Diastolic Function and Patient-Reported Quality of Life ... - Springer Link

Pediatr Cardiol (2012) 33:618–624 DOI 10.1007/s00246-012-0189-8

ORIGINAL ARTICLE

Diastolic Function and Patient-Reported Quality of Life for Adolescents and Adults With Repaired Tetralogy of Fallot: A Tissue Doppler Study Jimmy C. Lu • Timothy B. Cotts • Adam L. Dorfman

Received: 3 August 2011 / Accepted: 19 November 2011 / Published online: 12 February 2012 Ó Springer Science+Business Media, LLC 2012

Abstract Left ventricular systolic function is an important indicator of clinical well-being and outcomes for patients with repaired tetralogy of Fallot (TOF). This study tested the hypothesis that left ventricular diastolic function by pulsedwave tissue Doppler is associated with quality of life in this population. In this study, 38 subjects (age, 31.0 ± 14.1 years) with repaired TOF underwent echocardiogram and completed the Short-Form 36, version 2, a validated quality-of-life assessment, within a median of 0 days (range, 0–90 days). Available cardiovascular magnetic resonance data within 1 year after the echocardiogram were analyzed. The ratio of peak early inflow to peak early annular velocity (E/E0 ) at the lateral mitral annulus correlated inversely with the ability to participate in usual activities without physical limitations (r = -0.37; p = 0.02), whereas the right ventricular diastolic indices were not predictive. The relation of left ventricular diastolic function to quality of life was independent of left ventricular systolic function. This may be related to adverse ventricular–ventricular interactions J. C. Lu (&) T. B. Cotts A. L. Dorfman Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, University of Michigan, Congenital Heart Center, C.S. Mott Children’s Hospital, 1540 East Hospital Drive, Ann Arbor, MI 48109-4204, USA e-mail: [email protected] J. C. Lu A. L. Dorfman Division of Pediatric Radiology, Department of Radiology, University of Michigan, Congenital Heart Center, C.S. Mott Children’s Hospital, 1540 East Hospital Drive, Ann Arbor, MI 48109-4204, USA T. B. Cotts Division of Cardiology, Department of Internal Medicine, University of Michigan, Congenital Heart Center, C.S. Mott Children’s Hospital, 1540 East Hospital Drive, Ann Arbor, MI 48109-4204, USA

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because lateral mitral E/E0 correlated with tricuspid E/E0 (r = 0.46; p = 0.008) and the right ventricular myocardial performance index (r = 0.42; p = 0.01). Pulsed-wave tissue Doppler of the mitral annulus is a useful tool in this population and may potentially identify patients in need of intervention before the development of left or right ventricular systolic dysfunction. Keywords Adult congenital heart disease Diastolic function Quality of life Tetralogy of Fallot

Introduction Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease, with excellent long-term outcome after repair [18]. Whereas a great deal of focus in the literature has been on right ventricular performance in this population, left ventricular systolic dysfunction is the best predictor of adverse clinical outcomes such as death, sustained ventricular tachycardia, or progression to New York Heart Association (NYHA) class 3 or 4 [7, 9, 14]. Both left and right ventricular systolic dysfunction are associated with decreased patient-reported quality of life [16]. However, earlier indicators of ventricular impairment are needed because systolic function may not improve after pulmonary valve replacement [8, 21, 25]. Left ventricular diastolic dysfunction can precede systolic dysfunction in several pathologic processes [28] and has been associated with decreased quality of life for adults with structurally normal hearts [13, 20]. This study therefore aimed to evaluate the hypothesis that left ventricular diastolic parameters by tissue Doppler echocardiography predict patient-reported quality of life for patients with repaired TOF.

