JACC: CARDIOVASCULAR IMAGING VOL. -, NO.

-, 2019
ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

STATE-OF-THE-ART PAPER

Left Ventricular Diastolic Function

Understanding Pathophysiology, Diagnosis, and Prognosis
With Echocardiography

Sherif F. Nagueh, MD

ABSTRACT

Left ventricular diastolic function plays an important role in determining left ventricular filling and stroke volume.
Abnormal diastolic function has been recognized in many cardiovascular diseases and is associated with worse outcomes,
including total mortality and hospitalizations due to heart failure. Using echocardiography, it is possible to diagnose the
presence of diastolic dysfunction and the pathophysiologic mechanisms involved as they affect left ventricular and
left atrial structure and function. This review addresses the role of echocardiography in understanding the pathophysi-
ology of diastolic dysfunction, its diagnosis, and utility in predicting outcomes. (J Am Coll Cardiol Img 2019;-:-–-)
© 2019 by the American College of Cardiology Foundation.

A ssessment of left ventricular (LV) diastolic

function is essential to understanding car-
diac function and its alterations with cardio-
vascular diseases. In broad terms, one can focus on 2
main aspects: myocardial relaxation and chamber
stiffness. Notwithstanding, LV diastolic function is
modulated by right ventricular–LV interaction, left
atrial (LA) function, pericardial influence on LV
filling, LV systolic properties, LV systolic and dia-
stolic dyssynchrony, coronary blood flow, and tissue
perfusion. Assessment of LV relaxation and LV filling
pressure (LVFP) (Figure 1) by echocardiography
(Table 1) is potentially useful in identifying patients
in stage B heart failure, as will be discussed in other
reviews.
MYOCARDIAL RELAXATION
On a cellular level, detachment of actin myosin cross
bridges takes place during diastole and causes the
decline in cellular tension. Calcium uptake by the
sarcoplasmic reticulum occurs before detachment
(Figure 2). Calcium uptake is regulated by the sarco-
plasmic reticulum ATPase (SERCA2a) and phospho-
lamban. In patients with heart failure, there is
reduced expression of SERCA2a at the gene and pro-
tein level and slow relaxation. In the unphosphory-
lated state, phospholamban has an inhibitory effect
on SERCA2a, whereas phospholamban phosphoryla-
tion by cyclic adenosine monophosphate protein ki-
nase removes the inhibitory effect of phospholamban
(1). Cyclic adenosine monophosphate protein kinase
activation by beta-adrenergic agonists results in
positive lusitropic effects. Energy is needed for these
processes, and ischemia leads to impaired relaxation.
There are other proteins and enzymes that control
relaxation, but they will not be discussed, given the
scope of the review.
At the chamber level, myocardial relaxation is
measured by the rate of LV systolic pressure decay
during the isovolumic relaxation (IVR) period. A
normal LV exhibits faster pressure decline with low
minimal pressure. LV pressure decay usually
occurs with a monoexponential decay, though other

From the Methodist DeBakey Heart and Vascular Center, Houston Methodist, Houston, Texas. Dr. Nagueh has reported that he
has no relationships relevant to the contents of this paper to disclose.

Manuscript received August 27, 2018; revised manuscript received October 25, 2018, accepted October 25, 2018.

ISSN 1936-878X/$36.00 https://doi.org/10.1016/j.jcmg.2018.10.038

2 Nagueh JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019
Echocardiography and LV Diastolic Function - 2019:-–-

ABBREVIATIONS mathematical models have been used, relaxation (Figure 3). The reason for the latter obser-
AND ACRONYMS including a logistic model (1). The time con- vation is the delayed onset of e 0 with myocardial
stant of LV relaxation, or tau ( s ), can be disease, such that it occurs when LV diastolic pres-
s = time constant of left
ventricular relaxation
derived from LV pressure recordings ob- sure is equal to or higher than LA pressure (4,5).

