Does increased left ventricular end diastolic pressure with or

without symptoms lead to increased clinical events? A review of 3

year outcomes

Joshua Burkea
aWarwick Medical School, Gibbet Hill Road, Coventry CV4 7AL, United Kingdom

Abstract

A retrospective study comparing the relationship between raised left end diastolic pressure
(as expressed by the E/e′ ratio) and clinical events 3 years post attendance in a community
heart failure clinic.
Methods: Patients who met the criteria (preserved ejection fraction and symptomatic
breathlessness) were admitted and stratified into 4 groups. The first 2 based on grouping
patients based on E/e′ ratio of <15 or ≥15 and another group by E/e′ ratio of <18 or ≥18.
Hospital admissions and mortality outcomes were then compared and analysed after 3
years.
Results: 601 patients were screened of whom 176 were admitted into the study. At the end
of 3 years there were significantly poorer outcomes in both groups stratified by E/e′ ratio of
15 and 18. The most statistically significant increases in poor outcomes were for the E/e′
ratio ≥18 group. Cumulative clinical events (p = 0.008), Cardiovascular admissions (p =
0.03), Average length of stay for cardiovascular admissions, (p = 0.002) and All-cause
admissions (p = 0.002) were all increased in this group as compared to the <18 E/e′ group.
Conclusions: Our study adds support to the body of evidence around the progression from
diastolic dysfunction to HFpEF and suggests that higher E/e′ ratios, even in patients with no
specific heart failure symptoms, are associated with significantly worse outcomes 3 years
later. This suggests that identifying patients with vague non-cardiac symptoms who have a
raised E/e′ ratio earlier may be of benefit in reducing future mortality, mortality and
progression to heart failure.

Background

Heart failure definition and classification

There are two primary ways that heart failure (HF) is defined. One definition is that it a state
in which the heart’s output of blood is insufficient to meet the metabolic demands of the
body. Another more clinical definition is that HF is a syndrome in which patients have signs
and symptoms of HF (e.g. shortness of breath, fluid retention in the lungs or ankles) and
objective evidence of an abnormality of the structure or function of the heart at rest [1].

Heart failure has also been classified in many different ways. For example, it can be
classified as left vs right heart failure, systolic vs diastolic and by ejection fraction into: heart
failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection
fraction (HFrEF). The latter classification is utilised in this paper.

Heart failure with preserved ejection fraction

The European Society of Cardiology (ESC) defines HFpEF as when a patient has signs or
symptoms of HF with preserved ejection fraction and evidence of diastolic dysfunction. [2]
There is increasing interest in HFpEF for a number of reasons. Firstly, the morbidity and
mortality in HFpEF is similar to HFrEF but an effective treatment for the former is not
currently available [3]. Secondly, there is a rising prevalence of HFpEF relative to HFrEF.
Finally, diagnoses of HFpEF is recognised as being challenging [2].

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Banerjee et al. have suggested that the ESC definition above may be too broad, proposing
that another category be added called ‘pre-HFPEF’ which includes patients who are
symptomatic but have normal diastolic function [4]. The thinking behind this being that if
patients are identified earlier treatment may be initiated more early in the disease
progression.

Pathophysiology of HFpEF and E/e′ ratio

The pathophysiology of HFpEF (i.e why patients have HF symptoms with normal systolic
function) is thought to be due to left ventricular (LV) diastolic dysfunction [5]. This LV
diastolic dysfunction consists of a triad of lengthened isovolumetric LV relaxation, slower LV
filling and greater LV diastolic stiffness [5]. Clinically, the assessment of diastolic dysfunction
is most commonly done by echocardiography. Many measurements can be made but the
most important for assessing LV diastolic dysfunction are: 1) The early ventricular filling
velocity (E) and 2) the diastolic mitral annular velocity (e’). These values can be expressed
as a ratio E/e′ which is generally regarded as “the most feasible as well as among the most
reproducible methods or estimation of filling pressure” and thus LV diastolic dysfunction. [6]
The cut-off value of E/e′ used to designate diastolic dysfunction has been generally agreed
to be 15 [2].

