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European Journal of Heart Failure 2004 6(4):439-447; doi:10.1016/j.ejheart.2003.12.003
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© 2004 European Society of Cardiology

Echocardiographic indices of left ventricular diastolic dysfunction in 647 individuals with preserved left ventricular systolic function

Frants Pedersena,*, Ilan Raymonda, Lene H. Madsena, Jesper Mehlsenb, Dan Atarc and Per Hildebrandta

a Department of Cardiology and Endocrinology, Frederiksberg University Hospital Nordre Fasanvej 57, DK-2000 Frederiksberg-Copenhagen, Denmark
b Department of Clinical Physiology, Frederiksberg University Hospital Copenhagen, Denmark
c Division of Cardiology, Aker University Hospital Oslo, Norway

* Corresponding author. Tel.: +45-38164350; fax: +45-38164359. E-mail address: frants{at}dadlnet.dk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Appendix A
 Acknowledgments
 References
 
Background: Knowledge about the occurrence of isolated diastolic dysfunction (DD) in the general population is limited.

Aims: This population study was performed to assess the frequency and distribution pattern of echocardiographic indices of left ventricular (LV) DD in an elderly population aged 50–89 years in which LV systolic function is preserved.

Methods and results: The study population (n=764) recruited from the background population answered a heart failure questionnaire and underwent echocardiography. Excluding subjects with a LV ejection fraction <50% or atrial fibrillation, diastolic function was evaluated in 647 subjects. The frequency of impaired relaxation according to earlier guidelines was 0.5%, vs. 2.5% using age- and gender-specific normal values of ‘E/A-ratio’ and ‘deceleration time’. In a subpopulation of 167 participants, 6.6% had ‘pseudonormalisation’. No difference was found in the frequency of dyspnea in subjects with impaired relaxation or ‘pseudonormalisation’ compared to subjects with normal filling pattern.

Conclusion: The prevalence of LV impaired relaxation was highly dependent on the choice of normal (cut-off) values for Doppler indices. Furthermore, our findings suggest that either isolated DD is often asymptomatic, or that Doppler flow derived parameters as a diagnostic method for assessing DD have a low specificity when used as a screening tool in the general population.

Key Words: Diastolic dysfunction • Heart failure • Echocardiography • Epidemiology

Received January 31, 2003; Revised October 23, 2003; Accepted December 7, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Appendix A
 Acknowledgments
 References
 
Congestive heart failure (CHF) represents a major and growing public health concern both in terms of incidence, prevalence, morbidity, mortality, and economic burden. Despite significant progress in the prevention and treatment of cardiovascular disease over the last two decades, health care statistics indicate that the incidence and prevalence of CHF have steadily increased in recent years [1–3].

Traditionally, CHF has been understood as left ventricular (LV) systolic dysfunction. However, this concept has been challenged by both hospital-based reports and epidemiological investigations documenting a high proportion of patients with CHF having normal LV systolic function [4–6]. Today's definition of CHF, therefore embraces diastolic ventricular dysfunction, that is failure to produce an adequate cardiac output at a normal LV filling pressure despite the presence of normal ventricular systolic function [7–10]. In terms of pathophysiology, a normal forward cardiac output in these patients can only be maintained by a compensatory elevation of ventricular filling pressure [11,12].

While comprehensive evidence exists about the prevalence of CHF and LV systolic dysfunction, divergent data have been published about the occurrence of CHF on the basis of isolated DD. In a review surveying 31 published reports on the epidemiology of diastolic heart failure, the occurrence of normal ventricular systolic performance was found to vary widely, from 13 to 74% among patients with CHF [4]. One of the reasons for this disparity is the fact that the diagnosis of DD has been hampered by an ongoing disagreement as to which parameters to employ for diagnosis. Therefore, the ‘European study group on diastolic heart failure’ (ESGDHF) [13] and the ‘American Society of Echocardiography’ (ASE) [14] have published guidelines for diagnosing DD. Basically, their recommendations define the interpretation of Doppler flow measurements of LV diastolic function as assessed by echocardiography, and the ESGDHF [13] also published the corresponding invasive hallmarks of DD.

