Validation by Cardiac Catheterization of Noninvasive Estimation of Time Constant of Left Ventricular Pressure Decline as an Index of Relaxation by Speckle Tracking Echocardiography

Title

Validation by Cardiac Catheterization of Noninvasive Estimation

of Time Constant of Left Ventricular Pressure Decline as an

Index of Relaxation by Speckle Tracking Echocardiography( 本

文(Fulltext) )

Author(s)

吉眞, 孝

Report No.(Doctoral

Degree)

博士(医学) 甲第1102号

Issue Date

2019-03-25

Type

博士論文

Version

ETD

URL

http://hdl.handle.net/20.500.12099/77929

Validation by Cardiac Catheterization of Noninvasive

Estimation of Time Constant of Left Ventricular

Pressure Decline as an Index of Relaxation by Speckle

Tracking Echocardiography

Takashi Yoshizane, MD

_{, Itta Kawamura, MD, PhD}

_*

_{, Masanori Kawasaki, MD, PhD}

_,

Ryuhei Tanaka, MD, PhD

_{, Shingo Minatoguchi, MD}

_{, Maki Nagaya, MSc}

_{, Hidemaro Sato, MSc}

_,

Koji Ono, MD, PhD

_{, Shinji Tomita, MD, PhD}

_{, Hitoshi Matsuo, MD, PhD}

_,

Toshiyuki Noda, MD, PhD

_{, Takahiko Suzuki, MD, PhD}

_{, and Shinya Minatoguchi, MD, PhD}

There has been no established echocardiographic parameter to accurately assess left ventricu-lar (LV) relaxation. Impaired LV relaxation assessed by the time constant of LV pressure decline (Tau) is one of the major components of diastolic dysfunction. We sought to noninvasively es-timate Tau (eTau) by speckle tracking echocardiography (STE) and to validate the eTau against Tau by catheterization. Tau was reported to be calculated using the isovolumic relaxation time (IVRT), LV end-systolic pressure, and left atrial (LA) pressure. We reported that pulmonary capillary wedge pressure (ePCWP) can be noninvasively and accurately estimated as 10.8− 12.4× Log (LA active emptying function/minimum LA volume index). Therefore, the eTau by STE is noninvasively calculated using the formula: eTau= IVRT / (ln 0.9 × systolic blood pressure−ln ePCWP). Echocardiographic parameters were measured just before catheteriza-tion in 110 patients with cardiac disease (age 72± 8). There was a good correlation between the eTau and Tau by catheterization (r= 0.69, p <0.001), whereas IVRT and the e’ had a poor correlation with Tau (r= 0.33 and −0.33, respectively). The sensitivity and specificity of the eTau to predict prolonged Tau (>48 ms) was 77% and 91%, respectively, with area under curve of 0.87 using an optimal cutoff of 48 ms. Bland-Altman analysis revealed a good agreement between the eTau and Tau. In conclusion, this study demonstrated that the eTau by our non-invasive method has a good correlation with Tau obtained by cardiac catheterization. LV relaxation may be noninvasively and accurately estimated by STE. © 2018 Elsevier Inc. All rights reserved. (Am J Cardiol 2018;121:1645–1651)

Heart failure (HF) is a common cause of cardiovascular disease and death, and may occur in the presence of either a normal or abnormal left ventricular (LV) ejection fraction (EF). The prevalence of HF and hypertension (HTN) that is one of the most important risk factors for HF increase with age.1–3

The underlying pathophysiology in HF with preserved EF (HFPEF) involves a predominant abnormality in diastolic function.3,4_{Impaired relaxation and increased diastolic}

stiff-ness are the major components of diastolic dysfunction thought to lead to the elevation of filling pressure.1,3_{LV relaxation}

is impaired at first in diastolic dysfunction and even in the early stage of HTN.5 _{It is important to evaluate LV}

relax-ation represented by the time constant of pressure decline (Tau) and pulmonary capillary wedge pressure (PCWP) in heart disease, especially for the diagnosis and treatment of HFPEF.

