Pediatr Blood Cancer 2014;61:2059–2064

Association Between Right Ventricular Dysfunction and Restrictive Lung Diseasein Childhood Cancer Survivors as Measured by Quantitative Echocardiography

Amee Patel, DO,1 Constance Weismann, MD,2 Pnina Weiss, MD,1 Kerry Russell, MD, PhD,3 Alia Bazzy-Asaad, MD,1

and Nina S. Kadan-Lottick, MD, MSPH4*

INTRODUCTION

Pulmonary complications are the third leading cause of

treatment-related death in childhood cancer survivors [1,2].

Children who receive lung-toxic chemotherapy and/or thoracic

radiation for malignancy have an increased risk for developing

restrictive lung disease as a result of increased fibroblast activity [3].

In non-cancer patients with pulmonary fibrosis, right ventricular

(RV) dysfunction and pulmonary hypertension can develop as a

result of vascular remodeling of the pulmonary capillaries [4].

Recently, the St. Jude Lifetime Cohort study found an increased

prevalence of elevated tricuspid regurgitant jet velocity in a cross

sectional study of 485 adult survivors of childhood cancer with a

history of thoracic radiation, which is indicative of pulmonary

hypertension [5]. Therefore, childhood cancer survivors who have

received lung-toxic therapy may benefit from cardiac surveillance

independent of exposure to cardiotoxic chemotherapeutic agents.

The left ventricle (LV) is bullet-shaped and the main direction of

shortening is concentric allowing systolic function to be determined

by simple geometric calculations. As a result, left ventricular

systolic function can be easily assessed qualitatively and

quantitatively by two-dimensional echocardiographic methods [6].

In contrast, the geometry of the right ventricle is crescent shaped and

shortens longitudinally. Therefore, there are no reliable geometric

calculations to estimate RV function by 2-dimensional echocardi-

ography. Traditionally, RV systolic function is assessed qualitatively.

Qualitative measurements of the RV have limited diagnostic

accuracy when compared to the gold standard, which is cardiac

MRI [7]. There is evidence that the addition of quantitative

echocardiographic parameters may be helpful in identifying RV

dysfunction [8–10].

Tissue Doppler imaging (TDI) quantifies high amplitude, low

velocity signals of myocardial tissue motion. This allows measure-

ment of ventricular contractility by evaluating relative changes in

tissue velocity before global dysfunction is detected [11,12].

Isovolumetric acceleration (IVA) (Fig. 1) has been found to be

useful in identifying early right ventricular systolic impairment in

patients with restrictive lung disease secondary to systemic

sclerosis [13]. IVA is measured at the basal segment of the right

ventricle free wall and is a measurement that is independent of

preload and afterload, which suggests that LV function does not

affect this measurement directly [14,15]. This parameter has been

shown to correlate well to MRI-derived right ventricle ejection

fraction in patients with pulmonary arterial hypertension regardless

of the hemodynamics of the pulmonary circulation [8,16,17].

Unlike the IVA, tricuspid annular plane systolic excursion

(TAPSE) is load-dependent (Fig. 2). However, it is easy to measure

using TDI [18]. It has been a useful index for evaluating right

ventricular longitudinal function in patients with congestive heart

failure and in patients with systemic sclerosis [13,19]. In addition,

TAPSE is a simple, noninvasive measure of RV systolic function in

adult patients with pulmonary hypertension [20,21].

The use of quantitative echocardiographic parameters to detect

right ventricular dysfunction has not yet been studied in childhood

cancer survivors with restrictive lung disease. In this study, we

identified survivors who had received lung-toxic therapies at a

regional childhood cancer referral center. We then compared right

Background. Restrictive lung disease is a complication inchildhood cancer survivors who received lung-toxic chemotherapyand/or thoracic radiation. Left ventricular dysfunction is documentedin these survivors, but less is known about right ventricular (RV)function.Quantitative echocardiographymay help detect subclinicalRV dysfunction. The aim of this study was to assess RV functionquantitatively in childhood cancer survivors after lung-toxic therapy.Procedures. We identified records of 33 childhood cancer survivorswho (1) were treated with lung-toxic therapy and/or radiation, (2)were cancer-free for� one year after therapy, and (3) had pulmonaryfunction tests and echocardiograms from their most recent follow-upvisit. Results. Participants’ mean age was 11.6�4.5 years at cancerdiagnosis and 23�8.6 years at evaluation. The most commondiagnosis was lymphoma/leukemia (n¼27). Twenty-nine subjects

