A Framework for Assessing the Effect of Cardiac and Respiratory Motion for Stereotactic Arrhythmia Radioablation Using a Digital Phantom With a 17-Segment Model: A STOPSTORM.eu Consortium Study.

PURPOSE: The optimal motion management strategy for patients receiving stereotactic arrhythmia radioablation (STAR) for the treatment of ventricular tachycardia (VT) is not fully known. We developed a framework using a digital phantom to simulate cardiorespiratory motion in combination with different motion management strategies to gain insight into the effect of cardiorespiratory motion on STAR. METHODS AND MATERIALS: The 4-dimensional (4D) extended cardiac-torso (XCAT) phantom was expanded with the 17-segment left ventricular (LV) model, which allowed placement of STAR targets in standardized ventricular regions. Cardiac- and respiratory-binned 4D computed tomography (CT) scans were simulated for free-breathing, reduced free-breathing, respiratory-gating, and breath-hold scenarios. Respiratory motion of the heart was set to population-averaged values of patients with VT: 6, 2, and 1 mm in the superior-inferior, posterior-anterior, and left-right direction, respectively. Cardiac contraction was adjusted by reducing LV ejection fraction to 35%. Target displacement was evaluated for all segments using envelopes encompassing the cardiorespiratory motion. Envelopes incorporating only the diastole plus respiratory motion were created to simulate the scenario where cardiac motion is not fully captured on 4D respiratory CT scans used for radiation therapy planning. RESULTS: The average volume of the 17 segments was 6 cm3 (1-9 cm3). Cardiac contraction-relaxation resulted in maximum segment (centroid) motion of 4, 6, and 3.5 mm in the superior-inferior, posterior-anterior, and left-right direction, respectively. Cardiac contraction-relaxation resulted in a motion envelope increase of 49% (24%-79%) compared with individual segment volumes, whereas envelopes increased by 126% (79%-167%) if respiratory motion also was considered. Envelopes incorporating only the diastole and respiration motion covered on average 68% to 75% of the motion envelope. CONCLUSIONS: The developed LV-segmental XCAT framework showed that free-wall regions display the most cardiorespiratory displacement. Our framework supports the optimization of STAR by evaluating the effect of (cardio)respiratory motion and motion management strategies for patients with VT.

Effects of respiratory and cardiac motion on estimating radiation dose to the left ventricle during radiotherapy for lung cancer.

PURPOSE: Establish a workflow to evaluate radiotherapy (RT) dose variation induced by respiratory and cardiac motion on the left ventricle (LV) and left ventricular myocardium (LVM). METHODS: Eight lung cancer patients underwent 4D-CT, expiratory T1-volumetric-interpolated-breath-hold-examination (VIBE), and cine MRI scans in expiration. Treatment plans were designed on the average intensity projection (AIP) datasets from 4D-CTs. RT dose from AIP was transferred onto 4D-CT respiratory phases. About 50% 4D-CT dose was mapped onto T1-VIBE (following registration) and from there onto average cine MRI datasets. Dose from average cine MRI was transferred onto all cardiac phases. Cumulative cardiac dose was estimated by transferring dose from each cardiac phase onto a reference cine phase following deformable image registration. The LV was contoured on each 4D-CT breathing phase and was called clinical LV (cLV); this structure is blurred by cardiac motion. Additionally, LV, LVM, and an American Heart Association (AHA) model were contoured on all cardiac phases. Relative maximum/mean doses for contoured regions were calculated with respect to each patient's maximum/mean AIP dose. RESULTS: During respiration, relative maximum and mean doses on the cLV ranged from -4.5% to 5.6% and -14.2% to 16.5%, respectively, with significant differences in relative mean doses between inspiration and expiration (P < 0.0145). During cardiac motion at expiration, relative maximum and mean doses on the LV ranged from 1.6% to 59.3%, 0.5% to 27.4%, respectively. Relative mean doses were significantly different between diastole and systole (P = 0.0157). No significant differences were noted between systolic, diastolic, or cumulative cardiac doses compared to the expiratory 4D-CT (P > 0.14). Significant differences were observed in AHA segmental doses depending on tumour proximity compared to global LV doses on expiratory 4D-CT (P < 0.0117). CONCLUSION: In this study, the LV dose was highest during expiration and diastole. Segmental evaluation suggested that future cardiotoxicity evaluations may benefit from regional assessments of dose that account for cardiopulmonary motion.

