eur j heart fail 2005 vinereanu 820 8

www.elsevier.com/locate/heafai

The European Journal of Heart

Dow

‘‘Pure’’ diastolic dysfunction is associated with long-axis

systolic dysfunction. Implications for the diagnosis and

classification of heart failure

Dragos Vinereanu, Eleftherios Nicolaides, Ann C. Tweddel, Alan G. Fraser*

Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom

Received 20 July 2004; received in revised form 2 January 2005; accepted 3 February 2005

Available online 25 May 2005

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Abstract

Aims: To investigate regional systolic function of the left ventricle, to test the hypothesis that ‘‘pure’’ diastolic dysfunction (impaired global

diastolic filling, with a preserved ejection fraction �50%) is associated with longitudinal systolic dysfunction.

Methods and results: One hundred thirty subjects (31 patients with asymptomatic diastolic dysfunction, 30 with diastolic heart failure, 30

with systolic heart failure; and 39 age-matched normal volunteers) were studied by conventional and tissue Doppler echocardiography.

Global diastolic function was assessed using the flow propagation velocity, and by estimating left ventricular filling pressure from the ratio of

transmitral E and mitral annular ETDE velocities (E/ETDE); and global systolic function by measurement of ejection fraction. Radial and

longitudinal functions were assessed separately from posterior wall and mitral annular velocities. Global and radial systolic function were

similar in patients with ‘‘pure’’ diastolic dysfunction and normal subjects, but patients with either asymptomatic diastolic dysfunction or

diastolic heart failure had impaired longitudinal systolic function (mean velocities: 8.0T1.2 and 7.7T1.5 cm/s, respectively, versus 10.1T1.5cm/s in controls; p <0.001). In subjects with normal ejection fraction, global diastolic function correlated with longitudinal systolic function

(r=0.56 for flow propagation velocity, and r =�0.53 for E/ETDE ratio, both p <0.001), but not with global systolic function.

Conclusion: Worsening global diastolic dysfunction of the left ventricle is associated with a progressive decline in longitudinal systolic

function. Diastolic heart failure as conventionally diagnosed is associated with regional, subendocardial systolic dysfunction that can be

revealed by tissue Doppler of long-axis shortening. Diagnostic algorithms and definitions of heart failure need to be revised.

D 2005 European Society of Cardiology. Published by Elsevier B.V.

6,
2013
Keywords: Diastolic heart failure; Tissue Doppler echocardiography; Cardiac function

1. Introduction

Patients with symptoms and clinical signs of heart failure

but with apparently normal global systolic function of the

left ventricle on echocardiography are described as having

diastolic heart failure caused by pure diastolic dysfunction.

They constitute an important clinical group, which accounts

for 40–50% of cases of heart failure, especially in the

elderly [1–4]. In addition, asymptomatic diastolic dysfunc-

tion is reported to be present in 40–60% of those patients

1388-9842/$ - see front matter D 2005 European Society of Cardiology. Publish

doi:10.1016/j.ejheart.2005.02.003

* Corresponding author. Tel.: +44 2920 743489; fax: +44 2920 743500.

E-mail address: [email protected] (A.G. Fraser).

with coronary artery disease, hypertension, valvular heart

disease, hypertrophic cardiomyopathy, diabetes, or cardiac

amyloidosis, who develop heart failure [5,6].

Diagnosis of diastolic heart failure can be difficult

because published guidelines are complex, and thus

mechanisms of disease and optimal methods of treatment

remain controversial [5,6]. Better understanding of the early

stages of diastolic dysfunction and simple clear diagnostic

tests are needed.