had anthracycline exposure. Eleven of the 33 subjects demonstratedrestrictive pulmonary impairment (total lung capacity 3.69�1.5 L[69.3�22.4% predicted]). Among quantitative measures of RVfunction, isovolumetric acceleration (IVA), ameasure of contractility,was significantly lower in the group with restrictive lung disease(2.42�0.56 vs. 1.83�0.78m/sec2; P<0.05). There was a trendtowards lower tissue Doppler derived S’ and tricuspid annular planesystolic excursion in the group with restrictive lung disease. Subjectswith restrictive lung disease were found to have � 2 abnormalparameters (P<0.01). Conclusion. IVA may detect early RVdysfunction in childhood cancer survivors with restrictive lungdisease. Our findings require confirmation in a larger studypopulation and validation by cardiac MRI. Pediatr Blood Cancer2014;61:2059–2064. # 2014 Wiley Periodicals, Inc.

Key words: right ventricular dysfunction; tissue Doppler imaging; cardiac; pulmonary; childhood cancer; late effects; survivorship

1Section of Pediatric Respiratory Medicine, Yale University School of

Medicine, New Haven, Connecticut; 2Section of Pediatric Cardiology,

Yale University School ofMedicine, NewHaven, Connecticut; 3Section

of Cardiology, Yale University School of Medicine, New Haven,

Connecticut; 4Section of Pediatric Hematology-Oncology, Yale

University School of Medicine and Yale Cancer Center, New Haven,

Connecticut

Grant sponsor: American Cancer Society Scholar Grant; Grant number:

119700-RSGHP-10-107-01-CPHPS

Conflict of interest: None.

�Correspondence to: Nina S. Kadan-Lottick, Yale University School ofMedicine, Section of Pediatric Hematology-Oncology, 333 Cedar

Street, LMP 2073, New Haven, CT 06520-8064. E-mail: nina.kadan-

lottick@yale.edu

Received 6 January 2014; Accepted 19 May 2014

�C 2014 Wiley Periodicals, Inc.DOI 10.1002/pbc.25157Published online 17 August 2014 in Wiley Online Library(wileyonlinelibrary.com).

ventricular function among subjects with and without restrictive

lung disease. Our aim was to determine whether restrictive lung

disease in childhood cancer survivors is associated with RV

dysfunction using quantitative echocardiographic parameters.

METHODS

Study Population

Through a retrospective medical record review, we screened 646

childhood cancer survivors from the Yale-NewHavenHospital long-

term follow-up clinic as well as the Yale-New Haven tumor registry

and pulmonary function laboratory records. Subjects were selected if

they met the following inclusion criteria: diagnosis of any malignant

neoplasm at age� 21 years, treatment or follow-up care at Yale-New

Haven Hospital, history of exposure to a lung-toxic agent such as

thoracic radiation and/or chemotherapy (bleomycin, busulfan,

CCNU, BCNU), � 1 year status post completion of cancer-related

therapy, completion of echocardiogram after January 2011 (when

TDI was added to standard 2-dimensional echocardiography at

Yale), and availability of pulmonary function tests (spirometry and

lung volumes) within 2 years of the echocardiogram. One subject

was excluded from the study secondary to surgical biopsy of the

lung; none of the potential subjects were smokers. The Yale

University School of Medicine Institutional Review Board approved

this study for clinical investigation.

Pulmonary Function Testing

The pulmonary function test for each subject was read by a

pediatric pulmonologist at the time the test was originally performed.

For the current study, each pulmonary function test was reviewed a

second time by a senior pediatric pulmonary fellow (A.P.) who

resolved any discordant results with a third pulmonologist (P.W.).