2D = 2-dimensional
tained by high-fidelity pressure catheters and
is considered the gold standard for assess-
DT = deceleration time
ment of LV relaxation, albeit not practical.
E = peak early diastolic mitral
inflow velocity
Increased LV afterload results in slow and
0
e = mitral annulus early
delayed relaxation but the timing of the load
diastolic velocity has an effect as well (2). Preload effect on LV
HFpEF = heart failure with relaxation is more debatable, but load in-
preserved ejection fraction crease at the end of IVR period leads to an
HFrEF = heart failure with increase in isotonic relaxation rate (2).
reduced ejection fraction
IVR = isovolumic relaxation
ECHOCARDIOGRAPHIC INDICES THAT
ASSESS LV RELAXATION
LA = left atrial
LV = left ventricular
Echocardiography is the main imaging mo-
LVFP = left ventricular filling
dality for assessment of LV diastolic func-
pressure
tion. Its temporal resolution is highest and
PCWP = pulmonary capillary
wedge pressure the methodology is the most extensively
SERCA2a = sarcoplasmic
validated, including outcome prediction.
reticulum ATPase There are several echocardiographic signals
SRE = strain rate during early (3) that can be used to draw inferences about
diastole
LV relaxation (Table 2). However, they are
SRIVR = strain rate during affected by several hemodynamic variables.
isovolumic relaxation
Accordingly, one has to consider clinical
TR = tricuspid regurgitation
context, loading conditions, and technical
aspects when using these signals. Aside from the
variables in Table 2, there are 3 main signals:
myocardial or mitral annulus early diastolic velocity
by pulsed wave tissue Doppler (e0 ) (cm/s) and LV
global isovolumic and early diastolic strain rates (s –1).
Of the 3, e 0 has the highest feasibility, highest repro-
ducibility, and most consistent association with car-
diovascular outcomes.
MITRAL ANNULUS EARLY
DIASTOLIC VELOCITY
Animal studies have shown a significant inverse
relation between e 0 and s (4–6). Similar to the effect of
increased afterload on s , increased afterload leads to
reduced e 0 . Further, e 0 is affected by LV elastic recoil.
The smaller the LV end-systolic volume is, the faster
the recoil is, and the higher e 0 is. In animal studies,
this concept was examined using the difference be-
tween minimum and unstressed LV diameter (6), and
LV minimum pressure (4).
Importantly, the relation between e 0 and preload
depends on whether LV relaxation is normal or
impaired. With normal LV relaxation, transmitral
pressure gradient has a direct effect on e0 such that
higher gradients lead to increased e 0 (4,5). However,
the effect of LA pressure is minimal with impaired LV
Further, the time delay between mitral inflow early
diastolic velocity (E) and e 0 is directly related to s and
is an index of LV relaxation irrespective of mitral
valve disease (5,7,8).
A significant inverse linear relation between e0 and
s was observed in humans (9–11). Elegant studies have
shown the absence of an effect of preload changes on
e 0 when E was altered by load changes (9). There are
human studies showing the strong correlation of e 0
with interstitial fibrosis (12), beta-adrenergic receptor
density (12), myocardial tumor necrosis factor alpha,
and inducible nitric oxide synthase levels, which
have inotropic and lusitropic effects (13), as well as
gene and protein expression of SERCA2a and phos-
phorylated phospholamban (14) (Figure 4).
Some diseases affect the clinical application of e0 to
the evaluation of diastolic function. For example,
septal e 0 is preserved, whereas lateral e 0 is reduced in
patients with pericardial constriction, as outward LV
chamber motion is restricted by the taut pericardium.
This finding is referred to as annulus reversus (15).
Other disease states that can lead to reduced e 0
include mitral stenosis and moderate-to-severe mitral
annulus calcification (8,16). Conversely, hemody-
namically significant mitral regurgitation in patients
with normal LV ejection fraction (LVEF) can lead to
increased e0 (8), with a significant association be-
tween e0 and diastolic flow volume across the mitral
annulus. In normal LV, e 0 is directly related to LVFP
(4–6) and should not be used in conjunction with E to
draw inferences about LVFP (3).
Given the direct relation between E and LA pres-
sure, the inverse relation between E and s , the inverse
relation between e0 and s , and the minimal effect of
LA pressure on e 0 in the presence of myocardial dis-
ease, the dimensionless E/e 0 ratio can be used to es-
timate LA pressure (11,17). E/e 0 ratio has been
evaluated in several patient populations, including
patients with heart failure with reduced ejection
fraction (HFrEF) and heart failure with preserved
ejection fraction (HFpEF), albeit some studies re-
ported lower accuracy than others (18–21). It can be
calculated using septal, lateral, or average e 0 . An
average ratio <8 is associated with normal LVFP, and
a ratio >14 is associated with elevated LVFP. Few
studies showed E/e 0 can track changes in pulmonary
wedge pressure in ambulatory patients (22) and pa-
tients with acute decompensated heart failure (23).
When e 0 is heavily affected by factors other than LV
relaxation, E/e 0 ratio should not be used to estimate
JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019
- 2019:-–-
LVFP, as in patients with pericardial constriction,
moderate and severe mitral annulus calcification,
mitral stenosis, and severe mitral regurgitation with
normal LVEF (24). In patients with left bundle branch
block or paced rhythm, it is preferable to consider
other variables in addition to E/e 0 ratio including LA
volume and pulmonary artery systolic pressure since
weaker correlations were observed between septal
and lateral E/e0 ratio and LVFP (25). Doppler echo-
cardiography proved useful in identifying patients
with LV assist device and increased wedge pressure
(26). E/e 0 ratio was shown to have a strong significant
correlation with collagen expression and cross linking
in HFpEF patients (27). Further, lateral E/e 0 ratio was
highly accurate in identifying patients with HFpEF
(86% correctly identified) when diastolic dysfunction
was diagnosed using pressure-volume loops obtained
by conductance catheters (21).
MYOCARDIAL DIASTOLIC
STRAIN RATE SIGNALS
Inferences can be drawn about LV global diastolic
function using longitudinal/circumferential diastolic
strain rate during IVR (SRIVR) and early diastole (SR E ).
Animal studies have shown a significant inverse cor-
relation among SR IVR, SR E, –dP/dt, and s (28). The
correlation was stronger between invasive measure-
ments of LV relaxation and SR IVR (Figure 5). Similar to
e 0 , LVFP has a direct effect of increasing SRE in the
presence of normal but not impaired LV relaxation
(28). There are animal studies showing significant
correlations between longitudinal and radial SR E and
the extent of replacement fibrosis (29). Human
studies reported significant associations of SR IVR and
SR E with the SERCA2a gene and protein expression
(14).
SR IVR and SR E can correct for the effect of LV
relaxation on E. E/SR IVR or E/SR E (cm) ratios have a
direct relation with mean wedge pressure (28,30),
albeit the relation of E/SRIVR with wedge pressure is
stronger when compared with E/SRE (28). E/SRIVR was
more accurate than E/e 0 ratio in detecting elevated
LVFP in presence of segmental dysfunction and in
patients with normal EF (28). Although promising,
there are limitations, including image technical
quality, lack of standardization for diastolic SR mea-
surements, need for more training to achieve satis-
factory acquisition and analysis, and lower accuracy
with tachycardia as it relates to frame rate.
When considering indices of LV relaxation, it is
recommended to consider age-specific cutoff values.
Notwithstanding, there are older healthy individuals
who have normal LV relaxation and e 0 values close to
Nagueh 3
Echocardiography and LV Diastolic Function
F I G U R E 1 LA and LV Pressures
LV EDP
V-wave A-wave
LV RFW
LV
A-wave
Rapid Filling LV
LA Systole LA
Mean LAP LV pre-A
LVmin
The lowest left ventricular (LV) pressure is the minimum pressure (LVmin).
After mitral valve opening, LV pressure rises, producing rapid filling wave
(RFW) to LV pre–A-wave pressure (LV pressure before left atrial [LA]
contraction). LV pre–A-wave and LA mean pressures are similar in the
absence of mitral valve disease. When the LA contracts, LV pressure rises
(LV A-wave), ending with LV end-diastolic pressure (EDP). The highest LA
pressure (LAP) at end-systole is V-wave pressure. Pressure drops as the
mitral valve opens. In a normal LV, early diastolic pressure gradient (blue)
leads to peak early diastolic mitral inflow velocity (E). In late diastole, LA
contracts with rise in LAP (A-wave), and another positive pressure gradient
occurs (orange), which leads to mitral A velocity. Mean LAP is lower than
V-wave and A-wave pressures. Reprinted with permission of the American
Society of Echocardiography.
what is seen in normal young subjects. Further, some
elderly subjects have reduced diastolic reserve with
exercise despite e 0 that is appropriate for their age.
ELASTIC RECOIL AND IMAGING INDICES OF
ELASTIC RECOIL
LV elastic recoil during IVR contributes to the decline
in LV pressure. The giant protein titin acts as an
elastic spring that is compressed during systole and
its recoil during diastole plays an important role in LV
expansion (Figure 6). The protein has isoforms that
are more (N2BA) or less (N2B) compliant. The N2BA/
N2B ratio is increased in HFrEF patients when
compared with control subjects (31), whereas the
proportion of N2B is more prominent in HFpEF pa-
tients (32). Titin phosphorylation by protein kinase G
results in a more compliant molecule, whereas
protein kinase C phosphorylation and formation of
disulfide bonds result in a stiffer molecule (33). As
N2B is the stiffer isoform, restoring forces and elastic
recoil are normal in HFpEF but reduced in HFrEF
patients.
LV elastic recoil results in LV untwisting, which
can be measured by echocardiography. During sys-
tole, LV twisting takes place as the apex rotates in a
counterclockwise direction with the base rotating
4 Nagueh JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019
Echocardiography and LV Diastolic Function - 2019:-–-