Echocardiography has played a central role in the evalua-tion of diastolic funcevalua-tion.6–8_{However, there has been no}

established echocardiographic parameter to accurately and noninvasively assess LV relaxation. A more universally ap-plicable method for the quantification in the routine clinical setting remains to be described and validated. Therefore, the purpose of this study was to noninvasively evaluate Tau by echo (eTau) and to validate the accuracy of eTau against Tau obtained by cardiac catheterization.

Methods

One hundred and eighteen patients with cardiac disease were prospectively enrolled from August 2015 until September 2016. Exclusion criteria in patients were the presence of moderate to severe valvular heart disease, medical history of surgery for struc-tural heart disease, arrhythmia during the examination, and poor echocardiographic window to perform speckle tracking echocardiography (STE) analysis. Echocardiographic study was performed just before the left-sided heart catheterization. The present study was approved by the ethics committee of our in-stitution and all patients gave written informed consent before participation (IRA number 222).

Standard echo-Doppler and 2-dimensional STE examina-tions were performed using a commercially available ultrasound system (iE33, Philips Medical Systems, Andover,

a_{Gifu Prefectural General Medical Center, Gifu, Japan;}b_{Gifu Heart Center,} Gifu, Japan; c_{Gifu University Graduate School of Medicine, Gifu,} Japan;d_{Murakami Memorial Hospital, Gifu, Japan; and}e_{Sawada Hospital,} Gifu, Japan. Manuscript received December 6, 2017; revised manuscript re-ceived and accepted February 26, 2018.

See page 1651 for disclosure information. Funding sources: None.

*Corresponding author: Tel:+81 58 277 2277; fax: +81 58 277 3377. E-mail address:[email protected](I. Kawamura). 0002-9149/© 2018 Elsevier Inc. All rights reserved.

https://doi.org/10.1016/j.amjcard.2018.02.061

MA) that was equipped with a broadband (1 to 5 MHz) S5-1 probe. All echocardiographic measurements were made according to criteria of the American Society of Echocardiography.9_{We examined the following parameters}

within 1 hour before catheterization. LVEF was measured by bi-plane modified Simpson’s method. Doppler measure-ments of mitral inflow E-wave and A-wave velocity were obtained, and tissue Doppler measurement of mitral e’ wave

velocity was made at the septal and lateral annulus. The isovolumic relaxation time (IVRT) was measured as the time between the end of LV outflow wave and the beginning of inflow wave by Doppler echo.10,11_{LV longitudinal strain was}

measured from apical 2 and 4 chamber view. All measure-ments were performed 3 times and the average was used for further analysis. After measurements of the standard echocardiographic parameters, a time-LA volume curve was

Figure 1. (A) Time-left atrial volume curve obtained by speckle tracking echocardiography. (B) Left ventricular pressure acquisition by pressure wire catheter.

obtained by STE using QLab software (Philips Medical Systems, Andover, Massachusetts) to evaluate phasic LA volume and LA emptying function (Figure 1) as we previ-ously reported.12_{To optimize STE, images were obtained at}

a frame rate of 70 to 100 frames/s. We previously reported that the estimated PCWP (ePCWP) can be accurately and noninvasively calculated using the kinetics-tracking index (KT index): log10{left atrial (LA) active emptying function/LA

minimum volume index} and that the ePCWP had a strong correlation with PCWP obtained by right heart catheteriza-tion in patients with sinus rhythm.13_{The ePCWP was calculated}

as 10.8− 12.4 × KT index. Tau was reported to be com-puted with the use of the previously validated equation: Tau= IVRT/(ln LV end-systolic pressure−ln LA pressure).14,15

IVRT was noninvasively measured by Doppler echo.10_LV

end-systolic pressure can be derived by the following previously validated expression: LV end-systolic pressure= 0.9 x sys-tolic blood pressure16_{and LA pressure was reported to have}

an excellent correlation with PCWP (r= 0.95).17_{Thus, it may}

be possible to combine IVRT with noninvasive estimates of LV end-systolic pressure and LA pressure to calculate Tau. The eTau is noninvasively obtained using systolic blood pres-sure and ePCWP instead of LV end-systolic prespres-sure and PCWP, respectively, as the following formula: eTau= IVRT / (ln 0.9× systolic blood pressure—ln ePCWP). Blood pres-sure was meapres-sured during echocardiography examination. All measurements were performed 3 times and the average was used for further analysis.

