1

Echocardiographic Assessment of Left Ventricular Filling Pressures Using

Data from Invasive Left Ventricular Filling Pressures in Patients with

Normal Left Ventricular Ejection Fraction

Yi Liang MD, Xinxin Chen MD, Fen Zhang MD, Wei Yuan, MD, PhD,

Liangjie Xu MD, Jinchuan, Yan, MD, PhD

Corresponding authors

Jinchuan, Yan, MD, PhD

Professor of Medicine,

Director, Department of Cardiology

Affiliated Hospital of Jiangsu University, Zhenjiang, China

TeL:86-0511-85026551 Email: yanjinchuan@hotmail.com

Abstract

Objectives The aims of this study were to assess the accuracy of multiple

echo parameters of diastolic dynamics and the 2016 ASE/EACVI algorithm

to detect elevated invasive LV diastolic pressures in patients with normal

ejection fraction; the accuracy of the 2016 algorithm was compared to that

of a newly derived algorithm.

Background Echocardiographic assessment of left ventricular (LV) diastolic

function is an integral part of the routine examination. Simultaneous

measurements of LV pressures and echocardiographic parameters are sparse.

Methods Patients (n=120) underwent left heart catheterization and coronary

angiography for chest pain due to suspected coronary artery disease.

Transthoracic echocardiography and LV pressure recordings were

simultaneous. Receiver-operating characteristic curves were constructed to

2

define optimal cut points for multiple echocardiographic parameters. Five

were selected for new algorithm to estimate LV diastolic pressures: velocity

of tricuspid regurgitation (> 280cm/s), average e (Av e < 9), average E/e

ratio (AvE/e’>13), velocity of pulmonary vein A wave reversal (PV ArV >

32 cm/s) and left atrial volume index (LAVi >32 ml/m2). The accuracy of the

algorithm was examined for a LV pre-A >12 mmHg and LV end diastolic

pressure (LVEDP) i.e. post-A >15 mmHg.

Results All patients had a normal LV ejection fraction. Individual

echocardiographic parameters of diastolic function (n=12) had moderate

diagnostic utility. Using the algorithm of the 2016 guidelines, an elevated

LVEDP >15 mmHg was identified with an accuracy of 69.1% (60.1-77.3);

the newly derived algorithm that utilized the 5 echocardiographic variables

had an accuracy of 84.2% (76.4-90.2), p <0.001.

Conclusions Simultaneous recordings of LV diastolic parameters and

invasive LV pressures in a homogenous cohort confirmed that no single

echocardiographic parameter can accurately assess LV diastolic pressures.

Importantly, left ventricular diastolic pressures in patients with a normal

LVEF were fairly reliably assessed by the 2016 guidelines. The new

algorithm improved the accuracy of detecting abnormal LV filling pressures.

3

Keywords Left ventricular end diastole pressure• diastolic function•

echocardiography

Condensed Abstract

Echocardiographic assessment of left ventricular diastolic function is an

integral part of the routine examination. This study assessed the accuracy of

multiple echo parameters of diastolic dynamics to detect elevated LV

diastolic pressures in patients with normal ejection fractions. Invasive LV

pressures and echocardiography were performed simultaneously in 120

patients with chest pain suspected to be from coronary artery disease. No

single echocardiographic parameter had a high accuracy. When multiple

echocardiographic parameters were used in both the 2016 algorithm

(ASE/EACVI) and a new alternate algorithm, both exhibited good

diagnostic accuracy for elevated LVEDP and the new algorithm improved

the accuracy.

