Echocardiographic Indices Do Not Reliably Track Changes in...

Echocardiographic Indices Do Not Reliably Track Changes

in Left-Sided Filling Pressure in Healthy Subjects or Patients

with Heart Failure with Preserved Ejection Fraction

Bhella et al: E/E' & E/Vp Do Not Track Changes in PCWP in HFpEF

Paul S. Bhella MD, John Peter Smith Health Network, Fort Worth, TX;

Eric L. Pacini MD, Anand Prasad MD, Jeffrey L. Hastings MD,

Beverley Adams-Huett MS, Univ of Texas-Southwestern, Dallas, TX;

James D. Thomas MD, The Cleveland Clinic, Cleveland, OH;

Paul A. Grayburn MD, Baylor University Medical Center, Dallas, TX;

Benjamin D. Levine MD, Univ of Texas-Southwestern, Dallas, TX

Correspondence to Benjamin D. Levine, MD Institute for Exercise and Environmental Medicine 7232 Greenville Ave, Suite 435, Dallas, TX 75231. Telephone: (214) 345-4619 Fax: (214) 345-4618 E-mail: [email protected]

Journal Subject Codes: Congestive; Echocardiography

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amin D. Levine MD, Univ of Texas-Southwestern, Dallas, T

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amin D. Levine MD, Univ of Texas-Southwestern, Dallas, T

by guest on May 6, 2018

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Abstract

Background In select patient populations, Doppler echocardiographic indices may be used to estimate left sided filling pressures. It is not known, however, whether changes in these indices track changes in left-sided filling pressures within individual healthy subjects or patients with heart failure with preserved ejection fraction (HFpEF). This knowledge is important as it would support, or refute, the serial use of these indices to estimate changes in filling pressures associated with the titration of medical therapy in patients with heart failure. Methods and Results Forty seven volunteers were enrolled: 11 highly screened elderly outpatients with a clear diagnosis of HFpEF, 24 healthy elderly subjects and 12 healthy young subjects. Each patient underwent right heart catheterization with simultaneous transthoracic echo. Pulmonary capillary wedge pressure (PCWP) and key echo indices (E/e’ & E/Vp) were measured at two baselines and during four preload altering maneuvers: lower body negative pressure (LBNP) -15 mmHg; LBNP -30 mmHg; rapid saline infusion of 10-15 ml/kg; and rapid saline infusion of 20-30 ml/kg. A random coefficient mixed model regression of PCWP vs. E/e’ and PCWP vs. E/Vp was performed for: 1) a composite of all data points; 2) a composite of all data points within each of the three groups. Linear regression analysis was performed for individual subjects. With this protocol, PCWP was manipulated from 0.8 to 28.8 mmHg. For E/e’, the composite random effects mixed model regression was PCWP = 0.58×E/e’+7.02 (p<0.001) confirming the weak but significant relationship between these two variables.Individual subject linear regression slopes (range: -6.76 to 11.03) and r2 (0.00 to 0.94) were highly variable and often very different than those derived for the composite and group regressions. For E/Vp, the composite random coefficient mixed model regression was PCWP = 1.95×E/Vp +7.48 (p=0.005); once again, individual subject linear regression slopes (range: -16.42 to 25.39) and r2 (range: 0.02 to 0.94) were highly variable and often very different than those derived for the composite and group regressions.Conclusions Within individual subjects the non-invasive indices E/e’ and E/Vp do not reliably track changes in left-sided filling pressures as these pressures vary, precluding the use of these techniques in research studies with healthy volunteers or the titration of medical therapy in patients with HFpEF. Key Words: echocardiography; pressure; ultrasonics; Doppler; heart failure

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Abbreviations:

CHF: congestive heart failure

EF: ejection fraction

E/e’: the ratio of the peak early mitral inflow velocity over the mean of the early diastolic

mitral annular velocity as measured at the septal and lateral mitral annulus

E/Vp: the ratio of the peak early mitral inflow velocity over the color M-mode Doppler

flow propagation velocity

HFpEF: heart failure with preserved ejection fraction

LAP: left atrial pressure

LBNP: lower body negative pressure

PCWP: pulmonary capillary wedge pressure

TDI: tissue Doppler imaging

r2: coefficient of determination

SE: standard error of the estimate

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Several modalities of echocardiography including Doppler, tissue Doppler and color-M-

mode have shown promise in the estimation of left-sided filling pressures. Two indices:

a) the ratio of the peak early mitral inflow velocity over the early diastolic mitral annular

velocity (E/e’) 1; and b) the ratio of the peak early mitral inflow velocity over the color

M-mode Doppler flow propagation velocity (E/Vp) 2 have received recognition for their

utility in the one-time estimation of left sided filling pressures in healthy subjects 3 as

well as select patient populations with cardiovascular disease 4,5,6,7,8. Accordingly, their

application in the diagnosis of diastolic heart failure has been recommended by the

European Society of Cardiology 9. Conversely, these indices have proven to be less

reliable in alternate populations including primary mitral regurgitation 8, mitral stenosis 10,

symptomatic hypertrophic cardiomyopathy 11 and most recently, decompensated

advanced systolic heart failure 12, calling into question their broad applicability.

