REVIEW ARTICLE

Diastology 2010: clinical approach to diastolic heart failure

Hirotsugu Yamada • Allan L. Klein

Received: 27 May 2010 / Revised: 9 June 2010 / Accepted: 9 June 2010

� Japanese Society of Echocardiography 2010

Abstract The role of echocardiography in the evaluation

of left ventricular diastolic function is increasingly

important in both systolic and diastolic heart failure. In

routine clinical practice, the diastolic dysfunction associ-

ated with diastolic heart failure can mainly be evaluated by

Doppler echocardiography. In order to use echocardio-

graphic techniques for this purpose, one should recognize

the definition, terminology, epidemiology, and pathophysio-

logy of diastolic dysfunction and diastolic heart failure.

There are various echocardiographic parameters for this

purpose, including transmitral flow velocity, pulmonary

venous flow velocity, mitral annular velocity, flow propa-

gation velocity, left atrial size, strain, strain rate, twist, and

so on. However, no single Doppler echocardiographic

index has yielded a robust criterion for diastolic dysfunc-

tion and elevated left ventricular filling pressure. Thus,

multiple indices are required to increase the sensitivity of

the diagnosis. Clinicians who take care of heart failure

patients should continue to make critical use of a current

Doppler echocardiographic evaluation and utilize this

information to improve survival and quality of life in these

patients.

Keywords Diastole � Heart failure � Echocardiography �Tissue Doppler � LV filling pressures � Prognosis

Abbreviations

HF Heart failure

LV Left ventricle, left ventricular

EF Ejection fraction

LA Left atrial

RFP Restrictive filling pattern

E Peak early diastolic transmitral flow velocity

A Atrial systolic transmitral flow velocity

DT Deceleration time of the early diastolic flow

velocity wave

PVS1 First systolic pulmonary venous flow velocity

PVS2 Second systolic pulmonary venous flow velocity

PVD Diastolic pulmonary venous flow velocity

PVC Pulmonary venous flow velocity at mitral valve

closure

AR Atrial reversal pulmonary venous flow velocity

e0 Early diastolic mitral annular velocity

a0 Atrial systolic mitral annular velocity

TE-e0 Time interval between the onset of the early

diastolic transmitral flow velocity and that of the

early diastolic mitral annular velocity

Vp The slope of the flow propagation velocity

Introduction

The role of echocardiography in the management of con-

gestive heart failure (HF) is increasingly important in both

systolic and diastolic HF. Every patient with HF, regardless

of systolic or diastolic HF, has evidence of diastolic dys-

function, and approximately half of patients with overt HF

have diastolic dysfunction with preserved left ventricular

(LV) ejection fraction (EF) or diastolic HF. The diastolic

H. Yamada

Department of Cardiovascular Medicine, Institute of Health

Bioscience Research, The University of Tokushima Graduate

School of Medicine, Tokushima, Japan

A. L. Klein (&)

Department of Cardiovascular Imaging, Heart and Vascular

Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk J1-5,

Cleveland, OH 44195, USA

e-mail: kleina@ccf.org

123

J Echocardiogr

DOI 10.1007/s12574-010-0055-8

dysfunction associated with diastolic HF can mainly be

evaluated by Doppler echocardiography in routine clinical

practice. Estimation of LV filling pressure is most impor-

tant for managing both systolic and diastolic HF, and

reliable estimation of filling pressure is the most useful

information derived from the echocardiographic assess-

ment of diastole. This article reviews a state-of-the-art

practical approach to assessing diastolic dysfunction and

diastolic HF using echocardiography, beginning with an

overview of the background, clinical significance as well as

new methods in evaluating diastolic function in clinical

practice.

Definition and terminology

Diastolic dysfunction is a functional abnormality of myo-

cardial relaxation, filling, or distensibility in the diastolic

phase. Diastolic dysfunction occurs regardless of whether

the EF is normal or abnormal, or patients are symptomatic

or asymptomatic. Thus, diastolic dysfunction refers to

abnormal mechanical diastolic properties of the ventricle

and is present in virtually all patients with HF. If diastolic

function is truly normal then relaxation, filling, and dis-

tensibility must remain normal both at rest and during

stress of a variable heart rate, stroke volume, end-diastolic

volume, and blood pressure [1, 2].

In contrast, diastolic HF is defined as a clinical syn-

drome characterized by the symptoms and signs of HF, a

preserved EF, and abnormal diastolic function [1]. Dia-

stolic HF occurs when the ventricular chamber is unable to

accept an adequate volume of blood during diastole, at

normal diastolic pressures, and at volumes sufficient to

maintain an appropriate stroke volume. In other words, it is

the situation with impaired capacity of the ventricles to fill

without a compensatory increase in left atrial (LA) pres-

sure. Diastolic HF can produce symptoms that occur at rest

or with ordinary physical activity.

The terms ‘‘diastolic HF’’ and ‘‘systolic HF’’ are often

used instead of ‘‘HF with preserved EF’’ or ‘‘HF with

reduced EF’’, respectively but this is controversial.

Recently ‘‘HF with preserved EF’’ has become the more

accepted term used by the American Heart Association and

the American College of Cardiology rather than ‘‘diastolic

HF’’ [3]. However, ‘‘diastolic HF’’ is still familiar to the

clinician and describes patients with symptoms and signs

of HF with a normal pump function and abnormal diastolic

function. For the purpose of this review, we will use the

‘‘diastolic HF’’ term.