Nevertheless, these guidelines were seriously disputed by a recent large-scale investigation by Schirmer et al. [15], providing the first large database of normal values of two transmittal diastolic flow parameters stratified by age and gender.

Against this background, we embarked on a population study large enough to shed light on the true frequency and distribution pattern of the recommended diastolic Doppler-flow derived parameters.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 Appendix A
 Acknowledgments
 References
 
2.1. Study design
Every Danish citizen and resident is registered with one general practitioner (GP). The study population 50–89 years old was recruited from four GPs situated in the same local area and stratified into four age groups, we attempted to invite at least 150 subjects in each age decade. The inclusion criterion was age between 50 and 89 years. Exclusion criteria were inability to co-operate (e.g. due to dementia), residency in a nursing home, or lack of response to two written invitations. An invitation to participate in the study was sent to all persons between 50 and 89 years of age assigned to the first two GPs (n=702). From the third GP, persons aged 60–89 years (n=308) and from the last GP only persons aged 80–89 years (n=78) were invited.

Of 1088 invited individuals, 764 participated in the study (response rate 70.2%). Each participant answered a heart failure questionnaire and clinical work-up, ECG and echocardiography were performed. In three cases, it was impossible to assess LV contractile function by echocardiography. Subjects with an LV ejection fraction <50% (approx. wall motion index (WMI) <1.6, n=59) or atrial fibrillation (n=19) were excluded. Of the remaining 683 subjects, a total of 647 individuals (Table 1) had an adequate Doppler tracing quality on their echocardiograms to allow a measurement of both E/A-ratio and deceleration time (DT) of the early diastolic transmitral E wave. We chose not to exclude persons with tachycardia unless measurements were unacceptable because of fusion of E and A waves.


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  		Table 1 Age and gender distribution of the study population

 
Comparison of the study population and the background population has been described in detail in a previous paper [16]. Compared to the background population, it should be taken into account, that the study population in this paper does not include subjects with LV ejection fraction <50% (approx. WMI<1.6) and/or atrial fibrillation.

Additionally, in a subgroup of 167 subjects both isovolumetric relaxation time (IVRT) and flow propagation velocity (Vp) were measured. At the time of the study, Vp represented a novel diagnostic entity introduced in the literature. The local ethics committee approved the study, and the subjects gave written informed consent.

2.2. Questionnaire
The questionnaire explored medical history, symptoms, drug history and smoking habit. Symptoms of heart failure were recorded from questions on ankle swelling and breathlessness. The degree of breathlessness was recorded from the questionnaire based on a modification of the WHO-classification [17] (grade 1=dyspnea by vacuum-cleaning/climbing stairs to the 2nd floor, grade 2=when walking on the level, grade 3=when dressing/at minimum exertion). The WHO-classification of dyspnea grade 1 and 2+3 corresponds approximately to the New York Heart Association (NYHA) functional classification II and III, respectively.

2.3. Measurements
Blood pressure was measured twice after at least 15 min of rest. Heart rate was measured during echocardiography and a 12-lead standard electrocardiogram was recorded.

2.4. Echocardiography
A transthoracic echocardiographic examination was performed with each participant in left lateral recumbent position using standard equipment (either HPTM Sonos 5500, AcusonTM 128/10c, or VingmedTM 750). The subjects were submitted to two-dimensional apical two- and four-chamber views and in the parasternal long-axis and short-axis views [18]. LV systolic function was visually assessed using a nine-segment model [19] and wall motion score was graded as described by Berning et al. [20]. The score 3 was used for hyperkinesias, 2 for normokinesia, 1 for hypokinesia, 0 for akinesia, and –1 for dyskinesia. WMI was calculated by dividing the sum of the scores in each segment by nine and by multiplying the WMI by 30; LV ejection fraction was estimated [20]. Systolic function was evaluated off-line in a blinded fashion by two experienced cardiologists. The aortic, mitral and tricuspid valves were evaluated by Color- and continuous wave-Doppler technique.