It has been proposed that non-invasive indices of left-sided filling pressures be used to

titrate medical therapy in patients with heart failure 4, 7, 13. Doing so would require

demonstration that changes in non-invasive indices accurately track changes in left-sided

filling pressures within individuals as filling pressures vary. To accomplish this goal, we

sought to make multiple, simultaneous measures within individual subjects as preload

was manipulated using lower body negative pressure and rapid saline infusion. Study

groups included healthy subjects across a broad age range and elderly outpatients with

heart failure with preserved ejection fraction (HFpEF).

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pertrophic cardiomyopathy 11 and most recently, decompensa

c heart failure 12, calling into question their broad applicabilia



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Methods

Subjects

Three study groups were evaluated: 1) elderly outpatients with heart failure with

preserved ejection fraction (HFpEF) (n=11); 2) healthy elderly subjects (n=24); and 3)

healthy young subjects (n=12).

Patients over the age of 65 years with a discharge diagnosis of congestive heart failure

(CHF) were considered for the HFpEF group if they had a clear history of CHF by

Framingham criteria 14 with an ejection fraction (EF) > 50% documented at the time of

their index hospitalization. In addition, all HFpEF patients were required to have either

an elevated brain natriuretic peptide level (BNP), documented pulmonary congestion by

chest X-ray or evidence of elevated left sided filling pressures by right heart

catheterization at the time of their index hospitalization. Exclusion criteria included other

conditions that might explain the hospitalization, including the presence of atrial

fibrillation at the time of the hospitalization, prior coronary artery bypass grafting

(CABG), active myocardial ischemia, unrevascularized obstructive coronary disease

(>50% lesions by prior angiography), stable angina, recent (< 1 year) myocardial

infarction, renal failure (creatinine > 2.5 g/dl) or dialysis dependence, severe COPD/or

pulmonary disease, active malignancy, moderate or severe valvular heart disease, and

warfarin use. HFpEF patients enrolled in the study also participated in additional testing

beyond the scope of this manuscript; additional details regarding the screening of

HFpEF patients are available elsewhere15, 16.

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vidence of elevated left sided filling pressures by right heart t

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The healthy elderly study group consisted of subjects over the age of 65 used previously

in our research 17, 18. All elderly subjects were carefully screened for hypertension and

cardiac disease, including structural heart disease and hemodynamically significant

obstructive coronary disease, using a history and physical examination as well as resting

and post-exercise transthoracic echocardiograms. Additional exclusion criteria for this

group included the presence of valvular heart disease, atrial flutter or fibrillation, renal

insufficiency, chronic lung disease, regular cigarette smoking within the past 10 years or

the use of cardiovascular medications. The healthy young study group consisted of

subjects under the age of 50 used previously in our research 18. These subjects underwent

a similar screening protocol as the healthy elderly subjects described above.

All subjects signed an informed consent approved by the institutional review boards of

the University of Texas-Southwestern Medical Center at Dallas, Medical City Hospital,

Dallas, Texas, Doctors Hospital Dallas, Texas or Presbyterian Hospital of Dallas.

Experimental Protocol

Subjects were studied in the resting supine or left lateral position. A 6 Fr balloon-tipped

fluid-filled catheter (Edwards Lifesciences, Irvine, California) was placed with

fluoroscopic guidance through an antecubital vein into the pulmonary artery. The

catheter was connected to a physiologic pressure transducer with the zero reference point

placed 5.0 cm below the sternal angle. The wedge position of the catheter tip was

confirmed fluoroscopically and by the presence of an appropriate pulmonary capillary

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wedge pressure (PCWP) waveform. The PCWP balloon was inflated during data

collection at each loading condition; in between data collections, the balloon was deflated.

After 30 minutes of quiet supine rest, baseline data were collected. Cardiac filling was

then decreased using lower body negative pressure (LBNP) as previously described 19.

The levels of LBNP used were -15 and -30 mm Hg. Due to large body habitus limiting

use of the LBNP apparatus in 2 of the HFpEF subjects, head-up tilt at (20 and 40 or 60

degrees) was used instead of LBNP, with the pressure transducer zero position carefully

adjusted to the level of the right atrium documented by flouroscopy and

echocardiography. Five minutes into each level of cardiac unloading, three measures of

the mean PCWP were obtained at end-expiration using a previously described technique

20. These measurements were then averaged; Doppler echocardiography immediately

followed.

After release of the negative pressure (or return to supine position) and confirmed return

to hemodynamic baseline, cardiac filling was increased through a rapid infusion of warm

(37°C) isotonic saline solution at 100-200 mL/min. The above measures were repeated

after the infusion of 10-15 mL/kg and 20-30 mL/kg with smaller volumes generally used

in the HFpEF patients to keep the PCWP < 25 mmHg and to avoid inducing pulmonary

edema.