Virtually all patients with HF, whether the diastolic or

systolic type, will have some degree of diastolic abnor-

malities and elevated LV filling pressures. From this point

of view, evaluation of diastolic function is needed in any

case of congestive HF regardless of whether the EF is

normal or reduced.

Many clinical conditions cause HF with preserved EF.

These include not only diastolic dysfunction but also val-

vular disease, pericardial disease, arrhythmias, intracardiac

mass, as well as others. However, diastolic dysfunction is

the most common cause of HF with preserved EF and is

associated with decreased LV distensibility, delayed

relaxation, and abnormal filling. It is important to recog-

nize that preserved EF does not mean that the contractile

function is normal. Indeed, patients with diastolic HF often

have some abnormality of systolic dysfunction which

cannot be expressed by an EF. In addition, comorbidities

such as hypertension, renal dysfunction, tachycardia, and

anemia are commonly associated with the development of

diastolic HF in these patients.

Epidemiology and prognosis of diastolic dysfunction

We retrospectively evaluated diastolic filling patterns

obtained by using Doppler echocardiography in 520

consecutive patients referred to our laboratory for trans-

thoracic echocardiograms and applied the standard

guidelines used to characterize LV diastolic function [4].

Patients were classified by the Canadian consensus

guidelines using transmitral and pulmonary venous

Doppler echocardiographic parameters to have normal

diastolic function or mild (abnormal relaxation), mild-to-

moderate, moderate (pseudonormal), or severe (restric-

tive) diastolic dysfunction. LV diastolic dysfunction was

present in 290 (56%) patients, whereas 167 (45%) patients

with a normal LV EF had abnormal diastolic function.

Patients with progressively more abnormal diastolic pat-

terns had greater structural abnormalities with larger LA

and LV size and lower LV EF. In the subset of patients

with clinical evidence of congestive HF (99 patients), the

prevalence of primary diastolic HF was 38% and most

patients had underlying coronary or hypertensive heart

disease.

Diastolic HF can occur alone (isolated diastolic HF) or

in combination with systolic HF. Frequency of diastolic

HF in overt HF and that of diastolic HF in the community

varies widely, probably because of the differences in

definitions of diastolic HF among the studies. Owan et al.

[5] reported that the prevalence of HF with preserved EF

among patients with a discharge diagnosis of HF increased

significantly from 1987 to 2001. Their data showed that

the number of admissions for HF with preserved EF

increased during the study period, whereas the number of

admissions for HF with reduced EF did not change

(Fig. 1). This is partly because treating clinicians are more

aware of diastolic HF, and because many people live

J Echocardiogr

123

longer. More recently, Redfield et al. [6] investigated the

prevalence of diastolic dysfunction assessed by Doppler

echocardiography including tissue Doppler imaging in

2042 randomly sampled subjects in Olmsted County,

Minnesota. Overall, 20.8% of the population had mild

diastolic dysfunction, 6.6% had moderate diastolic dys-

function, and 0.7% had severe diastolic dysfunction. 5.6%

of the population had moderate or severe diastolic dys-

function with normal EF. A similar study was performed

in Augsburg, Germany by Fischer et al. [7]. The overall

prevalence of diastolic abnormalities, as defined by the

European Study Group on Diastolic HF [i.e., age-depen-

dent isovolumic relaxation time (92–105 ms) and ratio of

early diastolic transmitral flow velocity to atrial systolic

transmitral flow velocity (E/A ratio 1–0.5)] was 11.1%.

The prevalence was 3.1% when only subjects treated with

diuretics or with LA enlargement were considered (sug-

gesting diastolic dysfunction). Significantly higher rates of

diastolic abnormalities were observed in men as compared

to women. Independent predictors of diastolic abnormali-

ties were arterial hypertension, evidence of LV hypertro-

phy, and coronary artery disease. Interestingly, in the

absence of these predisposing conditions, diastolic abnor-

malities (4.3%) or diastolic dysfunction (1.1%) were rare,

even in subjects older than 50 years of age (4.6%) and

(1.2%), respectively. The prevalence of diastolic abnor-

malities and diastolic dysfunction is higher than that of

systolic dysfunction and is increased (despite age-depen-

dent diagnostic criteria) in the elderly. However, in the

absence of risk factors for diastolic abnormalities or dia-

stolic dysfunction, namely LV hypertrophy, arterial

hypertension, coronary artery disease, obesity, and diabe-

tes, the condition is rare even in elderly subjects. These

observations suggest that diastolic dysfunction is more

common than systolic dysfunction in community-dwelling

patients.

Whether diastolic HF leads to a similar or better outcome

than systolic HF is still unknown. Earlier data from the

1980s and 1990s suggested that diastolic HF carries a better

prognosis than systolic HF [8]. Participants in the

Framingham Heart Study, for example, were followed for

6 years: those with diastolic HF were found to have an

annual mortality of 9% as compared with 18% among those

with systolic HF [8]. More recent investigations suggest that

mortality for the 2 conditions may be similar (Fig. 2) [5, 9].