RELATIVE TELOMERE LENGTH OF PERIPHERAL BLOOD LYMPHOCYTES AND STRUCTURAL AND FUNCTIONAL STATE OF THE LEFT VENTRICLE MYOCARDIUM IN CLEAN-UP WORKERS OF THE CHORNOBYL ACCIDENT WHO SUFFERED FROM STENOTIC CORONARY ATHEROSCLEROSIS. / VIDNOSNA DOVZhYNA TELOMER LIMFOTsYTIV PERYFERYChNOÏ KROVI TA STRUKTURNO-FUNKTsIONAL'NYI STAN MIOKARDA LIVOGO ShLUNOChKA SERTsIa V UChASNYKIV LIKVIDATsIÏ NASLIDKIV ChORNOBYL'S'KOÏ AVARIÏ ZI STENOZUIuChYM ATEROSKLEROZOM KORONARNYKh ARTERII.

The objective was to analyze the relative telomere length (RTL) of peripheral blood lymphocytes depending onmyocardium structural and functional state in emergency workers (EW) of the Chornobyl accident who suffered fromcoronary arteries stenotic atherosclerosis. MATERIALS AND METHODS: There were examined 60 male EW who operated at the Chornobyl nuclear power plant at1986 and 25 male non-irradiated persons (control group - CG) with coronary heart disease (CHD). Everyone EW andCG patients were almost healthy before the accident. During the period 2016-2021, they underwent a comprehen-sive clinical and laboratory examination, echodopplercardiographic examination and determination of RTL by fluo-rescent hybridization in situ using laser flow cytometry. RESULTS: EW almost did not differ from CG according to its clinical characteristics, the presence of risk factors,indices of systolic and diastolic heart functions, as well as RTL. The analysis of variance showed that RTL was influ-enced by the fact of irradiation in combination with obesity (p = 0.020). At normal body weight, RTL average valuein CG was significantly higher than in EW (p = 0.023). According to the results of hierarchical cluster analysis of twovariables as RTL and end-diastolic volume normalized by body surface area (EDV/BSA), EW and CG patients togeth-er were divided into two subgroups. The first subgroup (1st cluster) differed from the second (2nd cluster) by signi-ficantly larger average values of left ventricle (LV) EDV and end-systolic volume (ESV) as well as EDV/BSA andESV/BSA, LV myocardial mass (MM) and MM/BSA, reduced ejection fraction (EF). In patients of the 1st cluster telom-eres were significantly shorter than in the 2nd one (10,3 ± 1.7 vs. 14.3 ± 2.0 at p = 0.000). The increase of myocar-dial mass and LV wall thickness caused the development of its hypertrophy. The number of people with hypertrophyLV was significantly higher among patients of the 1st cluster (91.6 vs. 67.2 %, p < 0.001) due to eccentric hypertro-phy LV. Accordingly, concentric hypertrophy LV was more common among patients in the 2nd cluster (24.6 vs. 4.2 %at p < 0.01). Patients of the 1st cluster was characterized by a more severe course of heart failure. CONCLUSIONS: In patients who suffered from CHD with stenotic atherosclerosis of the coronary arteries and wereexposed to radiation 30-35 years earlier, having normal body weight, there was a reduction in telomere. Hierarchicalcluster analysis proved to be a good tool that allows by the value of RTL and EDV/BSA to separate the group ofpatients with the most severe clinical course of CHD and LV systolic dysfunction among patients with the samepathology.

Variation of heart and lung radiation doses according to setup uncertainty in left breast cancer.

PURPOSE: Breast radiotherapy set-up is often uncertain. Actual dose distribution to normal tissues could be different from planned dose distribution. The objective of this study was to investigate such difference in dose distribution according to the extent of set-up error in breast radiotherapy. MATERIALS AND METHODS: A total of 50 Gy with fraction size of 2 Gy was given to 30 left breasts with different set-ups applying a deep inspiration breath holding (DIBH) or a free breathing (FB) technique. Under the assumption that errors might come from translational axes of deep or caudal directions, the isocenter was shifted from the original tangential alignment every 2.5 mm to simulate uncertainty of deep and caudal tangential set-up in DIBH and FB. Changes were evaluated for dosimetric parameters for the heart, the left ventricle (LV), the left anterior descending coronary artery (LAD), and the ipsilateral lung. RESULTS: On the original plan, mean doses of heart and ipsilateral lung were 2.0 ± 1.1 Gy and 3.7 ± 1.4 Gy in DIBH and 8.4 ± 1.3 Gy and 7.8 ± 1.5 Gy in FB, respectively. The change of dose distribution for the heart in DIBH was milder than that in FB. The deeper the tangential set-up, the worse the heart, LV, LAD, and ipsilateral lung doses, showing as much as 49.4%, 56.4%, 90.3%, and 26.1% shifts, respectively, in 5 mm DIBH setup. The caudal set-up did not show significant dose difference. In multiple comparison of DIBH, differences of mean dose occurred in all 7.5 mm deep set-ups for the heart (p = 0.025), the LV (p = 0.049), and LAD (p = 0.025) in DIBH. CONCLUSIONS: To correct set-up error over indicated limitation for deep tangential set-up in DIBH at 5 mm action level, mean heart and ipsilateral lung doses are expected to increase approximately 50% and 25%, respectively.

