Evaluation of Cardiotoxicity in HER-2-Positive Breast Cancer Patients Treated With Radiation Therapy and Trastuzumab.

PURPOSE: Trastuzumab is associated with cardiac dysfunction in patients with human epidermal growth factor receptor 2 (HER-2)-positive breast cancer. The current study examines the effect of radiation therapy (RT) on cardiotoxicity in this patient population. METHODS AND MATERIALS: The Herceptin Adjuvant (HERA) trial is a phase 3 prospective, randomized clinical trial that established the efficacy of trastuzumab in HER-2-positive breast cancer. The current study is a retrospective analysis of 3321 trial patients treated with trastuzumab, with or without RT. Cardiac function was closely monitored over a median follow-up period of 11 years. The primary endpoint of the current study was to determine the effect of RT on left ventricular ejection fraction (LVEF) and the occurrence of cardiovascular events. RESULTS: Patients were divided into 3 groups: 1270 patients received trastuzumab and left-sided RT (group 1); 1271 patients received trastuzumab and right-sided RT (group 2); and 780 patients received trastuzumab with no RT (group 3). The incidence of decline in LVEF documented by echocardiography was 9.18%, 8.99%, and 8.80%, respectively, with no significant differences among the 3 groups (P = .073). The incidence of cardiovascular events was low in all groups, with the lowest incidence noted in group 3 (0.62%) followed by group 2 (0.92%) and group 1 (1.08%) (P = .619). Univariate and multivariate competing-risks regression showed that left-sided and right-sided RT delivery did not significantly increase the risk of LVEF decline or cardiovascular events. CONCLUSIONS: Our analysis of the HERA trial suggests that RT does not significantly increase the risk of cardiotoxicity in HER-2-positive breast cancer patients treated with trastuzumab. Continued monitoring of patients is needed to investigate late effects of contemporary treatments for breast cancer patients.

Trabalho Miocárdio: uma revisão sistemática do novo método de ecocardiografia e aplicações clínicas / Myocardial Work: a systematic review of novel echocardiography method and clinical applications

Fundamento: O trabalho miocárdico (MW) é uma nova modalidade de imagem que surgiu como uma forma potencial de avaliação da função ventricular esquerda (VE) em vários cenários clínicos. Ele calcula curvas de tensão de ecocardiografia de rastreamento de manchas (STE) com uma curva de pressão LV estimada utilizando curvas padrão de pressão arterial braquial de forma não invasiva. Objetivo: O objetivo desta pesquisa foi fornecer um resumo do conhecimento atual da MW não invasiva e suas aplicações clínicas, incluindo insuficiência cardíaca (IC), doença arterial coronariana (DAC), cardiomiopatia (CMP) e hipertensão (HTN). Além disso, são discutidas as limitações e recomendações da MW na prática clínica. Métodos: Pesquisamos no banco de dados online PubMed para nossa coleta de dados. Usamos as seguintes palavras-chave; (trabalho construtivo do miocárdio) OU (trabalho septal desperdiçado)) OU (trabalho miocárdico global)) OU (trabalho miocárdico)) OU (trabalho construtivo do miocárdio) OU (ecocardiografia nova). Revisamos ainda doze estudos com leitura de texto completo e incluídos nesta revisão sistemática. Resultados: Embora os índices de MW, particularmente GWI e GCW, tenham mostrado uma boa correlação com FE e parâmetros de deformação, a oportunidade de oferecer informações incrementais que não são afetadas pelas condições de carga tornou a aplicação de MW particularmente útil em uma variedade de configurações clínicas. Conclusão: Comparado ao FE e GLS, o MW é um teste promissor com maior sensibilidade e acurácia na identificação de indivíduos com doença cardiovascular. Os médicos também devem depender dos sintomas e dos achados do ECG até que uma extensa pesquisa multicêntrica validando essa estratégia seja feita para estabelecer o valor incremental da MW na avaliação ecocardiográfica diária. (AU)