T A B L E 1 Hemodynamic Determinants of Echocardiographic Variables

Echocardiographic Variables Hemodynamic Determinants

1. Mitral E/A Ratio E velocity is dependent on LA-LV pressure gradient in early diastole and therefore LV relaxation and LA “v” pressure. A-wave
velocity depends on LA-LV pressure gradient during late diastole, and therefore LV stiffness and LA contractility.
Increased ratio usually predicts elevated LV filling pressure in patients with myocardial disease but is not useful in
normal subjects.
2. DT of mitral E velocity (ms) Influenced by the rate of decline in LA-LV pressure gradient after mitral valve opening, and therefore LV stiffness. When LV
relaxation is slow, LV relaxation also affects DT.
3. IVRT (ms) IVRT depends on LV relaxation, LA “v” pressure, LV end-systolic pressure, and heart rate. In patients with impaired LV
relaxation, IVRT <70 ms is usually associated with increased LA pressure.
4. Pulmonary vein systolic-to-diastolic (S/D) S velocity is influenced by LA pressure, LA contractility and relaxation, LA stiffness, and LV and RV contractility. D velocity is
velocity ratio influenced by changes in LA pressure in early diastole and LV relaxation. S/D is inversely related to LA pressure and is
most reliable in patients without mitral valve disease and with depressed LVEF.
5. Pulmonary vein atrial reversal duration In patients with normal LA systolic function, the time difference between duration of pulmonary vein flow and mitral inflow
minus mitral A velocity duration (Ar-A) during atrial contraction is directly related to LV pressure rise with LA contraction and LV end-diastolic pressure.
(ms)
6. LA maximum volume index LA volume is directly but weakly related to LV filling pressure. In addition it has been shown to be a predictor of stroke and
development of heart failure.
7. Peak velocity of tricuspid regurgitation jet In patients without pulmonary disease, there is a direct relation between pulmonary artery systolic pressure and LA
by continuous-wave Doppler (m/s) pressure, as increased LA pressure causes group II pulmonary hypertension.
8. End-diastolic velocity of pulmonary In patients without pulmonary disease, there is a direct relation between pulmonary artery diastolic pressure and LA
regurgitation jet by continuous-wave pressure, as increased LA pressure causes group II pulmonary hypertension.
Doppler (m/s)
9. Color M-mode Vp and E/Vp ratio Vp is dependent on LV relaxation. As Vp corrects for the effect of LV relaxation on E, E/Vp ratio relates directly to LA
pressure.
10. e0 (cm/s), acquired by pulse tissue The hemodynamic determinants of e’ velocity are LV relaxation, restoring forces and filling pressure. In myocardial disease,
Doppler (recommended to measure at LV filling pressure has limited effects on e0 .
septal and lateral annulus and to consider
average e0 )
11. Mitral E/e0 ratio e0 is dependent on LV relaxation. As e0 corrects for the effect of LV relaxation on E, E/e0 ratio relates directly to LA pressure.
12. TE-e0 time interval (ms) Delayed onset of e0 compared with onset of E occurs in the setting of LV diastolic dysfunction and feasibility increases with
single beat acquisition of both signals using dual Doppler probe.
13. Diastolic SRIVR (s–1) Relates to LV relaxation. Since SRIVR corrects for the effect of LV relaxation on E, E/SRIVR ratio relates directly to LA
pressure.
14. Diastolic SRE (s–1) Relates to LV relaxation and LV filling pressures. As SRe corrects for the effect of LV relaxation on E, E/SRe ratio relates
directly to LA pressure.
15. LA reservoir strain Reflects LA reservoir function and related inversely to LA pressure. In conjunction with LA pressure, can be used as an index
of LA stiffness.

For technical aspects, details on hemodynamic determinants, clinical applications, and limitations, see Nagueh et al. (3,24).
DT ¼ deceleration time; e0 ¼ mitral annulus early diastolic velocity; E ¼ peak early diastolic mitral inflow velocity; IVRT ¼ isovolumic relaxation time; LA ¼ left atrial; LV ¼ left ventricular; LVEF ¼ left
ventricular ejection fraction; SRE ¼ strain rate during early diastole; SRIVR ¼ strain rate during isovolumic relaxation time; TE-e0 ¼ time delay between onset of E and e0 ; Vp ¼ flow propagation velocity.

clockwise. LV twist depends on loading conditions
and myocardial contractility. It is abnormally reduced
in HFrEF patients but is normal with LV diastolic
dysfunction and normal EF, irrespective of presence
or absence of heart failure (34,35), though HFpEF
patients have reduced LV twist with exercise. In an
animal model, LV untwisting rate was significantly
different between ventricles with different end-
systolic volumes despite very similar s (35). In hu-
man studies, LV peak untwisting rate was related to
LV twist and LV end-systolic volume (surrogate of
restoring forces) in HFrEF and HFpEF patients.
However, it was related to s only in HFrEF patients
(35). As predicted based on titin isoforms expression
in HFrEF and HFpEF, peak untwisting rate is normal
in HFpEF patients with stronger restoring forces but
reduced in HFrEF with a higher N2BA/N2B ratio and
thus reduced restoring forces. Therefore, caution
should be exercised in drawing conclusion about LV
relaxation based on peak untwisting rate in patients
with normal EF. Apical untwisting rate was signifi-
cantly related to TTN N2B messenger RNA expression
in patients with dilated cardiomyopathy (Figure 7)
such that untwisting velocity was higher in apical
segments with a higher gene expression of the stiffer
N2B isoform (14).
LV CHAMBER STIFFNESS
Myocyte stiffness and fibrosis determine chamber
stiffness. Titin is the main protein responsible for
modulating myocyte stiffness. Myocyte stiffness is
reduced in HFrEF patients in whom the N2BA/N2B
ratio is higher than that in control subjects (31), but is
increased in HFpEF patients (32). Increased collagen I
expression, collagen crosslinks formation, and
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- 2019:-–- Echocardiography and LV Diastolic Function

F I G U R E 2 Actin and Myosin Cross Bridges

Systole Diastole

Ca2+ binding site

Ca2+

Actin
Myosin binding
site blocked

Myosin binding site exposed Myosin

During systole (left), calcium (yellow) is released from sarcoplasmic reticulum and binds troponin (violet). This causes tropomyosin (white) to
shift its position and exposes myosin binding sites on actin filament allowing for cross bridge formation. During diastole (right), active
calcium uptake by the sarcoplasmic reticulum results in another tropomyosin position shift that shields myosin binding sites on actin from
myosin heads. Reprinted with permission from the American Society of Echocardiography.

advanced glycation end products lead to increased
stiffness (1,27).
Myocardial stiffness and LV chamber stiffness can
be measured using conductance catheters, with ma-
nipulations in venous return to alter LV volumes and
pressure, which is not practical. Inferences can be
drawn about chamber stiffness based on LVFP, as
increased stiffness is associated with elevated LV late
diastolic pressures and, later on, LA pressures.
Notwithstanding, pressure measurements are also
dependent on volume status and with increased LV
end-diastolic volume, LV end-diastolic pressure in-
creases along the same pressure volume curve.
Imaging provides valuable insights into the pres-
ence of abnormally increased chamber stiffness as
well as the underlying pathologic findings leading to
increased stiffness. For example, the presence of LV
hypertrophy and LV mass/volume ratio can be quan-
tified. Replacement and interstitial fibrosis can be
assessed by cardiac magnetic resonance.
Echocardiographic approaches to assess LV stiff-
ness include deceleration time of E or deceleration