4

Abbreviations

Ar-A = Pulmonary vein atrial reversal duration – Mitral A duration

ArV = Pulmonary vein atrial reversal velocity

ASE = American Society of Echocardiography

Av = Average

CAD = Coronary artery disease

CI = Confidence interval

DD = Diastolic dysfunction

DT = E wave deceleration time

EACVI = European Association of Cardiovascular Imaging

e sep = e velocity at the septum

e lat = e velocity at the lateral wall

HFpEF = Heart failure with preserved ejection fraction

HFrEF = Heart failure with reduced ejection fraction

IVRT = Isovolumic relaxation time

LA = Left atrial

LAVi = Left atrial volume index

LV = Left ventricular

LVEF = Left ventricular ejection fraction

5

LVEDP = Left ventricular end diastolic pressure

MV A = mitral A wave duration

NPV = Negative predictive value

PPV = Positive predictive value

PV D = pulmonary vein D velocity

PV S = pulmonary vein S velocity

ROC = Receiver-operating characteristic

STE = Speckle-tracking echocardiography

TRV = Tricuspid regurgitation maximum velocity

Vp = Color flow propagation velocity

6

The diagnosis of diastolic dysfunction is an important objective of clinical

cardiology, and echocardiographic assessment is the predominant method

applied. However, no single echocardiographic parameter can confirm the

diagnosis. The 2009 American Society of Echocardiography (ASE) and

European Association of Echocardiography (now European Association of

Cardiovascular Imaging [EACVI]) guidelines for assessment of diastolic

function were comprehensive, including both two-dimensional (2D) and

Doppler parameters to grade diastolic dysfunction and to estimate LV filling

pressures 1. These guidelines have been reported as too complex to use in

clinical practice. Accordingly, the ASE and EACVI recently developed a

new set of guidelines for the evaluation of LV diastolic function 2, which

include a practical, simplified algorithm for estimating LV filling pressures.

Several studies have validated these guidelines against an invasive reference

technique and found that the 2016 algorithm detected an elevated LVEDP

better than the 2009 proposal 3,4

. Our study aims were 1) to determine the

diagnostic accuracy of each Doppler and 2D parameter currently being used

to identify elevated LV diastolic pressure, 2) to derive an alternate grading

algorithm to predict the LV filling pressure and 3) to compare the new

algorithm with that of the 2016 Recommendation.

7

METHODS

Study population

This was a prospective study of consecutive patients undergoing a

conventional left heart catheterization for evaluation of known or suspected

coronary artery disease. The studies were completed from July 20, 2017 to

January 17, 2018 in the Affiliated Hospital of Jiangsu University, Zhenjiang,

China. The study protocol was approved by the Institutional Review Board

of Affiliated Hospital of Jiangsu University. Each patient signed the consent.

We excluded patients with atrial fibrillation, mitral valve surgery, mitral

stenosis, severe mitral annular calcification, severe mitral or aortic

regurgitation, hemodynamic instability and prior heart transplantation.

Patients were also excluded if image quality was inadequate, their LV

ejection fraction (LVEF) was < 50% by the echocardiographic biplane

method or their heart rate was >100 bpm at the time of examination.

Echocardiographic and imaging analysis

Imaging was performed with Vivid E 9 (General Electric, Milwaukee, WI,

USA). A complete echocardiographic study was performed using standard

views with care taken to avoid foreshortening. All images were recorded for

3 to 5 cardiac cycles. Mitral inflow velocities were obtained from the apical

window using pulsed wave Doppler with the sample volume placed at the

8

center of the leaflet tips. Pulmonary venous flow was recorded from one of

the pulmonary veins, guided by color Doppler. Color M-mode was recorded

in the apical 4-chamber view with the sample volume placed in the center of

mitral inflow as guided by color Doppler. Tissue Doppler velocities in early

diastole (e ) were recorded from both the septal and lateral sides of the

mitral annulus. Tricuspid regurgitation velocities were recorded by

continuous wave Doppler from multiple windows. All the images used to

assess the echocardiographic parameters of diastolic function were recorded

simultaneously with the invasive recording of LV diastolic filling pressure.

Measurements were performed using computerized off-line analysis stations

without knowledge of invasively derived hemodynamic data. LV volumes,

LVEF, and left atrial (LA) maximal volume were measured using the

bi-plane method recently recommended 5.

Color M-mode for LV flow propagation velocity (Vp), mitral annulus tissue

Doppler velocities , the velocity of tricuspid regurgitation, Doppler

parameters of mitral and pulmonary vein flow, LV isovolumic relaxation

time (IVRT), filling time (FT) and isovolumic contraction time (IVCT) were

measured according to the ASE recommendations 2 .

Valvular regurgitation, right ventricular function, all routine two-D

parameters, chamber volumes and left atrial volume index were evaluated

9

following American Society of Echocardiography (ASE) recommendations 6,

7.

The diagnostic ability of each echocardiographic parameter to correctly

classify abnormal pre-A wave pressure (>12 mmHg) and abnormal post-A

wave LV end-diastolic pressure (LVEDP) (>15 mmHg) was assessed by

creating a receiver-operating characteristic (ROC) curve for each parameter.

Cardiac catheterization

Left heart catheterization was performed according to standard procedures

by an interventional cardiologist blinded to the echocardiographic data.

Invasive LV pressure recordings were obtained using a 6-Fr pigtail catheter

(Impulse; Boston Scientific, Marlborough, MA) placed in the left ventricle

via femoral or radial arterial access. Continuous pressure tracings were

acquired over three consecutive cardiac cycles at end expiration. The

pre-A LV pressure was measured at beginning of the A wave; LVEDP was

measured after the A wave (Figure 1).