Pediatr Cardiol (2012) 33:618–624

Methods For this cross-sectional study, patients 14 years or older with repaired TOF were enrolled at the time of their clinic visit at the University of Michigan Congenital Heart Center between June 2008 and December 2009. Subjects were excluded if they had additional significant cardiac malformations (e.g., complete atrioventricular canal defect) or could not complete the quality-of-life assessment due to cognitive impairment. All the subjects and parents of minors provided informed consent. This study was approved by the institutional committee on human research. Two-dimensional transthoracic echocardiograms were performed using the Philips iE33 (Philips, Best, Netherlands) or the Acuson Sequoia C512 (Siemens, Erlangen, Germany). Pulsed-wave tissue Doppler samples were recorded at the lateral tricuspid and the medial and lateral mitral annuli, and peak early (E0 ), peak atrial (A0 ), and peak systolic (S0 ) annular velocities were measured. The myocardial performance index (MPI) was calculated from the pulsed-wave tissue Doppler tracings, which have been shown to correlate with values from spectral Doppler tracings with similar diagnostic value [5, 10, 11]. Peak early inflow velocity (E) was measured with pulsed-wave spectral Doppler at the leaflet tips of the corresponding atrioventricular valve. Left ventricular diastolic indices were compared with age-specific normative values from Nagueh et al. [19]. Subjects with echocardiograms performed more than 3 months after the quality-of-life assessment were excluded. For the purposes of this study, quality of life was defined as the subject’s perception of health status and ability to function at home and in the workplace. At enrollment or on the day of the echocardiogram, subjects completed the Short-Form 36, version 2, a quality-of-life assessment clinically validated for patients 14 years or older [27]. This tool evaluates eight health domains (Table 1), with two component summary scores: the physical component summary and the mental component summary. The scores were normalized for age and compared with populationbased normative data. The primary outcome of interest for the potential predictors of patient-reported quality of life was the physical component summary, but subscales of physical functioning, role-physical, and general health also were chosen a priori to represent the physical impact of disease because they reflect physical limitations or a perspective of current and future overall health. Cardiovascular magnetic resonance data were retrospectively evaluated for patients with an examination performed within 1 year of echocardiographic and qualityof-life data. Right ventricular end-diastolic and end-systolic volumes and ejection fraction and left ventricular ejection fraction were evaluated.

619 Table 1 Subscales of the Short-Form 36, version 2 Two summary scores Physical component summary score Mental component summary score Eight subscales Physical functioning: ability to perform physical activities Role-physical: participation in work or usual activities without physical limitations Bodily pain: absence of pain that impacts normal activities General health: perception of general health and its likelihood to change Vitality: feeling of energy and subjective well-being Social functioning: ability to participate in social activities Role-emotional: participation in work or usual activities without emotional limitations Mental health: overall feeling of peace, happiness, and calm

Data are presented as mean ± standard deviation unless otherwise noted. Continuous variables were compared using Student’s t test. Correlation was evaluated by Pearson’s correlation coefficient. To evaluate magnitude of effect, odds ratios, with and without control for the other covariate, were calculated by conditional maximum likelihood estimate for an age-adjusted z-score of -1 or less (to represent a clinically important difference in quality of life), with 95% confidence intervals calculated by mid-p exact. Due to the sample size, for each parameter to be evaluated, the population was divided into quartiles to compare odds of a clinically important decrease in quality of life. A p value of 0.05 or less was considered statistically significant.

Results A total of 38 patients completed the Short-Form 36, version 2 within a median of 0 days (range, 0–90 days) from the echocardiogram. The patient characteristics are listed in Table 2. Tissue Doppler indices of the overall population are presented in Table 3. Markers of abnormal left ventricular diastolic function were common. The mitral E/A ratio was elevated in 10 (26.3%) of the 38 patients. Medial mitral E0 was below normal in 15 (39.5%) of the 38 patients, with medial mitral E/E0 higher than 15 in 5 patients (13.2%). Lateral mitral E0 was below normal in 10 (26.3%) of the 38 patients, with lateral mitral E/E0 higher than 15 in 2 patients (5.3%). Patient-reported quality of life in this population was similar to population-derived norms. There were statistically significant but small differences in physical component summary, physical functioning, role-physical, and general health scores. These differences were less than one standard deviation and likely are not clinically significant (Fig. 1).

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Table 2 Patient characteristics (n = 38) Male: n (%)

20 (53)

Age (years)

31.0 ± 14.1

Median age at repair (range)

2.6 (8 days–22 years)

Type of repair n (%) Transannular patch

17 (45)

Right ventricle-to-pulmonary artery conduit

8 (21)

Valve-sparing

1 (3)

Unspecified

12 (32)

End-diastolic forward flow in the main pulmonary artery

16 (42)

Exercise capacity (n = 7): n (%) Exercise duration (min)

10.6 ± 2.1

Maximum oxygen consumption (ml/kg/min)

25.3 ± 5.7

Fig. 1 Overall patient-reported quality of life. Horizontal dashed lines represent a population mean of 50.0, with standard deviation of 10.0. PCS physical component summary score, MCS mental component summary score, PF physical functioning, RP role-physical, GH general health *p \ 0.05

Cardiovascular magnetic resonance parameters (n = 18) Left ventricular ejection fraction (%) Right ventricular end-diastolic volume (ml/m2)

52.7 ± 5.7 156.8 ± 57.9

Right ventricular ejection fraction (%)

45.3 ± 9.0

Data are given as n (%) or mean ± standard deviation unless otherwise noted Table 3 Overall tissue Doppler indices (n = 38) Medial mitral annulus E/E0

10.5 ± 5.2

E0 /A0

1.6 ± 1.0

S0 (cm/s)

