Subclinical Cardiac Dysfunction Detected by Strain Imaging During Breast Irradiation With Persistent Changes 6 Weeks After Treatment

International Journal of

Radiation Oncology biology

physics

www.redjournal.org

Clinical Investigation

Subclinical Cardiac Dysfunction Detected by Strain Imaging During Breast Irradiation With Persistent Changes 6 Weeks After Treatment Queenie Lo, MBBS(Hons), BSc(Med), FRACP,*,y Leia Hee, BMedSc(Hons), MClinTRes, PhD,*,y,z Vikneswary Batumalai, BSc, MHlthSc,*,y,z Christine Allman, AMS, MSc,y Peter MacDonald, MBBS, PhD, FRACP,*,x Geoff P. Delaney, MBBS, MD, PhD, FRANZCR,*,y,z Denise Lonergan, MBBS, PhD, FRANZCR,y,z and Liza Thomas, MBBS(Hons), PhD, FRACP*,y *University of New South Wales, Sydney, NSW, Australia; yLiverpool Hospital, Sydney, NSW, Australia; zIngham Institute of Applied Medical Research, Liverpool, NSW, Australia; and xSt. Vincent’s Hospital, Sydney, NSW, Australia Received Aug 9, 2014, and in revised form Oct 22, 2014. Accepted for publication Nov 11, 2014.

Summary The acute adverse effects of chest radiation on cardiac function are not well characterized. Herein we report the findings of a longitudinal echocardiographic study of left-sided breast cancer patients undergoing chest radiation, utilizing 2dimensional strain imaging technique. The detection of subclinical cardiac deformation abnormalities despite normal traditional parameters of cardiac function has implications on the early detection and risk

Purpose: To evaluate 2-dimensional strain imaging (SI) for the detection of subclinical myocardial dysfunction during and after radiation therapy (RT). Methods and Materials: Forty women with left-sided breast cancer, undergoing only adjuvant RT to the left chest, were prospectively recruited. Standard echocardiography and SI were performed at baseline, during RT, and 6 weeks after RT. Strain (S) and strain rate (Sr) parameters were measured in the longitudinal, circumferential, and radial planes. Correlation of change in global longitudinal strain (GLS % and D change) and the volume of heart receiving 30 Gy (V30) and mean heart dose (MHD) were examined. Results: Left ventricular ejection fraction was unchanged; however, longitudinal systolic S and Sr and radial S were significantly reduced during RT and remained reduced at 6 weeks after treatment [longitudinal S (%) 20.44  2.66 baseline vs 18.60  2.70* during RT vs 18.34  2.86* at 6 weeks after RT; longitudinal Sr (s1) 1.19  0.21 vs 1.06  0.18* vs 1.06  0.16*; radial S (%) 56.66  18.57 vs 46.93  14.56* vs 49.22  15.81*; *P<.05 vs baseline]. Diastolic Sr were only reduced 6 weeks after RT [longitudinal E Sr (s1) 1.47  0.32 vs 1.29  0.27*; longitudinal A Sr (s1) 1.19  0.31 vs 1.03  0.24*; *P<.05 vs baseline], whereas circumferential strain was preserved throughout. A modest correlation between S and Sr and V30 and

Reprint requests to: Liza Thomas, MBBS(Hons), PhD, FRACP, Liverpool Hospital, Cardiology Department, Liverpool, NSW 2170, Australia. Tel: (þ61) 02-8738-7637; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 92, No. 2, pp. 268e276, 2015 0360-3016/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.11.016

Conflict of interest: none.

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stratification of patients at risk for radiation-induced heart disease.

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MHD was observed (GLS D change and V30 r Z 0.314, PZ.05; GLS % change and V30 r Z 0.288, PZ.076; GLS D change and MHD r Z 0.348, PZ.03; GLS % change and MHD r Z 0.346, PZ.031). Conclusions: Subclinical myocardial dysfunction was detected by 2-dimensional SI during RT, with changes persisting 6 weeks after treatment, though long-term effects remain unknown. Additionally, a modest correlation between strain reduction and radiation dose was observed. Ó 2015 Elsevier Inc. All rights reserved.