Electrophysiological and Pathological Impact of Medium-Dose External Carbon Ion and Proton Beam Radiation on the Left Ventricle in an Animal Model.

Background Medium-dose (25 gray) x-ray radiation therapy has recently been performed on patients with refractory ventricular tachyarrhythmias. Unlike x-ray, carbon ion and proton beam radiation can deliver most of their energy to the target tissues. This study investigated the electrophysiological and pathological changes caused by medium-dose carbon ion and proton beam radiation in the left ventricle (LV). Methods and Results External beam radiation in the whole LV was performed in 32 rabbits. A total of 9 rabbits were not irradiated (control). At the 3-month or 6-month follow-up, the animals underwent an open-chest electrophysiological study and were euthanized for histological analyses. No acute death occurred. Significant LV dysfunction was not seen. The surface ECG revealed a significant reduction in the P and QRS wave voltages in the radiation groups. The electrophysiological study showed that the local conduction times in each LV site were significantly longer and that the local LV bipolar voltages were significantly lower in the radiation groups than in the control rabbits. Histologically, apoptosis, fibrotic changes, and a decrease in the expression of the connexin 43 protein were seen in the LV myocardium. These changes were obvious at 3 months, and the effects were sustained 6 months after radiation. No histological changes were seen in the coronary artery and esophagus, but partial radiation pneumonitis was observed. Conclusions Medium-dose carbon ion and proton beam radiation in the whole LV resulted in a significant electrophysiological disturbance and pathological changes in the myocardium. Radiation of the arrhythmogenic substrate would modify the electrical status and potentially induce the antiarrhythmic effect.

The Importance of Radiation Dose to the Atherosclerotic Plaque in the Left Anterior Descending Coronary Artery for Radiation-Induced Cardiac Toxicity of Breast Cancer Patients?

PURPOSE: Radiation-induced acute coronary events (ACEs) may occur as a treatment-related late adverse effect of breast cancer (BC) radiation. However, the underlying mechanisms behind this radiation-induced cardiac disease remain to be determined. The objective of this study was to test the hypothesis that radiation dose to calcified atherosclerotic plaques in the left anterior descending coronary artery (LAD) is a better predictor for ACEs than radiation dose to the whole heart or left ventricle in patients with BC treated with radiation therapy. METHODS AND MATERIALS: The study cohort consisted of 910 patients with BC treated with postoperative radiation therapy after breast-conserving surgery. In total, 163 patients had an atherosclerotic plaque in the LAD. The endpoint was the occurrence of an ACE after treatment. For each individual patient, the mean heart dose, volume of the left ventricle receiving ≥5 Gy (LV-V5), mean LAD dose, and mean dose to calcified atherosclerotic plaques in the LAD, if present, were acquired based on planning computed tomography scans. Cox regression analysis was used to analyze the effects on the cumulative incidence of ACEs. RESULTS: The median follow-up time was 9.2 years (range, 0.1-14.3 years). In total, 38 patients (4.2%) developed an ACE during follow-up. For patients with an atherosclerotic plaque (n = 163), the mean dose to the atherosclerotic plaque was the strongest predictor for ACEs, even after correction for cardiovascular risk factors (hazard ratio [HR], 1.269; 95% CI, 1.090-1.477; P = .002). The LV-V5 was associated with ACEs in patients without atherosclerotic plaques in the LAD (n = 680) (HR, 1.021; 95% CI, 1.003-1.039; P = .023). CONCLUSIONS: The results of this study suggest that radiation dose to pre-existing calcified atherosclerotic plaques in the LAD is strongly associated with the development of ACEs in patients with BC.

Early Changes in Rat Heart After High-Dose Irradiation: Implications for Antiarrhythmic Effects of Cardiac Radioablation.

