and a compensatory increase in the flow velocity caused by atrial contraction. This is further reinforced by findings suggesting that diastolic dysfunction is caused by impaired myocyte handling of calcium, since the latter depends in part on autonomic nervous stimulation [27]. Therefore, diastolic dysfunction and cardiac autonomic dysfunction may well be related through a common pathophysiologic pathway.

E-deceleration time-based classifications of diastolic filling patterns have not been consistent across studies. Indeed in the current study, we originally classified patients as having restrictive diastolic filling based on a deceleration time of <150 ms, independent of age, a definition found in other studies [28]. This definition ignores the increased deceleration time seen in normal aging, and over classifies older patients as having a restrictive filling pattern. Thus, with the original cutpoint, we erroneously found that HRV was lower among patients with pseudonormal filling and did not decline further among those with restrictive filling, underscoring the importance of age-adjustment for this parameter. This problem is illustrated by existing studies. Vaskelyte et al [29], using our original definition for restrictive filling, reported that in patients with LVEF≤35% a restrictive pattern (E/A≥2 or an E/A ratio between 1 and 2 with a deceleration time<150 ms) correlated with high early postoperative mortality, morbidity and minimal improvement in LV systolic function. Several other authors, including as previously mentioned Poulsen et al, have defined restrictive LV filling as a deceleration time<140 ms independent of age [11]. Thus, Moller et al [30] reported that the presence of restrictive filling (deceleration time<140 ms) within 24 h of myocardial infarction predicted cardiac death and LV dilatation. Whalley et al [31] reported that hospital re-admission rates of patients with restrictive filling pattern (deceleration time<140 ms) were nearly double that of the delayed relaxation filling group (deceleration time>230 ms). On the other hand, Lavine [32] reported that both the early and ultimate development of CHF following a first MI was associated with restrictive diastolic filling indices (E-deceleration time 161±39 ms). It was also reported that EF<40% and E-deceleration time<200 ms were predictive of late CHF in patients without initial CHF.

Thus, we have found a marked disturbance in cardiac autonomic function, possibly beginning at the pseudonormal stage, but clearly evident at the restrictive stage of diastolic dysfunction in the presence of NYHA class II-III systolic heart failure with elevated BNP. Our results are consistent with the known elevated risk of adverse outcome in patients with restrictive compared to impaired relaxation filling patterns.

The cross-sectional nature of our study does not allow us to derive cause and effect conclusions about the relationship between autonomic and diastolic dysfunction. A further limitation of the current study is the lack of invasive intracardiac pressures to determine the precise magnitude of LV filling pressures [33,34]. Also, cardiovascular medications could affect loading conditions and HRV results, but all of the patients were receiving optimal medical therapy and had been stabilized before the pre-randomization Holter recording. ACE-inhibitor, diuretic and beta blocker use were similar between groups. Use of digitalis tended to be higher in patients with pseudonormal and restrictive filling than in patients with impaired relaxation, but this difference was not statistically significant. Finally, although there were virtually no significant clinical and demographic differences between the patients with pseudonormal and restrictive filling in our study, Table 1 suggests that significant differences, e.g., in NYHA functional class, prevalence of hypertension, heart rate or diastolic blood pressure, might have been found with a larger sample size. Mean values for HRV, however, were similar between these groups of patients, suggesting that most HRV results would not have changed with a larger study.


   5. Summary
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Summary
References
 
Depressed HRV, consistent with increased sympathetic activation and parasympathetic withdrawal, was associated with restrictive diastolic filling patterns compared to impaired relaxation patterns in patients with severe systolic heart failure, independent of NYHA class and the presence of diabetes mellitus. LVEF was not related to HRV. Thus, more severe diastolic dysfunction in patients with systolic HF is associated with greater cardiac autonomic dysfunction than milder diastolic dysfunction, even after adjustment for covariates. Further study is needed to verify these findings in a prospective series of patients and to elucidate the mechanisms underlying the disturbances in cardiac autonomic dysfunction associated with diastolic dysfunction in patients with severe systolic heart failure.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Summary
 References
 
{star} Research support: Study supported by Takeda Pharmaceuticals of North America, Lincolnshire, IL, USA. Back


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

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