2.5. LV diastolic function
To measure transmitral flow the pulsed Doppler sample window was positioned between the tips of the mitral valve leaflets [21]. The following transmitral flow variables were measured: peak flow velocity in early diastole (E wave) and during atrial contraction (A wave), and from these the peak E/peak A ratio was calculated as was the deceleration time (DT) of the peak E wave defined as the time elapsing from the E wave peak to the end of the deceleration slope extrapolated to the zero line. Isovolumetric relaxation time (IVRT), defined as the time interval from closure of the aortic valve to opening of the mitral valve, was measured by continuous-wave Doppler with the cursor positioned between the anterior mitral valve and the aortic valve. Finally, the preload-independent parameter ‘color M-mode Doppler flow propagation velocity’ (Vp) [22] was measured in the apical four-chamber view with the M-mode cursor positioned through the center of inflow, as the slope of the first aliasing velocity (45 cm/s) during early filling, from the mitral valve plane to 4 cm distally into the LV cavity [23]. All measurements were obtained as the mean values of three consecutive heart cycles.

2.6. Normal values of diastolic indices
In an attempt to estimate the prevalence of DD in the population, we applied recently published age- and gender-specific 2.5%- and 97.5% percentiles for normality of E/A-ratio and DT (Appendix). These cut-off points are based on ‘The Tromsø Study’ [15], in which impaired relaxation was defined by an E/A-ratio<2.5th percentile and a DT>97.5th percentile in a normal subgroup stratified by age and gender [15]. Furthermore, we used the guidelines from the ESGDHF [13] in which the definition of DD is based on fixed cut-off values for subjects above the age of 50. Impaired relaxation according to these guidelines is defined as an E/A-ratio<0.5 and a DT>280 ms or IVRT>105 ms. According to the ASE recommendations [14] impaired relaxation was defined by E/A-ratio less than 1.0. To identify pseudo-normal filling pattern [23–25], the proposed cut-off values by Garcia et al. [23] were used, in which ‘pseudo-normalization’ of transmitral flow occurs at an E/A-ratio between 1.0 and 2.0 with a Vp<45 cm/s.

2.7. Statistics
Verification of normal distribution of data was accomplished with histograms. Pearson Chi-square Test was used to compare independent groups with categorical data and for n<5, Fisher's exact test was used. Mann–Whitney test and Kruskal–Wallis test were used to test for differences between two or more independent groups with numerical data. P-values <0.05 were considered significant. All tests were computed using the SPSS-9.0 software (SPSS Inc, Chicago, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 Appendix A
 Acknowledgments
 References
 
Basic demographics of the study population (n=647) are shown in Table 2. No significant difference in gender was found between the examined population (n=647) and the background population (n=28.285), for the four age groups. Dyspnea (≥grade 1) was reported in 180 (27.8%) participants, 31.7% of the women and 22.3% of the men (P=0.01), about half of them reporting slight dyspnea (=grade 1). Ankle swelling was reported in 19.9% (n=129) of subjects, again more common in women (25.1%) than in men (12.5%) (P<0.0001).


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  		Table 2 Baseline characteristics, median (2.5–97.5th percentile) or percent of total for men and women

 
Two medical doctors evaluated reproducibility in 138 consecutively recruited persons as the variability between Doppler indices measured off-line. For the E wave, the mean differences±S.D. between measurements were 0.38±5.2 and 0.87±5.2 cm/s, for intra-observer number 1 and inter-observer pairs, respectively. For the A wave, the corresponding values were –0.86±4.7 and 1.30±6.7 cm/s. For the E/A-ratio, the values were 0.016±0.087 and –0.0043±0.087. For the DT, the values were –5.5±21.7 and –5.9±24.3 ms. For the IVRT, the values were –1.4±5.9 and 7.1±9.8 ms, for Vp, the values were 0.99±5.5 and 0.31±6.1 cm/s.