Background Noninvasive cardiac radioablation is employed to treat ventricular arrhythmia. However, myocardial changes leading to early-period antiarrhythmic effects induced by high-dose irradiation are unknown. This study investigated dose-responsive histologic, ultrastructural, and functional changes within 1 month after irradiation in rat heart. Methods and Results Whole hearts of wild-type Lewis rats (N=95) were irradiated with single fraction 20, 25, 30, 40, or 50 Gy and explanted at 1 day or 1, 2, 3, or 4 weeks' postirradiation. Microscopic pathologic changes of cardiac structures by light microscope with immunohistopathologic staining, ultrastructure by electron microscopy, and functional evaluation by ECG and echocardiography were studied. Despite high-dose irradiation, no myocardial necrosis and apoptosis were observed. Intercalated discs were widened and disrupted, forming uneven and twisted junctions between adjacent myocytes. Diffuse vacuolization peaked at 3 weeks, suggesting irradiation dose-responsiveness, which was correlated with interstitial and intracellular edema. CD68 immunostaining accompanying vacuolization suggested mononuclear cell infiltration. These changes were prominent in working myocardium but not cardiac conduction tissue. Intracardiac conduction represented by PR and QTc intervals on ECG was delayed compared with baseline measurements. ST segment was initially depressed and gradually elevated. Ventricular chamber dimensions and function remained intact without pericardial effusion. Conclusions Mononuclear cell-related intracellular and extracellular edema with diffuse vacuolization and intercalated disc widening were observed within 1 month after high-dose irradiation. ECG indicated intracardiac conduction delay with prominent ST-segment changes. These observations suggest that early antiarrhythmic effects after cardiac radioablation result from conduction disturbances and membrane potential alterations without necrosis.

Cardiac substructures exposure in left-sided breast cancer radiotherapy: Is the mean heart dose a reliable predictor of cardiac toxicity?

PURPOSE: This study aimed to assess radiation dose distribution to cardiac subvolumes in left-sided breast cancer radiotherapy (LBCRT) and to clarify whether the mean heart dose (MHD) reliably reflects cardiac substructures exposure. MATERIALS AND METHODS: Fifty women referred for adjuvant LBCRT were prospectively evaluated. All patients received 3D-conformal hypofractionated radiotherapy (40Gy delivered in 15 fractions of 2.67Gy±boost of 13.35Gy). Cardiac substructures were contoured using the F. Duane's cardiac atlas. Dose distribution to cardiac chambers, left main (LM), left anterior descending (LAD), left circumflex (LCx) and right coronary artery (RCA)) was assessed. Dosimetric associations were analysed. RESULTS: The mean MHD was 3.08Gy (EQD2=3.67Gy). The mean Dmean/Dmax LAD was 11.45Gy (EQD2=13.64Gy)/29.5Gy (EQD2=35.15Gy). Low doses were delivered to LM, LCx, and RCA (Dmean≤1.3Gy). The left ventricle (LV) was the most exposed cardiac chamber with Dmean/Dmax of 4.78Gy/37Gy. The strongest correlation with MHD was found for Dmean LAD (r=0.81). For every 1Gy increase in MHD, Dmean LAD rose by 3.4Gy. However, the proportion of variance in Dmean LAD predictable from MHD was moderate (R2=0.65). For all other cardiac substructures, R2 values were<0.7. CONCLUSION: Our study showed high exposure of LAD and LV in LBCRT. With poor predictive value, MHD may underestimate doses to cardiac substructures. For optimal heart sparing radiotherapy, we recommend to consider LV and LAD as separate organ at risk.

Colchicine treatment early after infarction attenuates myocardial inflammatory response demonstrated by 14C-methionine imaging and subsequent ventricular remodeling by quantitative gated SPECT.