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Echocardiography

For all subjects, at each level of cardiac loading and unloading, a transthoracic

echocardiogram was obtained using an ATL (Advanced Technology Laboratories,

Bothell, Washington) HDI 5000CV (software version 10.1) or an iE33 (Philips

Healthcare, Bothell, WA) ultrasound machine. Traditional apical 4- and 5- chamber

views were used for all measures. Care was taken to obtain all images in the traditional

imaging planes by an experienced echocardiographer. All images were evaluated blindly

offline by an experienced sonographer in the Cleveland Clinic echo core laboratory; this

reader was unaware of the resultant changes in PCWP associated with preload

manipulation.

Doppler Measurements

Similar to measurements of the PCWP, all Doppler indices were obtained at end-

expiration with three values averaged per stage of preload manipulation. Pulse-waved

Doppler, using a sample volume of 2.0 mm placed at the tips of the mitral

valve leaflets, was used to determine peak velocities of mitral inflow (E and A velocities).

For tissue Doppler measurements, the septal and lateral walls were highlighted in the

apical 4-chamber view. Using pulse-wave Doppler, a sample volume of 4.0 mm was

placed at the septal side of the mitral annulus; the resulting early diastolic waveform

velocity was recorded. This process was then repeated for the lateral side of the mitral

annulus. Values were averaged to obtain TDI emean21 which is abbreviated as e’

throughout the rest of the manuscript. A color M-mode image of left ventricular inflow

was obtained with the sampling area positioned to extend from mid-atrium to the apex,

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directly through the mitral valve orifice. The scale was reduced sufficiently to result in

clear aliasing within the early portion of the mitral inflow. The resulting mitral inflow

spatiotemporal velocity profile pattern was used to derive the early propagation velocity

of mitral inflow (Vp) as previously described 22.

Statistical Analysis

Numerical data are presented as mean ± standard deviation. Random coefficient mixed

models analysis was performed to estimate regression parameters between non-invasive

estimates of left-sided filling pressure (i.e. E/e’ and E/Vp) and invasive measures of left-

sided filling pressure (PCWP) in instances in which group data was comprised of

multiple data points from individual subjects, thereby accounting for the correlation

within individual subjects. Linear regression analysis was performed to estimate

regression parameters between non-invasive estimates of left-sided filling pressure and

invasive measures of left-sided filling pressure in instances in which: 1) group data was

comprised of single data points from individual subjects; or 2) a single subject’s data was

being regressed. Standard error of the estimate (SE) was determined for the slope

coefficient in each simple linear regression. As clinicians and researchers are generally

interested in estimating the PCWP by the non-invasive measures of E/e’ or E/Vp, PCWP

was set as the dependent variable and E/e’ and E/Vp as the independent variables in the

analyses except in the group data for each stage of preload manipulation. All analyses

were performed by use of commercial software (SigmaPlot 11.0, Systat Software. Inc,

Chicago, IL and SAS version 9.2, SAS Institute, Cary, NC).

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Results

Characteristics for each of the three study groups are presented in Table 1. Additional

characteristics of the HFpEF patients 15, 16, healthy elderly subjects 17, 18 and healthy

young subjects 18 can be found elsewhere.

Alterations in Preload

The mean PCWP, mean E/e’ and mean E/Vp (± standard deviation) by group for each

stage of preload manipulation are presented in Figure 1. The application of LBNP at

levels of -15 and -30 mmHg lowered PCWP in each group; the rapid infusion of warm

saline at 10-15 and 20-30 mL/kg increased PCWP in each group. With this protocol, a

range of PCWP from 0.8 mmHg to 28.8 mmHg was achieved.

E/e’ and PCWP

In the composite of all subjects, the random coefficient mixed model regression was

PCWP = 0.58×E/e’+7.02 (p<0.001) (Table 2); this relationship was based on 267 paired

measurements of E/e’ and PCWP (Figure 2). The linear regression slopes of the 47

individual subjects who comprised this composite varied greatly, ranging from -6.76 to

11.03. Individual coefficients of determination (r2) also varied greatly, ranging from 0.00

to 0.94.

In healthy subjects, group random coefficient mixed model regression slopes ranged from

0.07 in the young group to 0.93 in the elderly group. Within the individual subjects who

comprised these groups, linear regression slopes ranged from negative to steeply positive

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and r2 ranged from low to high. Based on linear regression slopes, in 10 healthy subjects

changes in E/e’ and PCWP were discordant (E/e’ decreased as PCWP increased) whereas

in the other 24, changes were concordant.

Using only baseline measures, the HFpEF group’s linear regression was PCWP =

0.52×E/e' + 6.85 (p=0.04, r2 = 0.42, SE = 1.99) (Figure 3). However, with preload

manipulations the linear regression slopes of the individual HFpEF patients varied greatly,

ranging from -1.44 to 4.42. Likewise, individual HFpEF patient r2 varied from 0.01 to

0.82. Based on linear regression slopes, in 3 HFpEF patients changes in E/e’ and PCWP

were discordant whereas in the other 8, changes were concordant. To further

characterize these relationships, the linear regression slopes of E vs. PCWP and e’ vs.

PCWP in individual HFpEF patients are presented in Figure 4.

E/Vp and PCWP

In the composite of all subjects, the random coefficient mixed model regression was

PCWP = 1.95×E/Vp +7.48 (p=0.005) (Table 3); this relationship was based on 256 paired

measurements (Figure 5). Within this composite, the linear regression slopes of 46

individual subjects ranged from -16.42 to 25.39 while r2 ranged from 0.00 to 0.94.