Left-sided heart catheterization was performed by a stan-dard approach. Hemodynamic data were collected using a 0.014-inch French pressure wire with a micromanometer at its tip (Certus, St. Jude Medical, Minnesota and Verrata, Volcano, Tokyo, Japan) placed inside a fluid-filled catheter and the wire was connected to a transducer (Meritrans, MeriMedical Systems, UT and Smart Map, Volcano, Tokyo, Japan) as Herberg et al described,18_{and the pressure}

ob-tained by the pressure wire was calibrated against the pressure measured simultaneously with the fluid filled lumen at end-diastole. LV pressure by the pressure wire was recorded at end expiration for 3 consecutive cardiac cycles to obtained Tau (Figure 1) and Tau was derived from a monoexponential fit to the LV pressure decay with a zero asymptote,19_because

many clinical studies and the European guidelines for the di-agnosis of HFPEF have used the Tau derived from the zero-asymptote method.20_{Abnormal LV relaxation was defined as}

Tau>48 ms. The pressure measurements were performed by investigators who were unaware of the echocardiographic data. We determined the interobserver variability of the IVRT, the ePCWP, and the eTau estimated by the novel method in 25 randomly selected recordings that were measured by 2 ob-servers using STE in a blinded manner. Likewise, we determined the intraobserver variability of the IVRT, the ePCWP, and the eTau estimated by the novel method in 25 randomly selected recordings that were measured twice by 1 observer. The data are expressed as the mean± 1 standard deviation. The relationships between Tau by catheterization and e’, E velocity, IVRT, longitudinal strain, and eTau were tested by simple linear regression analysis. Multivariate re-gression analysis was performed using stepwise forward selection to identify the independent predictors of Tau. Bland-Altman analysis was used to determine the agreement between

the 2 methods. Receiver operating characteristic curve (ROC) analysis was used to determine the optimal cutoff values and sensitivity and specificity of the echocardiographic param-eters to predict a prolonged Tau (>48 ms). A p-value of <0.05 was considered to be significant. Statistical analyses were per-formed using SPSS statistical software, version 21.0 (IBM Corp., Armonk, New York).

Results

One patient with mitral stenosis, 4 patients with atrial fi-brillation during examination, and 3 patients with poor echocardiographic imaging were excluded. Finally we en-rolled 110 patients including 65 patients with angina pectoris,

Table 1

A. Patients’ characteristics (n= 110). B. Echocardiographic parameters and he-modynamic data

A Valuable

Age (years) 72± 8

Male/Female 82/28

Body surface area (m2_{) 1.67± 0.19}

Heart Rate (beat/min) 67± 12

Systolic blood pressure (mm Hg) 128± 20

Diastolic blood pressure (mm Hg) 70± 13

Angina pectoris 65 (59%)

Prior myocardial infarction 17 (15%)

Hypertensive heart disease 16 (15%)

Congestive heart failure 9 (8%)

Paroxysmal atrial fibrillation 4 (4%)

ARBs and/or ACEIs 52 (47%)

Beta blockers 35 (32%)

Calcium channel blockers 53 (48%)

Diuretics 12 (11%) Statin 68 (62%) Digitalis 1 (1%) Antiplatelet agents 86 (78%) Anticoagulant agents 11 (10%) Antidiabetic agents 43 (39%) B Valuable LV end-diastolic dimension (mm) 45.7± 5.1 LV mass index (g/m2_{) 101.9± 100.6} LV ejection fraction (%) 62.8± 11.1 e’ (cm/s) 6.0± 2.1 E/e’ 11.7± 4.4