Background: Myocardial work (MW) is a novel imaging modality that has emerged as a potential left ventricular (LV) function assessment in various clinical settings. MW calculates speckle-tracking echocardiography strain curves with an estimated LV pressure curve by non-invasively utilizing standard brachial blood pressure curves. Objective: This study aimed to provide a summary of current knowledge of non-invasive MW and its clinical applications, including in heart failure, coronary artery disease, cardiomyopathy, and hypertension. In addition, the limitations, and recommendations of MW in clinical practice are discussed. Methods: We searched the PubMed database using the following keywords: (myocardial constructive work) OR (wasted septal work) OR (global myocardial work) OR (myocardial work) OR (myocardial constructive work) OR (novel echocardiography). We further subjected 12 studies to full-text review and included them in this systematic review. Results: While MW indices, particularly global work index and global constructed work, have shown good correlations with ejection fraction (EF) and strain parameters, the opportunity of offering incremental information that is unaffected by loading conditions has made MW application particularly useful in a variety of clinical settings. Conclusion: Compared to EF and global longitudinal strain, MW is a promising test with higher sensitivity and accuracy for identifying individuals with cardiovascular disease. Clinicians should also evaluate symptoms and electrocardiographic findings until extensive multicenter studies validating this strategy are performed to establish the incremental value of MW in daily echocardiographic assessments.(AU)

Segmental Cardiac Radiation Dose Determines Magnitude of Regional Cardiac Dysfunction.

Background Subclinical left ventricular dysfunction detected by 2-dimensional global longitudinal strain post breast radiotherapy has been described in patients with breast cancer. We hypothesized that left ventricular dysfunction postradiotherapy may be site specific, based on differential segmental radiotherapy dose received. Methods and Results Transthoracic echocardiograms were performed at baseline, 6 weeks, and 12 months postradiotherapy on 61 chemotherapy-naïve women with left-sided breast cancer undergoing tangential breast radiotherapy. Radiation received within basal, mid, and apical regions for the 6 left ventricular walls was quantified from the radiotherapy treatment planning system. Anterior, anteroseptal, and anterolateral walls received the highest radiation doses, while inferolateral and inferior walls received the lowest. There was a progressive increase in the radiation dose received from basal to apical regions. At 6 weeks, the most significant percentage deterioration in strain was seen in the apical region, with greatest reductions in the anterior wall followed by the anteroseptal and anterolateral walls, with a similar pattern persisting at 12 months. There was a within-patient dose-response association between the segment-specific percentage deterioration in strain at 6 weeks and 12 months and the radiation dose received. Conclusions Radiotherapy for left-sided breast cancer causes differential segmental dysfunction, with myocardial segments that receive the highest radiation dose demonstrating greatest strain impairment. Percentage deterioration in strain observed 6 weeks postradiotherapy persisted at 12 months and demonstrated a dose-response relationship with radiotherapy dose received. Radiotherapy-induced subclinical cardiac dysfunction is of importance because it could be additive to chemotherapy-related cardiotoxicity in patients with breast cancer. Long-term outcomes in patients with asymptomatic strain reduction require further investigation.

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.

Cardiovascular event risk estimated after coronary revascularization and optimal medical therapy: J-ACCESS4 prognostic study.

BACKGROUND: An assessment of cardiac events and survival using quantitative gated myocardial single-photon emission computed tomography (SPECT) (J-ACCESS) associated several risk factors with cardiac events in Japan. The clinical course after revascularization and/or optimal medical therapy (OMT) was followed in patients with coronary artery disease (CAD) at moderate-to-high risk estimated by software incorporating the J-ACCESS risk model. The present study aimed to determine the relevance of changes in estimated risk to outcomes of these therapies. METHODS: This study included 494 patients with possible or definite CAD who underwent initial pharmacological stress 99mTc-tetrofosmin myocardial perfusion SPECT (MPS) before and eight months after therapy. Major cardiac event risk during 3 years of follow-up was calculated using an equation based on that in the J-ACCESS study. Patients with ≥ 10% cardiac event risk estimated at the first MPS (n = 31) were analyzed and followed up for at least 1 year. RESULTS: Estimated risk was reduced by ≥ 5% in 14 patients (45%) after therapy. During a follow-up period of 22.1 ± 6.7 months, one patient without such reduction had a major cardiac event. Mean %summed stress scores significantly decreased from baseline to follow-up in patients with and without risk reduction. Left ventricular ejection fraction (LVEF [%]) at rest was significantly increased at the second, compared with the first MPS between patients with, than without risk reduction (57 ± 17 vs. 45 ± 16%, p = 0.001 and 50 ± 11 vs. 49 ± 9%, p = 0.953, respectively). CONCLUSIONS: A reduction in cardiac ischemia and an increase in LVEF by revascularization and/or OMT were necessary to avoid cardiac events among patients with moderate-to-high estimated risk, and changes in event risk were quantifiable.