In healthy subjects, group random coefficient mixed model regression slopes ranged from

1.64 in the elderly group to 7.07 in the young group; in HFpEF patients, this group

regression slope was 2.51. Once again, within the individual subjects who comprised

these groups, linear regression slopes ranged from steeply negative to steeply positive

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and r2 ranged from low to high. Based on linear regression slopes, in 12 healthy subjects

changes in E/Vp and PCWP were discordant whereas in the other 24, changes were

concordant; in HFpEF patients these numbers were 5 and 6, respectively.

Discussion

The key finding of this study is that as left-sided filling pressures are manipulated in

healthy individuals or in outpatients with HFpEF, the relationship between non-invasive

indices (E/e’ and E/Vp) and the PCWP is highly variable, with individual subject linear

regression slopes ranging from steeply negative to steeply positive and coefficients of

determination ranging from very low to very high. Consequently, non-invasive indices

do not adequately track changes in left-sided filling pressures as these pressures vary

within individual subjects.

Limitations of Non-Invasive Indices in the One-Time Estimation of Left-Sided

Filling Pressures

There are several known limitations of E/e’ and E/Vp in the one-time estimation of left-

sided filling pressures. Published linear regressions relating E/e’ and E/Vp with invasive

measures are generally derived from a composite of data points from individual subjects,

each data point representing a single, simultaneous measure of the non-invasive index

and PCWP. As each subject contributes only one paired measurement to the composite,

these regressions consequently reflect the relationship for the population rather than for

the individual subjects which comprise the population. For this reason population based

linear regressions often poorly predict left-sided filling pressures in individual subjects as

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reflected by their wide confidence intervals. Furthermore, the utility of non-invasive

estimates of left sided filling pressure appears to be highly dependent on the population

studied. While non-invasive indices have been validated in populations of healthy

subjects as well as in select patients depressed systolic heart failure 2, cardiac

transplantation 4 , atrial fibrillation 5, sinus tachycardia 6 and hypertrophic

cardiomyopathy 7, others have shown that they fail to accurately estimate left-sided

filling pressures in patients with mitral valve disease 8, 10, symptomatic hypertrophic

cardiomyopathy 11 and decompensated advanced systolic heart failure 12.

Non-Invasive Indices Do Not Accurately Track Changes in Left-Sided Filling

Pressures

Despite these limitations, some have suggested that serial measures of non-invasive

indices might allow for the estimation of directional changes in left-sided filling pressures

in response to therapy or worsening of heart failure within an individual subject. This

thought is based on the presumption that changes in non-invasive indices should track

changes in invasive measures within individuals in accordance with population based

regressions 4, 7, 13. Our data refute this presumption. The group means (of E/e’ and E/Vp)

tended to track preload manipulation well (Figure 1) and our population-based random

coefficient mixed model regressions suggested a weak but significant relationship

between PCWP and E/e’ and PCWP and E/Vp (Figures 2, 4). However, as filling

pressures were manipulated in the individual subjects who comprised these groups,

significant variability was observed within individual subjects with regression slopes

ranging from steeply negative to steeply positive and coefficients of determination

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ranging from very low to very high. This broad variability demonstrates that E/e’ and

E/Vp are not able to accurately track changes in left-sided filling pressures in individual

patients.

To illustrate this point, our HFpEF group’s baseline linear regression (PCWP = 0.52×E/e'

+ 6.85 [p=0.04, r2 = 0.42, SE = 1.99]; Figure 3) is similar to previously published

regressions with the exception of a lower standard error of the estimate (SE), which has

ranged from 3.4 7 to 3.9 mmHg 1, 6 in prior studies. Yet despite this favorable group

baseline regression, as filling pressures were manipulated within the individual HFpEF

patients who comprised the group, E/e’ responded unpredictably with individual linear

regressions varying profoundly in terms of slope (patient slopes: -1.44, -1.34, -0.68, 0.19,

1.55, 1.73, 2.45, 2.65, 2.69, 3.83, 4.42) and coefficient of determination (range: 0.00 –

0.82). Examples of the primary data for PCWP, E and e’ in two HFpEF patients are

presented in Figure 6. In the top example, PCWP and E/e’ were concordant (the patient

with a slope of 4.42) while in the bottom example, the two were discordant (the patient

with a slope of -1.44). These examples illustrate the broad individual variability

observed with this index as preload is manipulated. Similar findings were observed

between PCWP and E/Vp in these HFpEF patients and between PCWP and E/e’ and

PCWP and E/Vp in our healthy subjects.

To better understand the limitations of E/e’ as an index to track changes in left-sided

filling pressures, individual linear regression slopes for E vs. PCWP and e’ vs. PCWP

were examined in HFpEF patients. As demonstrated in Figure 4, E showed a degree of

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ing profoundly in terms of slope (patient slopes: -1.44, -1.34

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preload dependence that was generally similar among individual HFpEF patients.