7.8 ± 2.2

MPI Lateral mitral annulus

0.58 ± 0.20

E/E0

7.2 ± 3.4

E0 /A0

2.0 ± 0.8

S0 (cm/s)

9.5 ± 2.6

MPI

0.54 ± 0.29

Lateral tricuspid annulus E/E0

5.9 ± 3.7

E0 /A0

1.9 ± 0.8

S0

9.2 ± 2.3

MPI

0.59 ± 0.20

MPI myocardial performance index Data are given as mean ± standard deviation unless otherwise noted

There was a relation between patient-reported quality of life and left ventricular diastolic indices but not right ventricular diastolic indices. Role-physical scores correlated inversely with medial mitral E/E0 (r = -0.32; p \ 0.05) and lateral mitral E/E0 (r = -0.37; p = 0.02), but only lateral mitral E/E0 predicted a clinically important decrease in role-physical scores (Fig. 2). After adjustment

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Fig. 2 Odds ratios for a Short-Form 36 age-adjusted z-score of -1 or lower for patients in the highest quartile of lateral mitral E/E0 (a) or medial mitral E/E0 (b). PCS physical component summary score, PF physical functioning, RP role-physical, GH general health

for left ventricular systolic function (lateral S0 velocity), lateral mitral E/E0 remained an independent predictor of decreased role-physical scores, with an odds ratio of 10.3 (95% confidence interval, 1.16–257). Tricuspid E/A, E/E0 , and E0 /A0 did not correlate with quality-of-life scores or predict clinically significant decreases in quality of life. Left ventricular diastolic function was related to some parameters of right ventricular function. Lateral mitral E/E0 correlated with tricuspid E/E0 (r = 0.46; p = 0.008) and right ventricular MPI (r = 0.42; p = 0.01). For 18 patients


who had a cardiovascular magnetic resonance exam within 39 ± 29 days of their echocardiogram, lateral mitral E/E0 did not correlate with right ventricular end-diastolic volume or ejection fraction. Left ventricular diastolic function did not relate to left ventricular systolic function, and the ejection fraction by cardiovascular magnetic resonance did not differ significantly for patients in the top quartile of lateral mitral E/E0 (51.4 ± 5.5 vs 53.2 ± 5.9%; p = 0.57). Left ventricular systolic function also predicted patientreported quality of life. Lateral mitral S0 correlated with role-physical scores (r = 0.35; p = 0.03) and predicted a clinically important decrease in role-physical scores (Fig. 3a). Patients in the lowest quartile of medial mitral S0 also demonstrated a clinically important decrease in physical functioning scores (Fig. 3b). Tricuspid S0 did not

Fig. 3 Odds ratios for a Short-Form 36 age-adjusted z-score of -1 or lower for patients in the lowest quartile of lateral mitral S0 (a) or medial mitral S0 (b), or in the highest quartile of the right ventricular myocardial performance index (MPI) (c). PCS physical component summary score, PF physical functioning, RP role-physical, GH general health

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correlate with quality-of-life scores; nor did it correlate with right ventricular ejection fraction by cardiovascular magnetic resonance. As a measure of global ventricular function, impaired right ventricular MPI trended with clinically important decreases in physical functioning scores (Fig. 3c), although this did not meet statistical significance, and there was no linear relation between left or right ventricular MPI and patient-reported quality of life.

Discussion The aforementioned data demonstrate that left ventricular diastolic parameters are associated with patient-reported quality of life in repaired TOF independently of left ventricular systolic function, whereas right ventricular diastolic parameters are not. Left ventricular systolic function also is associated with quality of life in these patients. Left ventricular systolic function is known to be a clinical indicator of well-being and a predictor of outcome in this population. Using cardiovascular magnetic resonance, we have previously shown that left ventricular ejection fraction less than 55% is associated with clinically significant decreases in quality of life [16]. Depressed left ventricular ejection fraction was the strongest predictor of a major adverse event or impaired clinical status in multivariate models [7, 14] and is a risk factor for sudden death in this population [9]. These data demonstrate that left ventricular diastolic indices also are an important clinical indicator of wellbeing given their association with quality of life. The strength of correlation was modest, as expected, consistent with the complex multifactorial nature of quality of life. Left ventricular diastolic dysfunction in this population may be related to adverse ventricular–ventricular interactions. A dilated or poorly compliant right ventricle could potentially affect left ventricular filling. Left ventricular end-diastolic volume increases with relief of right ventricular volume overload after pulmonary valve replacement [4, 8]. Cheung et al. [3] demonstrated decreased left ventricular global and circumferential strain with right ventricular dilation. Although left ventricular diastolic function did not correlate with right ventricular end-diastolic volume, it did correlate with measures of right ventricular diastolic and global dysfunction. This is consistent with data demonstrating abnormal right ventricular diastolic function such as end-diastolic forward flow in the main pulmonary artery, in both normal-sized right ventricles as evidence of restrictive right ventricular physiology [6], and in dilated right ventricles as evidence of an overdistended right ventricle [12, 16, 26]. Left ventricular diastolic dysfunction could be an indicator of adverse ventricular–ventricular interactions and could potentially