Introduction Breast cancer is the leading cause of cancer-related death in women worldwide (1). Radiation therapy (RT) is used in the management of approximately 80% of early breast cancer patients (2) and is effective in the local control of disease, thereby improving mortality (3). However, radiation is potentially associated with cardiac toxicity (4), with variable latency in the development of cardiotoxic effects (5). Echocardiographic strain and strain rate imaging have detected subclinical myocardial changes in various disease processes including diabetes (6), hypertension (7), and infiltrative cardiomyopathies (8). Strain imaging can also monitor patient treatment response in a variety of conditions (9-11). More recently strain imaging has been used for the early detection of chemotherapy-related cardiotoxicity (12, 13). Erven et al (14, 15) have utilized Doppler myocardial strain imaging in their studies of breast cancer patients undergoing combined chemo-radiotherapy. In this study we examined the application of 2-dimensional (2D) speckle strain imaging for the detection of subclinical left ventricular (LV) abnormalities, if any, in the acute phase of RT in breast cancer patients who did not receive chemotherapy. We also sought to determine whether there was a correlation between the altered strain parameters and radiation dose.

Methods and Materials Patient population Fifty-eight female breast cancer patients were screened from Liverpool Hospital and Campbelltown Hospital; 8 did not fulfill inclusion criteria, 6 withdrew consent, and 4 patients had technical problems with echocardiograms. Forty women of the 58 were prospectively enrolled (April 2009 to November 2012). Inclusion criteria were histologically proven left-sided breast cancer treated with surgery (lumpectomy or mastectomy with or without axillary dissection), who were chemotherapy naı¨ve and were only treated with adjuvant RT to the chest with no nodal RT. Hormonal treatment was administered in the case of hormone receptor positivity (nZ22). Exclusion criteria were prior chemotherapy or RT, previous ischemic heart disease, heart failure, or significant valvular disease. All recruited subjects were in sinus rhythm and had no history of arrhythmias. The study

protocol was approved by the hospital and local area health service ethics committee; recruited patients provided written, informed consent.

Radiation technique All patients underwent a routine pre-treatment noncontrast computed tomography scan for RT planning. Breast RT was performed with tangential photon beams, with attempts made to minimize the amount of heart in the RT field, although no attempts were made to shield the heart if this compromised the dose to the breast. Patients were treated supine on a breast board. Six megavolts and/or a mix of 6 MV and 18 MV were used. Treatment was either standard (50 Gy in 25 fractions) or hypofractionated (42.4 Gy in 16 fractions) protocols. In the case of breast-conserving surgery, an additional dose was delivered (10 Gy in 5 fractions or 16 Gy in 8 fractions) as the “boost phase” to the tumoral cavity at the radiation oncologists’ discretion. As the contribution to the total heart dose is negligible, the boost dose was excluded from analysis.

Radiation doseefunction relations The RT planning computed tomography images were imported into a 3-dimensional treatment planning system (Xio V4.4.0; Elekta, Stockholm, Sweden) and were orientated to correspond to the echocardiographic apical 4-chamber view with myocardial segments defined similar to segmental analysis performed on echocardiography. The extent of heart tissue within the plane of the RT beam was determined; the heart and LV were volumed according to a validated voluming atlas (16). The average segmental RT doses were obtained from the dosimetry of each patient. Both RT time course and spatial distribution were correlated to strain (S) and strain rate (Sr) parameters. Dose-volume histograms were analyzed for the volume of heart receiving 25 Gy (V25) and 30 Gy (V30). Mean heart and mean LV dose were also obtained.