The pulmonary function tests were categorized as consistent or not

consistent with restrictive lung disease. Restrictive lung disease was

defined as total lung capacity (TLC) less than 80% of predicted,

forced vital capacity (FVC) less than 80% of predicted, and FEV1/

FVC ratio greater than 80%, per the National Health and Nutrition

Examination Survey (NHANES) criteria for both spirometry and

lung volumes [22].

Echocardiography

Previously performed routine echocardiograms, completed

between January 2011 and January 2013, were reviewed by one

of the investigators (C.W.), a pediatric cardiologist, whowas blinded

to the pulmonary function status of the subjects. Echocardiograms

were performed using the Philips IE33 (Philips Medical Systems,

Andover, MA), Vivid E9 (GE Medical Systems, Milwaukee, WI),

and the Siemens Sequoia SC2000 (SiemensMedical Solutions USA,

Mountain View, CA) equipment. Probe frequency was selected as

appropriate for patient size. Left ventricular size, systolic and

diastolic function was assessed by Simpson’s method, M-mode,

pulse wave and tissue Doppler imaging (TDI). Systolic and end-

diastolic right ventricular pressures were estimated using the

velocity across the tricuspid (TRJV) and pulmonary regurgitation

jets, respectively. Qualitative assessment of right ventricular status

included size, presence or absence of a pericardial effusion, and

flattening of the interventricular septum in systole. Quantitative

parameters of RV systolic function were derived from an apical four-

chamber view utilizing pulse wave TDI and M-mode at the lateral

tricuspid valve annulus. RV isovolumetric acceleration (IVA), RV

tissue Doppler S’, and tricuspid annular plane systolic excursion

(TAPSE)were alsomeasured (Figs. 1 and 2). Allmeasurementswere

averaged over three beats. Normal values for the TDI parameters are

as follows: TRJV� 2.7m/s, TDI S’� 10cm/s, TAPSE� 2 cm, and

IVA�1.7m/s2 [23]. Normal values for left-sided echocardiographic

parameters are as follows: Simpsons ejection fraction > 55%, left

ventricular fractional shortening� 28%, mitral valve inflow at early

diastole � 1m/s, mitral valve inflow at late diastole � 0.5m/s [24].

Statistical Analysis

Descriptive statistics were used to characterize the subject

sample in terms of demographics, cancer diagnosis, and treatment

exposures. Mean values and frequencies of values in the abnormal

range for the different parameters of quantitative TDI were

compared in subjects with and without restrictive lung disease.

Comparisons between groups were done with the Wilcoxon Rank

test and Fisher Exact test; analyses were two-sided with a P value

< 0.05 designated as statistically significant. All analyses were

completed with the Statistical Package for Social Sciences (SPSS

version 19, IBM, Chicago, Illinois, 2010).

RESULTS

Thirty-three childhood cancer survivors met eligibility criteria

(Table I). Of these, 22 subjects had normal lung function and 11

Fig. 1. Tissue Doppler Imaging at the lateral tricuspid valve annulus

(TDI S’): maximal systolic velocity [cm/s] and Isovolumetric

acceleration (IVA) [m/s2]: measure of RV contractility.

Fig. 2. Tricuspid annular plane systolic excursion (TAPSE): M-Mode

measurement [cm].

Pediatr Blood Cancer DOI 10.1002/pbc

2060 Patel et al.

TABLE I. Characteristics of Subjects With Normal Lung Function Versus Restrictive Lung Disease

Normal lung function (n¼ 22) Restrictive lung disease (n¼ 11) P-value�

Total lung capacityMean absolute value (L) 5.03� 1.51 3.69� 1.50 0.01Percent predicted 97.7� 14.9 69.3� 22.4 0.0008

Primary Cancer Diagnosis n(%)Hodgkin lymphoma 17 (77%) 4 (36%) 0.006Non-Hodgkin lymphoma 2 (9%) 0 0.99CNS tumors 2 (9%) 1 (9%) 0.99Leukemia 1 (5%) 3 (27%) 0.10[Ewing Sarcoma 0 1 (9%) 0.35Wilms Tumor 0 1 (9%) 0.35Thyroid carcinoma 0 1 (9%) 0.35