Statistical analysis

Baseline characteristics are presented as mean ±SD for continuous variables

or numbers (percentage) for categorical variables. Comparison of baseline

characteristic between two groups was performed using ANOVA or χ2 test

as appropriate. The ROC curves were generated using MedCalc®

software.

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The sensitivity, specificity, accuracy and 95% confidence interval for the

comprehensive echocardiography algorithm to detect elevated left

ventricular diastolic pressures were calculated using MedCalc® software.

For these calculations the indeterminate cases (Class I diastolic dysfunction)

were classified as elevated diastolic pressures. Statistical significance was

defined as a 2-tailed p < 0.05 for all tests. A statistical comparison of the

differing algorithms was assessed by comparing the areas under the ROC

curves.

RESULTS

Baseline characteristics of study subjects

None of the 120 patients had structural heart disease or atrial fibrillation.

Invasive LV pre-A pressure was normal in 39 (33%) and elevated in 81 (77%)

patients; The LVEDP was normal in 43 (36%) and elevated in 77 (64%)

cases. The high frequency of elevated LV diastolic pressures is likely due to

the high prevalence of hypertension and/or coronary aretery disease.

Additional clinical characteristics of the two study groups are listed in Table

1. When patients with normal diastolic pressures were compared to those

with either an elevated pre-A LV pressure or an elevated LVEDP, there were

no significant intergroup differences.

Echocardiographic measurements of study subjects

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Echocardiographic parameters of the two patient groups, as defined by the

invasive LV filling pressures, are listed in Table 2. Significant intergroup

differences were found in most of the two-dimensional and Doppler

parameters of diastolic function. Notably, no significant differences were

observed for the mitral E/A ratio, A duration, and pulmonary vein S/D ratio

in both pre-A and LVEDP groups. Significant differences were found for

both the septal e and lateral e when using > 15 mmHg as the elevated

threshold.

The sensitivity and specificity, derived from the ROC curves, for the

cut-points of each echocardiographic parameter of diastolic function are

listed in Table 3. The areas under the ROC curves for the detection of an

abnormal LVEDP>15 mmHg for each echocardiographic parameter of

diastolic dysfunction are listed in Table 4 and shown in Figure 2. There

was no diagnostic value for the mitral E/A, the mitral deceleration time and

the pulmonary vein ratio of systolic and diastolic velocities (PV S/D).

A new algorithm to predict elevated LVEDP in patients with normal

LVEF

The comparison of the ROC curves showed that there was no single

parameter that could reliably predict an elevated LVEDP in patients with a

normal LVEF. Based upon the optimal value derived from the ROC curves,

12

a new algorithm was constructed using the following measurements; 1)

average e (Av e ), 2) average E/e (Av E/e ), 3) velocity of pulmonary vein

A wave reversal (PV ArV), 4) tricuspid regurgitation velocity and 5) left

atrial volume index (LAVi). The optimal value (criterion) used to define

abnormal for each of the echocardiographic parameters was the value with

the highest specificity/sensitivity for the diagnosis of elevated LV pressure

(MedCalc software). Note that all of these variables, except the PV ArV,

were also used in the 2016 guidelines but with different optimal values.

Variables not used had lesser areas under the ROC curves. When ≤1 of the 5

variables met the cut off threshold, LVDP was categorized as normal. If 2

variables met the cutoff threshold, LVDP then might be normal or mildly

elevated and so classified as grade I diastolic dysfunction. If ≥3 parameters

met the cutoff threshold, LV diastolic dysfunction was classified as Grade II

diastolic dysfunction. See Figure 3 to compare the 2016 algorithm with the

proposed algorithm. The application of the new algorithm is illustrated in

Figure 4.

In the new algorithm we classified the LV diastolic pressure of patients as

normal when only 1 abnormal parameter was present; 2 abnormal

parameters indicated a mild to moderate elevation of LVEDP (defined as

16-26mmHg). Of the 17 patients in this study group with 2 abnormal

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parameters, 12 had elevated LVEDP and 5 had normal LVEDP (≤15

mmHg). There were 54 (70%) patients with 3 or more abnormal

parameters, all of them with elevated LVEDP (≥15 mmHg). Viewed in an

alternate way, the patients with a very high LVEDP, we found that there

were no false negatives among the 24 of 26 patients with LVEDP > 26

mmHg. In our study population there were no patients with a Grade 3

(restrictive filling pattern) since patients with structure and myocardial

diseases were excluded.