Isovolumic relaxation time (ms) 106.9± 21.4

LV longitudinal strain (%) -20.8± 6.2 ePCWP (mm Hg) 10.2± 3.5 eTau (ms) 43.2± 9.7 Tau (ms) 44.1± 8.3 LV end-diastolic pressure (mm Hg) 11.9± 4.3 Negative dp/dt (mm Hg/ms) 1370± 300

LV= left ventricular; e’ = early diastolic mitral annular velocity; E/e’ = ratio of early diastolic LV inflow velocity (E) to e’; ePCWP= estimated pul-monary capillary wedge pressure obtained by echocardiography; eTau= estimated Tau obtained by echocardiography; negative dp/dt= negative peak instantaneous rate of LV pressure decline; ARB= angiotensin II receptor blocker; ACEI= angiotensin-converting enzyme inhibitor.

1647 Methods/Noninvasive Evaluation of Diastolic Function

17 patients with previous myocardial infarction, 16 patients with hypertensive heart disease, 9 patients with congestive heart failure, and 4 patients with paroxysmal atrial fibrilla-tion. The patients’ clinical characteristics are listed inTable 1A, and echocardiographic and hemodynamic variables are listed

inTable 1B. LVEF in the patients was 63± 11% (range: 41%

to 81%). The e’ and E/e’ in the patients were 6.0± 2.1 (range: 1.1% to 14.3%) and 11.7± 4.4 (range: 1.2% to 29.0%), re-spectively. The eTau estimated by echo was 43± 10 ms (range: 26 to 67 ms). The ePCWP assessed using KT index had a good correlation with LV end-diastolic pressure (r= 0.65, p <0.001). Tau obtained by catheterization was 44± 8 ms (range: 20 to 63 ms). There was a good correlation between the eTau es-timated by STE and Tau obtained by cardiac catheterization (r= 0.693, p <0.001) (Figure 2andTable 2). The results of linear regression analysis to evaluate the relationship between Tau obtained by catheterization and echo parameters are shown

inFigure 2and listed inTable 2. Multiple regression

analy-sis revealed that the eTau was the best independent predictor of Tau measured by catheterization among the various echocardiographic parameters (Table 3). Bland-Altman analy-sis revealed a good agreement between the eTau and Tau with

neither fixed nor proportional bias (Figure 3) and Kappa co-efficient for prolonged Tau and eTau was 0.679 (p<0.001). The accuracy of this eTau was examined in patients with de-pressed EF<50% versus those with normal EF. Thirteen patients had the reduced EF (43.1± 2.7%; range: 41% to 49%), a mean eTau of 48.2± 7.1 ms (range: 32 to 66 ms), and Tau of 47.5± 8.1 ms (range: 36 to 58 ms). Nighty-seven pa-tients had normal EF (65.7± 7.4%; range: 50% to 81%), a mean eTau of 42.9± 8.9 ms (range: 25 to 71 ms), and Tau

Figure 2. Correlations of echocardiographic parameters with Tau obtained by catheterization. e’= early diastolic mitral annular velocity; E/e’ = ratio of early diastolic LV inflow velocity (E) to e’; IVRT= isovolumic relaxation time; L-strain = LV longitudinal strain; eTau = estimated Tau obtained by echocardiography.