Echocardiographic examination A comprehensive transthoracic echocardiogram was performed at baseline (pre-RT), during RT (at 4 weeks for the standard protocol and at 3 weeks for the hypofractionated protocol) and 6 weeks after RT using Vivid 7 or E9 ultrasound

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Fig. 1. Two-dimensional speckle tracking strain imaging of a chest radiation study patient. (A) Longitudinal strain. (B) Longitudinal strain rate from apical 4-chamber view. scanners (GE Vingmed, Horten, Norway) equipped with a 2.5-MHz broadband transducer. Two-dimensional, Doppler, and M-mode measurements were performed, and framerate optimized (60 frames per second) LV apical 2-, 3-, 4-chamber, and midlevel short axis views were stored for offline 2D speckle tracking strain analysis. All echocardiograms were performed by 2 research sonographers. Bi-plane Simpson’s LV ejection fraction (LVEF), tissue velocity, and 2D S and Sr were measured in the longitudinal,

circumferential, and radial planes using dedicated software (Echopac, GE Vingmed). Strain traces were obtained throughout the cardiac cycle after semiautomated tissue tracking and analyzed as an average of 3 cardiac cycles. Segmental analysis of the LV (6 segments in the 3 apical and short-axis planes) was performed (Fig. 1A-D). Global S and Sr values were also obtained. Change from baseline (D change) was the difference in global longitudinal strain (GLS) between the baseline and final study; percentage

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(Continued) (C) Radial strain. (D) Circumferential strain from parasternal short-axis view.

change (% change) was calculated as D change divided by the baseline value, expressed as a percentage. Reduction of global longitudinal, radial, and circumferential strain by 10% to 19% and 20% from baseline were assessed.

Statistics Continuous variables are presented as mean  standard deviations, whereas categorical data are presented

as percentages. Repeated-measures analysis of variance was performed to examine within-patient differences. For continuous variables, Spearman coefficient of correlation was computed, and for categorical variables the Mann-Whitney test was used to examine correlation with RT dose. All tests were 2-sided, with a P value of .05 considered significant. Statistical analysis was performed with SPSS 18 (SPSS, Chicago, IL).

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Results

Table 2

Cardiovascular risk factors and hormonal treatment Parameter

Study population Baseline patient demographics, cardiovascular risk factors, and hormonal treatment are summarized in Tables 1 and 2. Of the 40 patients, 38 had all 3 studies; 2 patients were unable to undergo their second echocardiogram owing to RT-related skin reactions. Strain analysis could not be performed on the baseline study of 1 patient because of technical limitations; hence comparisons were performed on 39 patients.

Smoking Diabetes Hypertension Dyslipidemia Increased BMI Family history of IHD Estrogen receptor antagonist/ aromatase inhibitor

Frequency (%) 13 8 17 21 27 6 22

(32.5) (20) (42.5) (52.5) (67.5) (15) (55)

Abbreviation: IHD Z ischemic heart disease. Other abbreviation as in Table 1.

Radiation data Thirty patients received the standard RT protocol, and 10 received the hypofractionated protocol. Mean ( standard deviation) cumulative dose to tumor bed was 58.9  9.5 Gy. Mean V25 and V30 dose of the heart were 2.5%  2.1% and 2.2%  2.0%, respectively. Average mean heart dose (MHD) was 2.5  1.3 Gy, whereas mean LV dose was 4.8  2.7 Gy.

unchanged during RT but were reduced at 6 weeks after treatment (Table 3). Contrary to these observations, circumferential strain was preserved throughout RT (Fig. 2D, Table 3). Only in 8 of 39 was global circumferential strain reduced by >10%, with none reaching 20% (Table 4). A modest correlation was observed between GLS (D change and % change of strain) and V30 and MHD (Fig. 3A-D).