Except for DT, the distribution patterns of diastolic indices in the population are slightly skewed. Of note, there is no obvious cut-off limit for any of the parameters depicted.

Median values of Doppler indices stratified according to the different age groups are shown in Fig. 1 and Table 3. E/A-ratio decreased with age (P<0.0001) to reach a plateau in septuagenarians. DT increased with age throughout all age decades (P<0.0001). IVRT was almost constant in the age group above 60 years. Vp decreased from the sixtieth to the seventieth age decade (P<0.047) without decreasing further in the eightieth age decade.


Figure 1
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  		Fig. 1 Median values of Doppler indices related to age groups. E indicates peak E-wave; A, peak A-wave; E/A-ratio, peak E/peak A-wave; DT, deceleration time; IVRT, isovolumetric relaxation time; and Vp, flow propagation velocity.

 


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  		Table 3 Median values of diastolic indices in age groups

 
The prevalence of impaired relaxation was significantly higher (P<0.0001) using age- and gender-specific percentiles for normality according to ‘The Tromsø Study’ [15] compared to fixed cut-off values recommended by the ESGDHF [13]: 2.5% (95% CI 1.3–3.7) and 0.5% (95% CI 0.1–1.4), respectively. All individuals in the latter subgroup (diagnosed according to the ESGDHF guidelines) were also diagnosed with impaired relaxation by the Tromsø criteria. The prevalence of impaired relaxation according to the ‘Tromsø Study’ [15] increased significantly with age (P<0.003), particularly in septuagenarians and above (Table 4): 0–1.5% of the participants in their 5th and 6th decennium had impaired relaxation, while 4.6% of the septuagenarians and 6.0% of the octogenarians had impaired relaxation. E/A-ratio was less than 1.0 in 65.8% of subjects, which defines impaired relaxation according to recommendations from the ASE [14].


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  		Table 4 Prevalence of impaired relaxation in the study population related to age

 
Vp was assessed in 167 participants aged 60–89 years (median age, 74.1 years). We found that 6.6% (95% CI 2.8–10) of this subgroup analyzed had a ‘pseudo-normal’ flow pattern according to cut-off values of Garcia et al. [23]. In the same subpopulation 23.4% had impaired relaxation, using IVRT >105 ms as a cut-off value, as recommended by the ESGDHF [13].

When the assessed occurrence of DD in the population was related to symptoms, only 25.0% of the subjects with impaired relaxation according to ‘The Tromsø Study’ complained of dyspnea, a frequency not significantly different from that seen in individuals with normal relaxation (27.9%; Table 5). Forty-six percent of the subjects with a ‘pseudo-normal’ flow pattern had dyspnea vs. 39.1% of subjects without ‘pseudo-normal’ flow pattern, which was not significantly different.


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  		Table 5 Prevalence of diastolic dysfunction and dyspnea in the population

 
The age- and gender-specific prevalence proportions obtained in the study sample have been applied to the background population, excluding the expected proportion with LV ejection fraction <50% (approx. WMI<1.6) and/or atrial fibrillation. The estimated overall prevalence proportions of impaired relaxation according to ‘The Tromsø Study’ and ‘pseudo-normal’ flow pattern were 2.6% and 5.6%, respectively.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 Appendix A
 Acknowledgments
 References
 
The main goal of the present study was to shed light on the true frequency and distribution pattern of echocardiographic indices of LV diastolic dysfunction (DD) in elderly subjects with preserved LV contractility, thus enabling us to extrapolate to the prevalence of isolated diastolic heart failure. Among 647 individuals aged 50 to 89 years and recruited randomly from an urban population segment, 2.5% had the diagnosis of impaired relaxation confirmed when recently reported age-specific criteria were applied, and as few as 0.5% were diagnosed based on the ESGDHF guidelines. Intriguingly, when DD was related to symptoms, only 25% of the subjects with impaired relaxation had complaints of dyspnea, a finding not significantly different from that seen in individuals with normal relaxation.