It has been well known that the mitral restrictive filling

pattern (RFP) is an important prognostic indicator in

patients with HF. The Meta-analysis Research Group in

Echocardiography (MeRGE) has been established to

determine whether the RFP is predictive of mortality

independently of EF in patients with congestive HF [10].

Overall, RFP was associated with higher all-cause mor-

tality than the non-RFP: hazard ratio 2.42 (95% CI 2.06,

2.83). The RFP was associated with higher mortality

compared with the non-RFP group regardless of EF

(Fig. 3). In multivariable analysis the RFP, EF, New York

Heart Association class, and age were independent pre-

dictors of mortality. The prevalence of the RFP was

inversely related to EF but remained a predictor of mor-

tality even in those patients with preserved EF.

In the observation by Redfield et al. [6], mild, moderate,

or severe diastolic dysfunctions were predictive of all-

cause mortality during a median of 3.5 person-years of

follow-up (Fig. 4). The percentage of participants with

recognized congestive HF increased according to the

severity of systolic or diastolic dysfunction, clearly indi-

cating that diastolic as well as systolic dysfunction is

associated with congestive HF. The diastolic dysfunction

was predictive of all-cause mortality even when controlling

for age, sex, and EF.

These observations suggest that diastolic dysfunction,

particularly of a moderate or severe degree, is a powerful

Fig. 1 Secular trends in the prevalence of heart failure with

preserved ejection fraction. Left panel shows the increase during the

study in the percentage of patients with heart failure who had

preserved ejection fraction. Right panel shows that the number of

admissions for heart failure with preserved ejection fraction increased

during the study period, whereas the number of admissions for heart

failure with reduced ejection fraction did not change. Adapted from

Owan et al. [5]

J Echocardiogr

123

predictor for increased morbidity and mortality in the

community. Some studies also suggest that patients with

diastolic HF are older and more likely to be female than

those with systolic HF (Fig. 5) [11]. The observation that

22–29% of patients with diastolic HF die within 1 year of

hospital discharge and 65% die within 5 years is a remin-

der that we are dealing with a lethal condition [12]. Owan

et al. also showed that there has been little improvement in

90

85

80

75

70

0 50 100 150 200 250

Days

Preserved ejection fraction

Reduced ejection fraction

300 350 400

95

10

8

6

4

2

0

Sur

viva

l

0 1 2 3 4 5

Years

P=0.03

Preserved ejection fraction

Reduced ejection fraction

Fig. 2 Kaplan–Meier survival curves for patients with heart failure and preserved or reduced ejection fraction. Left panel is redrawn from Owan

et al. [5] and right panel is redrawn from Bhatia et al. [9]

Fig. 3 Kaplan–Meier survival curves for patients with heart failure with restrictive filling pattern versus non-restrictive filling pattern by group

of LV ejection fraction. Adapted from Meta-analysis Research Group in Echocardiography (MeRGE) Heart Failure Collaborators [10]

Fig. 4 Kaplan–Meier mortality curves for participants with normal diastolic function versus subjects with mild or moderate or severe diastolic

dysfunction. Adapted from Redfield et al. [6]

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123

the survival rate among patients with diastolic HF com-

pared to the survival rate improvement among patients with

systolic HF.

Diseases and cardiac remodeling with diastolic HF

Among the various underlying diseases causing diastolic

HF (Table 1), hypertensive heart disease is the most

common and ischemic heart disease is the second most

common in clinical practice. Diastolic HF is typically

associated with significant remodeling that affects the LV

and LA chambers, the cardiomyocytes, and the extracel-

lular matrix. The structural remodeling that occurs in dia-

stolic HF differs dramatically from that in systolic HF

(Fig. 6). In diastolic HF, the diameter of cardiomyocyte

increases with little or no change in length; this corre-

sponds to the increase in LV wall thickness with no change

in LV volume. By contrast, in systolic HF, the cardio-

myocytes are elongated with little or no change in diameter

which corresponds to the increase in LV volume with no

change in LV wall thickness. In diastolic HF, the amount of

collagen increases with a corresponding increment in the

width and continuity of the fibrillar components of the

extracellular matrix. In systolic HF, there is degradation

and disruption of the fibrillar collagen. In end-stage systolic

HF, replacement fibrosis and ischemic scarring may result

in an overall increase in fibrillar collagen within the

extracellular matrix.

Assessment of diastolic function

Clinical assessment of diastolic function is made by clinical

examination, cardiac catheterization, radionuclide angiog-

raphy, echocardiography, magnetic resonance imaging or

computed topographic scanning, and exercise testing.

Echocardiography is a powerful tool that enables the clini-

cian to noninvasively obtain parameters of flow, pressure,

and resistance and thus evaluate intracardiac hemodynamics

in the diastolic phase of the cardiac cycle.

Regardless of the etiology, abnormalities in diastolic

function can result in an increase in LV end-diastolic

pressure (LVEDP), mean LA pressure, and pulmonary

capillary wedge pressure. All these pressures are com-

monly referred to as LV filling pressure. During diastole,

there is a continuum between the pulmonary capillary

bed, pulmonary veins, LA, and the LV. An initial increase

in LV end-diastolic pressure followed by an increase in

LA and pulmonary capillary pressure can subsequently

contribute to pulmonary congestion and HF symptoms.