Echocardiographic parameters

Discussion No significant change was observed in LVEF (Fig. 2A, Table 3), whereas in contrast GLS and Sr were significantly reduced during RT compared with baseline (Fig. 2B, C, Table 3) and persisted to 6 weeks after RT (Table 3). No significant difference was observed between the second and third measurements. In 16 of 39 participants (41%), GLS was reduced by 10% to 19% after RT, and by 20% in 6 of 39 participants (15%) (Table 4). Similarly, radial strain was significantly reduced during RT and remained reduced at 6 weeks after treatment (Fig. 2D, Table 3). In 6 of 39 patients (15%), global radial strain was reduced by 10% to 19%, whereas 15 of 39 patients (38%) had reduction of 20% (Table 4). Global longitudinal early and late diastolic strain rate remained

Table 1

The myriad of published data on radiation-induced heart disease (RIHD) favor a comprehensive long-term follow-up of RT patients. An expert consensus for multimodality imaging evaluation of RIHD has been published (17), further highlighting the importance of this issue. Despite insights gathered from recent studies, little is known about the prevalence of subclinical cardiac involvement immediately following thoracic irradiation. The present study demonstrates alterations in myocardial mechanics by 2D strain imaging in the acute phase of RT. A differential reduction of longitudinal and radial strain and strain rate with relatively preserved circumferential parameters was observed during treatment and persisted for 6 weeks after RT completion.

Patient demographics Parameter

Age (y) Height (cm) Weight (kg) BMI (kg/m2) SBP (mm Hg) DBP (mm Hg) Mean dose to tumor bed (Gy) Mean V30 heart (%) Mean V25 heart (%) Mean heart dose (Gy) Mean LV dose (Gy)

Mean  SD 60.2 160.3 74.0 28.8 132 77 58.9 2.2 2.5 2.5 4.8

          

9.1 6.2 15.9 6.1 18 8 9.5 2.0 2.1 1.3 2.7

Abbreviations: BMI Z body mass index; DBP Z diastolic blood pressure; LV Z left ventricular; SBP Z systolic blood pressure.

Deformation parameters compared with traditional indices of systolic function Left ventricular ejection fraction is used for monitoring systolic function in patients undergoing chemotherapy. It provides a quantitative global assessment of LV systolic function and is a powerful prognostic marker for adverse cardiac events, particularly in myocardial infarction and heart failure (18, 19). The current definition of cardiotoxicity according to the Cardiac Review and Evaluation Committee is either a cardiomyopathy with decreased LVEF, a reduction of LVEF 5% to <55% with symptoms of heart failure, or

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A

B

80

-2

P=NS

70

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6 weeks post RT

-7

60 (%) 50 LVEF

40

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30

-17

20

C

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§

§

§ P<.05 compared to baseline

-22

D

1.3

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60 S Sr

0.3

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(s-1) -0.2

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40 (%) 20

Radial strain

0 Baseline

-0.7 §

-1.2

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-20

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§ § P<.05 compared to baseline

-40

Fig. 2. Time course of changes in (A) left ventricular ejection fraction (LVEF), (B) global longitudinal strain, (C) longitudinal systolic and diastolic strain rate (Sr), and (D) global circumferential and radial strain. RT Z radiation therapy. an asymptomatic reduction of LVEF 10% to <55% (20). Despites its merits, LVEF has limitations, including geometric assumptions for its calculation, its dependence on image quality with inherent foreshortening of the LV, and that it is load dependent (21, 22). Importantly, unlike strain imaging, LVEF is a measure of global function and more specifically evaluates LV radial function and cannot assess segmental function. Despite the preservation of LVEF, reductions in strain parameters were detected as early as 3 to 4 weeks after the commencement of RT and persisted to 6 weeks after RT. These findings are in keeping with a study by Erven et al (15) that demonstrated reduction in systolic S and Sr derived using Doppler tissue imaging, despite preserved

Table 3

LVEF, albeit in a group that had received chemotherapy as well.