Aims and objectives

The study aims to compare the relationship between raised left end diastolic pressure (as
expressed by the E/e′ ratio) and clinical events 3 years post attendance in the patient’s first
heart failure clinic. The cohort was divided into those that had diastolic dysfunction and those
that did not (i.e. the proposed ‘pre-HFpEF’ category mentioned above) based on E/e′ ratio.
The cut-offs used for this distinction were E/e′ ratio of 15, while the study was also designed
with the idea of stratifying the groups by E/e′ ratio of 18 if the data allowed this. Clinical
events that were measured included: cardiac admissions, non-cardiac admissions, total all-
cause admissions and cumulative clinical events (including deaths). In addition, average
length of admission was compared between groups.
The overall aim was to investigate the 3 year clinical outcomes of patients in the early stages
of diastolic dysfunction and shed light on whether a higher E/e′ ratio at initial presentation
was associated with poorer clinical outcomes as suggested by Banerjee et al. [4]
Method
Study Design and Patient selection
The project used a retrospective, observational, single centre, cohort study of patients with
left ventricular diastolic dysfunction, and breathlessness. A list of patients who attended a
community heart failure clinic between 1.1.12 and 1.1.14 was generated and patients were
admitted into the study if they met the following criteria:

 Inclusion criteria
o First clinic appt. after 1.1.2012
o First clinic appt. prior to 1.1.2014
o Symptomatic breathlessness (NYHA II or above)
o Preserved LV systolic function (LVEF equal to or greater than 45%)

 Exclusion criteria
o HFrEF (LVEF<45%)
o Previous HFpEF diagnosis
o Raised JVP / Pulmonary Oedema / signs of HFpEF

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The data points collected included the following:
 Patient age
 Date of first heart failure clinic visit
 E/e′ ratio - a measurement of pressure in the heart
 Initial signs (ankle oedema, raised jugular venous pulse, bi-basal crepitations) and
symptoms (breathlessness, cough, orthopnoea, palpitations, dizziness, syncope,
chest pain, paroxysmal nocturnal dyspnoea)
 Number and length of subsequent hospital admissions and deaths

The cohort was stratified into 4 groups: the first 2 based on grouping patients based on E/e′
ratio of <15 or ≥15 as per Banerjee et al. [4]. The latter 2 were grouped by E/e′ ratio of <18
or ≥18, the idea of this being to investigate whether increased E/e′ ratio was associated with
worse outcomes. Comparisons between these 4 groups were carried out for both the total
number and length of admissions for the following categories: cardiac admissions, non-
cardiac admissions, All-cause admissions, and cumulative clinic events including deaths.

Statistical analysis
Statistical analysis on the collected data were carried out on IBM SPSS v23 software.
Descriptive statistics on the dataset was performed using the ‘Explore’ and ‘Frequencies’
options. This analysis revealed that the independent variables in the cohort did not follow a
normal distribution and thus comparison of statistically significant difference between the
different E/e′ groupings was carried out using the Mann-Whitney U Test.

Ethical considerations
This was a retrospective study analysing anonymised routine clinic data and thus approval
was obtained from BSREC and GafREC.

Results

E/e′ grouping and comparison

Comparison between the groups with an E/e′ cut-off of 15 revealed that there were
statistically significantly increased cardiovascular admissions over a 3 year period (both in
number and length). However the most striking and important difference was in the groups
stratified by E/e′ ratio of <18 or ≥18 where there was statistically significant increases in poor
outcomes for the ≥18 group. Cumulative clinical events (p = 0.008), Cardiovascular
admissions (p = 0.03), Average length of stay for cardiovascular admissions, (p = 0.002) and
All-cause admissions (p = 0.002) were all increased in this group as compared to the <18
E/e′ group.

Graph 1 shows mean admissions for the above categories at E/e′ <18 and E/e′
≥18. This graph shows the obvious difference in mean between groups. The fact that
the error bars overlap for all the groups calls into question whether the significance is
reliable – this is further commented on in the discussion.

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Table 1: Comparison of outcomes between cohort groups stratified by E/e′ < 15 vs E/e′ ≥ 15.
p-Values in bold indicate statistically significant results.