Consequently, assessment of diastolic function can be

used to grade the degree of diastolic function and provide

an estimate of LV filling pressure. The current assessment

of diastolic function by echocardiography is accomplished

by the evaluation of multiple Doppler parameters

including (1) transmitral flow velocities, (2) pulmonary

venous flow velocities, (3) tissue Doppler mitral annular

velocities, and (4) propagation velocity of mitral inflow

by color M-mode (Table 2; Fig. 7). Other echocardio-

graphic parameters that sometimes add useful information

for the evaluation include Tei index, pulmonary valve

regurgitant flow velocity, estimated pulmonary artery

pressure from tricuspid regurgitant flow velocity, B bump

on the mitral valve M-mode echocardiogram, LA volume

index, and size and respiratory change of the inferior vena

cava. However, there is not one parameter that clearly

defines diastolic dysfunction and predicts elevated filling

pressure.

Fig. 5 Systolic function by

gender among participants with

congestive heart failure. Mildmildly reduced systolic

function, Mod/Sev moderately

to severely reduced systolic

function. Adapted from

Kitzman et al. [11]

Table 1 Underlying diseases causing diastolic heart failure

Hypertensive heart disease

Ischemic heart disease

Diabetes

Hypertrophic, dilated, and restrictive cardiomyopathies

Constrictive pericarditis

Sleep apnea

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Echocardiographic evaluation

Transmitral flow velocity

The initial primary assessment of diastolic function is an

evaluation of the transmitral flow velocity pattern and the

grade of diastolic dysfunction is classically categorized

into four abnormal grades according to this flow velocity

pattern. The pattern is typically obtained using pulsed

Doppler echocardiography at the tips of the mitral valve

leaflet in the apical 4-chamber view. Usually, the peak

early diastolic transmitral flow velocity (E) and atrial sys-

tolic transmitral flow velocity (A), the E/A ratio, and the

deceleration time of the E wave (DT) are measured from

the flow velocity pattern. The diastolic dysfunction is

classified into mild or grade 1 (impaired relaxation pat-

tern); moderate or grade 2 (pseudonormal); severe or grade

3 (restrictive filling); and grade 4 (irreversible restriction)

(Figs. 8, 9). Table 2 illustrates which parameters help

define each diastolic filling pattern [4, 13, 14]. Normal

Fig. 6 Isolated cardiac muscle

cells (left) and scanning electron

micrographs (right) taken from

an animal model of dilated

cardiomyopathy that produces

systolic heart failure (bottom),a normal heart (middle), and an

animal model of pressure-

overload hypertrophy that

produces diastolic heart failure

(top). Arrows indicate fibrillar

components of the extracellular

matrix. Adapted from

Aurigemma et al. [2]

Table 2 Criteria used to define the grade of diastolic dysfunction

Criteria Normal

young

Normal

adult

Impaired

relaxation

(grade 1)

Pseudonormal

(grade 2)

Restrictive

reversible

(grade 3)

Restrictive

irreversible

(grade 4)

E/A ratio 1–2 1–2 \1.0 1–1.5 (reverses with

Valsalva maneuver)

[1.5 1.5–2.0 (Doppler values similar

to grade 3 except no change

with Valsalva maneuver)

Deceleration time (ms) \240 150–240 C240 150–200 \150 \150

IVRT (ms) 70–90 70–90 [90 \90 \70 \70

PVS2/PVD ratio \1 C1 C1 \1 \1 \1

PV AR—MV Awave duration (ms)

C30 B0 B0 or C30 C30 C30 C30

AR velocity (cm/s) \35 \35 \35 C35 C35 C35

Propagation velocity (cm/s) [55 [55 [45 \45 \45 \45

Mitral e0 velocity (cm/s) [10 [8 \8 \8 \8 \8

Left atrium Normal Normal Normal or mildly

enlarged LA

Mild to moderate LA

enlargement

Severe LA

enlargement

Severe LA

enlargement

AR atrial reversal, D diastolic wave, E/A ratio of early to late diastolic filling velocities, IVRT isovolumic relaxation time, LA left atrial, MVmitral valve, PV pulmonary vein, S systolic wave (adapted from Garcia et al. [13], Bursi et al. [14], and Yamada et al. [4])

J Echocardiogr

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young subjects have an E[A pattern (normal). The higher

E represents rapid decrease of LV pressure in the early

diastole due to preserved LV myocardial relaxation. In this

case, most of the filling from LA to LV is completed by

E wave and there is not much remaining blood in the LA,

thus generating a small A wave.

Patients with an E\A pattern have abnormal myocardial

relaxation (grade 1) usually associated with normal LA

pressures. The abnormality in diastole initially occurs in

impairment of relaxation. When relaxation is slowed and

incomplete, early LV diastolic pressures rise, early diastolic

suction falls, and these decrease the E velocity. Thus, LV

filling becomes increasingly dependent on an increase in LA

contraction to push blood into the LV during late diastole if

LA function is not impaired. Subsequently, the transmitral

flow velocity pattern shows E/A\ 0.8. The majority of

subjects aged C60 years without histories of cardiovascular

disease have E\A pattern and DT[ 200 ms and can be

considered normal for age. The mean LA pressure is usually

not elevated in patients with grade 1 diastolic dysfunction,

except for some patients with severely impaired myocardial

relaxation, as in chronic hypertensive heart disease or

hypertrophic cardiomyopathy. In these diseases, the grade 1

filling pattern can be altered to a grade 2 filling pattern using

a diastology exercise stress test or by preload augmentation

(Fig. 10) [15, 16].