OBJECTIVE: Colchicine has been used as an anti-inflammatory agent and may be cardioprotective after acute myocardial infarction (AMI). We investigated how colchicine administration after AMI affects the myocardial inflammatory response using 14C-methionine and subsequent ventricular remodeling using single-photon emission computed tomography (SPECT) in a rat model of AMI. METHODS: The left coronary artery (LCA) was occluded for 30 min followed by reperfusion. 14C-methionine was injected at 20 min before sacrifice. The LCA was re-occluded at 1 min before sacrifice and 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) was injected. Colchicine was administered intraperitoneally from day 1 to the day before 14C-methionine injection. Dual-tracer autoradiography of the left ventricular short-axis slices was performed. The methionine uptake ratio in an ischemic area was calculated. 99mTc-MIBI gated SPECT assessed end-diastolic volume (EDV), end-systolic volume (ESV) and left ventricular ejection fraction (LVEF). On Cluster of Differentiation 68 with 4',6-diamidino-2-phenylindole (CD68/DAPI) staining the positive myocardial cell percentage in an ischemic area was calculated. RESULTS: In control rats, 14C-methionine uptake ratios on day 3 and 7 were 1.87 ± 0.15 and 1.39 ± 0.12, respectively. With colchicine, the uptake was reduced on days 3 (1.56 ± 0.26, p = 0.042) and 7 (1.23 ± 0.10, p = 0.030). Colchicine treated rats showed smaller EDV, ESV, and higher LVEF compared with control rats. At 8 weeks, those in control rats were 864 ± 115 µL, 620 ± 100 µL, 28.4 ± 2.5%, and in colchicine rats 665 ± 75 µL, 390 ± 97 µL, 42.2 ± 8.5% (p = 0.012, 0.0061, 0.0083), respectively. In control rats, CD68/DAPI positive myocardial cell percentages on days 3 and 7 were 38.4 ± 1.9% and 24.0 ± 2.4%, respectively. With colchicine, the percentages were reduced significantly on both days 3 (31.5 ± 2.0%, p < 0.0001) and 7 (12.0 ± 1.6%, p < 0.0001) as compared with the control. CONCLUSIONS: Short-term colchicine treatment after AMI attenuated the post-AMI inflammatory response and subsequent ventricular remodeling and dysfunction. 14C-methionine imaging and gated 99mTc-MIBI SPECT would be feasible to monitor the effectiveness of anti-inflammatory therapy and left ventricular function.

Drift and termination of spiral waves in optogenetically modified cardiac tissue at sub-threshold illumination.

The development of new approaches to control cardiac arrhythmias requires a deep understanding of spiral wave dynamics. Optogenetics offers new possibilities for this. Preliminary experiments show that sub-threshold illumination affects electrical wave propagation in the mouse heart. However, a systematic exploration of these effects is technically challenging. Here, we use state-of-the-art computer models to study the dynamic control of spiral waves in a two-dimensional model of the adult mouse ventricle, using stationary and non-stationary patterns of sub-threshold illumination. Our results indicate a light-intensity-dependent increase in cellular resting membrane potentials, which together with diffusive cell-cell coupling leads to the development of spatial voltage gradients over differently illuminated areas. A spiral wave drifts along the positive gradient. These gradients can be strategically applied to ensure drift-induced termination of a spiral wave, both in optogenetics and in conventional methods of electrical defibrillation.

Focus on stereotactic radiotherapy: A new way to treat severe ventricular arrhythmias?

Ventricular tachycardia has a significant recurrence rate after ablation for several reasons, including inaccessible substrate. A non-invasive technique to ablate any defined areas of myocardium involved in arrhythmogenesis would be a potentially important therapeutic improvement if shown to be safe and effective. Early feasibility studies of single-fraction stereotactic body radiotherapy have demonstrated encouraging results, but rigorous evaluation and follow-up are required. In this document, the basic concepts of stereotactic body radiotherapy are summarized, before focusing on stereotactic arrhythmia radioablation. We describe the effect of radioablation on cardiac tissue and its interaction with intracardiac devices, depending on the dose. The different clinical studies on ventricular tachycardia radioablation are analysed, with a focus on target identification, which is the key feature of this approach. Our document ends with the indications and requirements for practicing this type of procedure in 2020. Finally, because of the limited number of patients treated so far, we encourage multicentre registries with long-term follow-up.

Matched-pair dosimetric comparison of cardiac radiation exposure between deep-inspiration breath-hold whole-breast radiation therapy with Active Breathing Coordinator and interstitial multicatheter high-dose-rate brachytherapy as accelerated partial breast irradiation in adjuvant treatment of left-sided breast cancer after breast-conserving surgery.