T A B L E 2 Indices of LV Relaxation

Parameter Relation With Time Constant of LV Relaxation Limitation

1. IVRT IVRT increases as s is prolonged. IVRT is shortened when LA pressure increases.

2. Noninvasive s based on IVRT/(Ln LV end-systolic pressure  Ln LA pressure) Systolic blood pressure can be different from LV end-systolic
LV and LA pressures pressure and noninvasive estimation of LA pressure is needed.
estimation The use of multiple measurements and estimations can lead to
inaccurate values.
3. AR CW Doppler A. LV dP/dt tmin can be derived as (4VAR2  1,000/20), where V AR Validation applied to few patients and method depends on high-
is aortic regurgitation velocity in m/s at 20 ms after the onset quality AR signals with complete jet.
of regurgitation.
B. s is the time interval between the onset of AR and the regur-
gitant velocity corresponding to (11/e)1/2 of maximal AR
velocity.
4. MR CW Doppler A. LV dP/dt tmin can be derived as: [4(VMR2 )2  (VMR1 )2  Validation applied to relatively few patients and method depends
1,000/20], where VMR is mitral regurgitation velocity in m/s, on high-quality MR signals with complete jet.
20 ms apart.
B. s is the time interval between dP/dtmin to the point at which
the MR velocity is (1/e)1/2 of MR velocity at the time of
dP/dtmin .

s ¼ time constant of left ventricular relaxation; AR ¼ aortic regurgitation; CW ¼ continuous wave; MR ¼ mitral regurgitation; other abbreviations as in Table 1.
6 Nagueh JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019
Echocardiography and LV Diastolic Function - 2019:-–-

F I G U R E 3 Relation Among LAP, LV Pressure, and Doppler Velocities

Impaired Relaxation
Normal
Normal LAP High LAP
Diastolic Function

80
LV and LA
Pressures
(mmHg)
0
Fluids E
80
A
E
Mitral Inflow

Diuretics
Velocities

A E
A
(cm/s)

0
DT DT DT
IVRT IVRT IVRT
Tissue Doppler

0
Velocities
(cm/s)

e’ e’ a’
10 a’
a’
e’

(Left) With normal diastolic function, LAP and LV pressure are normal with predominant early diastolic filling, short isovolumic relaxation time
(IVRT), and deceleration time (DT). Mitral annulus early diastolic velocity (e0 ) exceeds a0 . Onset of e0 precedes onset of E. (Middle) With
impaired LV relaxation but normal LAP, early diastolic transmitral pressure gradient is reduced, leading to reduced E and prolonged DT and
IVRT. Due to increased LA volume before LA contraction, LA contractility increases, leading to increased late diastolic transmitral pressure
gradient, increased mitral A velocity, and decreased E/A ratio. e0 is delayed and reduced with increased a0 . (Right) With impaired LV
relaxation but increased LAP, E increases with short DT and IVRT. Due to increased late diastolic LV pressures and LA afterload, mitral A
velocity decreases, leading to an increased E/A ratio. e0 is delayed and reduced with decreased a0 . Increased intravascular volume in patients
with grade I diastolic dysfunction leads to an increase in LAP and a pattern of predominant early LV filling (shift to right). Diuretics in patients
with increased LAP shift mitral inflow pattern to one of predominant late diastolic filling. Reprinted with permission from the American
Society of Echocardiography. Abbreviations as in Figure 1.

time (DT), which shortens with increased operating
chamber stiffness (36,37). The second measurement is
A-wave transit time: the time interval between the A-
wave at mitral valve tips and its recording at LV
outflow tract. It could be measured as time interval
between A-wave peaks or A-wave onsets at both lo-
cations. With increased late diastolic LV chamber
stiffness (A-wave rise in LV pressure divided by
difference in LV diastolic volume before and after LA
contraction) and with increased LV end-diastolic
pressure, A-wave transit time shortens (38,39).
NONINVASIVE ASSESSMENT LV DIASTOLIC FUNCTION
AND ESTIMATION OF LVFP (MEAN WEDGE PRESSURE OR
LV PRE A-WAVE PRESSURE). The most robust assess-
ment of LV diastolic function and LVFP is achieved by
consideration of clinical status, 2-dimensional (2D),
and Doppler findings. American Society of Echocar-
diography/European Association of Cardiovascular
Imaging 2016 guidelines are based on recognition of
myocardial disease (24). Presence of myocardial
disease can be inferred based on a constellation of
findings including clinical, 2D and Doppler observa-
tions. For example, patients with hypertensive car-
diovascular disease and LA enlargement or pathologic
LV hypertrophy have diastolic dysfunction. Likewise,
patients with systolic dysfunction have diastolic
dysfunction. This can be detected by reduced EF,
mitral annulus systolic velocity, mitral annulus plane
systolic descent, and LV global longitudinal strain
(24). Therefore, the assessment of diastolic function
in patients with normal EF should not be based only
on Doppler signals.
In the absence of myocardial disease after careful
consideration of clinical, 2D findings and specific
Doppler signals (see the following pertaining to pul-
monary vein flow, changes in mitral inflow with Val-
salva, L-wave velocity, and tricuspid inflow), the 2016
American Society of Echocardiography/European As-
sociation of Cardiovascular Imaging guidelines
recommend relying on 4 parameters. These include
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F I G U R E 4 Relation of e 0 to Gene and Protein Expression of SERCA2a

10 10
r = 0.7 r = 0.8
p = 0.003 p = 0.001
8 8
Average e' (cm/s)

Average e' (cm/s)

6 6

4 4

2 2

0 0
0.0 0.5 1.0 1.5 2.0 2.5 0.0 0.2 0.4 0.6 0.8 1.0
SERCA 2a mRNA Expression Ratio SERCA 2a Protein Expression Ratio
Patients/Control Patients/Control

(Left) Direct relation between average e0 and SERCA2a messenger RNA expression ratio in patients with dilated cardiomyopathy versus
control subjects. (Right) Direct relation between average e0 and sarcoplasmic reticulum ATPase (SERCA2a) protein expression ratio in patients
with dilated cardiomyopathy versus control subjects. Reprinted with permission from Cordero-Reyes et al. (14). Abbreviation as in Figure 3.

annular e 0 , average E/e 0 ratio, peak tricuspid regurgi-
tation (TR) velocity, and LA maximum volume index.
When the majority of findings (4/4, 3/4, 3/3, 2/3, or
2/2) fall within normal or abnormal range, one can
conclude normal or abnormal diastolic function.
However, without a clear majority (2/4, 1 of 2, or only
1 parameter available) an indeterminate diastolic
function status may be concluded. The writing group
sought to avoid false calls of diastolic dysfunction
and to achieve high specificity, hence relying on more
variables and clearly abnormal values. The cutoff
values were based on findings from a recent multi-
center multinational study of normal subjects with
images analyzed in a core laboratory (24). Annular e 0
was not recommended as the sole index of diastolic
dysfunction given the presence of relatively lower
values in 10% to 20% of the normal population who
do not have any other abnormal findings and who
have normal values for other Doppler and 2D indices
of diastolic function. Age-specific cutoff values are
more accurate for septal or lateral e0 (albeit more
cumbersome to apply, and more challenging to
identify patients with asymptomatic LV diastolic
dysfunction when other variables in addition to e 0 are
needed). The range of normal values was summarized
in 2009 guidelines (3).
Once myocardial disease is ascertained or with
diastolic dysfunction ascertained as descried previ-
ously, the clinical application of mitral inflow to
estimate LVFP becomes less challenging as patients
with E/A ratio $2 usually have elevated LVFP,
whereas patients with a ratio #0.8 and E #50 cm/s
have normal LVFP (40). For values in between,
average E/e 0 ratio, LA maximum volume index, peak
TR velocity, and pulmonary venous S/D ratio should
be considered (in patients with depressed EF).
Concordance is sought between the variables
(Figure 8), and if 1/2 or 2/4 signals give discordant
conclusions, then LVFP is considered indeterminate.
The yield of indeterminate studies can be reduced by
paying attention to technical details during acquisi-
tion and analysis, executing a complete examination
so as not to miss acquiring peak TR velocity from
multiple windows and pulmonary venous flow, and
considering key Doppler findings that by themselves
support the diagnosis of elevated LVFP. The latter
include pulmonary vein Ar-wave velocity and time
difference between its duration and that of mitral A
velocity (Ar-A $35 ms occurs with elevated LV end-
diastolic pressure), changes in mitral inflow pattern
with Valsalva, L-wave velocity $50 cm/s, and
comparing mitral inflow with tricuspid inflow, as they
usually track each other except when LA or right atrial
pressure is elevated and the other pressure is normal
(24).
LA STRAIN. LA volumes are related to LA pressure.
Accordingly, LA maximum and minimum volumes
8 Nagueh JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019
Echocardiography and LV Diastolic Function - 2019:-–-