Differential alterations in strain parameters Various studies in oncology (23, 24) and other disease states (11, 25) have demonstrated that reduction in GLS is a sensitive tool in detection of subclinical cardiac dysfunction. We also observed a radial strain reduction in a similar manner. Such a pattern of early longitudinal and radial strain reduction was reported by Stoodley et al (12), in breast cancer patients after anthracycline chemotherapy. Compared with GLS, radial strain has a greater variability

Strain (S) and strain rate (Sr) parameters

Parameter LVEF (%) Longitudinal Syst S (%) Longitudinal S Sr (s1) Longitudinal E Sr (s1) Longitudinal A Sr (s1) Circumferential S (%) Radial S (%)

Baseline 63 20.44 1.19 1.47 1.19 18.52 56.66

      

5 2.66 0.21 0.32 0.31 3.45 18.57

During RT 62 18.6 1.06 1.37 1.13 19.20 46.93

      

4 2.70* 0.18* 0.28 0.30 3.30 14.56*

6 weeks after RT

P

      

NS <.05 <.05 <.05 <.05 NS <.05

62 18.34 1.06 1.29 1.03 19.30 49.22

4 2.86* 0.16* 0.27* 0.24* 2.86 15.81*

Abbreviations: LVEF Z left ventricular ejection fraction; NS Z nonsignificant; RT Z radiation therapy. Other abbreviation as in Table 1. * P<.05 versus baseline.

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Table 4

Percentages of LVEF and strain reduction change before and after RT

Parameter LVEF Longitudinal S Circumferential S Radial S

Before RT 63 20.44 18.52 56.66

   

5 2.66 3.45 18.57

After RT

% (n) with 10%-19% reduction

% (n) with 20 reduction

   

0 41 (16/39) 21 (8/39) 15 (6/39)

0 15 (6/39) 0 38 (15/39)

62.4 18.34 19.30 49.22

4 2.86* 2.86 15.81*

Abbreviations as in Tables 1 and 3. * P<.05 versus baseline.

subsequent inflammatory response driving the vascular damage (31). However, a similar altered strain pattern has been reported in long-term survivors of Hodgkin lymphoma treated by mediastinal RT with or without anthracycline (32) and may suggest a persistence of this early insult.

of range and confidence intervals (26) and wider interobserver variability (27), hence cautious interpretation of radial strain reduction is required. In contrast to GLS and radial strain, circumferential strain remained largely unchanged. This differential alteration may be attributable to cardiac myofiber orientation. The subendocardial layer responsible for long-axis contraction is often first affected by disease. A reduction in longitudinal function is an early and accurate marker of LV dysfunction with susceptibility to varying etiologies, including ischemia, fibrosis, and hypertrophy (28-30). The reduction in strain parameters in the acute phase of RT may correlate at a cellular level to early events in the postradiation cascade involving endothelial cell loss with a

Proposed mechanism of RIHD There are several possible pathophysiologic mechanisms for RIHD. An animal model (33) demonstrated ultrastructural radiation damage to capillary networks during the asymptomatic phase of the disease, causing endothelial cytoplasm swelling, inflammation, and eventual destruction of the lumen. This results in myocyte ischemia, occurring

A

B 10.00 % Change in Global Strain

Delta Change of Global Strain

2.00 0.00 -2.00 -4.00 -6.00

-10.00 -20.00 -30.00 -40.00

-8.00 0.00

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-8.00 0.00

4.00 2.00 Mean Dose to Heart (Gy)

6.00 rho=0.348, P=.03

0.00

2.00 4.00 Mean Dose to Heart (Gy)

6.00 rho=0.346, P=.031

Fig. 3. Correlation between global longitudinal strain (D change and % change of strain) and V30 (A, B) and mean heart dose (C, D).

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within months after RT, reduced collateral flow, and vascular reserve that is often subclinical with progressive myocardial fibrosis (34). Second, it has been proposed that radiation causes damage to major epicardial arteries, with this phenomenon occurring in a time frame of years to decades after RT, a process similar to that of atherosclerosis (35). Third, a sustained inflammatory response and DNA injury attributable to nuclear factor-lB activation in irradiated human arteries has been proposed and supported by in vitro findings (36, 37).