Table 2

Correlation between echocardiographic parameters and Tau

R P-value

e’ -0.326 <0.001

E 0.023 0.811

Isovolumic relaxation time 0.326 <0.001

LV longitudinal strain 0.393 <0.001

eTau 0.693 <0.001

e’= early diastolic mitral annular velocity; E’ = early diastolic LV inflow velocity.

of 43.7.± 8.8 ms (range: 20 to 63 ms). Overall, good corre-lations were noted in both groups (EF<50%: r = 0.68; normal EF: r= 0.75; both p <0.001). The ROC curve analysis for pre-dicting prolonged Tau (>48 ms) was shown inFigure 4, and the sensitivity and specificity are listed in Table 4. The intraobserver correlation coefficient and difference in the IVRT, the ePCWP, and the eTau estimated using the novel method were 0.99 and 1.68±1.53, 0.94 and 0.06 ± 0.68, and 0.97 and 0.20± 1.40, respectively. The interobserver correlation coefficient and difference in the IVRT, the ePCWP and the eTau estimated using the novel method were 0.98 and 1.12 ±2.01, 0.86 and −1.64 ±0.70, and 0.98 and −0.24 ± 1.22, respectively.

Discussion

The present study demonstrated that the eTau noninvasively assessed by echocardiography using the formula: IVRT/(ln 0.9× systolic blood pressure−ln ePCWP) had a strong cor-relation with Tau invasively obtained by catheterization in both patients with preserved EF and reduced EF. Among all the ultrasound parameters measured, the multivariate regres-sion analysis revealed that the eTau obtained by echo was the best predictor of Tau. The ROC curve analysis revealed a good sensitivity and specificity of the eTau for predicting pro-longed Tau. The eTau is a useful predictor of LV relaxation and may have utility and value in the routine clinical prac-tice for the diagnosis and treatment in cardiac disease, especially HFPEF.

Impaired LV relaxation and increased diastolic stiffness are the major components of diastolic dysfunction.21 _LV

isovolumic relaxation can be quantified by the invasive mea-surement of LV pressure with a high-fidelity micromanometer

catheter and calculation of Tau.19,22_{However, there has been}

no established echocardiographic parameter to noninvasively and accurately assess LV relaxation. Doppler echocardiographic measure and tissue Doppler velocity have been used exten-sively to estimate LV diastolic performance. However, most Doppler parameters derived from such velocity profiles have several limitations.14

Nishimura et al23_{demonstrated that the estimated Tau using}

the Doppler mitral regurgitation signal had a good correla-tion with Tau when a zero asymptote was used. However, only patients with chronic mitral regurgitation were included and the correlation of percentage change of Doppler-derived Tau and that in catheter-derived Tau was poor, which demon-strated that Doppler-derived Tau may not be sufficiently accurate for detecting small changes in Tau.23_{IVRT is easily}

measured by Doppler echocardiography as a direct estima-tion of Tau.24_{However, IVRT has limited accuracy, given the}

confounding influence of preload on it, which opposes the effect of impaired LV relaxation. In the present study, IVRT had a significant but poor correlation with Tau. To over-come this limitation, it is possible to combine IVRT with noninvasive estimates of LV end-systolic pressure and LA pres-sure to derive Tau.14_{This approach has been validated and}

can be used to provide a quantitative estimate of Tau in place of a qualitative assessment of LV relaxation.15,24_{The e’ that}

represents regional tissue velocity was considered a surro-gate maker for Tau6 _{and has been thought to reflect LV}

relaxation.7_{However, the e’ is affected not only by active}

re-laxation but also by elastic recoil and lengthening load.25_In

the present study, the e’ had a significant but poor correla-tion with Tau. Likewise, the E-wave that is also affected by loading conditions26_{had no significant correlation with Tau}

in the present study. The STE derived parameters may have a better correlation with LV relaxation than the tissue Doppler-derived parameters.17,27_{Hayashi et al}27_{demonstrated that the}

correlation of peak longitudinal strain was the strongest to predict Tau among the STE derived parameters. However, the correlation coefficient was not so good (r= −0.45, p <0.001)27

and in our study the value was also not so strongly corre-lated with Tau. LV global strain measurement by 2-dimensional STE has several limitations such as out of plane phenom-enon and poor reproducibility.