Conversely, the response of e’, which also demonstrated a degree of preload dependence,

was highly variable between individual HFpEF patients with steeply elevated slopes in 5

patients and more mildly elevated slopes in the other 6. This degree of preload

dependence contrasts prior reports of the preload independence of e’ 1 falling more in line

with reports demonstrating a varying strength of relationship between e’ and left sided

filling pressures 3, 6, 7, 23. Of the two measures, the broad variability observed in the

denominator of E/e’ would appear to primarily account for the broad variability observed

in individual E/e’ slopes. As a collective, these observations illustrate the point that the

inter-individual slope of the preload manipulated E/e’ relationship is so highly variable

that it is impossible to reliably track changes in filling pressures in a given individual

without first establishing the slope of the relationship in that given individual. This is, of

course, impractical to perform in patients with clinical heart failure and hence,

demonstrates an important limitation of this index.

A limited number of studies have previously attempted to assess the feasibility of serial

measures of non-invasive indices to track changes in left-sided filling pressures

associated with medical therapy or exercise. Mullens et al examined the ability of the

non-invasive index E/Ea to track changes in filling pressures between admission and the

48 hour time point in 51 patients admitted to the intensive care unit with advanced

decompensated heart failure. Over the course of these 48 hours, the change in PCWP

ranged from -24 to 16 mmHg; however, the authors found no correlation between

absolute changes in the E/Ea ratio and PCWP 12. More recently, Maeder et al

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demonstrated that E/e’ failed to reflect PCWP in exercising patients with heart failure

with normal ejection fraction 24. In another study, Dokainish et al correlated the change

in E/E’ with the change in PCWP in 9 patients hospitalized in the intensive care unit

before and after 48 hours of treatment with intravenous diuretics (n=5) and/or ionotropes

(n=8) 13. While these authors did show a correlation between change in PCWP and

change in E/E’ based on the group’s composite data, the linear regression slopes of the

individual subjects were not presented. Additional studies have also reported correlations

between changes in PCWP and changes in E/E’ 4, 7; however, again, the linear regression

slopes of the individual subjects who made up these populations were not presented,

calling into question the ability of these population based indices to accurately predict

changes in left-sided filling pressures within individual subjects.

Study Limitations

Although great care was taken to obtain all echocardiographic measures in traditional

imaging planes, subtle variations are often unavoidable and occasionally, representative

measures could not obtained or interpreted. Overall, subtle variation in imaging planes

was felt to be a random phenomenon which was equally distributed amongst all measures

obtained. There were few instances of unobtainable or uninterpretable measures. For

E/e’, only 15 of the 282 possible measures (5%) could not be obtained or interpreted; for

E/Vp, this number was 20 of the 276 possible measures (7%). Finally, we used PCWP as

a measure of left-sided filling pressures rather than directly measured left atrial pressure

(LAP). However previous studies have shown that in the absence of anatomic

obstruction between the pulmonary capillary and the left ventricle, PCWP correlates

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closely with left ventricular end-diastolic pressure and is widely used as a surrogate for

LAP 23, 24.

Conclusion

As filling pressures are manipulated, the relationship between non-invasive indices (E/e’

and E/Vp) and the pulmonary capillary wedge pressure is highly variable in healthy

patients and patients with HFpEF, with individual subject linear regression slopes ranging

from steeply negative to steeply positive and coefficients of determination ranging from

very low to very high. Consequently, within individual subjects, non-invasive indices do

not reliably track changes in left-sided filling pressures, precluding the use of these

techniques in research studies with healthy volunteers or to titrate medical therapy in

patients with HFpEF.

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Acknowledgements

We would like to acknowledge our research team for the invaluable contributions: Mrs.

Diane Bedenkop, Mr. Colin Connor, Mr. Daniel Creson, Mrs. Peggy Fowler, Mr. Cyrus

Oufi, Ms. Tiffany VanGundy and Dr. Murugappan Ramanathan.

Sources of Funding

This project was supported by the NIH (Grant R01 AG17479). Additional support for

statistical analyses was provided by the National Institutes of Health Clinical and

Translational Science Award (Grant UL1 RR024982).

Disclosures

None.

Disclosures



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2. Garcia M, Ares M, Asher C, Rodriguez L, Vandervoort P, Thomas J. An index of early left ventricular filling that combined with pulsed doppler peak e velocity may estimate capillary wedge pressure. Journal of the American College of Cardiology. 1997;29:448-454

3. Firstenberg MS, Levine BD, Garcia MJ, Greenberg NL, Cardon L, Morehead AJ, Zuckerman J, Thomas JD. Relationship of echocardiographic indices to pulmonary capillary wedge pressures in healthy volunteers. Journal of the American College of Cardiology. 2000;36:1664-1669

4. Sundereswaran L, Nagueh SF, Vardan S, Middleton KJ, Zoghbi WA, Quiñones MA, Torre-Amione G. Estimation of left and right ventricular filling pressures after heart transplantation by tissue doppler imaging. The American Journal of Cardiology. 1998;82:352-357

5. Sohn D-W, Song J-M, Zo J-H, Chai I-H, Kim H-S, Chun H-G, Kim H-C. Mitral annulus velocity in the evaluation of left ventricular diastolic function in atrial fibrillation. J Am Soc Echocardiogr. 1999;12:927-931