Correlation between reduction in strain parameters and radiation dose Although previous data have shown that RT doses >30 Gy are relevant to increased RIHD risk (38), other groups have observed increased cardiac mortality even after exposure to doses of <5 Gy (39). Recently Darby et al (40) reported a linear increase of 7.4% in major coronary events per gray. Thus, the nature and magnitude of damage from lower RT doses is not well characterized, nor is it clear whether there is a threshold dose below which there is no risk. Because our study focused on breast tangents alone and nodal stations were not targeted, as expected our mean heart dose was much lower than that of other groups such as Erven et al (14, 15), who included patients receiving adjuvant chemotherapy and irradiated internal mammary nodes (IMN), which would translate to substantially higher heart dose. Yet, despite the fact that the mean heart radiation dose in our study was relatively low (2.5  1.3 Gy), a modest correlation between the reduction in GLS (% and D change) and V30 and MHD was observed. This suggests a significant impact even of a low RT dose and volume of heart exposed to RT. Previous large-scale studies (41, 42) by Taylor et al have shown that heart disease risk increases with escalating MHD. In addition, Erven et al (14) reported a dose-related reduction in myocardial function after acute RT by Doppler myocardial strain, although more than half of the cohort in that study had received prior adjuvant chemotherapy. Certain chemotherapeutic agents, such as anthracyclines, are potentially cardiotoxic and may have an additive effect to that seen with radiation (43). We deliberately excluded patients who received chemotherapy to avoid potential confounding effects of these treatments. However, our study findings may have significant clinical implications for breast cancer patients receiving adjuvant cardiotoxic chemotherapy, given that cardiotoxicity may be additive. Moreover, patient cohorts of early node-negative breast cancer are of particular long-term toxicity interest because of their good prognosis. Of note, we observed in our study heterogeneity in changes of S and Sr in response to RT. Darby et al (40) reported that women with pre-existing cardiac risk factors have greater risk of a major coronary event after RT. Further consideration may be required in women with bigger

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reductions in strain parameters (ie >20%), who may be more susceptible to RIHD and may explain why some women develop RT-induced cardiac toxicity at low doses.

Limitations We acknowledge the relatively small sample size and short follow-up of our study; however, we sought to assess the early effects of RT and to determine the utility of strain imaging for subclinical cardiac dysfunction. A clinical and echocardiographic follow-up with the current cohort, now at least 24 months after RT, is currently underway to assess longer-term changes. We did not recruit patients with right-sided breast cancer; however, Erven et al (20) included patients with rightsided cancer in their study and observed a significant reduction in strain only in patients with left-sided breast cancer who received RT.

Conclusion We report results of a longitudinal study that utilized 2D strain for the assessment of acute-phase radiation effect on the left ventricle in chemotherapy-naı¨ve patients, demonstrating a reduction in strain parameters with a modest correlation with radiation dosage, that was still evident 6 weeks after treatment completion. Although the relevance of strain reduction as a marker for future adverse events requires further study, strain imaging may have a potential role for screening and identification of “at-risk patients” undergoing oncological treatments who, with close monitoring, may have improved outcomes.

References 1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61:69-90. 2. Delaney G, Barton M, Jacob S. Estimation of an optimal radiotherapy utilization rate for breast carcinoma: A review of the evidence. Cancer 2003;98:1977-1986. 3. Clarke M, Collins R, Darby S, et al., Early Breast Cancer Trialists’ Collaborative Group. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and on 15year survival: An overview of the randomised trials. Lancet 2005;366: 2087-2106. 4. Gagliardi G, Lax I, Ottolenghi A, et al. Long-term cardiac mortality after radiotherapy of breast cancerdapplication of the relative seriality model. Br J Radiol 1996;69:839-846. 5. Sardaro A, Petruzzelli MF, D’Errico MP, et al. Radiation-induced cardiac damage in early breast cancer patients: Risk factors, biological mechanisms, radiobiology, and dosimetric constraints. Radiother Oncol 2012;103:133-142. 6. Fang ZY, Schull-Meade R, Downey M, et al. Determinants of subclinical diabetic heart disease. Diabetologia 2005;48:394-402. 7. Yuda S, Short L, Leano R, et al. Myocardial abnormalities in hypertensive patients with normal and abnormal left ventricular filling: A study of ultrasound tissue characterization and strain. Clin Sci (Lond) 2002;103:283-293.