E/e′ <15 E/e′ ≥15 p-Value

Number of patients (N) 137 39 -
Age 76.4 ± 10.8 81.3 ± 6.00 0.02
NT-proBNP (pmol/l) 171 ± 427 227 ± 371 0.01
E/e′ 10.0 ± 2.83 20.5 ± 6.55 <0.01
Cardiovascular admissions at 3 years:
Number 53 26
Mean 0.39 0.59 0.004
Average length of stay for cardiovascular
admissions (days): 2.2 ± 6.9 3.44 ± 7.04 0.005
Non-cardiac admissions at 3 years:
Number 158 48
Mean 1.15 1.23 0.72
Average length of stay for non-cardiac
admissions: 10.1 ± 19.6 13.2 ± 34.1 0.95
All-cause admissions at 3 years:
Number 211 74
Mean 1.54 1.90 0.13
Average length of stay for All-cause
admissions (days): 12.4 ± 20.8 17.1 ± 34.7 0.47
Cumulative clinical events (including
deaths) at 3 years:
Number 254 85
Mean 1.85 2.18 0.19

Table 2: Comparison of outcomes between cohort groups stratified by E/e′ < 18 vs E/e′ ≥ 18.
p-Values in bold indicate statistically significant results.

E/e′ <18 E/e′ ≥18 p-Value

Number of patients (N) 155 21 -
Age 76.9 ± 10.4 82.2 ± 6.38 0.03
NT-proBNP 164 ± 401 331 ± 489 0.002
E/e′ 10.7 ± 3.38 24.0 ± 7.29 <0.01
Cardiovascular admissions at 3 years:
Number 61 18
Mean 0.39 0.86 0.03
Average length of stay for cardiovascular
admissions (days): 2.2 ± 6.6 5.00 ± 8.82 0.002
Non-cardiac admissions at 3 years:
Number 179 27
Mean 1.15 1.29 0.21
Average length of stay for non-cardiac
admissions: 10.3 ± 21.3 15.5 ± 36.6 0.34
All-cause admissions at 3 years:
Number 240 45
Mean 1.55 2.14 0.02
Average length of stay for All-cause
admissions (days): 12.4 ± 22.6 20.4 ± 35.9 0.051
Cumulative clinical events (including
deaths) at 3 years:
Number 284 55
Mean 1.83 2.62 0.008

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Graph 1

Discussion
This study aimed to look at the 3 year clinical outcomes of patients in the early stages of
diastolic dysfunction who attended a community heart failure clinic. In doing so it was hoped
that additional support for the hypothesis that raised E/e′ ratio is associated with poorer
clinical outcomes could be found, as well as investigating if higher E/e′ ratios at initial
presentation were associated with worse long term clinical outcomes. The results add
support to this theory as well as providing strong evidence that, even in patients with no
clear heart failure symptoms (the ‘pre-HFpEF’ group), a higher E/e′ ratio is associated with
significantly increased hospital admissions and lengthier admissions.
Limitations
There were several limitations to this study. First of all, the sample size of the E/e′ ≥18 group
was low (N = 21) which makes the statistical significance of the results harder to verify. As
graph 1 indicates the 95% confidence intervals for the means all overlapped which brings
some doubt on the statistical significance of the results. However Payton et al. [7] and others
have shown that overlapping confidence intervals need not necessarily render these results

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insignificant. However, it is clear that increasing the size of the E/ e′ ≥18 group would likely
make the results more robust.
Another obvious limitation was the fact that this was a retrospective study. This meant that
the records we were using had not been designed for our study and this caused frustration
at times. For example, there were many patients for which we could not obtain records of
echocardiographic findings. I
Finally, it was noticed during data collection that there appeared to be correlation between
certain co-morbidities (e.g. COPD) and worse prognosis or mortality, it would be interesting
to investigate these correlations further by gathering and analysing these co-morbidity and
mortality data thoroughly. Unfortunately we were not able to get access to mortality data for
confidentiality reasons.
Conclusion
Several previous papers have explored the link between diastolic dysfunction, including
Kane et al. who showed a correlation between diastolic dysfunction and the subsequent
development of heart failure in the population-based Olmsted County Heart Function Study
[8]. Our study adds support to this hypothesis and suggests that identifying patients with
vague non-cardiac symptoms who have a raised E/e′ ratio earlier may be of benefit in
reducing future mortality, mortality and progression to heart failure.

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