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Cardiac tissue remodeling as a new marker to predict cardiac dysfunction induced by radiotherapy.

ABSTRACT: The contribution of radiotherapy, per se, in late cardiotoxicity remains controversial. An experimental model was developed, in which rat hearts were exposed to a range of ionizing radiation doses, to clarify its impact on the development of early cardiac dysfunction. Rat’s hearts were exposed to daily doses of 0.04, 0.3 and 1.2 Gy, for 23 days, achieving cumulative doses of 0.92, 6.9 and 27.6 Gy, respectively. Myocardial deformation, assessed by global longitudinal strain, was impaired (a relative percentage reduction of > 15% from baseline) in a dose-dependent manner. Moreover, by scanning electron microscopy, the microvascular density in the cardiac apex was significantly decreased exclusively at 27.6 Gy dosage. Prior to GLS impairment detection, several tools (qRT-PCR, mass spectrometry and western blot) were used to assess cardiac tissue remodeling. The number/expression of several genes, proteins and KEGG pathways, related to inflammation, fibrosis and cardiac muscle contraction, were found to be differently expressed in the cardiac tissue, according to the cumulative dose. Subclinical cardiac dysfunction occurred in a dose-dependent manner as detected by cardiac tissue remodeling, a predictor of the severity of global longitudinal strain impairment. Moreover, there is no dose threshold below which no myocardial deformation impairment was detected. These findings may contribute to i) develop new markers and explore non-invasive magnetic resonance imaging to assess cardiac tissue remodeling as an early predictor of cardiac dysfunction; ii) improve radiation-based diagnostic and therapeutic cardiac procedures; iii) highlight the need for personalized clinical approaches.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Heart

SUBMITTER: Hugo Osorio

LAB HEAD: Susana Constantino Rosa Santos

PROVIDER: PXD033194 | Pride | 2022-09-08

REPOSITORIES: Pride

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Molecular Changes In Cardiac Tissue As A New Marker To Predict Cardiac Dysfunction Induced By Radiotherapy.

Ribeiro Sónia S Simões Ana Rita AR Rocha Filipe F Vala Inês Sofia IS Pinto Ana Teresa AT Ministro Augusto A Poli Esmeralda E Diegues Isabel Maria IM Pina Filomena F Benadjaoud Mohamed Amine MA Flamant Stephane S Tamarat Radia R Osório Hugo H Pais Diogo D Casal Diogo D Pinto Fausto José FJ Matthiesen Rune R Fiuza Manuela M Constantino Rosa Santos Susana S

Frontiers in oncology 20220726

The contribution of radiotherapy, <i>per se</i>, to late cardiotoxicity remains controversial. To clarify its impact on the development of early cardiac dysfunction, we developed an experimental model in which the hearts of rats were exposed, in a fractionated plan, to clinically relevant doses of ionizing radiation for oncological patients that undergo thoracic radiotherapy. Rat hearts were exposed to daily doses of 0.04, 0.3, and 1.2 Gy for 23 days, achieving cumulative doses of 0.92, 6.9, and ...[more]

PMID: 35957913

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Project description:The contribution of radiotherapy, <i>per se</i>, to late cardiotoxicity remains controversial. To clarify its impact on the development of early cardiac dysfunction, we developed an experimental model in which the hearts of rats were exposed, in a fractionated plan, to clinically relevant doses of ionizing radiation for oncological patients that undergo thoracic radiotherapy. Rat hearts were exposed to daily doses of 0.04, 0.3, and 1.2 Gy for 23 days, achieving cumulative doses of 0.92, 6.9, and 27.6 Gy, respectively. We demonstrate that myocardial deformation, assessed by global longitudinal strain, was impaired (a relative percentage reduction of >15% from baseline) in a dose-dependent manner at 18 months. Moreover, by scanning electron microscopy, the microvascular density in the cardiac apex was significantly decreased exclusively at 27.6 Gy dosage. Before GLS impairment detection, several tools (qRT-PCR, mass spectrometry, and western blot) were used to assess molecular changes in the cardiac tissue. The number/expression of several genes, proteins, and KEGG pathways, related to inflammation, fibrosis, and cardiac muscle contraction, were differently expressed in the cardiac tissue according to the cumulative dose. Subclinical cardiac dysfunction occurs in a dose-dependent manner as detected by molecular changes in cardiac tissue, a predictor of the severity of global longitudinal strain impairment. Moreover, there was no dose threshold below which no myocardial deformation impairment was detected. Our findings i) contribute to developing new markers and exploring non-invasive magnetic resonance imaging to assess cardiac tissue changes as an early predictor of cardiac dysfunction; ii) should raise red flags, since there is no dose threshold below which no myocardial deformation impairment was detected and should be considered in radiation-based imaging and -guided therapeutic cardiac procedures; and iii) highlights the need for personalized clinical approaches.