6. Nagueh SF, Mikati I, Kopelen HA, Middleton KJ, Quinones MA, Zoghbi WA. Doppler estimation of left ventricular filling pressure in sinus tachycardia : A new application of tissue doppler imaging. Circulation. 1998;98:1644-1650

7. Nagueh SF, Lakkis NM, Middleton KJ, Spencer WH, III, Zoghbi WA, Quinones MA. Doppler estimation of left ventricular filling pressures in patients with hypertrophic cardiomyopathy. Circulation. 1999;99:254-261

8. Bruch C, Stypmann J, Gradaus R, Breithardt G, Wichter T. Usefulness of tissue doppler imaging for estimation of filling pressures in patients with primary or secondary pure mitral regurgitation. The American Journal of Cardiology.2004;93:324-328

9. Paulus WJ, Tschöpe C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, Marino P, Smiseth OA, De Keulenaer G, Leite-Moreira AF, BorbÃ©ly A, Ã‰des In, Handoko ML, Heymans S, Pezzali N, Pieske B, Dickstein K, Fraser AG, Brutsaert DL. How to diagnose diastolic heart failure: A consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the heart failure and echocardiography associations of the european society of cardiology. European Heart Journal. 2007;28:2539-2550

10. Diwan A, McCulloch M, Lawrie GM, Reardon MJ, Nagueh SF. Doppler estimation of left ventricular filling pressures in patients with mitral valve disease. Circulation. 2005;111:3281-3289

11. Geske JB, Sorajja P, Nishimura RA, Ommen SR. Evaluation of left ventricular filling pressures by doppler echocardiography in patients with hypertrophic cardiomyopathy: Correlation with direct left atrial pressure measurement at cardiac catheterization. Circulation. 2007;116:2702-2708

The Americannnnnnn J J J J J

hun H-H-H-H-H-H-H G,G,G,G,G,G,G, K K K K K KKimimimimimimim H Hvelocity in the evaluation of left t i l di t li f ctionoSe ao 5S Appler estimation of left ventricular filling pressures in patient

velocity in the evaluation of left ventricular diastolic functionon. J Am Soc Echocardiogr. 1999;12:927-931 SF, Mikati I, Kopelen HA, Middleton KJ, Quinones MA, Zoestimation of left ventricular filling pressure in sinus tachycaon of tissue doppler imaging. Circulation. 1998;98:1644-165SF, Lakkis NM, Middleton KJ, Spencer WH, III, Zoghbi WAppler estimation of left ventricular filling pressures in patient



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13. Dokainish H, Zoghbi WA, Lakkis NM, Al-Bakshy F, Dhir M, Quinones MA, Nagueh SF. Optimal noninvasive assessment of left ventricular filling pressures: A comparison of tissue doppler echocardiography and b-type natriuretic peptide in patients with pulmonary artery catheters. Circulation. 2004;109:2432-2439

14. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: The framingham study. N Engl J Med. 1971;285:1441-1446

15. Drazner MH, Prasad A, Ayers C, Markham DW, Hastings J, Bhella PS, Shibata S, Levine BD. The relationship of right- and left-sided filling pressures in patients with heart failure and a preserved ejection fraction. Circ Heart Fail. 2010;3:202-206

16. Prasad A, Hastings JL, Shibata S, Popovic ZB, Arbab-Zadeh A, Bhella PS, Okazaki K, Fu Q, Berk M, Palmer D, Greenberg NL, Garcia MJ, Thomas JD, Levine BD. Characterization of static and dynamic left ventricular diastolic function in patients with heart failure with a preserved ejection fraction / clinical perspective. Circulation: Heart Failure. 2010;3:617-626

17. Arbab-Zadeh A, Dijk E, Prasad A, Fu Q, Torres P, Zhang R, Thomas JD, Palmer D, Levine BD. Effect of aging and physical activity on left ventricular compliance. Circulation. 2004;110:1799-1805

18. Prasad A, Popovic ZB, Arbab-Zadeh A, Fu Q, Palmer D, Dijk E, Greenberg NL, Garcia MJ, Thomas JD, Levine BD. The effects of aging and physical activity on doppler measures of diastolic function. Am J Cardiol. 2007;99:1629-1636

19. Levine BD, Lane LD, Buckey JC, Friedman DB, Blomqvist CG. Left ventricular pressure-volume and frank-starling relations in endurance athletes. Implications for orthostatic tolerance and exercise performance. Circulation. 1991;84:1016-1023

20. Prasad A, Okazaki K, Zadeh AA, Dijk E, Fu Q, Thomas JD, Levine BD. Abnormalities of doppler measures of diastolic function in the healthy elderly are not related to alterations of left atrial pressure. Circulation. 2005;111:1499-1503

21. Sohn D-W, Chai I-H, Lee D-J, Kim H-C, Kim H-S, Oh B-H, Lee M-M, Park Y-B, Choi Y-S, Seo J-D, Lee Y-W. Assessment of mitral annulus velocity by doppler tissue imaging in the evaluation of left ventricular diastolic function. Journal of the American College of Cardiology. 1997;30:474-480