Using standard echocardiograpic methods, diastolic

dysfunction is usually diagnosed as the cause of dyspnoea

when Doppler assessment of transmitral flow is abnormal

and left ventricular ejection fraction is normal. Transmitral

flow reflects global filling and it becomes abnormal (E/

Failure 7 (2005) 820 – 828

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Table 1

Echocardiographic criteria for diastolic dysfunction in patients with normal

systolic function

Criterion of diastolic

dysfunction

Asymptomatic diastolic

dysfunction (N =31)

Diastolic heart

failure (N =30)

Number (%) Number (%)

IVRT<30y>92 ms,

IVRT30 – 50y>100 ms,

IVRT>50y>105 ms

28 (90%) 26 (87%)

E/A<50y<1 and

DT<50y>220 ms,

E/A>50y<0.5 and

DT>50y>280 ms

1 (3%) 4 (13%)

S/D<50y>1.5,

S/D>50y>2.5

0 (0%) 0 (0%)

PVA velocity>35 cm/s 6 (19%) 11 (37%)

PVA duration�MVA

duration>30 ms

4 (13%) 6 (20%)

IVRT=isovolumic relaxation time indexed for age groups; E/A=ratio of

peak early to peak atrial Doppler transmitral flow velocities indexed for age

groups; DT=deceleration time of E-wave; S/D=ratio of pulmonary vein

systolic and diastolic flow velocities indexed for age groups; PVA=pulmo-

nary venous atrial flow; MVA=transmitral atrial flow.

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A<1) only when more than 50% of ventricular segments

have impaired relaxation, so it is insensitive to less

extensive diastolic dysfunction [7]. Ejection fraction may

be measured accurately by planimetry of left ventricular

end-diastolic and end-systolic areas, but it reflects only

global function; furthermore, ejection fraction derived by

the Teichholz method, which is calculated by making

simplistic geometric assumptions, measures only radial left

ventricular systolic function [8]. Current guidelines include

no assessment of regional longitudinal left ventricular

function, yet this is the most sensitive marker of early

changes in systolic function with age or disease [9–11].

Longitudinal descent of the mitral annulus towards the apex

in systole is governed by the subendocardial fibres [12],

which are most vulnerable to ischemia [13] and most

affected by interstitial fibrosis [14].

In this study we investigated the relationships between

early changes in systolic function and abnormalities of

ventricular filling, in order to test the hypothesis that

patients with ‘‘pure’’ diastolic dysfunction also have

impaired longitudinal systolic function. If this is true, then

it might be possible to diagnose subclinical changes and

early disease in patients at risk of heart failure, and to

monitor changes more effectively during treatment designed

to influence the natural history of heart failure.

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2. Methods

2.1. Subjects

In a cross-sectional study, 91 patients from a total of

129 undergoing echocardiographic studies performed in a

specialist outpatient clinic, fulfilled the criteria for

diastolic or systolic dysfunction. Diagnosis of diastolic

dysfunction was based on the echocardiographic criteria

published by the European Study Group on Diastolic

Heart Failure [5]. Diagnosis of systolic dysfunction was

based on an impaired ejection fraction (<50%), as

recommended by Vasan et al. [6].

Underlying diagnoses in the patients are presented in

Table 2. Patients were excluded if they were not in sinus

rhythm, or if they had ventricular aneurysm or severe

regional wall motion abnormalities, mitral or aortic stenosis,

obstructive (intraventricular gradient>30 mm Hg) hyper-

trophic cardiomyopathy, more than mild aortic regurgita-

tion, severe mitral regurgitation, pericardial disease, cor

pulmonale, or severe renal or hepatic failure.

We defined 31 patients to have ‘‘asymptomatic diastolic

dysfunction’’ because they had no signs or symptoms of

congestive heart failure, but they did have echocardio-

graphic criteria of diastolic dysfunction and a normal

ejection fraction (Table 1). Another 30 patients were defined

to have ‘‘diastolic heart failure’’ because they had signs or

symptoms of congestive heart failure (dyspnoea, gallop

sounds, and/or lung crepitations) [5], with echocardio-

graphic criteria of diastolic dysfunction and a normal

ejection fraction (Table 1). Finally, 30 patients had ‘‘systolic

heart failure’’ based on symptoms and an impaired ejection

fraction. The 91 patients were compared with 39 healthy

volunteers matched for age.