Comparison between the 2016 Guidelines and the new algorithm

The accuracy of the various algorithms for detecting abnormal LV filling

pressures was then assessed. The sensitivity was 87 % (CI 5.1-94.6%),

specifity was 54.6 % (CI 41.8-66.9%) and accuracy was 69.2 % (CI

60.1-77.3%) as estimated by the 2016 guidelines for LEDVP >15 mmHg.

When LVEDP was estimated by the new algorithm, the sensitivity was 90.3 %

(CI 81.0-96.0%), specifity was 75% (CI 60.4-86.4 %) and accuracy was 84.2%

(CI 76.4-90.2) p<0.001 (Tables 5 and 6).

Although our cutpoints for the parameters in our proposed algorithm

differed slightly from those In the 2016 guidelines, the major difference

between the 2016 algorithm and our newly proposed version is that the 2016

14

guidelines did not incorporate the pulmonary vein atrial reversal velocity

(PArV). When this is added as a fifth echo parameter to the 4 already in

the 2016 guideline, the accuracy is significantly improved and becomes

fairly similar to that of the newly proposed algorithm (p = 0.052, Figures

5).

Discussion

The current study was designed to evaluate all individual echocardiographic

parameters of diastolic function as to their ability to detect both an abnormal

LV diastolic pre-A pressure >12 mmHg and an elevated LVEDP > 15 mmHg

in patients with normal LVEF. Our results confirmed that no single

echocardiographic variable can identify patients with elevated LV filling

pressures with acceptable accuracy. Although the algorithm of the 2016

guidelines had an acceptable accuracy for the detection of an elevated

LVEDP, we derived a new algorithm to estimate invasive LV pre-A and

post-A pressure based upon ROC analysis of individual parameters. This

algorithm used new cut-points for some of the echocardiographic variables

and also incorporated the pulmonary vein atrial reversal velocity. When we

compared the accuracy of the 2016 guidelines with our proposed algorithm

in the same population, we found that the proposed algorithm had an

improved accuracy.

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Our study had several important features: 1. echocardiography was

performed simultaneously with invasive LV diastolic pressure recordings; 2.

ROC curves for each parameter were used to determine the optimal cut-point

for defining an abnormal LV filling pressure and 3. all study patients had a

normal LVEF.

Several studies have assessed the utility of the 2016 guidelines. Sato K et al.

compared the 2016 algorithm with the 2009 guidelines to predict the LVEDP

in 460 patients with a normal LVEF. The echocardiogram was completed

within 24 hours of the invasive study 4. They did not assess the actual

accuracy of either algorithm. They found that the 2016 guidelines resulted in

reclassification of many patients. Using multivariable analysis only the

average E/e and LV volume index had a statistically significant association

with LVEDP. Balaney et al. assessed the 2016 algorithm to detect an

elevated pre-A wave pressure > 12 mmHg in a study of 90 patients. The

echocardiogram was performed immediately prior to the invasive study 3.

The 2016 and the 2009 guidelines had very similar sensitivities and

specificities and a concordance with the invasive LVEDP in approximately

74%. A comprehensive assessment of the 2016 guidelines was recently

carried out in 450 patients from 6 cardiac centers 8. Right or left heart

catheterization was performed shortly before or after the echocardiographic

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assessment. The study found that individual echocardiographic parameters

had only a modest correlation with the invasive pressures in a cohort with

normal as well as depressed LVEF. Specifically, they observed an accuracy

of 84% using the 2016 gudelines to detect elevations of the pulmonary

capillary pressure in patients with a normal LVEF. Lancellotti et al

performed a multicenter assessment of the 2016 guidelines in 159 patients

from 9 centers; 120 had a normal LVEF 9

. Echo-Doppler parameters were

performed nearly simultaneously (within 1/2 h the invasive and non-invasive

assessment of LVFP) with the invasive LV pressures. The 2016 guidelines

had an improved accuracy as compared to the 2009 guidelines. The

correlations between individual echo-Doppler parameters and LVEDP > 15

mmHg were generally poor. ROC curves were not performed to select the

cutpoints; rather, the 2016 consensus determined guidelines were used. We

believe that our study is unique in that the cutpoints were determined from

ROC curves rather than from expert consensus. Nevertheless, the differences

in cutpoints for the individual parameters for the 2 approaches were small

(Figure 3)

The prognostic value of the 2016 guidelines was assessed in a retrospective

Danish study 10

. They proposed a modified algorithm that began with the

AVe ; when this was < 7 cm/s, the other variables of E/A, LAVi > 34ml/m2,

17

and an E/e´ ≥13 were applied similar to the 2016 guidelines. This

modification performed quite well in predicting adverse outcomes over a 10

year period of observation.