Several epidemiological investigations have documented that nearly half of the population suffering from CHF in the community have normal LV systolic function [5,6,26,27]. Predominant underlying causes and often encountered contributors to cardiac dysfunction are aortic and mitral valve defects, LV dilatation and elevated pulmonary artery/right ventricular pressure. Also, isolated DD has been claimed as one of the foremost alternative explanations for CHF when systolic function is preserved.

Initially, impaired LV diastolic function was assessed by invasive measurements at cardiac catheterization. To date, these invasive parameters, e.g. isovolumic time constant of relaxation ({tau}) and LV end-diastolic pressure are still regarded the ‘gold-standard’ for assessing LV diastolic function [10,12,13]. Later, the introduction of Doppler echocardiography has provided non-invasive methods of quantifying LV diastolic function in terms of chamber filling dynamics [13,14]. Importantly, these non-invasive approaches have enabled large-scale epidemiological investigations.

Doppler indices of transmitral flow (ex. E/A-ratio and DT) have been shown to correlate well with LV filling pressures in subgroups of patients with systolic dysfunction [28,29], but the correlation has been poorer in patients with normal systolic function [12]. While undoubtedly useful, there are problems with the interpretation of Doppler indices. One important limitation is that these measurements reflect filling and not function and are dependent on patients characteristics such as heart rate, gender and age, as well as physiologic variables such as preload, LV relaxation, elastic recoil, left atrial pressure and LV compliance [12].

The ESGDHF guidelines [13] have put forward the following definition of diastolic heart failure: (1) signs or symptoms of CHF; (2) normal or near normal LV systolic function (LVEF≥45%); and (3) objective evidence of DD. Unfortunately, because reference values hitherto were based on relatively small study samples limiting the possibility for age stratification of Doppler indices that vary with age, the limitations of these recommendations were soon discovered. In 2000, Schirmer and colleagues [15] provided the first large age- and gender-specific normality database for the Doppler-flow derived parameters E/A-ratio and DT. Furthermore, a new echocardiographic modality, Vp, has been introduced, which is postulated to be less dependent upon loading conditions [22,24,25].

In view of the mentioned limitations, we applied both the current guidelines and the age-specific cut-off values to our Doppler-flow measurements in the present study.

Impaired relaxation: While it is reassuring to learn that subjects diagnosed with impaired relaxation based on recommendations from the ESGDHF were also diagnosed with impaired relaxation according to the Tromsø criteria, it is not surprising that the ignorance of age-specificity drastically lowers the prevalence of abnormal measurements, particularly in a cohort of elderly people. This fact supports the need for age- and gender-specificity.

The study population was stratified into four age groups. Therefore, the estimated overall prevalence proportion of impaired relaxation according to ‘The Tromsø Study’ (2.6%) and ‘pseudo-normalization’ pattern (5.6%) for the background population were calculated. These results are supposed to reflect the prevalence in the background population, with its current age- and gender structure, and they did not differ considerably from the prevalence proportions in the study sample.

Two thirds of the population had impaired relaxation according to guidelines from the ASE [14], consistent with the fact, that in individuals older than 70 years the E/A-ratio is usually less than 1.0. As recommended in the guidelines, the degree of impaired relaxation should be judged by the decrease in E/A-ratio and increase in DT.

The prevalence of increased IVRT in the subpopulation according to the ESGDHF Guidelines [13] was surprisingly high, 23.4%, supporting the theory that IVRT is either a very sensitive [10] or less reliable [9] parameter for diagnosing impaired relaxation.