Project description:<h4>Background</h4>In the case of breast cancer (BC), radiotherapy (RT) helps reduce locoregional recurrence and BC-related deaths but can lead to cardiotoxicity, resulting in an increased risk of long-term major cardiovascular events. It is therefore of primary importance to early detect subclinical left ventricular (LV) dysfunction in BC patients after RT and to determine the dose-response relationships between cardiac doses and these events.<h4>Methods</h4>Within the frame of the MEDIRAD European project (2017-2022), the prospective multicenter EARLY-HEART study (ClinicalTrials.gov Identifier: NCT03297346) included chemotherapy naïve BC women aged 40-75 years and treated with lumpectomy and adjuvant RT. Myocardial strain analysis was provided using speckle-tracking echocardiography performed at baseline and 6 months following RT. A global longitudinal strain (GLS) reduction >15% between baseline and follow-up was defined as a GLS-based subclinical LV dysfunction. Individual patient dose distributions were obtained using multi-atlas-based auto-segmentation of the heart. Dose-volume parameters were studied for the whole heart (WH) and left ventricle (LV).<h4>Results</h4>The sample included 186 BC women (57.5 ± 7.9 years, 64% left-sided BC). GLS-based subclinical LV dysfunction was observed in 22 patients (14.4%). These patients had significantly higher cardiac exposure regarding WH and LV doses compared to patients without LV dysfunction (for mean WH dose: 2.66 ± 1.75 Gy versus 1.64 ± 0.96 Gy, <i>p</i> = 0.01). A significantly increased risk of subclinical LV dysfunction was observed with the increase in the dose received to the WH [ORs from 1.13 (V<sub>5</sub>) to 1.74 (D<sub>mean</sub>); <i>p <</i>0.01] and to the LV [ORs from 1.10 (V<sub>5</sub>) to 1.46 (D<sub>mean</sub>); <i>p <</i>0.01]. Based on ROC analysis, the LV-V<sub>5</sub> parameter may be the best predictor of the short-term onset of subclinical LV dysfunction.<h4>Conclusion</h4>These results highlighted that all cardiac doses were strongly associated with the occurrence of subclinical LV dysfunction arising 6 months after BC RT. Whether measurements of GLS at baseline and 6 months after RT combined with cardiac doses can early predict efficiently subclinical events occurring 24 months after RT remains to be investigated.

Project description:<h4>Introduction</h4>This study aimed to evaluate the efficacy of the mean heart dose (MHD) as a predictor of radiation exposure to cardiac substructures and its association with markers of subclinical cardiotoxicity in breast cancer (BC) patients undergoing radiotherapy (RT). Although MHD provides an overall estimate of cardiac exposure, it does not capture the heterogeneous dose distribution across critical cardiac substructures.<h4>Materials and methods</h4>In an ambispective study design, dosimetric parameters, including MHD and dose-volume metrics for the left anterior descending artery (LAD), left circumflex artery (LCx), and left main coronary artery (LMCA), were analyzed in a cohort of BC patients receiving adjuvant RT. Early cardiotoxicity markers, such as N-terminal pro-B-type natriuretic peptide (NT-proBNP), ejection fraction (EF), and the Tei index, were evaluated. The relationship between MHD and radiation doses to specific cardiac substructures, as well as their association with cardiac biomarker levels, was assessed.<h4>Results</h4>Among 104 patients, the overall MHD was 6.4 ± 5.4 Gy. Left-sided BC patients received a significantly higher MHD of 10.5 ± 4.37 Gy. The LAD mean dose was 16.12 ± 15.19 Gy for the entire cohort, increasing to 30.17 ± 5.74 Gy in left-sided cases. Patients with higher MHDs were more likely to receive elevated doses to the LMCA and LCx; however, a notable discrepancy was observed in LAD dose correlation. Regression analysis showed that MHD explained only 9.4% of the variance in LAD mean dose compared to 65% for LMCA. Receiver operating characteristic (ROC) analysis identified heart Dmax (43.12 Gy), heart V25 (13%), and LAD mean dose (28.92 Gy) as strong predictors of subclinical cardiotoxicity, whereas MHD was not.<h4>Conclusion</h4>Our findings confirm that MHD is an inadequate surrogate for predicting the heterogeneous dose distribution among cardiac substructures. Elevated NT-proBNP levels and reduced EF were significantly associated with higher substructure doses, highlighting the need for individualized, substructure-specific dose constraints in RT planning. These findings support the use of advanced cardiac-sparing techniques such as deep inspiration breath-hold (DIBH), intensity-modulated radiotherapy (IMRT), and proton therapy.