F I G U R E 5 LV SR IVR

A B
0.8
SRe
0.6
0.4 SRivr
0.2
0
–0.2 0.2 0.4 0.6 0.8 1.2

–0.4

Global Strain Rate During IVR (1/S)

–0.6
–0.8 ECG
–1

C D
Global Strain Rate During IVR (1/S)

0.7 0.8

0.6 0.7
0.6
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.1 0.1
0.0 0.0
0 1000 2000 3000 4000 5000 6000 0 20 40 60 80 100
–dP/dt (mm Hg/s) Tau (ms)

(A) Left ventricular (LV) longitudinal diastolic strain rate (SR) in apical 4 chamber view. (B) Recording of LV strain rate with electrocardiogram
(ECG). LV diastolic SR during isovolumic relaxation (SRivr). LV diastolic SR during early diastole (SRe). (C) Significant correlation between SRivr
and –dP/dt (r ¼ 0.71, p < 0.001). (D) A significant correlation between SRivr and time constant of left ventricular relaxation (tau) (r ¼ –0.83,
p < 0.001). Obtained from a series of canine experiments in which LV load and lusitropic status were altered. Reprinted with permission from
Wang et al. (28).

have a direct relation with LA pressure, albeit with
wide scatter (40,41). LA strain measured by tissue
Doppler and speckle tracking can be used to gain
insight into LA reservoir, conduit, and pump func-
tions (Figure 9). Significant inverse correlations be-
tween LA reservoir strain and wedge pressure and LV
end-diastolic pressure irrespective of LVEF were re-
ported (42). A recent study, showed LA strain can
track grade of LV diastolic dysfunction (43). However,
LA reservoir strain also depends on LV systolic func-
tion which
descent and LA expansion. Therefore, LA strain can
be normal despite elevated LVFP in patients with
normal LV longitudinal function. Aside from drawing
inferences about LVFP, LA strain can be used to
compute LA stiffness. LA stiffness can be measured
invasively or estimated noninvasively (44) as the ra-
tio of LA pressure or its surrogate: E/e 0 ratio to LA
systolic strain (related to systolic change in LA
volume). The latter method is best regarded as a
surrogate of LA stiffness given the imperfect relation
between its components and LA pressure and vol-
ume. HFpEF patients have abnormally reduced LA
strain and abnormally increased LA stiffness (44,45).
Further, LA stiffness has a direct relation with pul-
monary artery systolic pressure and pulmonary
vascular resistance (44–46). LA volumetric changes
and LA strain are independent predictors of outcome
in HFpEF patients (45,46). The impact of atrial
determines mitral annulus systolic fibrillation, mitral annular calcification, and mitral
valve disease on the relation of LA strain with LVFP
has not been evaluated, which may pose important
limitations to the application of LA strain to draw
inferences about LVFP.
DIASTOLIC STRESS TEST. A subset of patients with
HFpEF have normal LVFP at rest but increased LVFP
with exercise. Accordingly, it is important to evaluate
JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019 Nagueh 9
- 2019:-–- Echocardiography and LV Diastolic Function

LV filling not only at rest, but also with exercise in

F I G U R E 6 Titin Location in the Sarcomere and Its Structure
symptomatic patients with normal LVFP at rest, and
there is a separate review that addresses this topic (24). Full length titin
NONINVASIVE ESTIMATION OF LVFP IN SPECIAL T2
POPULATIONS. There are specific populations where M-line
the general algorithm does not apply and certain
Doppler signals are more useful than others. Table 3
presents a summary of the recommendations for
assessment of LVFP in these patients (24).
CONTROVERSIES REGARDING THE RELATION OF Z-line Z-line
Spring element
DOPPLER SIGNALS TO LVFP IN PATIENTS WITH
DEPRESSED LVEF. It is important to recognize the N2B
limitations of the echocardiographic signals used to N2B

assess diastolic function (Table 4), and to review the

published studies with these limitations in mind. An
0
observational study reported on low accuracy of E/e
ratio in predicting mean wedge pressure in patients
with acute decompensated heart failure (47). Pulmo-
nary capillary wedge pressure (PCWP) was measured
N2B N2A
N2BA
Titin spans half the sarcomere length (the gene has 363 exons) and extends
from the Z-line to the M-line. It is responsible for generation of passive
tension. The molecule is made up of spring elements. Stretch of the sarco-

in a supine position, but imaging was acquired in left
lateral decubitus position. Oxygen saturation was not
obtained to verify the catheter was indeed in the
wedge position, and the text first stated fluoroscopy
was used, but lack of its use was mentioned as a
mere leads to straightening of the tandem Ig segment, followed by the
amino acid repeats segment (or proline, glutamate, valine, and lysine
[PEVK] repeats) and N2B segments. The composition of the extensible re-
gion is shown below. The Ig domain is shown in red, the PEVK domain in
yellow, and the unique sequence in blue. The N2BA isoform has more Ig
tandem repeat segments and PEVK segments. Reprinted with permission

limitation. PCWP was <15 mm Hg in many patients 12 from Fukuda et al. (33). T2 ¼ titin degradation product.

h after admission in New York Heart Association

functional class III to IV, which is highly unusual. For
these reasons, it is very likely that the PCWP mea-
surements were not accurate in some patients.
Doppler illustrations raised other concerns. One of
the figure examples (47) showed poor alignment of
Doppler beam for lateral e 0 and a sample volume in LA
wall instead of mitral annulus. The displayed Doppler
spectral envelope was broad and poorly defined, and
of suboptimal quality to include in the analysis. Other
studies had different findings in a similar patient
HFpEF patients merit additional discussion. First, the
study was limited to only 10 patients, as 1 could not
be satisfactorily imaged. The 10 patients had a sur-
prisingly normal wedge pressure around 10 mm Hg,
F I G U R E 7 Relation of Apical Untwisting Velocity to Gene Expression of TTN N2B
(Smaller Titin Isoform That Contains N2B Element)
0
r = –0.85
Apical Untwisting Rate (degrees/s)

population that support the role of echocardiography –10 p < 0.01

in HFrEF patients (22,23). Importantly, in a recent
multicenter study, echocardiographic assessment
–20
was more accurate than clinical evaluation, which
included physical examination performed by cardi-
ologists, chest x-ray findings, and natriuretic peptide –30

levels (40).
–40
CONTROVERSIES REGARDING THE RELATION OF
DOPPLER SIGNALS TO LVFP IN PATIENTS WITH
NORMAL LVEF. AS e 0 is directly related to transmitral –50
0 1000 2000 3000 4000
pressure gradient in normal hearts (4,6), it no longer
mRNA Expression level
corrects for the effects of LV relaxation on E and thus TTN N2B for LV Apex
E/e 0 ratio does not track LVFP. One study looked at
the relation between E/e 0 ratio and wedge pressure in Relation between apical untwisting velocity to TTN N2B messenger RNA (mRNA)
normal subjects and in 11 HFpEF patients (48). expression in the left ventricular (LV) apex from patients with dilated cardiomyopathy.
Expectedly, E/e 0 did not predict wedge pressure Reprinted with permission from Cordero-Reyes et al. (14).
changes in normal subjects. The findings in the 11
10 Nagueh JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019
Echocardiography and LV Diastolic Function - 2019:-–-