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.

Early Cardiac Effects of Contemporary Radiation Therapy in Patients With Breast Cancer.

PURPOSE: To characterize the early changes in echocardiographically derived measures of cardiac function with contemporary radiation therapy (RT) in breast cancer and to determine the associations with radiation dose-volume metrics, including mean heart dose (MHD). METHODS AND MATERIALS: In a prospective longitudinal cohort study of 86 patients with breast cancer treated with photon or proton thoracic RT, clinical and echocardiographic data were assessed at 3 time points: within 4 weeks before RT initiation (T0), within 3 days before 6 weeks after the end of RT (T1), and 5 to 9 months after RT completion (T2). Associations between MHD and echocardiographically derived measures of cardiac function were assessed using generalized estimating equations to define the acute (T0 to T1) and subacute (T0 to T2) changes in cardiac function. RESULTS: The median estimates of MHD were 139 cGy (interquartile range, 99-249 cGy). In evaluating the acute changes in left ventricular ejection fraction (LVEF) from T0 to T1, and accounting for the time from RT, age, race, preexisting cardiovascular disease, and an interaction term with anthracycline or trastuzumab exposure and MHD, there was a modest decrease in LVEF of borderline significance (0.22%; 95% confidence interval [CI], -0.44% to 0.01%; P = .06) per 30-day interval for every 100 cGy increase of MHD. Similarly, there was a modest worsening in longitudinal strain (0.19%; 95% CI, -0.01% to 0.39%; P = .06) per 30-day interval for each 100 cGy increase in MHD. We did not find significant associations between MHD and changes in circumferential strain or diastolic function. CONCLUSIONS: With modern radiation planning techniques, there are modest subclinical changes in measures of cardiac function in the short-term. Longer-term follow-up studies are needed to determine whether these early changes are associated with the development of overt cardiac disease.

Adjuvant Trastuzumab Emtansine (T-DM1) and Concurrent Radiotherapy for Residual Invasive HER2-positive Breast Cancer: Single-center Preliminary Results.

OBJECTIVES: The treatment of nonmetastatic HER2-positive breast cancer with residual invasive disease using concurrent Trastuzumab emtansine (T-DM1) and radiotherapy appears to be an effective option. Our aim was to evaluate the acute side effects of this treatment regime. METHODS: Fourteen patients were treated between March 2019 and April 2020 concurrent T-DM1 and radiotherapy. Left ventricular ejection fraction was assessed at baseline, before and after radiotherapy. All toxicities were evaluated using Common Terminology Criteria of Adverse Events (CTCAE) version 3.0. RESULTS: The median age was 55 years (range 36 to 72). All patients received total dose of 50 Gy for the breast/ chest wall, 10 patients got lymph node irradiation, 4 patients received an additional tumor bed boost. The most common side effect was grade 1 radiodermatitis. A reversible grade 2 left ventricular ejection fraction decrease occurred in 2 patients. During our examination 3 patients showed alanine aminotransferases increase after the cycle 4 of T-DM1, 1 patient had grade 1, 1 patient grade 2, and 1 patient grade 3 alanine aminotransferase increases. CONCLUSIONS: The acute toxicity rate especially focusing on skin and cardiac toxicity were assumed acceptable in our cohort. To safely administer this concomitant treatment, further examination and prospective data are needed.

ST2 levels increased and were associated with changes in left ventricular systolic function during a three-year follow-up after adjuvant radiotherapy for breast cancer.