Age of diagnosis (yrs)Mean� standard deviation (range) 12.5 � 4.6 (7.9–17.1) 9.8� 3.9 (5.9–13.7) 0.06

Age at the time of analysis (yrs)Mean� standard deviation (range) 19.6 � 7.8 (11.8-27.4) 23.9 � 9.6 (14.3–33.5) 0.30

Elapsed time since completion of therapy (yrs)Mean� standard deviation (range) 7.6� 5.8 (1.8–13.4) 13.8� 9.3 (4.5–23.1) 0.06

Female Gender n(%) 10 (45%) 3 (27%) 0.46Race n(%)

White 17 (77%) 9 (82%) 0.99Black 3 (14%) 1 (9%)Other 2 (9%) 1 (9%)

Lung-Toxic Therapy n(%)Lung radiation only 4 (18%) 5 (45%) 0.39Chemotherapy only 5 (23%) 0 0.29Both radiation & chemotherapy 13 (59%) 6 (55%) 0.76

Anthracyclineexposure n(%) 95% (21) 73% (8) 0.78

�Fisher Exact test or Wilcoxon Rank test, as appropriate.

Fig. 3. Mean echocardiographic measurements (with 95% confidence interval) in subjects with normal lung function versus restrictive lung

disease. Of note, mean isovolumetric acceleration (IVA) in subjects with normal lung function was significantly greater than in the group with

restrictive lung disease (Panel A).

Pediatr Blood Cancer DOI 10.1002/pbc

Right Ventricular Dysfunction and Lung Disease 2061

subjects had restrictive lung disease. Mean age at cancer diagnosis

in the group with normal lung function was slightly greater than

those with restrictive lung disease (12.5� 4.6 vs. 9.8� 3.9 years;

P¼ 0.06). Therewas an overall predominance of lymphoma in both

groups; a higher proportion of subjects with Hodgkin lymphoma

had normal lung function (P¼ 0.006). There was no difference in

the frequency of other diagnoses between the groups. A greater

proportion of subjects with normal lung function received

anthracyclines, but the difference was not statistically significant.

Mean values of left ventricular function parameters were compared

between both groups. There was no statistical difference between

patients with normal lung function versus thosewith restrictive lung

diseasewith respect to the Simpsons ejection fraction, LV fractional

shortening, mitral valve inflow at early diastole, and mitral value

inflow at late diastole (data not shown).

Quantitative Right Ventricular Measurements

First, mean values of right ventricular function parameters were

compared in the two groups with and without restrictive lung

disease. Subjects with restrictive lung disease had a lowermean IVA

(1.83� 0.92 vs. 2.41� 0.57; 0¼ 0.02) than those with normal lung

function (Fig. 3). While the group with restrictive lung disease also

had higher mean TRJVand lower TAPSE, the differences were not

statistically significant.

The frequencies of right ventricular TDI values in the

abnormal range were then compared. Fifty-five percent of

subjects with restrictive lung disease had an abnormal IVA versus

5% (P¼ 0.003) in the group with normal lung function (Table II).

Similar to the analysis of the mean values, frequencies of

abnormal TRJV, TDI S’, and TAPSE did not meet statistical

TABLE II. Comparison of Right Ventricular Parameters by Tissue Doppler Imaging in Subjects With Normal Lung Function Versus

Restrictive Lung Disease

Echocardiographic parameter Normal Range

N (%) with abnormal echo value

P-value

Normal lung function

(n¼ 22)

Restrictive lung disease

(n¼ 11)

TRJV � 2.7m/s 2 (10%) 4 (40%) 0.07

TDI S’ � 10 cm/s 5 (23%) 4 (36%) 0.68

TAPSE � 2 cm 7 (32%) 7 (64%) 0.14

IVA � 1.7m/s2 1 (5%) 6 (55%) 0.003

� 2 abnormal echo parameters 4 (18%) 8 (73%) 0.01

TRJV, tricuspid regurgitant jet velocity; TDI S’, Right ventricular S’; TAPSE, Tricuspid annular plane systolic excursion; IVA, Isovolumetric

acceleration.