In contrast, the eTau noninvasively estimated by KT index had a strong correlation with Tau and was an independent pre-dictor of Tau. The degree of accuracy of the eTau would be adequate for the quantification of LV diastolic function. LV relaxation is impaired at first in patients with diastolic dys-function and even in the early stage of HTN and LV

Table 3

Multiple regression analysis among echocardiographic parameters

Model Unstandardized Coefficients Standardized Coefficients T Sig. 95.0% Confidence Interval for B VIF

B Std. Error Beta Lower Bound Upper Bound

Constant 34.193 5.204 6.571 <0.001 23.875 44.511

eTau 0.761 0.082 0.809 9.265 <0.001 0.598 0.924 2.228

L-Strain 0.224 0.091 0.158 2.452 0.016 0.043 0.405 1.221

e’ -0.898 0.267 -0.214 -3.358 0.001 -1.428 -0.368 1.182

IVRT -0.121 0.038 -0.275 -3.196 0.002 -0.196 -0.046 2.161

L-strain= LV longitudinal strain; e’ = early diastolic mitral annular velocity; IVRT = Isovolumic relaxation time; VIF = variance inflation factor.

Figure 3. Bland-Altman analysis to compare Tau measured by catheteriza-tion and eTau estimated by echocardiography.

1649 Methods/Noninvasive Evaluation of Diastolic Function

hypertrophy.28,29_{Thus, the eTau and the ePCWP may become}

a novel and useful index to evaluate LV relaxation and dia-stolic function for the diagnosis and treatment of heart disease, especially HFPEF.

There are several limitations in this study. First, al-though we focused on the noninvasive estimation of the time constant of LV relaxation and showed that there is a good reproducibility in the assessment of the eTau, there are several noninvasive measurements, each with its errors to some extent. Second, the index of LV isovolumic relax-ation cannot be considered an index of “intrinsic” relaxrelax-ation rate unless loading conditions are held constant.22_One

prac-tical way to overcome this limitation is to examine the indices of relaxation over a range of loads. The time of onset of active relaxation depends on systolic events such as the duration of contraction.30 _{Therefore, the rate and}

extent of relaxation, in addition to being dependent on ven-tricular load, are also dependent on the duration of systole.30

Thus, a complex interaction between events traditionally considered to occur during systole can affect the measure-ment and interpretation of active relaxation.22_{Third, none}

of our patients had moderate to severe valvular heart disease or acute coronary syndrome, thus, the utility of this method in patients with valvular heart disease or acute coronary syndrome is unknown. In conclusion, this study demon-strated that the eTau by our noninvasive method has a good correlation with Tau by catheterization and that the eTau is a more powerful and useful predictor of LV relaxation than any other ultrasound parameters. The eTau can be noninvasively and accurately estimated by echocardiography and may have utility and value in the routine clinical prac-tice for the diagnosis and treatment in diastolic dysfunction.

Figure 4. Receiver operating characteristic curves for e’, IVRT, L-strain and eTau to distinguish patients with prolonged Tau obtained by catheterization>48 ms. AUC= area under the curve, e’ = early diastolic mitral annular velocity; IVRT = isovolumic relaxation time; L-strain = LV longitudinal strain; eTau = esti-mated Tau obtained by echocardiography.

Table 4

Sensitivity, specificity, PPV, and NPV of echocardiographic parameters to predict prolonged Tau (>48 ms)

Category AUC P-value Cutoff level Sensitivity Specificity PPV NPV

e’ 0.655 0.013 5.15 53 71 41 80

IVRT (ms) 0.685 0.003 112.00 60 70 43 82

L-Strain (%) 0.736 <0.001 -20.05 77 65 45 88

eTau (ms) 0.869 <0.001 47.50 77 91 77 91

e’= early diastolic mitral annular velocity; IVRT = isovolumic relaxation time; L-strain = LV longitudinal strain; eTau = estimated Tau obtained by echocardiography; AUC= area under the curve; PPV = positive predictive value; NPV = negative predictive value.

Disclosures

The authors have no conflicts of interest to disclose.

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1651 Methods/Noninvasive Evaluation of Diastolic Function