Normal subjects had no cardiovascular symptoms and no

history of heart disease, diabetes mellitus or hypercholester-

olemia. They all had a normal resting electrocardiogram and

a normal transthoracic echocardiographic study.

The protocol was approved by the Local Research Ethics

Committee, and each subject gave informed consent.

2.2. Echocardiography

Subjects were studied by one echocardiographer (D.V.),

by conventional and tissue Doppler echocardiography

(Vingmed System 5, GE Vingmed, Horten, Norway), using

a 1.5–2.5 MHz transducer. Heart rate and blood pressure

were measured after 15 min of rest, just before the

echocardiographic study. The electrocardiogram was

recorded simultaneously. Digital echocardiographic data

containing a minimum of 3 consecutive beats were acquired

during passively held end-expiration and transferred to a

Macintosh computer for measurement. All measurements

were taken as the mean of 3 consecutive beats.

Standard echocardiographic studies consisted of M-

mode, cross-sectional, and Doppler blood flow measure-

ments. M-mode tracings from the parasternal long-axis view

were used to measure diameter of the aortic root, diameter

of the left atrium, and end-diastolic diameter of the right

ventricle; and septal thickness, left ventricular diameter, and

posterior wall thickness in systole and diastole. Cross-

sectional images were recorded from the apex for measure-

ment of end-diastolic and end-systolic areas.


Fig. 1. Example of a tissue Doppler trace recorded from the lateral site of

the mitral annulus. S—peak systolic velocity; E—early diastolic velocity;

A—atrial velocity. Each division on the scale represents 1 cm/s.

D. Vinereanu et al. / The European Journal of Heart Failure 7 (2005) 820–828822


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Pulsed-wave Doppler of transmitral flow was used to

assess global diastolic function, with the sample volume

placed at the tips of the mitral leaflets in the apical 4-

chamber view. The following Doppler indices were meas-

ured: peak early velocity (E), peak atrial velocity (A), E-

wave deceleration time, and atrial wave duration. Mitral E/A

ratio was calculated. Isovolumic relaxation time was

measured on the pulsed-wave Doppler trace recorded with

the sample volume placed between mitral inflow and aortic

outflow. Left ventricular inflow was also recorded by colour

M-mode echocardiography in the apical 4-chamber view,

and flow propagation velocity (FPV) was measured as the

slope of the first aliasing velocity from the mitral tips to a

position 4 cm distally into the left ventricle [15,16]. E/FPV

ratio was calculated [16]. Pulmonary venous flow record-

ings were obtained from the apical 4-chamber view, with the

sample volume placed 1 cm into the right upper pulmonary

vein, and the following parameters were measured: peak

systolic velocity (S), peak diastolic velocity (D), peak atrial

velocity (A), and atrial wave duration.

Data analysis. Analysis was performed off-line for the

calculation of left ventricular volumes, ejection fraction, end-

systolic wall stress, and left ventricular mass. Left ventricular

volumes and mass were indexed by body surface area.

Left ventricular volumes and ejection fraction were

calculated by the modified biplane Simpson’s method

[17]. Fractional shortening and radial ‘‘ejection fraction’’

(using the Teichholz formula) were also calculated [8].

End-systolic wall stress (ESWS) in 103 dynes/cm2 was

calculated according to the following validated formula:

ESWS ¼ 0:334� SBP

� LVESD= 1þLVSPW=LVESDð Þ � LVSPWð Þ½

where SBP is the systolic blood pressure (mm Hg) measured

by a cuff sphygmomanometer, LVESD is the left ventricular

end-systolic diameter, and LVSPW is the left ventricular

end-systolic posterior wall thickness (cm) [18].

Left ventricular mass was estimated by the method of

Devereux with the application of the Penn convention:

LVmass gð Þ ¼ 1:04��IVSDþ LVDPW þ LVEDDð Þ3

� LVEDD3�� 13:6

where IVSD is the septal thickness, LVDPW is the posterior

wall thickness, and LVEDD is the left ventricular diameter,

all measured at the end of diastole [19].