BACKGROUND AND PURPOSE: To compare dosimetrically the radiation exposure to heart, left ventricle (LV), and left anterior descending artery (LAD) between whole-breast radiotherapy (WBRT) with Active Breathing Coordinator (ABC; ABC-WBRT) and interstitial multicatheter high-dose-rate (HDR) brachytherapy as accelerated partial breast irradiation (ABPI; imHDR-APBI) for left-sided breast cancer (BCA) after breast-conserving surgery (BCS). MATERIALS AND METHODS: Between January 2016 and December 2019, 32 and 20 patients were treated with ABC-WBRT (63 Gy/2.25 Gy) and imHDR-APBI (32 Gy/4 Gy), respectively. Among them a matched-pair analysis was performed according to tumor location (clock position) before BCS as well as planning target volume of imHDR-APBI and boost volume of ABC-WBRT. This yielded 17 pairs of patients for whom dosimetric parameters for heart, LV, and LAD were evaluated. The Mann-Whitney test was used for comparison after adjusting for equivalent dose in 2­Gy fractions (EQD2). In addition, a second analysis of ABC-WBRT to 40.05 Gy in 15 fractions was performed in order to account for the EQD2 difference between the 63-Gy ABC-WBRT and the imHDR-APBI protocol. RESULTS: Tumor location for the 17 pairs of patients relative to breast quadrant was as follows: upper outer 8, lower outer 5, upper inner 3, and lower inner 1. There was no difference regarding mean heart dose (MHD) and V5, whereas D25%, D45%, V10, and V25 significantly favored imHDR-APBI. Likewise, mean dose- and V5-LV did not differ, while Dmax- and V23-LV were significantly higher for ABC-WBRT. For LAD, Dmax, D25%, and V30 significantly favored imHDR-APBI without differences for mean dose and V40. When comparing imHDR-APBI with the 40.05 Gy ABC-WBRT schedule, MHD and mean dose LV were significantly lower in favor of ABC-WBRT. CONCLUSION: ABC-WBRT and imHDR-APBI yield similar low heart and LV exposure for left-sided BCA after BCS, whereas LAD can be better spared with imHDR-APBI.

Dosimetric evaluation of left ventricle and left anterior descending artery in left breast radiotherapy.

INTRODUCTION: We evaluated the dosimetric results of the identification of the left ventricle (LV) and left anterior descending artery (LAD) as organs at risk (OARs) in adjuvant radiotherapy (RT) after breast-conserving surgery (BCS). MATERIALS AND METHODS: Twenty-two patients who had previously received RT in our center were evaluated retrospectively. All patients had undergone BCS operation for left breast cancer. LV and LAD were contoured as OARs on the same simulation CTs for these patients whose treatment was previously completed in which LV and LAD were not defined as OARs. Complying with the initial plans, intensity-modulated RT plans with 7-9 fields were made on the computer. Planning target volume (PTV), homogeneity index (HI), conformity index (CI), monitor unit (MU) values, and doses of OARs were compared using the Wilcoxon signed-rank test (p < 0.05). RESULTS: There were no significant differences in PTV 50 (D 50% and D 98%), PTV 60 (D 2% and D 50%), HI, CI, and MU values when treatment plans and control plans were compared (p > 0.05). While it was possible to protect the heart, LAD, and LV better, LAD and LV were not contoured in the treatment plans, and they received higher doses compared to the control plans (p < 0.05). There was no significant difference in the other OARs. CONCLUSION: In conclusion, it is essential to define the lower anatomical regions of the heart as OARs. Otherwise, the doses taken by these regions are ignored and may be maintained less than possible. In our study, it was shown that LV and LAD doses were significantly reduced even in the same center and planning by the same team.

Catheter-Free Arrhythmia Ablation Using Scanned Proton Beams: Electrophysiologic Outcomes, Biophysics, and Characterization of Lesion Formation in a Porcine Model.

BACKGROUND: Proton beam therapy offers radiophysical properties that are appealing for noninvasive arrhythmia elimination. This study was conducted to use scanned proton beams for ablation of cardiac tissue, investigate electrophysiological outcomes, and characterize the process of lesion formation in a porcine model using particle therapy. METHODS: Twenty-five animals received scanned proton beam irradiation. ECG-gated computed tomography scans were acquired at end-expiration breath hold. Structures (atrioventricular junction or left ventricular myocardium) and organs at risk were contoured. Doses of 30, 40, and 55 Gy were delivered during expiration to the atrioventricular junction (n=5) and left ventricular myocardium (n=20) of intact animals. RESULTS: In this study, procedural success was tracked by pacemaker interrogation in the atrioventricular junction group, time-course magnetic resonance imaging in the left ventricular group, and correlation of lesion outcomes displayed in gross and microscopic pathology. Protein extraction (active caspase-3) was performed to investigate tissue apoptosis. Doses of 40 and 55 Gy caused slowing and interruption of cardiac impulse propagation at the atrioventricular junction. In 40 left ventricular irradiated targets, all lesions were identified on magnetic resonance after 12 weeks, being consistent with outcomes from gross pathology. In the majority of cases, lesion size plateaued between 12 and 16 weeks. Active caspase-3 was seen in lesions 12 and 16 weeks after irradiation but not after 20 weeks. CONCLUSIONS: Scanned proton beams can be used as a tool for catheter-free ablation, and time-course of tissue apoptosis was consistent with lesion maturation.