TABLE III. Characteristics of Subjects With Abnormal IVA

Subject

number Cancer diagnosis

Gender

(M/F)

Age at

diagnosis

(yrs)

Age at

evaluation

(yrs)

Restrictive

lung disease

(yes/no)

Cumulative dose

of lung toxic

chemotherapy

(bleomycin,

busulfan, BCNU,

CCNU)

Chest

radiation

Cumulative

dose of

doxorubicin

1 ALL Male 17 33 No None TBI (dose unknown) Yes (dose unknown)

2 ALL Male 8 19 Yes None 1.3� 103 cGy 270mg/m2

3 Ewing sarcoma Male 10 30 Yes None 1.5� 103 cGy 370mg/m2

4 Hodgkin lymphoma Female 17 29 No Bleomycin 45 iu/m2 2.27� 103 cGy 180mg/m2

5 Hodgkin lymphoma Female 5 16 Yes None 1.4� 103 cGy None

6 Hodgkin lymphoma Male 16 18 No Bleomycin 144 iu/m2 2.1� 103 cGy 540mg/m2

7 Hodgkin lymphoma Male 14 20 Yes Bleomycin 163 iu/m2 None 620mg/m2

8 Hodgkin lymphoma Female 17 19 No Bleomycin 187 iu/m2 2.1� 103 cGy 625mg/m2

9 Hodgkin lymphoma Female 12 19 No Bleomycin (dose

unknown)

2.1� 103 cGy 240mg/m2

10 Hodgkin lymphoma Female 10 15 No Bleomycin 88 iu/m2 2.1� 103 cGy 220mg/m2

11 Medulloblastoma Male 8 27 Yes None 5.0� 103 cGy None

12 Non- Hodgkin

lymphoma

Female 12 21 No BCNU (dose

unknown)

TBI (dose unknown) 300mg/m2

13 Non-Hodgkin

lymphoma

Male 15 23 No None 4.5� 103 cGy 300mg/m2

14 Wilms tumor Male 4 27 Yes None 1.2� 103 cGy 230mg/m2

IVA, isovolumetric acceleration; All, acute lymphoblastic leukemia; BCNU, Carmustine; CCNU, Lomustine; cGy, centigray; TBI, total body

irradiation.

Pediatr Blood Cancer DOI 10.1002/pbc

2062 Patel et al.

significance criteria between the subjects with and without

restrictive lung disease. However, a greater proportion of subjects

with restrictive lung disease had two or more abnormal

echocardiographic parameters when compared to those with

normal lung function (P< 0.01). Table III shows characteristics of

the subjects with an abnormal IVA at the time of echocardio-

graphic evaluation.

DISCUSSION

Our results suggest that IVA or a combination of quantitative

echocardiographic parameters may detect subclinical RV dysfunc-

tion in childhood cancer survivors with restrictive lung disease.

Quantitative echocardiography has been shown to be more sensitive

in detecting right ventricular dysfunction than qualitative echocar-

diography in patients with congenital heart disease, systemic

sclerosis and pulmonary arterial hypertension [13,16,20,25,26].

Our study included echocardiographic parameters of the isovolumic

contraction phase (IVA) and the ejection phase (S’ and TAPSE).

Interestingly, only the former was abnormal in patients with

restrictive lung disease, when used in isolation. IVA is thought to be

a marker of contractility that is resistant to acute changes in

loading conditions [27]. Previous studies support that IVA may

be superior to ejection phase indices in detecting ventricular

dysfunction [13,28].

IVA at the lateral tricuspid valve annulus is obtained from

tissue Doppler images, which can be obtained routinely in most

pediatric echocardiography laboratories. Incorporating IVA

measurements into clinical practice may prompt further evaluation

to utilize cardiac MRI and/or cardiac catheterization, which are

two methods of describing RV systolic function. The utilization of

IVA may allow earlier medical intervention and may ultimately

improve survival especially if the childhood cancer survivor is

asymptomatic.