OBJECTIVES: To search for biomarkers of RT-induced cardiotoxicity, we studied the behavior of ST2 during RT and three years after RT, and the associations with echocardiographic changes. MATERIALS AND METHODS: We measured soluble ST2 (ng/ml) in serum samples from 63 patients receiving RT for early breast cancer. Sampling and echocardiography were performed at baseline, after RT and at the three-year follow-up. Patients were grouped by >15% (group 1) and ≤15% (group 2) relative worsening in global longitudinal strain (GLS). RESULTS: ST2 levels tended to increase during RT, from a median (interquartile range; IQR) of 17.9 (12.4-22.4) at baseline to 18.2 (14.1-23.5) after RT (p = 0.075). By the three-year follow up, ST2 levels increased to 18.7 (15.8-24.2), p = 0.018. The increase in ST2 level was associated with worsening cardiac systolic function at three-year follow-up, GLS (rho = 0.272, p = 0.034) and left ventricular ejection fraction (LVEF) (rho = â”€0.343, p = 0.006). Group 1 (n = 14) had a significant increase in ST2 levels from 17.8 (12.3-22.5) at baseline to 18.4 (15.6-22.6) after RT, p = 0.035 and to 19.9 (16.0-25.1) three years after RT, p = 0.005. ST2 levels were stable in group 2 (n = 47): 17.8 (12.3-22.0) at baseline, 17.7 (12.6-23.5) after RT and 18.0 (15.5-22.4) at three years. CONCLUSION: ST2 may be useful for determining which patients are at risk for long-term cardiovascular toxicity following adjuvant breast cancer RT, but prospective clinical studies are needed to confirm this hypothesis.

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.

Left ventricular function after noninvasive cardiac ablation using proton beam therapy in a porcine model.

BACKGROUND: Noninvasive cardiac ablation of ventricular tachycardia (VT) using radiotherapy has recently gained interest among electrophysiologists. The effects of left ventricular (LV) ablative radiation treatment on global LV function and volumes are unknown. OBJECTIVE: The purpose of this study was to investigate the effects of noninvasive ablation on LV function over time. METHODS: Twenty domestic swine underwent proton beam treatment of LV sites in a dose-finding design and were followed for up to 40 weeks by cardiac magnetic resonance imaging at 4-week intervals. Doses investigated were either 40 Gy at 1 site (n = 8) or 30 Gy at 2 sites (n = 4) in the low-dose group and 40 Gy at 3 sites (n = 8) in the high-dose group. RESULTS: LV mean dose (13.2 ± 1.8 Gy vs 4.6 ± 1.8 Gy) and the volume receiving at least 20 Gy (V20Gy) (24.7% ± 4.8% vs 6.4% ± 3.0%) differed significantly between groups. Dose-dependent effects on left ventricular ejection fraction (LVEF) and LV end-diastolic volume became manifest about 3 months after treatment. LVEF decline was correlated to mean dose (correlation coefficient ρ = -0.69; P = .008) and V20Gy (ρ = -0.66; P = .01), as was LV dilation (ρ = 0.72; P = .005; and ρ = 0.75, P = .003 respectively). CONCLUSION: Possible adverse effects on LV function, seen about 3 months after treatment, are dose dependent. Therefore, precise target definition and focused energy delivery are paramount in catheter-free ablation.

Cardiac Function After Radiation Therapy for Breast Cancer.

PURPOSE: The main purpose of this study was to test the hypothesis that incidental cardiac irradiation is associated with changes in cardiac function in breast cancer (BC) survivors treated with radiation therapy (RT). METHODS AND MATERIALS: We conducted a cross-sectional study consisting of 109 BC survivors treated with RT between 2005 and 2011. The endpoint was cardiac function, assessed by echocardiography. Systolic function was assessed with the left ventricular ejection fraction (LVEF) (n = 107) and the global longitudinal strain (GLS) of the left ventricle (LV) (n = 52). LV diastolic dysfunction (n = 109) was defined by e' at the lateral and septal region, which represents the relaxation velocity of the myocardium. The individual calculated RT dose parameters of the LV and coronary arteries were collected from 3-dimensional computed tomography-based planning data. Univariable and multivariable analysis using forward selection was performed to identify the best predictors of cardiac function. Robustness of selection was assessed using bootstrapping. The resulting multivariable linear regression model was presented for the endpoints of systolic and diastolic function. RESULTS: The median time between BC diagnosis and echocardiography was 7 years. No relation between RT dose parameters and LVEF was found. In the multivariable analysis for the endpoint GLS of the LV, the maximum dose to the left main coronary artery was most often selected across bootstrap samples. For decreased diastolic function, the most often selected model across bootstrap samples included age at time of BC diagnosis and hypertension at baseline. Cardiac dose-volume histogram parameters were less frequently selected for this endpoint. CONCLUSIONS: This study shows an association between individual cardiac dose distributions and GLS of the LV after RT for BC. No relation between RT dose parameters and LVEF was found. Diastolic function was most associated with age and hypertension at time of BC diagnosis. Further research is needed to make definitive conclusions.