[Subclinical heart injury in patients receiving hypofractionated radiotherapy after breast conserving surgery: a preliminary analysis of prospective study].

Objective: To evaluate the incidence of early cardiac injury in patients with left-sided breast cancer receiving hypofractionated radiotherapy after breast conserving surgery, and to investigate the correlation between cardiac injury and hypofractionated radiotherapy dose. Methods: We prospectively enrolled 103 breast cancer patients who received whole breast with or without regional nodal irradiation after breast conserving surgery using either deep inspiration breath-hold (DIBH) or free breathing (FB) radiotherapy technique. Cardiac examinations that included N-terminal pro-B-type natriuretic peptide (NT-proBNP), electrocardiogram, and myocardial perfusion imaging were performed routinely before and after radiotherapy. The effects of heart dose, systemic therapy and individual factors (Framingham score) on the incidence of cardiac events were analyzed. Results: The median age was 48 years. The mean dose (Dmean) of the heart, left anterior descending coronary artery (LAD), left ventricular (LV), and right ventricular (RV) were 4.0, 16.9, 6.3, and 4.4 Gy, respectively. With a median follow-up of 13.4 months, no patient had clinical cardiac abnormalities. The incidence rates of subclinical cardiac events at 1- 6- and 12-month were 23.5%, 31.6%, and 41.3%, respectively. The DIBH group had a lower mean dose, maximum dose, and V5-V40 in the heart, LAD, LV, and RV than the FB group (P<0.001). Univariate analysis showed an increased incidence of subclinical cardiac events with heart Dmean >4 Gy, LAD V40 > 20%, LV Dmean >6 Gy, RV Dmean >7 Gy, or cumulative doses of anthracycline or taxane > 300 mg/m(2) (All P<0.05). Anti-HER2 targeted therapy, endocrine therapy and Framingham score were not associated with the incidence of subclinical cardiac events (all P>0.05). Multivariate analysis demonstrated that Dmean of LV and RV were independently associated with the increased incidence of subclinical cardiac events. Conclusions: Early subclinical heart injury are found in patients with left-sided breast cancer after hypofractionated radiotherapy. The increased incidence of subclinical cardiac events after radiotherapy is positively associated with the cardiac radiation doses.

Novel Methodology to Investigate the Effect of Radiation Dose to Heart Substructures on Overall Survival.

PURPOSE: For patients with lung cancer treated with radiation therapy, a dose to the heart is associated with excess mortality; however, it is often not feasible to spare the whole heart. Our aim is to define cardiac substructures and dose thresholds that optimally reduce early mortality. METHODS AND MATERIALS: Fourteen cardiac substructures were delineated on 5 template patients with representative anatomies. One thousand one hundred sixty-one patients with non-small cell lung cancer were registered nonrigidly to these 5 template anatomies, and their radiation therapy doses were mapped. Mean and maximum dose to each substructure were extracted, and the means were evaluated as input to prediction models. The cohort was bootstrapped into 2 variable reduction techniques: elastic net least absolute shrinkage and selection operator and the random survival forest model. Each method was optimized to extract variables contributing most to overall survival, and model coefficients were evaluated to select these substructures. The most important variables common to both models were selected and evaluated in multivariable Cox-proportional hazard models. A threshold dose was defined, and Kaplan-Meier survival curves plotted. RESULTS: Nine hundred seventy-eight patients remained after visual quality assurance of the registration. Ranking the model coefficients across the bootstraps selected the maximum dose to the right atrium, right coronary artery, and ascending aorta as the most important factors associated with survival. The maximum dose to the combined cardiac region showed significance in the multivariable model, a hazard ratio of 1.01/Gy, and P = .03 after accounting for tumor volume (P < .001), N stage (P < .01), and performance status (P = .01). The optimal threshold for the maximum dose, equivalent dose in 2-Gy fractions, was 23 Gy. Kaplan-Meier survival curves showed a significant split (log-rank P = .008). CONCLUSIONS: The maximum dose to the combined cardiac region encompassing the right atrium, right coronary artery, and ascending aorta was found to have the greatest effect on patient survival. A maximum equivalent dose in 2-Gy fractions of 23 Gy was identified for consideration as a dose limit in future studies.

Effect of radiotherapy on coronary arteries and heart in breast-conserving surgery: a dosimetric analysis.