Pseudonormal pattern: Another difficulty with the interpretation of Doppler indices of diastolic filling is the vexing problem of pseudo-normalization, in which the transmitral flow pattern cannot be distinguished from that seen in normal subjects, despite abnormal diastolic function. To reveal pseudo-normalization, we applied a relatively new echocardiographic modality, flow propagation velocity (Vp). The prevalence of pseudo-normal pattern was 6.6% assessed by Vp. The median age in the subpopulation was higher (74.1 years) compared to the median age in the whole study population (65.7 years). Although Vp was only measured in a subpopulation of 167 subjects, the parameter decreased significantly with age, which might indicate that normal values of Vp need to be stratified by age in the elderly.

Forty-six percent of subjects with pseudo-normalization had complaints of dyspnea, a frequency not significantly different from that seen in subjects without pseudo-normalization. While impaired relaxation has been proposed to identify subjects with early stage DD and does not necessarily imply symptoms or increased filling pressure [12,14], pseudo-normal pattern should represent a moderate stage of DD, consistent with increased filling pressure at rest. The prevalence of asymptomatic pseudo-normalization could be compared to the prevalence of asymptomatic systolic dysfunction in the community, which has been reported in about half of patients with systolic dysfunction [30].

On the basis of the various patterns of transmitral Doppler flow encountered, we deducted a pathophysiologic model of the various disease states as depicted in Fig. 2. The graph shows a schematic drawing of how the continuum of the gradual alterations of the E/A-ratio and the DT (solid lines) correlate with the different clinical conditions in diastolic heart failure, i.e. impaired relaxation, pseudo-normalization and restrictive flow pattern. The highlighted areas over/under the dotted lines represent the diagnosed cases, according to increased/decreased values of E/A-ratio and DT. As illustrated by the arbitrarily positioned horizontal (dotted lines) and vertical cut-off lines, the location of the age-specific cut-off values is instrumental in defining the size and extent of the highlighted areas under the curves, and hence, the number of individuals with diagnosed disease.


Figure 2
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  		Fig. 2 Schematic drawing of expected mitral inflow (upper panel) and the respective Doppler indices E/A-ratio and deceleration time (DT).

 
One important limitation of the study is that the diastolic parameters measured were not assessed against an invasive gold standard. However, this would not have been feasible in a population segment such as the one used in this particular investigation. Furthermore, an objective assessment of possible exercise limitations in subjects with diastolic filling abnormalities was not evaluated in this study.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
Appendix A
 Acknowledgments
 References
 
In this age-controlled population study, the prevalence of impaired relaxation was highly dependent on the choice of normal (cut-off) values for Doppler-flow derived parameters. Furthermore, there was no difference in the frequency of dyspnea in subjects with impaired relaxation or pseudonormal flow pattern compared to subjects with normal filling pattern.

Our findings suggest that either isolated DD is often asymptomatic, or that Doppler flow derived parameters as a diagnostic method for assessing DD have a low specificity when used as a screening tool in the general population.


   Appendix A
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Appendix A
Acknowledgments
 References
 
Reference values used in the present study according to ‘The Tromsø Study’ (17).
Age groups E/A-ratio
 Deceleration time (ms)
 Deceleration time (ms)



(years) 2.5% percentile 97.5% percentile 97.5% percentile
 2.5% percentile




Male and female Male and female Male Female Male DT Female DT
50–59 0.78 1.61 285 240 145 135
60–69 0.61 1.55 305 275 140 130
70–90 0.64 1.50 300 280 140 140

E/A-ratio indicates peak E/peak A wave.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Appendix A
 Acknowledgments
References
 
This study was supported by grants from The Copenhagen Hospital Corporation (H:S).


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Appendix A
 Acknowledgments
 References
 

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 ESC Textbook of Cardiovascular MedicineHome page
J. McMurray, M. Petrie, K. Swedberg, M. Komajda, S. Anker, and R. Gardner
CHAPTER 23 Heart Failure
ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter.
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