Long-axis function by tissue Doppler. To obtain record-

ings of mitral annular motion in the longitudinal axis, we

used colour-guided pulsed wave tissue Doppler from the

apical 4-chamber view for the lateral and medial sites, and

from the apical 2-chamber view for the anterior and inferior

sites. The pulsed sample volume was placed over the mitral

annulus in systole. From the waveforms (Fig. 1) we

measured the peak systolic velocity (S) during ejection,

and the peak diastolic velocities during early filling (ETDE)

and atrial contraction (ATDE). Four-site averaged velocities,

and the ETDE/ATDE and E/ETDE ratios [20], were calculated.

Short-axis function by tissue Doppler. Pulsed-wave tissue

Doppler of the basal posterior wall was recorded from the

parasternal long-axis view. The sample volume was placed

over the myocardium in systole, above the insertion of the

papillary muscle.

2.3. Reproducibility

We have reported detailed studies of reproducibility in our

laboratory elsewhere [11,21]. Ninety-five percent confidence

limits of a single estimate of the measurements were

calculated as 2SD/�2, and reported as percent from the mean

value [22]. Reproducibility of flow propagation velocity, E/

FPVratio, and E/ETDE ratio in our laboratory is <10%, similar

with the values reported by other studies [15,16,20].

2.4. Statistical analysis

Statistical analysis was performed with SPSS software

(version 10.0) (SPSS Chicago, Illinois). Results are presented

as mean valueT standard deviation. Differences between

groups were tested for significance using analysis of variance

(ANOVA), with subgroup analysis by the Scheffe F test.

Comparisons of non-parametric data were performed by chi-

square test. Linear regression was used to investigate the

relation between two parametric variables. Multiple linear

regression analysis was used to assess the influence of

selected variables on parameters of global diastolic function.

A p <0.05 for a two-tailed test was considered significant.

3. Results

3.1. Subjects

General and standard echocardiographic characteristics

of the study groups are given in Tables 2 and 3.


Table 2

Clinical details of the patient groups

ADD

(n =31)

DHF

(n =30)

SHF

(n =30)

p ANOVA

Underlying disease (n, %)

Ischaemic heart disease 1 (3%) 14 (47%) 15 (50%) <.01

Hypertension 11 (36%) 9 (30%) 1 (3%) <.01

Hypertrophic

cardiomyopathy

5 (16%) 7 (23%) 0 (0%) <.01

Dilated cardiomyopathy 0 (0%) 0 (0%) 14 (47%) <.01

Diabetes mellitus 14 (45%) 0 (0%) 0 (0%) <.01

NYHA class (n, %)

I 31 (100%) 0 (0%) 0 (0%) <.01

II 0 (0%) 23 (77%) 10 (33%) <.01

III 0 (0%) 7 (23%) 18 (60%) <.01

IV 0 (0%) 0 (0%) 2 (7%) <.01

Medication (n, %)

ACE inhibitors 17 (55%) 8 (27%) 29 (97%) <.001

Diuretics 5 (16%) 23 (77%) 29 (97%) <.001

Spironolactone 0 (0%) 0 (0%) 9 (30%) <.001

Digoxin 0 (0%) 0 (0%) 5 (17%) <.01

Beta-blockers 2 (7%) 8 (27%) 4 (13%) ns

Amiodarone 0 (0%) 1 (3%) 3 (9%) <.001

Calcium antagonists 2 (7%) 8 (27%) 2 (7%) <.05

Statins 10 (32%) 7 (23%) 12 (40%) ns

ADD=asymptomatic diastolic dysfunction; DHF=diastolic heart failure;

SHF=systolic heart failure.