Background There are certain risks of radiotherapy (RT), especially patients with left-sided breast cancer have a higher tendency to develop cardiac complications than the right-sided cancers. This study aims to perform a dosi-metric analysis the effect of RT on coronary arteries and heart in breast-conserving surgery. Patients and methods A total of 40 patients with early stage right and left-sided breast carcinomas (T1/T2 + N0) were randomly selected. RT was delivered to the entire breast, and tumor beds were boosted in these patients using tangential fields with computed tomography based planning. The doses for Left anterior descending coronary artery (LAD), left circumflex coronary artery (LCx), right ventricle (RV), left ventricle (LV), and heart were recorded and median values compared between groups. Results The highest mean of radiation dose in patients with left-sided breast cancer was to LAD 2402.48 ± 838.39 cGy, while the highest mean dose in right-sided breast cancer patients was to RV 130.18 ± 24.92. The highest maximum dose of radiotherapy was applied to heart at left-sided breast cancer patients as well as at right-sides prients. The mean V5 of the LV was 18.68% (6.89-31.69), mean V25 of the LV was 5.22% (0.45-16.54), mean V5 in bilateral ventricles was 23.73% (2.56-26.89), and mean V25 in bilateral ventricles 6.78% (0.63-13.63). Conclusions Especially in left-sided breast cancer, the most direct and best strategy to reduce and protect radiation-induced cardiac injury is to balance dose constraints between several high-dose regions of cardiac substructures and the mean heart dose.

Left Ventricular Speckle Tracking Echocardiography Changes Among Early-stage Breast Cancer Patients Three Years After Radiotherapy.

BACKGROUND/AIM: Chest radiotherapy (RT) doubles late cardiac mortality. This study aimed to evaluate the evolution of cardiac changes in speckle tracking echocardiography during a three-year follow-up. MATERIALS AND METHODS: This prospective study included 81 chemotherapy-naïve early-stage breast cancer patients who were evaluated at baseline, immediately after RT and three years after RT. Sixty-one patients had left-sided (LSBC) and 20 right-sided breast cancer (RSBC). RESULTS: Global longitudinal strain (GLS) declined from baseline -18.0±3.3% to -17.0±3.0% (p=0.015) at the three-year follow-up examination. A decline over 15% (GLS15) was observed in 19 (27%) patients. GLS15 was independently associated with aromatase inhibitor use (ß=-1.977, p=0.001). In regional analysis, patients with LSBC had apical strain decline by 3.2±5.5% (p<0.001) and patients with RSBC showed basal rotation decline by 1.8° (-0.2°, 3.8°) (p=0.030). CONCLUSION: Even contemporary RT induced progressive global and regional decline in speckle tracking analysis. The regional changes complied with RT fields.

Adjuvant radiotherapy-induced cardiac changes among patients with early breast cancer: a three-year follow-up study.

Background: In this study, we evaluate the evolution of cardiac changes during a three-year follow-up after adjuvant breast radiotherapy (RT). Methods: Sixty patients with left-sided and 20 patients with right-sided early stage breast cancer without chemotherapy were included in this prospective study. Echocardiography and cardiac biomarkers were evaluated before, immediately after and 3 years after RT. Radiation doses to cardiac structures were calculated. Results: In echocardiography, left ventricle (LV) systolic measurements had impaired at 3 years compared to baseline: the mean global longitudinal strain (GLS) worsened from -18 ± 3 to -17 ± 3 (p = .015), LV ejection fraction from 62 ± 5% to 60 ± 4% (p = .003) and the stroke volume from 73 ± 16 mL to 69 ± 15 mL (p = .015). LV diastolic function was also negatively affected: the isovolumetric relaxation time was prolonged (p = .006) and the first peak of diastole decreased (p = .022). Likewise, left atrial (LA) measurements impaired. These changes in echocardiography were more prominent in left-sided than in right-sided patients. The concurrent aromatase inhibitor (AI) use was associated with GLS impairment. In all patients, the N-terminal pro-brain natriuretic peptide (proBNP) values were median (interquartile range) 74 (41-125) ng/L at baseline, 75 (41-125) ng/L at the end of RT and 96 (56-162) ng/L at 3 years (p < .001 from baseline to 3 years). However, proBNP did not increase in right-sided patients. Conclusion: During the 3-year follow-up after RT, negative subclinical changes in cardiac biomarkers and in LV systolic and diastolic function were observed. The measured changes were more pronounced in left-sided patients. In addition, AI use was associated with impaired cardiac systolic function.