The pseudonormal LV filling pattern (E/A ratio is

0.8–1.5, grade 2) is associated with an increase in mean LA

pressure as well as abnormal relaxation. When the myo-

cardium becomes stiff and the distensibility is reduced, LV

pressure rises rapidly through the diastole and the end-

diastolic pressure is significantly elevated. The increased

LV stiffness causes an increase in the crossing pressure of

LA and LV resulting in an increased pressure gradient and

an increased E velocity. Because the elevated LV end-

diastolic pressure causes an increased afterload for LA

contraction, there is a small A wave.

The RFP (E/A ratio[ 2) may improve to a pseudo-

normal LV filling pattern with a reduction in preload

(reversible restrictive grade 3) or may stay irreversible

(grade 4). The RFP may occasionally revert to impaired

relaxation with successful therapy in the reversible

restrictive patients, whereas in others, the LV filling

remains restrictive (grade 4) patients. The presence of an

irreversible RFP represents the most advanced abnor-

mality in diastolic function and conveys the worst

prognosis.

Pulmonary venous flow velocities

The pulmonary venous flow velocities used to be recorded

by transesophageal echocardiography. However, progress

Fig. 7 Grades of diastolic function. The Doppler echocardiography

measures associated with each diastolic filling pattern are shown.

Impaired relaxation (asterisk) (grade 1) can be associated with normal

(grade 1a) or elevated (grade 1b) left ventricular (LV) filling pressures.

The arrows indicate the dynamic nature of the diastolic filling patterns in

response to alterations in loading conditions.A atrial systolic transmitral

flow wave, a0 atrial systolic mitral annular velocity, Adur the A wave

duration, AR pulmonary venous atrial reversal, ARdur atrial reversal

duration, D pulmonary venous diastolic filling wave, E early diastolic

transmitral flow wave, e0 early diastolic mitral annular velocity,

S pulmonary venous systolic filling wave, s0 systolic mitral annular

velocity, Vp propagation velocity. Adapted from Garcia et al. [13]

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123

E

A E

AE

A

E

A

Normal Impaired relaxation Pseudonormal Restrictive

Diastolic dysfunction

Mild, Grade 1 Moderate, Grade 2 Severe, Grade 3

LV pressure

LA pressure

Fig. 8 Schematic

representation of left ventricular

(LV) and left atrial (LA)pressures (upper) andtransmitral flow velocity

patterns (lower) in normal

patients and in different types of

diastolic dysfunction. This

schema divides patients into

four filling patterns: normal

pattern of relaxation and filling;

impaired relaxation or grade 1

mild diastolic dysfunction;

pseudonormal relaxation, or

grade 2 moderate diastolic

dysfunction; and restrictive

filling pattern, or grade 3 severe

diastolic dysfunction. Adapted

from Zile and Brutsaert [1]

Fig. 9 Simultaneous recording

of transmitral flow velocity

pattern (upper) and mitral

annular velocity pattern (lower)in normal and each diastolic

dysfunction grades. E early

diastolic transmitral flow

velocity, A atrial systolic

transmitral flow velocity,

e0 early diastolic mitral annular

velocity, a0 atrial systolic mitral

annular velocity

Fig. 10 Diastology stress test.

Simultaneous Doppler

recordings of transmitral flow

(upper panel) and left

ventricular out flow tract flow

(lower panel) velocities atbaseline and during leg positive

pressure. Transmitral flow

velocity pattern changed from

relaxation abnormality pattern

to pseudonormal pattern with

the reduction of left ventricular

output by leg positive pressure

(90 mmHg)

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of technology enables clinicians to record these velocities

clearly by transthoracic echocardiography and the velocity

pattern sometimes offers useful information for estimating

filling pressure; i.e., differentiating pseudonormal mitral

patterns from normal patterns [17].

The pulmonary venous flow velocity pattern usually

consists of (1) first systolic (PVS1) and second systolic

(PVS2) waves; (2) a diastolic wave (PVD); and (3) an

atrial reversal wave (AR). The PVS1 wave reflects active

atrial relaxation and disappears in atrial fibrillation [18].

The PVS2 and PVD waves are represented by the X and

Y descents of the LA pressure tracing, respectively. The

PVS2 wave is generated by passive LA filling and descent

of mitral annulus, which could be influenced by LV

contraction [19], mitral regurgitation [20], and LA reser-

voir function [21]. The PVD wave represents conduit

function of LA and usually acts similar to the mitral

E velocity. The AR wave reflects atrial contraction

(booster pump function) and increases in the situation of

elevated LVEDP. There is also a distinct reversed wave

during early systole (pulmonary venous flow at mitral

valve closure: PVC) that is frequently observed in the

presence of an elevated LA pressure, such as in the set-

ting of mitral stenosis [22] or LA myxoma [23]. The PVC

develops in the presence of elevated LA pressure during

closure of the mitral valve resulting in regurgitant flow

from the LA into the pulmonary veins where resistance is

lower.