Cardiotoxicity Assessment After Different Adjuvant Hypofractionated Radiotherapy Concurrently Associated with Trastuzumab in Early Breast Cancer.

AIM: To evaluate cardiotoxicity in patients with human epidermal growth factor receptor 2+ (HER2+) breast cancer (29 left-sided, 23 right-sided) treated with adjuvant whole-breast hypofractionated radiotherapy (HRT) concurrently administered with the humanized monoclonal antibody to HER2, trastuzumab. PATIENTS AND METHODS: From February 2008 to June 2017, 52 patients received three-dimensional conformal RT, with different HRT schemes. Echocardiogram monitoring was used to evaluate the decrease in left ventricular ejection fraction (LVEF). RESULTS: At a median follow-up of 5 years, cardiotoxicity was as follows: among the 15 patients treated with 46 Gy: grade (G) 2 in two (13%), G1 in three (20%), and G0 in 10 (67%);in those treated with 39 Gy (16 patients): G1 in five (31%), and G0 in 11 (69%);among the 21 patients treated with 35 Gy: G2 in one (5%), G1 in five (24%), and G0 in 15 (71%). CONCLUSION: Trastuzumab was shown to be a safe adjuvant treatment when administered with concomitant HRT since it did not increase cardiotoxicity in those with left-sided breast cancer. No differences in LVEF were observed between the HRT schemes.

Institution of localized high-frequency electrical stimulation targeting early myocardial infarction: Effects on left ventricle function and geometry.

BACKGROUND: Although strategies have focused on myocardial salvage/regeneration in the context of an acute coronary syndrome and a myocardial infarction (MI), interventions targeting the formed MI region and altering the course of the post-MI remodeling process have not been as well studied. This study tested the hypothesis that localized high-frequency stimulation instituted within a formed MI region using low-amplitude electrical pulses would favorably change the trajectory of changes in left ventricle geometry and function. METHODS: At 7 days following MI induction, pigs were randomized for localized high-frequency stimulation (n = 5, 240 bpm, 0.8 V, and 0.05 ms pulses) or unstimulated (n = 6). Left ventricle geometry and function were measured at baseline (pre-MI) and at 7, 14, 21, and 28 days post-MI using echocardiography. MI size at 28 days post-MI was determined by histochemical staining and planimetry. RESULTS: At 7 days post-MI and before randomization to localized high-frequency stimulation, left ventricular ejection fraction and end-diastolic volume was equivalent. However, when compared with 7-day post-MI values, left ventricle end-diastolic volume increased in a time-dependent manner in the MI unstimulated group, but the relative increase in left ventricle end-diastolic volume was reduced in the MI localized high-frequency stimulation group. For example, by 28 days post-MI, left ventricle end-diastolic volume increased by 32% in the MI unstimulated group but only by 12% in the MI localized high-frequency stimulation group (P < .05). Whereas left ventricular ejection fraction appeared unchanged between MI groups, estimates of pulmonary capillary wedge pressure, a marker of adverse left ventricle performance and progression to failure, increased by 62% in the MI unstimulated group and actually decreased by 17% in the MI localized high-frequency stimulation group when compared with 7-day post-MI values (P < .05). MI size was equivalent between the MI groups, indicative of no difference in the extent of absolute myocardial injury. CONCLUSIONS: The unique findings from this study are 2-fold. First, targeting the MI region following the resolution of the acute event using a localized stimulation approach is feasible. Second, localized stimulation modified a key parameter of adverse post-MI remodeling (dilation) and progression to heart failure. These findings demonstrate that the MI region itself is a modifiable tissue and responsive to localized electrical stimulation.