The 2016 guidelines have performed well in predicting both an elevated

LVEDP and adverse outcomes. Our proposed new algorithm classified the

LV diastolic pressure of patients as normal when none or 1 abnormal

parameter was present; 2 abnormal parameters indicated a mild to moderate

elevation of LVEDP (defined as 16-23 mmHg); of the 17 patients in this

group, 12 had elevated LVEDP and 5 had normal LVEDP (≤15 mmHg).

There were 54 (70%) patients with 3 or more abnormal parameters, all of

them with elevated LVEDP (≥15 mmHg).

Patients with diastolic dysfunction and a normal LVEF are very common in

clinical practice. Significant abnormalities in active relaxation and passive

stiffness are the mechanisms of elevated diastolic pressures in these patients

11. These pathophysiological changes may occur as early manifestations of

diastolic dysfunction. Echocardiographic parameters change as both LV

relaxation and LV stiffness are altered; the velocity of mitral annulus e

reflects LV early relaxation, and the velocity and duration of pulmonary vein

A wave reversal will be increased as the LV stiffness increases. The LA

volume index is an indicator of long-term elevations of LV filling

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pressures 2. Recognition of abnormal LV filling pressures is important in

patients with dyspnea and suspected diastolic dysfunction. Because

stiffening of the left ventricle contributes to heart failure with preserved

ejection fraction, an accurate grading of diastolic dysfunction can lead to

possible successful medical treatment 12,13

.

Study limitations

This study was performed in a population with a relatively simple clinical

condition, that is chest pain with normal EF and no structural heart disease.

The proposed algorithm to estimate left ventricle diastolic filling pressures

may not be suitable in patients with more complex clinical conditions such

as infiltrative cardiomyopathy. Since the majority of cases in our study

population had coronary artery disease and/or hypertension, the results may

not be usable in the general patient population. Our study is hypothesis

generating since we did not test the new algorithm in another population.

The accuracy of the newly proposed algorithm will need to be validated in

additional patient groups with normal LVEF. We recognize that high quality

recordings from a pulmonary vein and measurement of the A reversal

velocity may be difficult in many patients yet was very successful (the

obtained rate was 92.9%) in this Chinese population; given the importance

of the A reversal velocity , the new algorithm may not be applicable when a

19

high quality assessment of pulmonary vein flow is not attainable.

It is important to recognize that our data relate to the assessment of LV

diastolic pressure, and not to diastolic dysfunction per se. While an increase

in LV diastolic pressure typically accompanies diastolic dysfunction,

pressures may be normal, especially at rest. Therefore, our data are most

applicable to the evaluation of pressure, and the approach to the presence or

absence of diastolic dysfunction remains best done using the 2016

ASE/EACVI recommendations.

CONCLUSION

The current study was novel in that the noninvasive and invasive data were

obtained simultaneously and optimal cutponts for each parameter were

determined from ROC curves. The ability of most but not all

echocardiographic variables to modestly reflect diastolic function was

confirmed. A new algorithm for estimating the invasive left ventricle

diastolic filling pressures was designed and compared to that proposed by

the 2016 guidelines for subjects with a normal LVEF. The diagnostic

accuracy of the 2016 guidelines had an acceptable accuracy, and in this

specific cohort the new algorithm had an improved accuracy.

Sources of Funding

This project was supported by social development project of Jiangsu

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Province (BE2017152, BE2016719) and Jiangsu medical innovation team

project (CXTDA2017010).

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Tables

Table 1 Clinical characteristics. Data are grouped by LV filling pressures

Variable LV filling pressure, pre-A LV filling pressure, end-diastolic

≤12

mm Hg

>12

mm Hg

p ≤15

mm Hg

>15

mm Hg

p

Patients, n=120 39 81 43 77

Male, n (%) 25

(64)

54

(67)

0.78 29 (67) 50 (65) 0.78

BSA, m2 1.80±0.21 1.82±9.18 0.64 1.81±0.2 1.81±0.1 0.83

Hypertension, n (%) 22 (56) 55 (68) 0.15 27 (63) 58 (75) 0.59

Diabetes, n (%) 6 (15) 10 (12) 0.75 5 (12) 13 (17) 0.57

CAD, n (%) 23

(64)

33

(41)