Our study has several limitations. First, our sample size was

small. However, despite the small sample size, there was a

significant decrease in the IVA in the group with restrictive lung

disease. Another limitation is that we did not compare the

echocardiographic findings to cardiac MRI, which is the gold

standard for diagnosing impairment of RV function [16,17]. In

addition, it is possible that anthracycline exposure confounded the

results because of direct cardiotoxic effects. However, if this were

the case, RV function should be worse in the group with a higher

exposure to anthracyclines (i.e., the non-restrictive lung disease

group). In contrast, we found that RV function was worse in the

restrictive lung disease group, which had fewer subjects with

anthracycline exposure. There was also no difference in LV

diastolic and systolic function between both groups. Finally, this

study examined patients at only one point of time. Because this

study is cross-sectional and not longitudinal in design, we are

unable to determinewhen RV dysfunction actually developed or the

direction of any causal relationship between RV and pulmonary

function. We plan to follow all patients from this study

longitudinally with serial echocardiograms and pulmonary function

tests to determine if there is temporal association between

pulmonary fibrosis and the development of RV dysfunction.

In conclusion, childhood cancer survivors who receive lung-

toxic chemotherapy and/or thoracic radiation are at increased risk

for restrictive lung disease and right ventricular dysfunction. Our

study suggests an abnormally low IVA or impairment of at least two

out of the four quantitative parameters (TAPSE, TDI S’, IVA,

TRJV) could be a sensitive tool to detect early RV dysfunction.

However, this study identifies each parameter as a single

measurement in one point of time. This may not be enough to

discriminate between children with or without RV dysfunction.

Therefore, it may be more helpful in a given child to follow changes

in IVA over a period of time. Additional studies would be needed to

identify subclinical right ventricular dysfunction through quantita-

tive echocardiographic measurements, which may indicate RV

pathology as well as insight for strategies for intervention and

prevention for further disease progression. Our results should be

validated in a larger sample size and compared to the gold standard-

cardiac MRI as well as correlate to patient-reported symptoms.

ACKNOWLEDGMENTS

Dr. Kadan-Lottick is supported in part by American Cancer

Society Scholar Grant 119700-RSGHP-10-107-01-CPHPS,a Team

Brent St. Baldrick’s Foundation Scholar award, and a Hyundai

Hope on Wheels award.

REFERENCES

1. Mertens A, Liu Q, Neglia J, et al. Cause-specific late mortality among 5-year survivors of childhood

cancer: The childhood cancer survivor study. J Natl Cancer Inst 2008;100:1368–1379.

2. AlehanD, SahinM, Varan A, et al. Tissue Doppler evaluation of systolic and diastolic cardiac functions in

long-term survivors of Hodgkin lymphoma. Pediatr Blood Cancer 2012;58:250–255.

3. Mulder R, Thonissen N, Pal H, et al. Pulmonary function impairment measured by pulmonary function

tests in long-term survivors of childhood cancer. Thorax 2011;66:1065–1071.

4. Han M, McLaughlin V, Criner G, et al. Cardiovascular involvement in general medical conditions:

Pulmonary diseases and the heart. Circulation 2007;116:2992–3005.

5. Armstrong G, Joshi V, Zhu L, et al. Increased tricuspid regurgitant jet velocity by Doppler

echocardiography in adult survivors of childhood cancer: A report from the St Jude Lifetime Cohort

Study. J Clin Oncol 2013;31:774–781.

6. Omenn S, Nishimura R, Appleton C, et al. Clinical utility of Doppler echocardiography and tissue

Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous

Doppler-catheterization study. Circulation 2000;102:1788–1794.

7. Voelkel N, Quaife R, Leinwand L, et al. Right ventricular function and failure: Report of a national heart,

lung, and blood institute working group on cellular and molecular mechanisms of right heart failure.

Circulation 2006;114:1883–1891.

8. Ling L, Obuchowski N, Rodriguez L, et al. Accuracy and interobserver concordance of

echocardiographic assessment of right ventricular size and systolic function: A quality control exercise.

J Am Soc Echocardiog 2012;25:709–713.

9. Bleeker G, Holman E, Abraham T, et al. Tissue Doppler imaging to evaluate right ventricular function.

InYu C, Marwick T, editors. Myocardial Imaging: Tissue Doppler and Speckle Tracking. Wiley-

Blackwell; 2007. 245–251.

10. Bleeker G, Steendijk P, Holman E, et al. Assessing right ventricular function: The role of

echocardiography and complementary technologies. Heart 2006;92:19–26.