In patients with impaired relaxation, the PVS2 and

PVS2/PVD ratio increase and the deceleration time of the

PVD wave prolongs, which compensates for the impair-

ment of early diastolic LV filling. In patients with

pseudonormal pattern, the PVS2 wave is decreased

(‘‘blunted’’) and the PVD wave increases resulting in a

decrease in PVS2/PVD ratio, which occurs with a large AR

wave ([35 cm/s). In patients with a restrictive mitral

inflow pattern (a deceleration time \150 ms), the pul-

monary venous flow shows a lower PVS2 and higher PVD

velocities (severely blunted systolic flow) and increased

atrial reversals (unless atrial systolic failure), suggesting

decreased LV operating compliance.

The AR wave is believed to be due to reflux flow into

the pulmonary veins during LA contraction. The AR wave

also disappears because of a lack of active LA contraction

in patients with atrial fibrillation. Increased AR velocity

([35 cm/s) suggests elevated LV filling pressures. How-

ever, patients with diastolic dysfunction may also have

concomitant LA contraction dysfunction and the AR

velocity may decrease in these patients, especially those

with restrictive pattern. A difference between the trans-

mitral A wave and pulmonary venous AR wave duration

greater than 30 ms also indicates elevated LV end-diastolic

filling pressures [24].

Mitral annular velocities

The mitral annular velocities obtained by the pulsed tissue

Doppler recording are now an important component in

interpreting the diastolic filling pattern, estimation LV

filling pressures, and differentiating constrictive pericardi-

tis from restrictive cardiomyopathies [25]. For the assess-

ment of diastolic function, measurements are made at the

septal and lateral mitral valve leaflet insertion points into

the mitral annulus in the apical 4-chamber view. In a

normal subject, the diastolic motion velocity of the mitral

annulus consists of two components—the early diastolic

wave (e0) and the atrial systolic wave (a0) [26, 27]. Thesevelocities change in parallel with the early diastolic (E) and

atrial systolic (A) transmitral flow velocities, respectively,

in normal subjects and most patients. However, the trans-

mitral and tissue Doppler variables show a difference in

waveforms depending on loading conditions, particularly

changes in preload [27, 28]. The tissue Doppler annular e0

velocity falls as myocardial relaxation worsens (prolonga-

tion of s) with progressive diastolic dysfunction. In con-

trast, the transmitral E wave velocity is preload dependent,

related to myocardial relaxation and LA pressures. The

E wave velocity falls initially in grade 1 diastolic dys-

function as myocardial relaxation worsens but increases

again as LA pressures rise in grade 2 and 3 diastolic dys-

function. Because the lateral e0 is typically greater than the

septal e0 [29], a different cutoff value should be used for

evaluating e0 as an index for ventricular relaxation. The

American Society of Echocardiography (ASE) guideline

for the assessment of diastolic function recommends that

septal e0 C8 and lateral e0 C10 are normal cutoff points.

Patients with septal e0\8 or lateral e0\10 are classified to

have diastolic dysfunction (Fig. 11) [30].

Time interval between E and e0

The time interval (TE-e0) between the onset of the early

diastolic transmitral flow velocity, as measured by con-

ventional Doppler echocardiography, and that of the early

diastolic mitral annular velocity, as measured by tissue

Doppler imaging, has been reported to be related to the

time constant of the LV pressure decay (s) in an animal and

human study [31, 32]. In a normal young heart, the e0 waveoccurs at the same time as, or earlier than, the E wave,

suggesting that the elastic recoil of the myocardium pro-

motes LV filling [31]. However, in patients with elevated

LV filling pressure, the E wave precedes the e0. This

finding suggests that a marked increase in LA pressure

causes the mitral valve to open earlier in the process of a

delay in the elastic recoil of the LV wall, and that the blood

pushed into LV from LA by elevated LA pressure expands

the LV wall, which generates the onset of e0. It was

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reported that the ratio of the isovolumic relaxation time to

TE-e0 can be used to estimate the mean pulmonary capil-

lary wedge pressure, even in patients with mitral valve

disease [33]. In the new ASE guidelines, an isovolumic

relaxation time/TE-e0 \2 is associated with elevated LV

filling pressures [30].

Color M-mode flow propagation velocity

The slope of the flow propagation velocity (Vp) during

early diastolic filling using color M-mode Doppler

expresses the pressure gradient between the mitral orifice

and apex. Vp [50 cm/s is considered normal and Vp

\50 cm/s is consistent with diastolic dysfunction [34, 35].

In patients with dilated cardiomyopathies, an E/Vp ratio

[2.5 can predict elevated pulmonary capillary wedge

pressures; however, Vp can be increased in patients with

normal LV volumes and EF despite impaired relaxation.

Consequently, the Vp is most reliable as an index of LV

relaxation in patients with depressed EF and dilated LV.

Left atrial size

While the mitral valve opens during ventricular diastole,

the chamber is directly exposed to LV pressure for a long

period of time. The LA also is an important transporting

chamber, which transmits blood from the pulmonary veins

to the LV during diastolic atrial filling and systolic atrial

emptying. Therefore, the LA size may be an important

index reflecting ‘‘disease history’’ in patients with LV

dysfunction, especially diastolic dysfunction [36]. Mea-

suring LA size is similar to measuring hemoglobin A1C in

diabetes—a long-term biomarker of average metabolic

state. The LA size is considered a long-term biomarker of

average LV diastolic pressure and diastolic dysfunction.