F I G U R E 8 Algorithm for Estimation of LV Filling Pressure

A Echocardiography Parameters for Estimation of LV Filling Pressure

Tricuspid Regurgitation Velocity Mitral Annular Velocity Mitral Flow Velocity

0 0 +
Velocity
Peak
Velocity e’
E A
– – 0

Parameter Cutoff Value

• Peak Tricuspid
>2.8 m/sec
Regurgitation Velocity
• E/e’ >14
• Left Atrial Maximal
Volume Index >34 ml/m2

B Algorithm for Estimating LV Filling Pressure in Depressed LVEF

or Normal EF and Myocardial Disease

Mitral Inflow

E/A ≤0.8 + E >50 cm/s

E/A Ratio ≤0.8 + E ≤50 cm/s or E/A ≥2
E/A >0.8 to <2

3 Criteria to be Evaluated
2 of 3 or • Ratio of mitral peak E velocity to 2 of 3 or
3 of 3 average annular e’ velocity 3 of 3
Negative (E/e’ ratio) Positive
• Peak tricuspid regurgitation velocity
• Left atrial maximal volume index

When only 2 criteria are available

1 Positive
2 Negative 2 Positive
1 Negative

Cannot
determine
Normal LAP LAP ↑LAP

(A) Tricuspid regurgitation velocity is related to pulmonary artery systolic pressure; e0 mitral annulus early diastolic velocity (E) and atrial
induced (A) mitral inflow velocities are related to LV diastolic function, and left atrial volume index is related to LAP. (B) In the algorithm to
estimate LV filling pressure, criteria of elevated LV filling pressure are E/A ratio $2 in the presence of myocardial disease, or if E/A ratio <2,
at least 2 of the 3 parameters shown must be above cutoff values (table in panel A). The algorithm is applied with depressed or normal LV
ejection fraction (LVEF) but with myocardial disease. Reprinted with permission from Andersen et al. (40). Abbreviations as in Figures 1 and 3.

with several having wedge pressure <10 mm Hg, and was evaluated in the 10 patients who had a narrow
only 1 patient had wedge pressure between 14 and 17 range of wedge pressure at baseline and mostly
mm Hg—see Figure 3 in Bhella et al. (48). When the normal, the correlation coefficient was 0.65 with
correlation between E/e0 ratio with wedge pressure p ¼ 0.04. With load manipulations, changes in E/e 0
JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019 Nagueh 11
- 2019:-–- Echocardiography and LV Diastolic Function

F I G U R E 9 LA Strain

A
28.000
Lateral LAs
Average LAs
22.400 Septal LAs

16.800

11.200

Lateral LAa
5.600
Average LAa
Septal LAa
0.000

B Normal Grade 1
50 50
Peak LA Strain (%)

Peak LA Strain (%)

40 40

30 30

20 20

10 10
40
0 0

30
Peak LA Strain (%)

20

10

Grade 2 0 Grade 3
50 50
Normal Grade 2
40 40
Peak LA Strain (%)

Peak LA Strain (%)

Grade 1 Grade 3

30 30

20 20

10 10

0 0

(A) Left atrial (LA) strain during the cardiac cycle. LA strain during systole recorded from septal and lateral LA walls during systole (LAs)
corresponding to reservoir function, and during late diastole (LAa) corresponding to pump function. (B) LA strain and left ventricular diastolic
dysfunction. Figure illustrates examples from patients with varying grades of diastolic dysfunction where LA strain decreases as left ventricular
diastolic dysfunction grade progresses from I to III. Reprinted with permission from Singh et al. (43).

ratio and PCWP were discordant in 3 patients,
whereas in the other 8 patients changes were
concordant (48). So, the findings in this paper,
despite its major limitations, are opposite to what was
perceived about utility of E/e 0 ratio in HFpEF pa-
tients. Another report in 118 patients with dyspnea
arrived at the conclusion of limited accuracy (49).
However, the majority were subjects without cardiac
disease given their normal LA volume index at 18  6
ml/m 2 and mean wedge at 12  5 mm Hg. There were
only 27 patients with LV hypertrophy and 26 patients
with wedge pressure >15 mm Hg. There were no data
on the performance of echocardiographic indices in
these patients, which is most relevant because E/e0
12 Nagueh JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019
Echocardiography and LV Diastolic Function - 2019:-–-