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3.2. Radial and global systolic function

Radial or short-axis systolic function (fractional short-

ening, end-systolic wall stress, and ejection fraction by

Table 3

General and echocardiographic characteristics of the study groups

ADD DHF

Age (years) 53T9 56T15Male (%) 80 64

Body surface area (m2) 1.98T0.23 1.94T0.29

Resting heart rate (bpm) 72T12 70T11Systolic BP (mm Hg) 151T22* 143T15*

Diastolic BP (mm Hg) 80T21 87T10**

Aortic diameter (mm) 34T5 34T5

Left atrial diameter (mm) 41T6 41T6Septal thickness (D) (mm) 12T3* 13T3*

EDDI (mm/m2) 26T3 26T4

PW thickness (D) (mm) 12T2* 12T2*

Fractional shortening (%) 37T7 36T8EF (Teichholz) (%) 75T8 74T8

LVMI (g/m2) 155T45 158T52

ESWS (103 dynes/cm2) 49T21 50T18

EF (Simpson) (%) 63T6 63T7RV diameter (mm) 22T3 20T3

FPV (cm/s) 40T12* 38T8*

E/FPV 1.9T0.7* 1.9T0.5*E/ETDE 8.3T3.1* 8.3T3.1*

ADD=asymptomatic diastolic dysfunction; DHF=diastolic heart failure; SHF=sy

diameter index; PW=posterior wall; EF=ejection fraction; LVMI=left ventri

FPV=flow propagation velocity; *p <0.001: ADD or DHF vs. normal subjects a

Teichholz method), and global systolic function (ejection

fraction by Simpson’s method), were not different between

patients with either asymptomatic diastolic dysfunction or

diastolic heart failure, and normal subjects (Table 3).

3.3. Long-axis systolic function by tissue Doppler

Patients with ‘‘pure’’ diastolic dysfunction had impaired

longitudinal systolic function of the left ventricle. Their

longitudinal systolic velocities were intermediate between

those of normal subjects and those of patients with systolic

heart failure (Table 4). With reference to normal ranges

(defined as the meanT2SD of the value in age-matched

controls), 16% of the patients with asymptomatic diastolic

dysfunction, 34% of the patients with diastolic heart failure,

and 90% of the patients with systolic heart failure had

impaired longitudinal systolic function (defined as a 4-site

mean velocity<7.05 cm/s). However, if we define the

normal ranges as the meanT95% confidence intervals of

the value in age-matched controls, 90% of the patients with

asymptomatic diastolic dysfunction, 87% of the patients

with diastolic heart failure, and all patients with systolic

heart failure had impaired longitudinal systolic function

(defined as a 4-site mean velocity<9.57 cm/s).

3.4. Short-axis systolic function by tissue Doppler

Radial left ventricular function was similar between

patients with ‘‘pure’’ diastolic dysfunction and normal

subjects, but significantly impaired in patients with systolic

heart failure (Table 4).

SHF Normal p

59T9 54T10 ns

77 79 ns

1.94T0.22 1.93T0.21 ns

73T16 69T12 ns

122T12 132T11 <.001

72T9 80T8 <.001

35T6 36T4 ns

48T8a 38T5 <.001

10T2 10T2 <.001

37T6a 26T2 <.001

10T1 10T1 <.001

18T7a 38T6 <.001

44T14a 76T7 <.001

195T60a 127T33 <.001

130T49a 50T15 <.001

32T10a 66T6 <.001

30T3a 22T4 <.001

30T7 62T13 <.001

3.1T1.1 1.2T0.2 <.001

14.0T4.7 5.8T1.4 <.001

stolic heart failure; BP=blood pressure; D=diastole; EDDI=end-diastolic

cular mass index; ESWS=end-systolic wall stress; RV=right ventricle;

nd SHF; **p <0.01: DHF vs. SHF; ap <0.01: SHF vs. other three groups.