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Lo et al.

8. Kato TS, Noda A, Izawa H, et al. Discrimination of non-obstructive hypertrophic cardiomyopathy from hypertensive left ventricular hypertrophy on the basis of strain rate imaging by tissue Doppler ultrasonography. Circulation 2004;110:3808-3814. 9. Mottram PM, Haluska B, Leano R, et al. Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation 2004;110:558-565. 10. Voigt JU, von Bibra H, Daniel WG. New techniques for the quantification of myocardial function: Acoustic quantification, color kinesis, tissue Doppler and “strain rate imaging” Z Kardiol 2000;89(Suppl. 1): 97-103. 11. Weidemann F, Breunig F, Beer M, et al. Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: A prospective strain rate imaging study. Circulation 2003; 108:1299-1301. 12. Stoodley PW, Richards DB, Hui R, et al. Two dimensional myocardial strain imaging detects changes in left ventricular systolic function immediately after anthracyclin chemotherapy. Eur J Echocardiogr 2011;12:945-952. 13. Sawaya H, Sebag IA, Plana JC, et al. Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclins, taxanes and trastuzumab. Circ Cardiovasc Imaging 2012;5:596-603. 14. Erven K, Jurcut R, Weltens C, et al. Acute radiation effects on cardiac function detected by strain rate imaging in breast cancer patients. Int J Radiat Oncol Biol Phys 2011;79:1444-1451. 15. Erven K, Florian A, Slagmolen P, et al. Subclinical cardiotoxicity detected by strain rate imaging up to 14 months after breast radiation therapy. Int J Radiat Oncol Biol Phys 2013;85:11721178. 16. Feng M, Moran JM, Koelling T, et al. Development and validation of a heart atlas to study cardiac exposure to radiation following treatment for breast cancer. Int J Radiat Oncol Biol Phys 2011;79:10-18. 17. Lancellotti P, Nkomo VT, Badano LP, et al. Expert consensus for multimodality imaging evaluation of cardiovascular complications of radiotherapy in adults: A report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. J Am Soc Echocardiogr 2013;26:1013-1032. 18. St. John Sutton M, Pfeffer MA, Plappert T, et al. Quantitative two dimensional echocardiograohic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. Circulation 1994;89:68-75. 19. Curtis JP, Sokol SI, Wang Y, et al. The association of left ventricular ejection fraction, mortality, and cause of death in stable outpatients with heart failure. J Am Coll Cardiol 2003;42:736-742. 20. Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002;20:12151221. 21. Kirkpatrick JN, Vannan MA, Narula J, et al. Echocardiography in heart failure. J Am Coll Cardiol 2007;50:381-396. 22. McGowan JH, Cleland JG. Reliability of reporting left ventricular systolic function by echocardiography: A systemic review of 3 methods. Am Heart J 2003;146:388-397. 23. Ho E, Brown A, Barrett P, et al. Subclinical anthracycline and trastuzumab induced cardiotoxicity in the long term follow up of asymptomatic breast cancer survivors: A speckle tracking echocardiographic study. Heart 2010;96:701-707. 24. Hare JL, Brown JK, Leano R, et al. Use of myocardial deformation imaging to detect preclinical myocardial dysfunction before

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25.

26.

27.

28.

29.

30. 31.

32.

33. 34.

35.

36.

37. 38.

39.

40.

41.

42.