0.13 25 (58) 41 (59) 0.36

24

ACE inhibitor, n (%) 25 (64) 43 (53) 0.25 27 (63) 45 (58) 0.64

ARB, n (%) 10 (26) 19 (23) 0.79 10 (23) 19 (25) 0.86

Spironolactone, n (%) 3 (8) 7 (9) 0.86 4 (9) 6 (8) 0.77

Hydralazine, n (%) 5 (13) 7 (9) 0.47 6 (14) 6 (8) 0.28

ß-blocker, n (%) 28 (72) 54 (67) 0.32 28 (65) 54 (70) 0.57

Nitrates, n (%) 11 (28) 30 (37) 0.34 13 ((30) 28 (36) 0.50

Urgent PCI, n (%) 8 (21) 15 (19) 0.79 9 (21) 14 (18) 0.71

SBP, mm Hg* 131±13 135±20 0.31 128±12 137±19 0.02

DBP, mm Hg* 79±9 79±10 0.80 79±8 78±10 0.80

Heart rate, bpm* 71±11 72±12 0.68 70±10 69±11 0.80

*Obtained at the time of echocardiography and cardiac catheterization

Table 2 Echocardiographic parameters. Data are grouped by LV filling pressures.

Variable LV filling pressure, pre-A LV filling pressure, end-diastolic

≤12

mm Hg

>12

mm Hg

p ≤15

mm Hg

>15

mm Hg

p

Number of patients 39 81 43 77

LVEF, % 64±7 64±10 0.72 64±7 64±10 0.72

LAVi, ml/BSA 24±6 31±8 0.0001 25±6 31±9 <0.0001

Vp, cm/sec 54±16 46±16 0.01 55±17 46±15 0.004

E velocity, cm/sec 75±20 79±20 0.34 73±20 80±20 0.05

A velocity, cm/sec 82±20 85±24 0.51 79±21 87±24 0.09

E/A ratio 0.95±0.3 1.0±0.34 0.48 1.0±0.3 1.00±0.4 0.63

DT, msec 200±42 205±62 0.67 201±44 203±62 0.89

25

MV A duration, msec 126±28 120±21 0.21 124±24 120±23 0.39

e septal (cm/sec) 6.5±2.0 6.0±1.8 0.14 6.9±1.9 5.9±1.7 0.003

e lateral, cm/sec 9.4±1.9 8.1±2.3 0.004 9.7±2.2 7.9±2.0 <0.0001

Av e , cm/sec 8.1±1.9 7.0±1.8 0.002 8.3±1.8 6.9±1.7 <0.0001

E/e ratio, septal 11.7±4.1 13.5±4.5 0.04 11.0±3.5 14.5±4.6 <0.0001

E/e ratio, lateral 7.9±2.8 10.1±3.6 0.002 7.8±2.5 10.7±3.5 <0.0001

Average (Av) E/e 10,0±3.2 12.2±3.8 0.003 9.4±2.8 12.6±4 <0.0001

IVRT/LV filling time 0.21±0.1 .29±0.1

1

0.0003 0.2±0.1 0.3±0.11 <0.0001

TR velocity, cm/sec 240±35 263±35 0.001 241±34 264±35 <0.0001

Pulmonary Vein Variables

S wave, cm/sec 61±13 60±14 0.94 59±11 61±15 0.55

D wave, cm/sec 45±11 46±17 0.84 45±13 46±17 0.88

S/D ratio 1.4±0.3 1.5±0.4 0.71 1.4±0.3 1.4±0.4 0.58

ArV, mm/sec 27±4 32±5 <0.0001 26±3 32±5 <0.0001

Ar duration, msec 119±20 144±26

<0.0001

116±17 148±24 <0.0001

Ar- A, msec -6±29 25±25 <0.0001 -8±26 32±5 <0.0001

26

Table 3 Sensitivity and specificity for specific cut points as derived from the ROC curves for

each echocardiographic parameter of diastolic function. Data are shown for both LVEDP >

15 mmHg and pre-A > 12 mmHg.