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Table 4

Myocardial velocities (cm/s) in the 4 groups

ADD DHF SHF Normal p

Longitudinal function

Lateral mitral annulus (S) 8.2T1.9* 7.9T2* 5.4T1.4a 10.4T1.8 <.001

Medial mitral annulus (S) 7.9T1.3* 7.6T1.6* 5.5T1.5a 9.6T1.9 <.001

Anterior mitral annulus (S) 7.6T1.6* 7.3T1.4* 5.7T1.4a 10.2T1.6 <.001

Inferior mitral annulus (S) 8.3T1.3* 8.0T1.9* 5.6T1.4a 10.1T1.7 <.001

Mean (S) 8.0T1.2* 7.7T1.5* 5.6T1.2a 10.1T1.5 <.001

Lateral mitral annulus (E) 9.6T3.1 8.6T2.6 6.6T2.0a 12.6T2.7b <.001

Medial mitral annulus (E) 7.3T1.8 6.5T2.1 5.9T1.9 9.9T2.2b <.001

Anterior mitral annulus (E) 8.8T2.8 7.6T2.2 6.9T2.1 12.3T2.6b <.001

Inferior mitral annulus (E) 7.6T1.9* 7.0T2.4 5.8T1.7 11.1T2.8b <.001

Mean E 8.3T2.1* 7.4T2.1 6.3T1.7 11.5T2.2b <.001

Radial function

Posterior wall (S) 7.4T1.9 7.1T1.5 4.9T1.5a 7.2T1.5 <.001

Posterior wall (E) 11.9T4.6 11.0T3.7 8.7T3.1a 13.4T3.9 <.001

ADD=asymptomatic diastolic dysfunction; DHF=diastolic heart failure; SHF=systolic heart failure; S=systolic velocities; E=early diastolic velocities;

*p <0.001: ADD or DHF vs. normal subjects and SHF; ap <0.01: SHF vs. other three groups; bp <0.01 normals vs. patients groups.




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3.5. Correlations between diastolic and systolic function

In the 100 subjects with normal ejection fraction, global

diastolic function correlated with longitudinal systolic

function (Fig. 2), but not with radial systolic function or

ejection fraction (Fig. 3 and Table 5). By multiple stepwise

regression (parameters entered: age, systolic and diastolic

blood pressure, heart rate, body mass index, long-axis

systolic velocity, radial systolic velocity, and global ejection

fraction), the best correlation of E/ETDE ratio was with an

association between long-axis systolic velocity and diastolic

blood pressure (r=0.56, r2=0.32, p <0.001). For the whole

group (i.e. including the patients with systolic heart failure),

the correlations of longitudinal systolic function with global

diastolic function were 0.66 for flow propagation velocity,

�0.61 for E/FPV ratio, and �0.66 for E/ETDE ratio (both

p <0.001). There was also a strong correlation (r=0.81,

p <0.001) between longitudinal diastolic and systolic

function, measured as 4-site mean velocities (Fig. 4).

Fig. 2. Correlations between longitudinal systolic and global diastolic function for

ETDE—ratio of mitral E velocity to lateral mitral annular ETDE velocity; S—4-sit

3.6. Reproducibility

Interobserver variability was T6.8% for the posterior

wall velocities, and between T2.0% and T6.1% for the

mitral annular velocities. Intraobserver variability was

similar: T2.7% for the posterior wall velocities, and

between T1.8% and T2.5% for the mitral annular velocities

[11,21].

4. Discussion

We have demonstrated that patients who would be

diagnosed to have ‘‘pure’’ diastolic dysfunction using

current guidelines, in fact have reduced longitudinal

systolic function. In these patients, normal global ejection

fraction is maintained by preservation of radial systolic

function. Our data suggest that ‘‘pure’’ diastolic dysfunc-

tion is therefore diagnosed erroneously, when systolic

subjects with normal ejection fraction. FPV—flow propagation velocity; E/

e mean systolic velocity of the mitral annulus.


Fig. 3. Correlations between global systolic and global diastolic function for subjects with normal ejection fraction. FPV—flow propagation velocity; E/ETDE—

ratio of mitral E velocity to lateral mitral annular ETDE velocity; EF—ejection fraction.


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function is assessed by established echocardiographic

techniques; these measure global function and short-axis

(radial) function, but not long-axis function which is most

sensitive for quantifying subendocardial disease. Tissue

Doppler reveals the subtle and progressive changes that

affect longitudinal systolic function.