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be an early indicator to help identify candidates for pulmonary valve replacement. The relation of left ventricular diastolic function and quality of life does not appear to be confounded by the right ventricular ejection fraction, which did not relate to the mitral E/E0 ratio, or by right ventricular end-diastolic volume and right ventricular diastolic dysfunction because these markers had no relation to quality of life, either in these data or from cardiovascular magnetic resonance-derived values [16]. This relation also does not appear to be confounded by left ventricular systolic function, based on correction for S0 velocity. Right ventricular systolic function also has been shown to correlate with exercise capacity [17, 24] and quality of life [16] in this population. The lack of association between tricuspid S0 velocity and quality of life fits with published data showing that the relation of tricuspid S0 with global right ventricular systolic function in this patient population is weak, particularly with dysfunction of the right ventricular outflow tract [15]. Tricuspid S0 velocity did not relate to right ventricular ejection fraction in this population. The use of right ventricular MPI as a marker of right ventricular function in patients with repaired TOF can be problematic because the period of isovolumetric relaxation may be decreased or absent [1]. However, MPI has been shown to have clinical value because it relates to right ventricular ejection fraction, exercise capacity, and quality of life in this population [2, 23]. Right ventricular diastolic dysfunction is common in patients with repaired TOF, with end-diastolic forward flow in the main pulmonary artery detected by cardiovascular magnetic resonance in more than two-thirds of patients [16, 26]. Although the lack of association between right ventricular diastolic dysfunction and quality of life could be related to limitations of statistical power, this finding is consistent with our prior report using other measures by cardiovascular magnetic resonance [16]. This may be due to the high prevalence of right ventricular diastolic dysfunction such that the degree of dysfunction has little discriminative use in this population. Alternatively, isolated right ventricular diastolic dysfunction may be well tolerated, as evidenced by quality of life similar to that of the overall population despite the high prevalence of abnormal diastolic function. However, clinical well-being may become affected with progression to right ventricular systolic dysfunction or left ventricular diastolic or systolic dysfunction. Longitudinal data would be required to test this hypothesis. Annular velocities by tissue Doppler imaging can be readily obtained, even in patients with poor acoustic windows [29]. Tissue Doppler imaging is widely available, rapid, and easily performed, with good reproducibility [22],

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making it a particularly attractive noninvasive option for routine follow-up evaluation of these patients. It offers information that is complementary to the volumetric data often obtained by cardiovascular magnetic resonance and may be an important adjunct for the clinical care of this population. This study has several limitations. The cross-sectional nature of this study prevents speculation on future decreases in quality of life or changes in quality of life after pulmonary valve replacement. We also are unable to determine whether patients in this population with left ventricular diastolic dysfunction will progress to systolic dysfunction. We recognize the limitations of S0 as a measure of systolic function but note that these findings are consistent with those using ejection fraction by cardiovascular magnetic resonance. A relatively limited definition for quality of life was used, focusing on patients’ functional ability and perception of their health status. Additional instruments could be used in further evaluations to address a broader definition. The significance of various measures relating to different scales is unclear and was not differentiated in this study because it was not known a priori which measures would most closely reflect patient-reported limitations in functional health status. Changes in quality of life would be expected to cross subscales, and the noted effects may be related to which subscales are most sensitive. Lack of statistical significance in other subscales and the physical component summary score (PCS) score may reflect power limitations with this small sample size. The discriminatory value of individual survey items could not be determined due to the small sample size. We do not believe that the subjective nature of patient-reported quality of life is a limitation because findings are consistent with published results. In addition, we believe that the use of patient-centered metrics is particularly relevant when criteria for intervention are unclear. Finally, many of these variables covary, either as different measures of diastolic dysfunction or due to ventricular–ventricular interactions. The small sample size prohibited a more detailed multivariate analysis. The wide confidence intervals, related to sample size, also limited ability to evaluate the relative strength of various predictors.

Conclusions Left ventricular diastolic dysfunction, as assessed by tissue Doppler indices, is associated with clinically important decreases in quality of life for a population of patients with repaired TOF, independently of systolic dysfunction.


Pulsed-wave tissue Doppler imaging is a readily available and useful tool in this population because left ventricular diastolic dysfunction may be an early indicator of an impaired ventricle and potentially a marker for intervention. Assessing tissue Doppler values over time in a cohort of TOF patients is warranted.

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