43.

conventional measures in patients undergoing breast cancer treatment with trastuzumab. Am Heart J 2009;158:294-301. Serri K, Reant P, Lafitte M, et al. Global and regional myocardial function quantification by two dimensional strain: Application in hypertrophic cardiomyopathy. J Am Coll Cardiol 2006;47:1175-1181. Yingchoncharoen T, Agarwal S, Popovic ZB, et al. Normal ranges of left ventricular strain: A meta-analysis. J Am Soc Echocardiogr 2013; 26:185-191. Oxborough D, George K, Birch KM. Intraobserver reliability of twodimensional ultrasound derived strain imaging in the assessment of the left ventricle, right ventricle and left atrium of healthy human hearts. Echocardiography 2012;29:793-802. Edvardsen T, Helle-Valle T, Smiseth OA. Systolic dysfunction in heart failure with normal ejection fraction: Speckle-tracking echocardiography. Prog Cardiovasc Dis 2006;49:207-214. Ganame J, Claus P, Uyttebroeck A, et al. Myocardial dysfunction late after low-dose anthracycline treatment in asymptomatic pediatric patients. J Am Soc Echocardiogr 2007;20:1351-1358. Takeda S, Rimmington H, Smeeton N, et al. Long axis excursion in aortic stenosis. Heart 2001;86:52-56. Stewart F, Hoving S, Russell N. Vascular damage as an underlying mechanism of cardiac and celebral toxicity in irradiated cancer patients. Radiat Res 2010;174:865-869. Tsai HU, Gjesdal O, Wethal T, et al. Left ventricular function assessed by two-dimensional speckle tracking echocardiography in long-term survivors of Hodgkin’s lymphoma treated by mediastinal radiotherapy with or without anthracycline therapy. Am J Cardiol 2011;107:472-477. Fajardo LF, Stewart JR. Pathogenesis of radiation-induced myocardial fibrosis. Lab Invest 1973;29:244-257. Schultz-Hector S, Trott KR. Radiation-induced cardiovascular diseases: Is the epidemiologic evidence compatible with the radiobiologic data? Int J Radiat Oncol Biol Phys 2007;67:10-18. Darby SC, Cutter DJ, Boerma M, et al. Radiation-related heart disease: Current knowledge and future prospects. Int J Radiat Oncol Biol Phys 2010;76:656-665. Halle M, Gabrielsen A, Paulsson-Berne G, et al. Sustained inflammation due to nuclear factor kappa B activation in irradiated human arteries. J Am Coll Cardiol 2010;55:1227-1236. Weintraub NL, Jones WK, Manka D. Understanding radiation-induced vascular disease. J Am Coll Cardiol 2010;55:1237-1239. Gagliardi G, Lax I, Soderstrom S, et al. Prediction of excess risk of long term cardiac mortality after radiotherapy of stage I breast cancer. Radiother Oncol 1998;46:63-71. Carr ZA, Land CE, Kleinerman RA, et al. Coronary heart disease after radiotherapy for peptic ulcer disease. Int J Radiat Oncol Biol Phys 2005;61:842-850. Darby SC, Ewertz M, McGale P, et al. Risk of ischaemic heart disease in women after radiotherapy for breast cancer. N Eng J Med 2013;368: 987-998. Taylor CW, Nisbet A, McGale P, et al. Cardiac exposures in breast cancer radiotherapy: 1950-1990s. Int J Radiat Oncol Biol Phys 2007; 69:1484-1495. Taylor CW, Bronnum D, Darby SC, et al. Cardiac dose estimates from Danish and Swedish breast cancer radiotherapy during 1977-2001. Radiother Oncol 2011;100:176-183. Meyer R, Gospodarowicz M, Connors J, et al., NCIC Clinical Trials group, Eastern Cooperative Oncology Group. ABVD alone versus radiation-based therapy in limited stage Hodgkin’s lymphoma. N Engl J Med 2012;366:399-408.