4.1. Tissue Doppler for the diagnosis of subendocardial

dysfunction

Functionally, there are two major myocardial layers of

the left ventricle. Mid-wall fibres are orientated in a

circumferential direction, and subendocardial fibres are

aligned longitudinally from apex to base. The first group

of fibres is responsible mainly for short-axis or radial

contraction of the left ventricle (analogous to the motion of

bellows), while the second group of fibres causes long-axis

contraction (which can be compared with the motion of a

piston) [12]. Longitudinal fibres are anatomically connected

Table 5

Correlations (r) between diastolic and systolic function in 100 subjects with

normal ejection fraction

Global diastolic

function

Regional diastolic

function

FPV E/FPV E/ETDE Longitudinal E Radial E

Global systolic function

EF (Teichholz) 0.18 �0.18 �0.15 0.11 0.17

EF (Simpson) 0.25 �0.03 �0.01 0.18 �0.05

Regional systolic function

Longitudinal S 0.56* �0.43* �0.54* 0.77* 0.40*

Radial

(posterior wall) S

0.16 �0.13 �0.16 0.20 0.62*

EF=ejection fraction; Longitudinal S=4-site mean mitral annular systolic

velocity; Radial S=posterior wall systolic velocity; FPV=flow propagation

velocity; E=peak early transmitral velocity; Longitudinal E=4-site mean

mitral annular early diastolic velocity; Radial E=posterior wall early

diastolic velocity; *p <0.001.

2013

with the mitral annulus, and so long-axis contraction results

in apical displacement of the mitral annulus in systole

[23,24], which can be measured accurately in terms of

velocities by pulsed-wave tissue Doppler echocardiography

[25]. Since longitudinal, subendocardial function is more

sensitive to ischemia and fibrosis, mitral annular velocities

are decreased in the subclinical stages of heart failure, as

has been shown in volume or pressure overload [10,11], as

well as in ischaemic heart disease [26]. Subendocardial

function and long-axis contraction also decrease with

ageing [27–29].

In a large number of subjects with normal ejection

fractions, we have shown that a decrease of subendocardial

systolic function parallels the impairment of global diastolic

function. The maintenance of ejection fraction in these

patients must be achieved by a compensatory mechanism,

which may be the preservation or augmentation of radial

contraction in the early stages of left ventricular dysfunction

[30].

To assess global diastolic function, we used new

criteria that are not affected by pseudonormalization

[31]. We found that 32% of variability in the E/ETDE

ratio, a non-invasive indicator of left ventricular filling

pressure [20], was related to longitudinal systolic velocity

and diastolic blood pressure.

4.2. Does ‘‘pure’’ diastolic dysfunction exist?

Initial studies reported that the prognosis of patients

with pure diastolic dysfunction is intermediate between

normal subjects and patients with reduced systolic

function, with an annual mortality <17.5% [3]. However,

more recent studies showed no differences in mortality

between patients with diastolic and systolic heart failure

[1,4]. Such studies suggest that diastolic and systolic heart

failure are the same disease, with the difference that so

called pure diastolic heart failure represents an earlier

stage in the natural history [32]. Our data also imply that

diastolic dysfunction with absolutely normal regional and


Fig. 4. Relation between 4-site mean systolic (S) and diastolic (ETDE) mitral annular velocities in the 4 study groups. ? Normal subjects; g patients with

asymptomatic diastolic dysfunction; r patients with diastolic heart failure; l patients with systolic heart failure.




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global systolic function, if it ever occurs, is extremely

rare; one example might be pericardial constriction.

Petrie et al. measured displacement of the mitral

annulus by M-mode echocardiography, and showed that

between 21% and 33% of patients with diastolic heart

failure had abnormal systolic mitral annular motion [33].