Normal LA size can be seen in grade 1; however, patients

with pseudonormal or restrictive filling certainly have a

dilated LA [37]. LA volume, measured by 2- or 3-dimen-

sional echocardiography, is more accurate than the LA

diameter determined using M-mode echocardiography. The

measurement of LA volume is highly feasible and reliable

in 2-dimensional echocardiographic studies, with the most

accurate measurements obtained using the apical 4-cham-

ber and 2-chamber views, and calculated by Simpson’s

method or area-length method. The LA volume is indexed

to body surface area and is considered to be abnormal when

it is[34 ml/m2 [38].

Strain and strain rate, twist, and more

Myocardial strain and strain rate are excellent parameters

for the quantification of regional contractility and may also

provide important information in the evaluation of diastolic

function. Furthermore, LV twist and the peak untwisting

rate are proposed to evaluate LV diastolic function

(Fig. 12) [39]. These myocardial deformation and torsion

measurements can be derived from tissue Doppler or from

speckle tracking techniques [40–44]. Wang et al. [45]

showed that in patients with systolic HF, the longitudinal,

circumferential, and radial strain, and LV twist measure-

ments are all impaired. In contrast, in patients with dia-

stolic HF, LV longitudinal and radial strains are reduced,

but circumferential strain and LV twist are preserved.

These measurements are only available with expensive

high-end ultrasound machines and research analytical

software. The analysis of strain and torsion remain

Septal e’

Lateral e’

LA volume

Normal function, Athlete’s heart, or

constrictionNormal function

Septal e’ ≥ 8

Lateral e’ ≥ 10

LA < 34 ml/m2

Septal e’ ≥ 8

Lateral e’ ≥ 10

LA ≥ 34 ml/m2

Septal e’ < 8

Lateral e’ < 10

LA ≥ 34 ml/m2

E/A < 0.8

DT > 200 ms Av. E/e 8

Ar-A < 0 msVal ΔE/A < 0.5

E/A 0.8-1.5

DT 160-200 ms Av. E/e 9-12

Ar-A ≥≤

30 msVal ΔE/A ≥ 0.5

E/A ≥ 2

DT < 160 ms Av. E/e ≥ 13

Ar-A ≥ 30 msVal ΔE/A ≥ 0.5

Grade 1 Grade 2 Grade 3

Fig. 11 Scheme for grading

diastolic dysfunction. Av.average, LA left atrium, Val.Valsalva. Adapted from Nagueh

et al. [30]

J Echocardiogr

123

investigational at present and are still not included in a

routine echocardiographic examination. Other limitations

of myocardial deformation and torsion measurements

include the Doppler angle dependency in the tissue

Doppler method and the requirement for high-quality 2D

images in speckle tracking—both need significant post

processing time. Evaluation of these new indices in patients

with diastolic HF revealed that most of the patients exhibit

some abnormality of regional systolic function, but it has

not been shown that such abnormalities are responsible for

the clinical syndrome. Additional investigation is required

with these new echocardiographic techniques.

Estimation of filling pressure

Patients with depressed EF

The mitral inflow pattern can be used to estimate filling

pressures with reasonable accuracy in patients with

depressed EF. Furthermore, the changes in the mitral flow

pattern can be used to track filling pressures in response

to medical therapy. In patients with impaired relaxation

patterns and peak E velocities\50 cm/s, LV filling pres-

sures are usually normal. Patients with restrictive filling

(E/A C 2) have an increased mean LA pressure (Fig. 13).

The use of additional Doppler parameters is recommended

in patients with E/A ratios C1 to\2.

The E/e0 ratio uses the tissue Doppler annular e0 velocityto adjust for the myocardial relaxation contribution to

mitral E velocity, thereby allowing an estimate of LV

filling pressures [28, 46]. The septal, lateral, or an average

of these velocities can be used to calculate the E/e0 ratio.Therefore, one should use different cutoff values for esti-

mating elevated filling pressures. When septal e0 is used, anE/e0 ratio B8 is associated with normal pulmonary capillary

wedge pressure and an E/e0 ratio C15 suggests an elevated

capillary wedge pressure [46]. There is a relatively wide

gray zone used in patients when the E/e0 falls between 9

and 14 and other Doppler parameters are necessary to

assess the LV filling pressures.

Using pulmonary venous flow velocity, PVS2/PVD\1,

AR velocity[35 cm/s, and AR–A duration C30 ms indi-

cates elevated LV filling pressures [24]. However,

recording of the AR wave is often challenging by trans-

thoracic approach.

The Valsalva maneuver is the most commonly used

method to alter loading conditions, reducing LV preload

with forceful expiration against a closed nose and mouth.

In normal subjects, there is a decrease in the mitral E and

A velocities but no change in E/A ratio. In patients with a

pseudonormal filling pattern, increased LA pressures are

Fig. 12 Examples of LV twist and its time derivative from 3 cases.

Top left the twist curve from a subject in the control group. Topmiddle from a patient with diastolic dysfunction and normal EF, topright the reduced twist from a patient with depressed EF. Lower left

the time derivative of LV twist from a normal subject, lower middlefrom a patient with diastolic dysfunction and normal EF, and lowerright from a patient with systolic dysfunction. Adapted from Wang

et al. [39]

J Echocardiogr

123

suppressed with the reduction in preload. The mitral

E velocity decreases, the DT prolongs, and the A velocity

remains unchanged or increases, unmasking an impaired

relaxation pattern. A reduction in the E velocity by 50%

and a reversal in the E/A ratio to \1 have been used as

diagnostic criteria for elevated LV filling pressure.