22. Popovic ZB, Prasad A, Garcia MJ, Arbab-Zadeh A, Borowski A, Dijk E, Greenberg NL, Levine BD, Thomas JD. Relationship among diastolic intraventricular pressure gradients, relaxation, and preload: Impact of age and fitness. Am J Physiol Heart Circ Physiol. 2006;290:H1454-1459

23. Nagueh SF, Sun H, Kopelen HA, Middleton KJ, Khoury DS. Hemodynamic determinants of the mitral annulus diastolic velocities by tissue doppler. J Am Coll Cardiol. 2001;37:278-285

24. Maeder MT, Thompson BR, Brunner-La Rocca H-P, Kaye DM. Hemodynamic basis of exercise limitation in patients with heart failure and normal ejection fraction. J Am Coll Cardiol. 2010;56:855-863

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adeh A, Dijk E, Prasad A, F Q, Torres P, Zhang R, Thomase ao, Popovic ZB, Arbab-Zadeh A, Fu Q, Palmer D, Dijk E, G e

MJ, Thomas JD, Levine BD. The effects of in and icamD Lane LD Buckey JC Friedman DB Blomqvist CG Left

adeh A, Dijk E, Prasad A, Fu Q, Torres P, Zhang R, Thomase BD. Effect of aging and physical activity on left ventriculaon. 2004;110:1799-1805 , Popovic ZB, Arbab-Zadeh A, Fu Q, Palmer D, Dijk E, Gre

MJ, Thomas JD, Levine BD. The effects of aging and physicameasures of diastolic function. Am J Cardiol. 2007;99:1629-D Lane LD Buckey JC Friedman DB Blomqvist CG Left



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Table 1. Group Characteristics Variable HFpEF (n=11) Healthy Elderly (n=24) Healthy Young (n=12) Age (years) 73.0 ± 6.8 69.2 ± 3.4 32.3 ± 9.0 Female (%) 64% 46% 25% Height (cm) 162.4 ± 9.6 169.3 ± 10.5 179.2 ± 8.2 Weight (kg) 88.9 ± 21.3 69.5 ± 12.5 74.9 ± 15.9 Body Mass Index (kg/m2) 33.6 ± 6.7 24.1 ± 2.8 23.1 ± 3.4 Body Surface Area (m2) 1.99 ± 0.27 1.80 ± 0.21 1.90 ± 0.27 Peak VO2 (ml/kg/min) 13.7 ± 3.4 29.9 ± 9.8 40.6 ± 10.1 Data are presented as mean ± standard deviation

Table 2. Summary Data for Non-Invasive Index E/e'

Average (Min - Max) Average (Min - Max)HFpEF (n=11) 60 PCWP = 0.83*E/e' + 3.93 0.04 1.46 (-1.44 - 4.42) 0.38 (0.01 - 0.82)Healthy Elderly (n=24) 137 PCWP = 0.93*E/e' + 4.60 0.008 3.12 (-2.37 - 11.03) 0.42 (0.00 - 0.94)Healthy Young (n=12) 70 PCWP = 0.07*E/e' + 10.33 0.91 -1.31 (-6.76 - 6.35) 0.27 (0.00 - 0.76)All Subjects (n=47) 267 PCWP = 0.58*E/e' + 7.02 <0.0001 1.60 (-6.76 - 11.03) 0.37 (0.00 - 0.94)

Table 3. Summary Data for Non-Invasive Index E/Vp

Average (Min - Max) Average (Min - Max)HFpEF (n=11) 59 PCWP = 2.51*E/Vp + 9.02 0.16 4.70 (-16.33 - 24.65) 0.41 (0.02 - 0.94)Healthy Elderly (n=24) 135 PCWP =1.64*E/Vp +7.54 0.06 4.40 (-12.54 - 25.39) 0.27 (0.00 - 0.66)Healthy Young (n=11) 62 PCWP = 7.07*E/Vp - 1.90 0.003 3.89 (-16.42 - 20.04) 0.30 (0.00 - 0.87)All Subjects (n=46) 256 PCWP = 1.94*E/Vp + 7.48 0.005 4.35 (-16.42 - 25.39) 0.31 (0.00 - 0.94)

Group (n = subjects)

Paired Data

Points (E/e' & PCWP)

Group Random Coefficient Mixed Model

Regressionp Value

Range of Individual Linear Regression Slopes Within

Group

Range of Individual r2

Within Group

Group (n = subjects)

Paired Data

Points (E/Vp & PCWP)


Regressionp Value


Group

Range of Individual r2

Within Group

137 PCWP = 0 93*E/e' + 4 60 0 008 3 12 ( 2 37 11 03) 0 42

a

e60 PCWP = 0.83*E/e' + 3.93 0.04 1.46 (-1.44 - 4.42) 0.38

gW

137 PCWP = 0 93*E/e' + 4 60 0 008 3 12 ( 2 37 11 03) 0 42

a for Non-Invasive Index E/e'

Average (Min - Max) Average60 PCWP = 0.83*E/e' + 3.93 0.04 1.46 (-1.44 - 4.42) 0.38

Paired Data

Points (E/e' & PCWP)


Regressionp Value


Group

RangW



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Figure Legends

Figure 1. E/e’ (top) and E/Vp (bottom) across filling pressures. Data represent group

means ± standard deviations at each stage of preload manipulation.