T A B L E 3 Estimation of LVFP in Special Populations

Disease Echocardiographic Variables and Abnormal Cutoff Values to Consider

1. Atrial fibrillation (3,19,24)
2. Sinus tachycardia (18,20)
3. Paced rhythm or left bundle
branch block (23–25)
4. Hypertrophic cardiomyopathy
(3,24)
5. Restrictive cardiomyopathy (3,24)
6. Noncardiac etiology of pulmonary
hypertension (3,24)
7. Mitral stenosis (3,8,24)
8. MR (3,8,24,61)
9. Moderate-to-severe mitral
annular calcification (16)
10. LV assist device (26)
Mitral: Peak acceleration rate of E ($1,900 cm/s2), IVRT (#65 ms). DT of E #160 ms predictive of elevated LVFP in patients with
depressed EF
Pulmonary veins: DT of pulmonary venous diastolic velocity (#220 ms)
TD and Vp: E/Vp ratio ($1.4), septal E/e0 ratio ($11)
Mitral: Mitral inflow pattern with predominant early LV filling in patients with EF<50% IVRT #70 ms is specific (79%). When E and A
velocities are fused, the presence of a compensatory period after premature beats often leads to separation of E and A velocities,
which can be considered for assessment of diastolic function
Pulmonary vein: Systolic filling fraction #40% is specific (88%)
TD: Average E/e0 ratio >14 (highest specificity but low sensitivity)
TD: Average E/e0 ratio is >14; E/e0 ratio has lower accuracy in this group and thus should be used in conjunction with other variables.
Pulmonary veins: Ar-A duration $30 ms
Peak TR velocity: >2.8 m/s
LA maximum volume index: >34 ml/m2
TD: Average E/e0 ratio >14
Pulmonary veins: Ar-A duration $30 ms
Peak TR velocity: >2.8 m/s
LA maximum volume index: >34 ml/m2
Mitral: DT (<140 ms), E/A ratio (>2.5), IVRT (<50 ms has high specificity)
TD: Average E/e0 >14
TD: With cardiac etiology, lateral E/e0 ratio is >13, whereas in patients with pulmonary hypertension due to a noncardiac etiology,
lateral E/e0 is <8
Peak TR velocity: Should not be used to draw inferences about LVFP in patients with pulmonary hypertension due to noncardiac
etiology
LA maximum volume index: Usually increased in patients with cardiac etiology for pulmonary hypertension and normal in noncardiac
etiology
Mitral: IVRT (<60 ms has high specificity), mitral A velocity (>1.5 m/s)
TD: IVRT/TE-e0 <4.2
Peak TR velocity: Peak velocity (>2.8 m/s)
Pulmonary veins: Ar-A duration ($30 ms)
Mitral: IVRT (<60 ms has high specificity)
TD: IVRT/TE-e0 (<5.6) may be applied in patients with depressed LV EF with MR and normal EF, average E/e0 (>14) may be considered
only in patients with depressed EF
Peak TR velocity: >2.8 m/s
E/A ratio <0.8 is usually associated with normal LVFP, E/A ratio >1.8 occurs with elevated LVFP, and when ratio is >0.8 but <1.8,
IVRT should be measured and if <80 ms, then LVFP is likely elevated, otherwise LVFP is normal
1. E/A ratio #1 and 1 of the 3 findings (RAP #10 mm Hg or sPAP #40 mm Hg, LA maximum volume index #33 ml/m 2 , E/e0
ratio #14) indicate PCWP #15 mm Hg
2. E/A ratio >2 and 1 of the 3 findings (RAP >10 mm Hg or sPAP >40 mm Hg, LA maximum volume index >33 ml/m 2 , E/e 0 >14)
indicate PCWP >15 mm Hg
3. If E/A ratio is >1 but #2, and 2 of 3 findings are present (RAP #10 mm Hg or sPAP #40 mm Hg, LA maximum volume
index #33 ml/m2 , E/e 0 ratio #14), then PCWP #15 mm Hg
4. If E/A ratio is >1 but #2, and 2 of 3 findings are present (RAP >10 mm Hg or sPAP >40 mm Hg, LA maximum volume index
>33 ml/m2 , E/e 0 >14) indicate PCWP >15 mm Hg

For detailed set of references, see Nagueh et al. (3,24).

A ¼ mitral late diastolic or atrial velocity; Ar ¼ pulmonary vein atrial reversal velocity; LVFP ¼ left ventricular filling pressure; MAC ¼ mitral annular calcification; PCWP ¼ pulmonary capillary wedge
pressure; RAP ¼ right atrial pressure; sPAP ¼ pulmonary artery systolic pressure; TD ¼ tissue Doppler; other abbreviations as in Tables 1 and 2.

and other echocardiographic indices are not accurate
and not recommended for estimating LVFP in normal
subjects. Finally, a meta-analysis arrived at similar
conclusions (50). It included a mixed bag of studies.
Some were simultaneous but
including studies where cardiac catheterization and
echocardiography were not even performed on the
same day. This is unacceptable given the large day-to-
day LVFP variations. Some studies used LV end-
diastolic pressure as the gold standard (which is
weakly related to Doppler indices of mean wedge
pressure as E/e0 ), whereas others used LV pre–A-wave
pressure, LV mean diastolic pressure, or wedge
pressure. Importantly, there was no uniform defini-
tion of diastolic dysfunction and HFpEF. There are
several situations in which E/e 0 ratio should not be
used, but were nevertheless included in some of
many were not, studies, as in patients with normal EF and moderately
severe or severe MR. The authors were not able to
screen for these other diagnoses and did not exclude
studies without an explicit statement about the
absence of these conditions. Studies on normal sub-
jects were included where E/e 0 ratio should not be
applied to estimate LVFP. It is also difficult to show a
significant correlation in normal subjects when all
subjects have normal LVFP. The authors extracted
JACC: CARDIOVASCULAR IMAGING, VOL.
- 2019:-–-
T A B L E 4 Limitations of Echocardiographic Variables
Echocardiographic Variables
1. Mitral E/A ratio
2. DT of E (ms)
3. IVRT (ms)
4. Pulmonary vein systolic-to-
diastolic (S/D) velocity ratio
5. Pulmonary vein atrial reversal
duration minus mitral A velocity
duration (Ar-A in ms)
6. LA maximum volume index
7. Peak velocity of TR jet by CW
Doppler (m/s), PA diastolic
pressure (mm Hg)
8. End-diastolic velocity of PR jet by
CW Doppler (m/s), PA systolic
pressure (mm Hg)
9. Color M-Mode Vp, and E/Vp ratio
10. e0 (cm/s)
11. Mitral E/e0 ratio
12. TE-e0 time interval (ms)
13. Diastolic SRIVR (s–1)
14. Diastolic SRe (s–1)
15. LA strain
For additional details, please see Nagueh et al. (24).
2D ¼ 2-dimensional; AV ¼ atrioventricular; PR ¼ pulmonary regurgitation; other abbreviations as in Tables 1 to 3.
data from scatter plots, which can be challenging to
identify small differences in LVFP or E/e0 ratio and
can lead to placing a given patient in the wrong
category. Further, there were discrepancies between
the number of patients in the text and the number of
data points shown in the graphs. From a methodology
perspective of a meta-analysis, it is most accurate to
use the actual data as opposed to summary statistics
and regression plots which was not done in this
meta-analysis.
WHY IS ASSESSMENT OF LV DIASTOLIC FUNCTION
IMPORTANT CLINICALLY? There
therapeutic, and prognostic reasons why assessment
of LV diastolic function is important clinically. From a
diagnostic perspective, elevation of LVFP is an
important reason for dyspnea in patients with HFrEF,
HFpEF, or valvular heart disease. However, a
-, NO. -, 2019 Nagueh 13
Echocardiography and LV Diastolic Function
Limitations
Age dependent, affected by arrhythmias, affected by LV volumes and elastic recoil, weak relation with LVFP in patients with
hypertrophic cardiomyopathy and coronary artery disease with EF >50%
Age dependent, not applicable in atrial flutter or merging of E and A velocities, weak relation with LV filling pressure in
patients with normal EF
More challenging to interpret in the setting of tachycardia, has many hemodynamic determinants that lead to opposing
changes in IVRT including heart rate, LV end-systolic pressure, left atrial pressure, and LV relaxation
Lower feasibility in the intensive care unit setting; lower accuracy in patients with atrial flutter or atrial fibrillation, mitral
valve disease, patients with hypertrophic cardiomyopathy, or coronary artery disease with normal LVEF
Lower feasibility in the intensive care unit setting, cannot be applied in patients with atrial flutter or atrial fibrillation, and
difficult to interpret in sinus tachycardia or AV block
Weakly related to LV filling pressure and does not track acute changes in filling pressure; the LA can be enlarged for reasons
other than diastolic dysfunction including bradycardia, high output states, atrial fibrillation or flutter, mitral valve
disease, athletes who are well hydrated; accuracy of LA volume determination is dependent on avoiding foreshortening
of the LA
Indirect estimate of LA pressure with no relation to LA pressure in group I pulmonary hypertension, can have low feasibility
in the absence of intravenous agitated saline or contrast administration, and with severe TR and low systolic right
ventricle to right atrial pressure gradient, accuracy heavily depends on correct estimation of right atrial pressure
No relation to LA pressure in group I pulmonary hypertension, has low feasibility in the absence of intravenous agitated
saline or contrast administration, and accuracy usually heavily dependent on correct estimation of right atrial pressure
Low feasibility and reproducibility, angulation between M-mode cursor and blood flow leads to underestimation of Vp; in
patients with normal LV volumes and EF but elevated LA pressure, Vp can be normal and E/Vp ratio may incorrectly
suggest normal LV filling pressures
Age dependent; cutoff value for normal values depends on sampling site; has lower accuracy in segmental dysfunction
particularly involving basal LV segments, pericardial constriction, heavy mitral annular calcification, prosthetic mitral
valve, surgical ring, and mitral valve disease
Age dependent; cutoff value for normal values depends on sampling site; does not relate with LV filling pressure in normal
subjects or patients with pericardial constriction, not reliable in patients with heavy mitral annular calcification,
prosthetic mitral valve, surgical ring, mitral stenosis, and primary mitral regurgitation; lower accuracy in patients with
left bundle branch block, pacemakers
More challenging to acquire with close attention needed to sample volume location, gain and filter settings as well as
matching RR intervals for mitral inflow and TD annular diastolic velocities
Satisfactory acquisition needed and can be limited with tachycardia, low frame rates, and suboptimal 2D images, no
standardization for diastolic strain rate measurements
Depends on both LV relaxation and LV filling pressure; satisfactory acquisition needed and can be limited with tachycardia,
low frame rates, and suboptimal 2D images; no standardization for diastolic strain rate measurements
Limited data on its accuracy in the presence of atrial arrhythmias, mitral valve disease, and MAC; dependent on LV systolic
function, which if reduced can be associated with reduced LA reservoir strain in the presence of normal LA pressure
noncardiac etiology as anemia, pulmonary paren-
chymal, and pulmonary vascular diseases can also
cause shortness of breath. Biomarkers can be used to
identify elevated LV end-diastolic wall stress. How-
ever, their level is affected by several variables
including age, gender, right ventricular function,
pulmonary disease, and creatinine clearance, to
mention a few. In comparison, cardiovascular imag-
ing, including echocardiography, provides a direct
and comprehensive assessment of LV and right ven-
tricular systolic and diastolic functions (including
are diagnostic, LVFP and mean right atrial pressure), valvular func-
tion, pericardial disease, and pulmonary artery pres-
sures. There are several studies that compared
head-to-head natriuretic peptide levels and Doppler-
assessed LVFP against mean wedge pressure;
Doppler had a stronger correlation with mean wedge
14 Nagueh JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019
Echocardiography and LV Diastolic Function - 2019:-–-