Parameters Criterion Sensitivity %

(95%CI)

Specificity %

(95%CI)

+PV -PV

TR V, cm/sec >15 >278 * 44.2 (32.8-55.9) 97.7 (87.7-99.6) 97.1 49.4

>12 >259 * 63.0 (51.5-73.4) 74.4 (57.9-86.9) 83.6 49.2

DT, cm/sec >15 <=168 * 32.5 (22.2-44.1) 81.4 (66.6-91.6) 75.8 40.2

>12 <=170 * 35.8 (25.5-47.2) 84.6 (69.5-94.1) 82.9 38.8

E/A >15 >1.2 * 28 (18.2-39.6) 81.4 (66.6-91.6) 72.4 39.3

>12 >1.2 * 28.4 (18.9-39.5) 84.6 (69.5-94.1) 79.3 36.3

e sep, cm/sec >15 <=7 * 83.1 (72.9- 90.7) 44.2 (29.1-60.1) 72.7 59.4

>12 <=7 * 82.7 (72.7- 90.2) 46.2 (30.1-62.8) 76.1 56.2

e lat cm/sec

>15 >7.8 * 80.5 (69.9-88.7) 62.8 (46.7-77.0) 79.5 64.3

>12 <9 * 76.5 (65.8-85.2) 53.9 (37.2-69.9) 77.5 52.8

Av e , cm/sec >15 <=8.5 * 87.0 (77.4-93.6) 46.5 (31.2-62.3) 74.4 66.7

>12 <=8.5 * 85.2 (75.5-92.1) 46.2 (30.1-62.8) 76.7 60.0

E/e septal >15 >12.7* 62.3 (50.6-73.1) 79.1 (64.0-89.9) 84.2 54

>12 >10.3 * 77.8 (67.2-86.3) 53.9 (37.2-69.9) 77.8 53.8

E/e lateral >15 >7.8 * 80.5 (69.9-88.7) 62.8 (46.7-77) 79.5 64.3

>12 >7.8 * 75.3 (64.5-84.2) 56.4 (39.6-72.2) 78.2 52.4

Av E/e >15 >10.5 * 66.2 (54.6-76.6) 76.7 (61.4-88.2) 83.6 55.9

>12 >8.8 * 80.3 (69.9-88.3) 51.3 (34.8-67.6) 77.4 55.6

Vp, cm/sec >15 <=55 * 82.9 (72.5-90.6) 47.6 (32.0-63.6) 74.1 60.6

>12 <=50 * 74.1 (63.1‑83.2) 56.8 (39.5‑72.9) 78.9 50

27

PV S/PV D >15 >1.33 * 61.0 (49.2-72.0) 51.2 (35.5-66.7) 69.1 42.3

>12 <=0.97 * 14.8 (7.9 -24.5) 97.44 (86.5-99.6) 92.3 35.5

ArV, cm/sec >15 >31 * 53.3 (41.5-64.7) 95.4 (84.2-99.3) 95.3 53.2

>12 >31 * 50.6 (39.3-61.9) 94.9 (82.6-99.2) 95.3 48.1

Ar-A, msec

>15 >7 * 88.3 (79.0- 94.5) 81.4 (66.6-91.6) 89.5 79.5

>12 >7 * 81.48 (71.3-89.2) 74.36 (57.9-86.9) 86.8 65.9

LAVi, ml/m2 >15 >31.5 * 48.1 (36.5-59.7) 92.9 (80.5-98.4) 92.5 49.4

>12 >26.8 * 73.75 (62.7-83.0) 76.92 (60.7-88.8) 86.8 48.1

IVRT, msec

>15 >99 * 80.5 (69.9-88.7) 69.8 (53.9-82.8) 82.7 66.7

>12 >99 * 77.8 (67.2-86.3) 69.2 (52.4 - 83.0) 84 60

IVRT/LFT >15 >0.27 * 55.8 (44.1-67.2) 90.7 (77.8-97.3) 91.5 53.4

>12 >0.27* 51.9 (40.5-63.1) 87.18 (72.6-95.7) 89.4 46.6

28

Table 4 Comparison of the areas of ROC curves for detection of a LVEDP >15

mmHg for each echocardiographic parameter of diastolic dysfunction

Echocardiographic parameter Area (95% CI) P value for Area > 0.5

TR V, cm/sec 0.71 (0.62, 0.79) 0.0001

E/A 0.52 (0.42, 0.61) 0.764

DT, msec 0.51 (0.41, 0.60) 0.891

Ar-A, msec 0.85 (0.77, 0.91) 0.0001

e septal, cm/sec 0.67 (0.58, 0.75) 0.001

e lateral, cm/sec 0.74 (0.65,0.82) 0.0001

e average, cm/sec 0.72 (0.63,0.80) 0.0001

E/ e septal 0.76 (0.66, 0.82) 0.0001

E/e lateral 0.75 (0.66, 0.82) 0.0001

E/e average 0.76 (0.68, 0.84) 0.0001

PArV, cm/sec 0.82 (0.74, 0.89) 0.0001

Vp, cm/sec 0.65 (0.56, 0.74) 0.005

LAVi, ml/BSA 0.74 (0.65, 0.82) 0.0001

PV S/D 0.53 (0.43, 0.62) 0.624

Table 5 Agreement between the observed LV filling pressures and the

29

echocardiographic estimates in patients with a normal LVEF

Echocardiographic algorithms Left ventricular filling pressure

Elevated (>15

mmHg)