11. Ho C, Solomon S. A clinician’s guide to tissue Doppler imaging. Circulation 2006;113:396–398.

12. Jassal D, Han S, Hans C, et al. Utility of tissue Doppler and strain rate imaging in the early detection of

trastuzumab and anthracycline mediated cardiomyopathy. J Am Soc Echocardiog 2009;22:418–424.

13. Schatteke S, Knebel F, Grohmann A, et al. Early right ventricular systolic dysfunction in patients with

systemic sclerosis without pulmonary hypertension: A Doppler tissue and speckle tracking

echocardiographic study. Cardiovasc Ultrasound 2010;8:3.

14. Haddad F, Hunt S, Rosenthal D, et al. Right ventricular function in cardiovascular disease. Part I:

Anatomy, Physiology, Aging, and Functional Assessment of the Right Ventricle. Circulation

2008;117:1436–1448.

15. Shimizu M, Nii M, Konstantinov I, et al. Isovolumic but not ejection phase doppler tissue indices detect

left ventricular dysfunction caused by coronary stenosis. J Am Soc Echocardiogr 2005;18:1241–1246.

16. Yang T, Liang Y, Zhang Y, et al. Echocardiographic parameters in patients with pulmonary arterial

hypertension: Correlations with right ventricular ejection fraction derived from cardiac magnetic

resonance and hemodynamics. PLoS ONE 2013;8:e71276, 1–6.

17. Puchalski M, Williams R, Askovich B, et al. Assessment of right ventricular size and function: Echo

versus magnetic resonance imaging. Congenit Heart Disease 2007;2:27–31.

18. Meluzin J, Spinarova L, Bakala J, et al. Pulsed Doppler tissue imaging of the velocity of tricuspid annular

systolic motion: A new, rapid, and non-invasive method of evaluating right ventricular systolic function.

Eur Heart J 2001;22:340–348.

19. Lee C-Y, Chang S-M, Hsiao S-H, et al. Right heart function and scleroderma: Insights from tricuspid

annular plane systolic excursion. Echocardiography 2007;24:118–125.

20. Forfia P, Fisher M, Mathai S, et al. Tricuspid annular displacement predicts survival in pulmonary

hypertension. Am J Respir Crit Care Med 2006;174:1034–1041.

21. Rudski L, et al. Guidelines for the echocardiographic assessment of the right heart in adults: A report from

the American Society of Echocardiography. J Am Soc Echocardiogr 2010;23:685–713.

22. Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur resp J

2006;5:948–968.

23. Rudski L, Lai W, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in

adults: A report from the American Society of Echocardiography. J Am Soc Echocardiogr 2010;23:685–

713.

24. Nagueh S, Appleton C, Gillebert T, et al. Recommendations for the evaluation of left ventricular diastolic

function by echocardiography. J Am Soc Echocardiogr 2009;22:107–133.

Pediatr Blood Cancer DOI 10.1002/pbc

Right Ventricular Dysfunction and Lung Disease 2063

25. Koestenberger M, Friedberg M, Ravekes W, et al. Non-invasive imaging for

congenital heart disease: Recent innovations in transthoracic echocardiography. J Clin Exp Cardiolog

2012; 2.

26. Lytrivi ID, Lai WW, Ko HH, et al. Color Doppler tissue imaging for evaluation of right

ventricular systolic function in patients with congenital heart disease. J Am Soc Echocardiogr

2005;18:1099–1104.

27. Vogel M, Schmidt M, Kristiansen S, et al. Validation of myocardial acceleration during isovolumic

contraction as a novel noninvasive index of right ventricular contractility: Comparison with ventricular

pressure-volume relations in an animal model. Circulation 2002;105:1693–1699.

28. Roche S, Vogel M, Pitkanen O, et al. Isovolumic acceleration at rest and during exercise in children:

Normal values for the left ventricle and first noninvasive demonstration of exercise-induced force-

frequency relationships. J Am Coll Cardiol 2011;57:1100–1107.

Pediatr Blood Cancer DOI 10.1002/pbc

2064 Patel et al.