Patients with normal (preserved) EF

The estimation of LV filling pressures in patients with

normal EF is more challenging than in patients with

depressed EF. However, the most commonly used and

easiest-to-interpret parameter to estimate filling pressure

is the E/e0 ratio in this patient group. An average E/e0

ratio B8 indicates patients with normal LV filling pres-

sures, whereas the ratio C13 indicates an increase in LV

filling pressures [47]. Other measurements are required

when the E/e0 ratio is between 9 and 13 (Fig. 14).

Maximal LA volume C34 ml/m2, AR–A duration

C30 ms, a change in E/A ratio with the Valsalva

maneuver of C0.5, systolic pulmonary artery pressure

[35 mmHg (in the absence of pulmonary disease), and

isovolumic relaxation time/TE-e0 \ 2 indicate elevated

LV filling pressure.

Mitral E/A

Normal LAP

Normal LAP

E/A < 1 and E ≤ 50 cm/s E/A ≥ 2, DT <150 msE/A 1 - < 2, or

E/A < 1 and E > 50 cm/s

E/e’ (average e’) > 15

E/Vp 2.5

S/D < 1

Ar – A > 30 ms

Valsalva ΔE/A > 0.5

PAS >35 mmHg

IVRT/T E-e’<2

E/e’(average e’) < 8

E/Vp <1.4

S/D >1

Ar – A < 0 ms

Valsalva ΔE/A < 0.5

PAS <30 mmHg

IVRT/T E-e’ >2

↑ LAP ↑ LAP

≥

≥

Fig. 13 Diagnostic algorithm

for the estimation of LV filling

pressures in patients with

depressed EFs. Adapted from

Nagueh et al. [30]

E/e’

↑ LAPNormal LAPNormal LAP

E/e’< 8

(Sep, Lat, or Av.)

Sep. E/e’> 15 or

Lat. E/e’ > 12 or

Av. E/e’ > 13

↑ LAP

E/e’ 9-14

LA volume ≥ 34 ml/m2

Ar – A ≥ 30 ms

Valsalva ΔE/A > 0.5PAS >35 mmHg

IVRT/T E-e’ <2

LA volume < 34 ml/m2

Ar – A < 0 ms

Valsalva ΔE/A < 0.5

PAS <30 mmHgIVRT/T E-e’ >2

Fig. 14 Diagnostic algorithm

for the estimation of LV filling

pressures in patients with

normal (preserved) EFs.

Adapted from Nagueh et al. [30]

J Echocardiogr

123

Therapy of diastolic dysfunction

The treatment goals of diastolic heart dysfunction are

similar to those of systolic heart dysfunction. Not only do

we seek to improve survival in our patients but we also aim

to improve our patients’ quality of life by reducing

symptoms, increasing exercise tolerance, and decreasing

hospitalizations.

The first target in treating diastolic dysfunction is

decreasing the filling pressure (pulmonary venous pres-

sure). We can reduce LV volume using diuretics and

vasodilators. Maintaining atrial contraction is important

because atrial fibrillation worsens the situation. Reducing

heart rate and increasing diastolic duration by any means

are effective in most cases.

The second goal is to prevent and/or treat pathologic

causes of diastolic dysfunction. Myocardial ischemia or

infarction is one of the major contributors to diastolic

dysfunction. Although there are no data demonstrating that

coronary revascularization leads to an improvement in

diastolic HF outcomes, revascularization and prevention of

ischemia may be effective to improve diastolic function. In

patients with LV hypertrophy, the prevention and reduction

of hypertrophy is essential. Lowering the blood pressure

allows the ventricle to relax more adequately thereby

increasing early diastolic filling and this may lead to

regression of the LV hypertrophy.

There have not been many large trials for the treatment

of diastolic HF. The CHARM-Preserved trial of patients

with HF and preserved EF indicated only a marginal ben-

efit of candesartan [48]. A recent trial using irbesartan also

failed to demonstrate the effect of angiotensin receptor

blockers to improve the survival of patients with diastolic

HF with preserved EF [49]. It would be important to have

large-scale clinical trials to guide the therapy of diastolic

HF; however, these trials will need standard definitions as

well as require a large sample size and a long follow-up

period to provide beneficial results [50].

Conclusions

Diastolic HF is becoming common and it is lethal.

Diagnosis and staging of diastolic dysfunction provide a

framework for the approach to management of individu-

als with diastolic HF. Echocardiography is a powerful

tool enabling the clinician to noninvasively assess dia-

stolic function [51]. This not only allows the clinician to

diagnose diastolic dysfunction but also provides infor-

mation regarding the underlying cardiac disease, filling

pressures, and prognosis. To date, no single Doppler

echocardiographic index of diastolic dysfunction has

yielded a robust criterion for elevated LV filling pressure

and multiple indices are required to increase the sensi-

tivity of the diagnosis. Clinicians who take care of HF

patients should continue to make critical use of current

Doppler echocardiographic evaluations and utilize this

information to improve survival and the quality of life in

these patients.

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