Project description:<h4>Introduction</h4>Re-irradiation is frequently performed in the era of precision oncology, but previous doses to organs-at-risk (OAR) must be assessed to avoid cumulative overdoses. Stereotactic magnetic resonance-guided online adaptive radiotherapy (SMART) enables highly precise ablation of tumors close to OAR. However, OAR doses may change considerably during adaptive treatment, which complicates potential re-irradiation. We aimed to compare the baseline plan with different dose accumulation techniques to inform re-irradiation.<h4>Patients & methods</h4>We analyzed 18 patients who received SMART to lung or liver tumors inside prospective databases. Cumulative doses were calculated inside the planning target volumes (PTV) and OAR for the adapted plans and theoretical non-adapted plans via (1) cumulative dose volume histograms (DVH sum plan) and (2) deformable image registration (DIR)-based dose accumulation to planning images (DIR sum plan). We compared cumulative dose parameters between the baseline plan, DVH sum plan and DIR sum plan using equivalent doses in 2 Gy fractions (EQD2).<h4>Results</h4>Individual patients presented relevant increases of near-maximum doses inside the proximal bronchial tree, spinal cord, heart and gastrointestinal OAR when comparing adaptive treatment to the baseline plans. The spinal cord near-maximum doses were significantly increased in the liver patients (D2% median: baseline 6.1 Gy, DIR sum 8.1 Gy, DVH sum 8.4 Gy, p = 0.04; D0.1 cm³ median: baseline 6.1 Gy, DIR sum 8.1 Gy, DVH sum 8.5 Gy, p = 0.04). Three OAR overdoses occurred during adaptive treatment (DIR sum: 1, DVH sum: 2), and four more intense OAR overdoses would have occurred during non-adaptive treatment (DIR sum: 4, DVH sum: 3). Adaptive treatment maintained similar PTV coverages to the baseline plans, while non-adaptive treatment yielded significantly worse PTV coverages in the lung (D95% median: baseline 86.4 Gy, DIR sum 82.4 Gy, DVH sum 82.2 Gy, p = 0.006) and liver patients (D95% median: baseline 87.4 Gy, DIR sum 82.1 Gy, DVH sum 81.1 Gy, p = 0.04).<h4>Conclusion</h4>OAR doses can increase during SMART, so that re-irradiation should be planned based on dose accumulations of the adapted plans instead of the baseline plan. Cumulative dose volume histograms represent a simple and conservative dose accumulation strategy.