C E NT R AL IL L U STR AT IO N Hemodynamic Variables That Characterize LV Diastolic Function and

Echocardiographic Surrogates

LV Diastolic Function

LV
LV LV Early
e’ e’
Relaxation Stiffness Diastolic
Recoil

SRIVR SRE DT A transit time LV Untwisting

rate

LV Filling Pressures

E/A E/e’ E/SRIVR E/SRE LA Strain

Nagueh, S.F. J Am Coll Cardiol Img. 2019;-(-):-–-.

Left ventricular (LV) diastolic function is characterized by LV relaxation, chamber stiffness, and early diastolic recoil, all of which determine LV filling pressure.
Echocardiographic signals significantly associated with LV relaxation are mitral annulus early diastolic velocity (e0 ), LV strain rate during isovolumic relaxation (SRIVR),
and LV strain rate during early diastole (SRE). Echocardiographic surrogates of LV chamber stiffness are deceleration time (DT), and A velocity transit time. Inferences
about early diastolic recoil can be obtained by LV untwisting rate and e0 . Echocardiographic estimation of LV filling pressure in patients with cardiac disease using
E/A ratio, average peak early diastolic mitral inflow velocity (E)/e0 ratio, E/SRIVR ratio, E/SRE ratio, and left atrial (LA) reservoir strain.

pressure, and E/e 0 ratio tracked changes in mean
wedge pressure, whereas B-type natriuretic peptide
levels did not (51). There are similar data in ambula-
tory HFrEF patients in which E/e0 ratio successfully
tracked changes in LA pressure (22).
Effective treatment is based on reaching the cor-
rect diagnosis. Accordingly, echocardiography can
lead to effective treatment through providing an ac-
curate depiction of cardiac structure and function.
Once treatment is started, its effects on hemody-
namics could be readily assessed by Doppler. This
includes changes in stroke volume, right ventricular
filling pressure and LVFP, and pulmonary artery
pressures. For example, E/e0 ratio tracked mean
wedge changes in a small group of patients admitted
with acute decompensated heart failure (23). There
are also data showing favorable effects of spi-
ronolactone on E/e 0 ratio in patients with HFpEF (52).
Importantly, a small randomized clinical trial showed
significantly lower rate of hospitalizations in HFrEF
patients randomized to medical treatment guided by
echocardiography versus patients treated according
to clinical assessment only (53).
For prognosis, there are numerous observational
studies from many countries across the globe
showing the independent prognostic value of cardiac
function indices in specific patient populations as in
patients with HFrEF, HFpEF, aortic stenosis, atrial
fibrillation, and coronary artery disease. For example,
mitral inflow velocities and deceleration time readily
JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019 Nagueh 15
- 2019:-–- Echocardiography and LV Diastolic Function

predict mortality and heart failure hospitalizations

in patients with HFrEF (54–56). Other indices as
pulmonary vein velocities, flow propagation veloc-
ity, e 0 , E/e 0 ratio, and atrial volumes are also pre-
dictive of outcome events (57–62). There
emerging data on the ability of LV diastolic strain
rate and LA strain to predict outcome in patients
with acute myocardial infarction and atrial fibrilla-
tion (63–66). Interestingly, LV global longitudinal
strain is an important predictor of outcome in pa-
tients with HFpEF (67). Notwithstanding, there is a
paucity of data with respect the general population
and it remains to be seen how specific treatment that
improves diastolic dysfunction leads to improved
outcomes.
CONCLUSIONS
LV diastolic function can be characterized by LV
relaxation, LV early diastolic recoil, and chamber
stiffness. These 3, in turn, determine LV filling pres-
sures. There are multiple echocardiographic parame-
ters that relate to each of the aspects of LV diastolic
function (Central Illustration) and can be applied for
diagnostic and prognostic purposes.
HIGHLIGHTS
 LV diastolic function determines symp-
toms and predicts outcome in patients
are with cardiovascular disease.
 Echocardiography is used to assess LV
diastolic function, and estimate LV filling
pressures.
 Recent American Society of Echocardi-
ography/European Association of Car-
diovascular Imaging guidelines were
validated against invasive gold standard,
with superior accuracy in predicting
outcomes.
 LV and left atrial function novel indices
and artificial intelligence have potential
to advance this field.
ADDRESS FOR CORRESPONDENCE: Dr. Sherif F.
Nagueh, Methodist DeBakey Heart and Vascular
Center, 6550 Fannin, SM-677, Houston, Texas 77030.
E-mail: snagueh@houstonmethodist.org.

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KEY WORDS diastole, Doppler,
echocardiography, filling pressure, left
atrium