Normal (≤15 mmHg)

2016 guidelines

Elevated 22 1

Normal 30 36

Indeterminate 25 6

2016 criteria plus

ArV > 32 cm/sec

Elevated 35 1

Normal 21 35

Indeterminate 21 7

Proposed:

LVEDP >15 mmHg

Elevated 55 2

Normal 10 36

Indeterminate 12 5

Proposed: pre-A >12

mmHg

Elevated 48 4

Normal 13 27

Indeterminate 20 8

30

Table 6 Comparison of different echocardiographic algorithms in predicting

abnormal LV filling pressures in patients with a normal LVEF

Algorithms Sensitivity

%

(95%CI)

Specificity

%

(95%CI)

+LR

%

(95%CI)

-LR

%

(95%CI)

+PV

%

(95%CI)

-PV

%

(95%CI)

Accuracy

%

(95%CI)

2016 guidelines for

LVEDP >15 mmHg

87

(75.1-94.6)

54.6

(41.8-66.9)

1.91

(1.4-2.5)

0.24

(0.1-0.5)

61.0

(54.1-67.5)

83.7

(71.4-91.4)

69.2

(60.1-77.3)

2016 criterion plus

ArV > 32 cm/sec

87.5

(76.9-94.5)

62.5

(48.6-75)

2.3

(1.6-3.3)

0.2

(0.1-0.4)

72.7

(65.3-79.1)

81.4

(68.9-89.6)

75.8

(67.2-83.2)

Newly proposed for

LVEDP >15 mmHg

90.3

(81.0-96.0)

75

(60.4-86.4)

3.6

(2.2-5.9)

0.13

(0.1-0.3)

84.4

(76.7-89.9)

83.7

(71.4-91.4)

84.2

(76.4-90.2)

Newly proposed for

pre-A >12 mmHg

84

(74.1-91.1)

69.2

(75.8-97.1)

2.7

(1.7-4.4)

0.2

(0.1-0.3)

85

(77.8-90.2)

67.5

(54.8-78.1)

79.2

(70.8-86.0)

31

Figure 1 These LV pressure waveforms were recorded from one patient

The solid arrow points to left ventricular minimal pressure (18 mmHg), the

dashed arrow to left ventricular pre-A pressure (28 mmHg), and the

dotted arrow to left ventricular end-diastolic pressure (37 mmHg). The

patient is a 59 years male with hypertension and coronary artery disease

(LCX stenosis 70%). Cardiac catheterization was performed for chest pain

and ST T changes.

32

Figure 2 Comparison of the ROC curve for each of the Doppler

parameters of diastolic function that are used to identify an LV end

diastolic pressure > 15 mmHg. The areas under the curves for most

parameters are similar and range from 0.65 to 0.85. There is no single

parameters that can reliably predict an elevated LV pressure. In particular,

the mitral valve E/A ratio and septal eˊ were not useful.

Abbreviations: AvE/e = average E/e ; LAVi = left atrial volume index;

ArV = pulmonary vein A reversal velocity; TR velocity = tricuspid

regurgitation velocity; E/e sep = the ratio when e is obtained at the

septum; E/e lat = the ratio when e is obtained from the lateral wall;

33

Figure 3 The proposed algorithm (A) and the 2016 guidelines

algorithm (B) are compared. The modest differences in the proposed

criteria are highlighted in red. Both identify patients as normal if there

are 0-1 abnormal criteria and as abnormal if there are ≥ 3 criteria.

However, the 2016 guidelines did not include the velocity of the

pulmonary vein A reversal.

34

Figure 4 Echocardiographic data from the same patient in Figure 1.

The left ventricular ejection fraction was 73%. The parameters shown in

this figure show a septal E/eˊ of 13.8, a pulmonary vein A reversal

velocity of 0.33 m/s and an increased TR velocity of 2.85 m/s; these 3

values plus the LA volume index of 35 ml/m2 indicate that the LV end

diastolic pressure is elevated (invasive LVEDP =37 mmHg), consistent

with diastolic dysfunction grade II.

35

Figure 5 Accuracies of 2 algorithms to detect a LVEDP > 15 mmHg.

The new algorithm showed a trend towards a greater accuracy when

compared to that of the 2016 algorithm that included the PArV

(pulmonary A reversal velocity), (p = 0.052).