Project description:<h4>Purpose</h4>Our purpose was to assess disease outcomes and late toxicities in pediatric patients with rhabdomyosarcoma treated with conformal photon radiation therapy (RT).<h4>Methods and materials</h4>Sixty-eight patients (median age, 6.9 years) were treated with conformal photon RT to the primary site on a prospective clinical trial. Target volumes included a 1-cm expansion encompassing microscopic disease. Prescribed doses were 36 Gy to this target volume and 50.4 Gy to gross residual disease. Chemotherapy consisted of vincristine/dactinomycin (n = 6), vincristine/dactinomycin/cyclophosphamide (n = 37), or vincristine/dactinomycin/cyclophosphamide-based combinations (n = 25). Patients were evaluated with primary-site magnetic resonance imaging, whole-body [<sup>18</sup>F]fluorodeoxyglucose positron emission tomography, and chest computed tomography for 5 years after treatment.<h4>Results</h4>Five-year disease-free survival was 88% for low-risk (n = 8), 76% for intermediate-risk (n = 37), and 36% for high-risk (n = 23) patients (P ≤ .01 for low risk/intermediate risk vs high risk). The cumulative incidence of local failure (LF) at 5 years for the entire cohort was 10.4%. Tumor size at diagnosis was a significant predictor of LF (P < .01). Patients with head and neck primary tumors (n = 31) had a 35% cumulative incidence of cataracts; the risk correlated with lens dose (P = .0025). Jaw dysfunction was more severe when the pterygoid and masseter muscles received a mean dose of >20 Gy (P = .013). Orbital hypoplasia developed more frequently after a mean bony orbit dose of >30 Gy (P = .041). Late toxicity in patients with genitourinary tumors included microscopic hematuria (9 of 14), bladder-wall thickening (10 of 14), and vaginal stenosis (2 of 5).<h4>Conclusions</h4>Long-term LF rates were low, and higher rates correlated with larger tumors. Treatment-related toxicities resulting in measurable functional deficits were not infrequent, despite the conformal RT approach.

Project description:<h4>Background and purpose</h4>We previously evaluated late cardiac disease in long-term survivors in the Childhood Cancer Survivor Study (CCSS) based on heart radiation therapy (RT) doses estimated from an age-scaled phantom with a simple atlas-based heart model (H<sub>Atlas</sub>). We enhanced our phantom with a high-resolution CT-based anatomically realistic and validated age-scalable cardiac model (H<sub>Hybrid</sub>). We aimed to evaluate how this update would impact our prior estimates of RT-related late cardiac disease risk in the CCSS cohort.<h4>Methods</h4>We evaluated 24,214 survivors from the CCSS diagnosed from 1970 to 1999. RT fields were reconstructed on an age-scaled phantom with H<sub>Hybrid</sub> and mean heart dose (D<sub>m</sub>), percent volume receiving ≥ 20 Gy (V<sub>20</sub>) and ≥ 5 Gy with V<sub>20</sub> = 0 ( [Formula: see text] ) were calculated. We reevaluated cumulative incidences and adjusted relative rates of grade 3-5 Common Terminology Criteria for Adverse Events outcomes for any cardiac disease, coronary artery disease (CAD), and heart failure (HF) in association with D<sub>m</sub>, V<sub>20</sub>, and [Formula: see text] (as categorical variables). Dose-response relationships were evaluated using piecewise-exponential models, adjusting for attained age, sex, cancer diagnosis age, race/ethnicity, time-dependent smoking history, diagnosis year, and chemotherapy exposure and doses. For relative rates, D<sub>m</sub> was also considered as a continuous variable.<h4>Results</h4>Consistent with previous findings with H<sub>Atlas</sub>, reevaluation using H<sub>Hybrid</sub> dosimetry found that, D<sub>m</sub> ≥ 10 Gy, V<sub>20</sub> ≥ 0.1%, and [Formula: see text] ≥ 50% were all associated with increased cumulative incidences and relative rates for any cardiac disease, CAD, and HF. While updated risk estimates were consistent with previous estimates overall without statistically significant changes, there were some important and significant (P < 0.05) increases in risk with updated dosimetry for D<sub>m</sub> in the category of 20 to 29.9 Gy and V<sub>20</sub> in the category of 30% to 79.9%. When changes in the linear dose-response relationship for D<sub>m</sub> were assessed, the slopes of the dose response were steeper (P < 0.001) with updated dosimetry. Changes were primarily observed among individuals with chest-directed RT with prescribed doses ≥ 20 Gy.<h4>Conclusion</h4>These findings present a methodological advancement in heart RT dosimetry with improved estimates of RT-related late cardiac disease risk. While results are broadly consistent with our prior study, we report that, with updated cardiac dosimetry, risks of cardiac disease are significantly higher in two dose and volume categories and slopes of the Dm-specific RT-response relationships are steeper. These data support the use of contemporary RT to achieve lower heart doses for pediatric patients, particularly those requiring chest-directed RT.