Similar results were reported by others, using either M-

mode echocardiography or tissue Doppler analysis of

mitral annular motion [34–37]. Mitral annular displace-

ment was independently correlated with diastolic filling in

patients with coronary heart disease; thus, given the same

level of ejection fraction, it was found that the greater the

impairment in diastolic filling, the lower the mitral

annular displacement [34]. Similarly, mitral annular

systolic velocities were lower in patients with diastolic

heart failure than in normal subjects, and 38% of patients

had velocities below the normal range [35]. However,

ejection fraction and fractional shortening were also

significantly lower in patients with diastolic heart failure,

and these investigators did not include an intermediate

group of asymptomatic patients with diastolic dysfunction

alone. Other investigators have also reported that longi-

tudinal velocities are decreased in patients with ‘‘pure’’

diastolic heart failure but in those studies also, ejection

fraction was lower in patients than in controls [38,39]. Yu

et al. showed that 14% of patients with asymptomatic

diastolic dysfunction and 52% of patients with diastolic

heart failure had reduced longitudinal systolic velocities

[39]. They did not find that radial function was

maintained in their patients with diastolic dysfunction,

but they had worse global systolic function, and it is

possible that radial compensatory changes may only be

observed in the initial stages of heart failure.

4.3. Implications for diagnosis of heart failure

We report a parallel impairment of global diastolic

dysfunction and longitudinal systolic function. We showed

that despite normal global systolic function, there is a

progressive decrease of both systolic and diastolic

longitudinal function of the left ventricle with increasing

severity of disease. The differences between patients with

asymptomatic diastolic dysfunction and those with dia-

stolic heart failure were not significant, but longitudinal

systolic and early diastolic velocities were all lower in the

symptomatic patients. Our study strongly supports the

hypothesis that diastolic dysfunction and diastolic heart

failure do not constitute a separate disease that is different

from systolic heart failure. Instead, there is continuous

spectrum of left ventricular function from normal, through

global diastolic dysfunction with subendocardial systolic

dysfunction, to severe combined systolic and diastolic

heart failure. It is therefore inappropriate to seek to define

discrete dichotomous diagnostic variables for ‘‘pure

diastolic dysfunction’’. These observations should now

be tested in large, prospective studies to investigate if

measurements of long-axis function can predict clinical

events in patients with heart failure, and if they can be





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used to monitor the effects of treatment on left ventricular

function.

4.4. Study limitations

The prevalences of hypertension and diabetes were

different between the three groups of patients (Table 2),

but this was expected because these conditions cause

diastolic dysfunction and reduced long-axis systolic

function. The differences in the prevalence of ischaemic

heart disease may have contributed to the degree of

impairment of subendocardial function. However, since we

excluded patients with ventricular aneurysm and severe

regional wall motion abnormalities, this factor is unlikely

to affect our results. Indeed, longitudinal velocities were

decreased homogeneously for all 4 investigated sites of

the mitral annulus (Table 4).

A small number of patients with hypertrophic cardio-

myopathy were studied, but none had significant outflow

tract obstruction or mitral regurgitation. We included these

patients because hypertrophic cardiomyopathy is associ-

ated with diastolic dysfunction, as diagnosed by traditional

echocardiographic criteria, and some patients progress to

congestive heart failure.

Medication was also different between the study groups

(Table 2). More patients with diastolic heart failure received

beta-blockers, but this was not statistically significant, and

the patients with diastolic heart failure still had higher

systolic velocities than the patients with systolic heart

failure. Verapamil was used in only 2 patients with

asymptomatic diastolic dysfunction. It would not be

possible to conduct a study of systolic and diastolic function

across the spectrum from normality to severe disease,

without including patients on drug treatment.

4.5. Conclusion

Worsening global diastolic dysfunction is associated

with a progressive decline in longitudinal systolic

function. This suggests that ‘‘pure’’ diastolic dysfunction

is diagnosed erroneously when systolic function is

assessed only by imprecise echocardiographic techniques,

such as those derived from M-mode measurements.

Since tissue Doppler longitudinal velocities reveal more

subtle changes of systolic function, they should be

studied and monitored when diagnosing left ventricular

dysfunction and while monitoring treatment for heart

failure. Diagnostic criteria for diastolic heart failure need

to be re-examined.

Acknowledgements

This study was supported by a grant from the Heart

Research Fund for Wales.

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