Figure 2. Composite of E/e’ vs. PCWP in all subjects. Group random coefficient mixed

model regressions (top) and individual linear regressions (bottom) are superimposed.

Individual linear regressions were highly variable in regards to slope and r2.

Figure 3. Top: E/e’ vs. PCWP in HFpEF patients at baseline with superimposed group

linear regression (one HFpEF patient could not adequately imaged at baseline). Bottom:

E/e’ vs. PCWP in individual HFpEF patients with superimposed linear regressions (note:

linear regressions are extended to axes). Again, individual linear regressions were highly

variable in regards to slope and r2.

Figure 4. Top: E vs. PCWP in individual HFpEF patients with superimposed linear

regressions. E demonstrated a degree of preload dependence which was similar between

individual HFpEF patients. Bottom: e’ vs. PCWP in individual HFpEF patients with

superimposed linear regressions. e’ varied greatly between individual HFpEF patients

accounting for the broad variability observed in individual E/e’ slopes as preload was

manipulated.

withthhhhhh s s s s s ssupupupupupupuperererererererimimimimimimimpopppppp

n

n

s s

(one HFpEF patient could not adequately imaged at baselin

n individual HFpEF patients with superimposed linear regrer

s are extended to axes). Again, individual linear regressions



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Figure 5. Composite of E/Vp vs. PCWP in all subjects. Group random coefficient mixed

model regressions (top) and individual linear regressions (bottom) are superimposed.

Again, individual linear regressions were highly variable in regards to slope and r2.

Figure 6. Effects of preload manipulation on PCWP, E, e’ and E/e’ slope in two HFpEF

patients. In the top example, increasing PCWP results in a positive E/e’ slope

demonstrating concordance between these measures. In the bottom example, increasing

PCWP results in a negative E/e’ slope demonstrating discordance. In 8/11 HFpEF

patients, PCWP and E/e’ were concordant whereas in the other 3, the two measures were

discordant. Mean PCWP was determined during the period of diastasis, thereby

minimizing the impact of large V waves on the mean PCWP observed in the top example.

er 3, the two memmmmmm

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mpact of large V waves on the mean PCWP observed in the mpact of large V waves on the mean PCWP observed in the



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PCWP (mmHg)

0 5 10 15 20 25 30

E/e

'

0

5

10

15

20

HFpEFHealthy ElderlyHealthy Young

PCWP (mmHg)

0 5 10 15 20 25 30

E/V

p

0.5

1.0

1.5

2.0

2.5

3.0

3.5


3

PCWP (mmHg)

5 10 15 20 25 3



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E/e'

0 5 10 15 20 25

PC

WP

(mm

Hg)

0

10

20

30


E/e'

0 5 10 15 20 25

PC

WP

(mm

Hg)

0

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2

E/e'

5 10 15 20 2



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E/e'

0 5 10 15 20 25 30

PC

WP

(mm

Hg)

0

10

20

30

Patient 1Patient 2Patient 3Patient 4Patient 5Patient 6Patient 7Patient 8Patient 9Patient 10

E/e'

0 5 10 15 20 25 30

PC

WP

(mm

Hg)

0

10

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30

Patient 1Patient 2Patient 3Patient 4Patient 5Patient 6Patient 7Patient 8Patient 9Patient 10Patient 11

E/e'

5 10 15 20 25 3



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E (cm/s)

0 20 40 60 80 100 120 140 160

PC

WP

(mm

Hg)

0

10

20

30


e' (cm/s)

0 2 4 6 8 10 12 14 16

PC

WP

(mm

Hg)

0

10

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30


20 40 60 80 100 120 140 1

E (cm/s)

20 40 60 80 100 120 140 1



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E/Vp

0 1 2 3 4 5

PC

WP

(mm

Hg)

0

10

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Hg)

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PCWP

E

e’ (septal)

PreloadManipulation

E/e'

0 5 10 15 20 25 30

PC

WP

(mm

Hg)

0

10

20

30

Application of LBNP Baseline Rapid Infusion of NS

Patient #1 (discordant)

PCWP

e’ (septal)

E/e'

0 5 10 15 20 25 30

PC

WP

(mm

Hg)

0

10

20

30

Patient #10 (concordant)

E

Mean PCWP = 7.2 mmHg Mean PCWP = 8.3 mmHg Mean PCWP = 12.0 mmHg Mean PCWP = 12.5 mmHg Mean PCWP = 16.7 mmHg

Mean PCWP = 18.9 mmHgMean PCWP = 16.3 mmHgMean PCWP = 9.6 mmHg Mean PCWP = 21.9 mmHgMean PCWP = 6.4 mmHg



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Thomas, Paul A. Grayburn and Benjamin D. LevinePaul S. Bhella, Eric L. Pacini, Anand Prasad, Jeffrey L. Hastings, Beverley Adams-Huett, James D.

Healthy Subjects or Patients with Heart Failure with Preserved Ejection FractionEchocardiographic Indices Do Not Reliably Track Changes in Left-Sided Filling Pressure in

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