Project description:BACKGROUND:Breast cancer (BC) radiotherapy (RT) can induce cardiotoxicity, with adverse events often observed many years after BC RT. Subclinical left ventricular (LV) dysfunction can be detected early after BC RT with global longitudinal strain (GLS) measurement based on 2D speckle-tracking echocardiography. This 6-month follow-up analysis from the BACCARAT prospective study aimed to investigate the association between cardiac radiation doses and subclinical LV dysfunction based on GLS reduction. METHODS:The patient study group consisted of 79 BC patients (64 left-sided BC, 15 right-sided BC) treated with RT without chemotherapy. Echocardiographic parameters, including GLS, were measured before RT and 6 months post-RT. The association between subclinical LV dysfunction, defined as GLS reduction > 10%, and radiation doses to whole heart and the LV were performed based on logistic regressions. Non-radiation factors associated with subclinical LV dysfunction including age, BMI, hypertension, hypercholesterolemia and endocrine therapy were considered for multivariate analyses. RESULTS:A mean decrease of 6% in GLS was observed (- 15.1% ± 3.2% at 6 months vs. - 16.1% ± 2.7% before RT, p = 0.01). For left-sided patients, mean heart and LV doses were 3.1 ± 1.3 Gy and 6.7 ± 3.4 Gy respectively. For right-sided patients, mean heart dose was 0.7 ± 0.5 Gy and median LV dose was 0.1 Gy. Associations between GLS reduction > 10% (37 patients) and mean doses to the heart and the LV as well as the V20 were observed in univariate analysis (Odds Ratio = 1.37[1.01-1.86], p = 0.04 for Dmean Heart; OR = 1.14 [1.01-1.28], p = 0.03 for Dmean LV; OR = 1.08 [1.01-1.14], p = 0.02 for LV V20). In multivariate analysis, these associations did not remain significant after adjustment for non-radiation factors. Further exploratory analysis allowed identifying a subgroup of patients (LV V20 > 15%) for whom a significant association with subclinical LV dysfunction was found (adjusted OR = 3.97 [1.01-15.70], p = 0.048). CONCLUSIONS:This analysis indicated that subclinical LV dysfunction defined as a GLS decrease > 10% is associated with cardiac doses, but adjustment for non-radiation factors such as endocrine therapy lead to no longer statistically significant relationships. However, LV dosimetry may be promising to identify high-risk subpopulations. Larger and longer follow-up studies are required to further investigate these associations. TRIAL REGISTRATION:ClinicalTrials.gov: NCT02605512, Registered 6 November 2015 - Retrospectively registered.

Project description:<h4>Purpose</h4>Incidental cardiac exposure during radiation therapy may cause heart disease. Dose-response relationships for cardiac structures (segments) may show which ones are most sensitive to radiation. Radiation-related cardiac injury can take years to develop; thus, studies need to involve women treated using 2-dimensional planning, with segment doses estimated using a typical computed tomography (CT) scan. We assessed whether such segment doses are accurate enough to use in dose-response relationships using the radiation therapy charts of women with known segment injury. We estimated interregimen and interpatient segment dose variability and segment dose correlations.<h4>Methods and materials</h4>The radiation therapy charts of 470 women with cardiac segment injury after breast cancer radiation therapy were examined, and 41 regimens were identified. Regimens were reconstructed on a typical CT scan. Doses were estimated for 5 left ventricle (LV) and 10 coronary artery segments. Correlations between cardiac segments were estimated. Interpatient dose variation was assessed in 10 randomly selected CT scans for left regimens and in 5 for right regimens.<h4>Results</h4>For the typical CT scan, interregimen segment dose variation was substantial (range, LV segments <1-39 Gy; coronary artery segments <1-48 Gy). In 10 CT scans, interpatient segment dose variation was higher for segments near field borders (range, 3-47 Gy) than other segments (range, <2 Gy). Doses to different left-anterior descending coronary artery (LADCA) segments were highly correlated with each other, as were doses to different LV segments. Also, LADCA segment doses were highly correlated with doses to LV segments usually supplied by the LADCA. For individual regimens there was consistency in hotspot location and segment ranking of higher-versus-lower dose.<h4>Conclusions</h4>The scope for developing quantitative cardiac segment dose-response relationships in patients who had 2-dimensional planning is limited because different segment doses are often highly correlated, and segment-specific dose uncertainties are not independent of each other. However, segment-specific doses may be reliably used to rank segments according to higher-versus-lower doses.

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