Radiotherapy-induced Early ECG Changes and Their Comparison with Echocardiography in Patients with Early-stage Breast Cancer.

BACKGROUND: Early electrocardiogram (ECG) changes after breast cancer radiotherapy (RT) have been reported, but their characteristics and associated factors are largely unknown. This study aimed to explore early RT-induced ECG changes and to compare them with echocardiography changes. MATERIALS AND METHODS: Sixty eligible patients with chemotherapy-naïve left-sided and 20 with right-sided breast cancer were evaluated with echocardiography, blood samples and ECG before and after RT. RESULTS: RT-induced ECG changes in the anterior leads. T-Wave changes were most frequent. T-Wave decline was associated independently with patient age (ß=-0.245, p=0.005), mean heart radiation dose (ß=1.252, p=0.001) and global systolic strain rate change (ß=7.943, p=0.002). T-Wave inversion was associated independently with mean heart radiation dose (ß=0.143, p<0.001), global longitudinal strain change (ß=0.053, p=0.017) and posterior calibrated integrated backscatter (ß=-0.022, p=0.049). CONCLUSION: RT-induced ECG changes were prevalent and associated with functional and structural changes in echocardiography. ECG could be used for post-RT cardiac screening.

Left Ventricular Strain in Chemotherapy-Naive and Radiotherapy-Naive Patients With Cancer.

BACKGROUND: We sought to investigate left ventricular (LV) function and mechanics in patients with cancer before they received chemotherapy or radiotherapy, as well as the relationship between cancer and reduced LV multidirectional strain in the whole study population. METHODS: The retrospective study involved 122 chemotherapy- and radiotherapy-naive patients with cancer and 45 age- and sex-matched controls with a cardiovascular risk profile similar to that of the patients with cancer. All the patients underwent echocardiographic examination before introduction of chemotherapy or radiotherapy. RESULTS: LV longitudinal (-19.1% ± 2.1% vs -17.8% ± 3.5%; P = 0.022), circumferential (-22.9% ± 3.5% vs -20.1% ± 4.1%; P < 0.001), and radial (40.5% ± 8.8% vs 35.2% ± 10.7%; P = 0.004) strain was significantly lower in the patients with cancer than in the control group. Endocardial and midmyocardial longitudinal LV strain was significantly reduced in the patients with cancer compared with the controls, whereas epicardial longitudinal strain was similar between these groups. Endocardial, midmyocardial, and epicardial circumferential strain was significantly lower in the chemotherapy- or radiotherapy-naive patients with cancer than in the controls. Cancer was associated with reduced longitudinal (odds ratio [OR], 9.0; 95% confidence interval [CI], 2.20-23.50; P < 0.001), reduced circumferential (OR, 7.1; 95% CI, 3.80-20.40; P < 0.001), and reduced radial strain (OR, 7.2; 95% CI, 3.41-25.10; P < 0.001) independent of age, sex, body mass index, diabetes, and hypertension. CONCLUSIONS: LV mechanics was impaired in the patients with cancer compared with the controls even before initiation of chemotherapy and radiotherapy. Cancer and hypertension were associated with reduced LV multidirectional strain independent of other clinical parameters. The present results indicate that cancer itself potentially induces cardiac remodelling independent of chemotherapy and radiotherapy.

No Acute Changes in LVEF Observed With Concurrent Trastuzumab and Breast Radiation With Low Heart Doses.

INTRODUCTION/BACKGROUND: Treatment for HER2-postitive breast cancer often includes trastuzumab, breast/chest wall (CW) radiation (RT), and anthracyclines, all of which have cardiac toxicity. We aimed to evaluate the relationship between heart dose and acute left ventricular ejection fraction (LVEF) changes in patients who received concurrent trastuzumab and breast/CW RT with and without anthracycline use. PATIENTS AND METHODS: We retrospectively reviewed all nonmetastatic breast cancer patients from 2008 to 2015 who received concurrent trastuzumab and breast/CW RT. Baseline LVEF was compared with the LVEF closest to treatment completion as well as with the lowest post-treatment LVEF. LVEF changes were correlated with laterality, heart dosimetric parameters, and doxorubicin use. RESULTS: Eighty-eight patients were included in our analysis. The median follow-up was 45 months. Forty-one patients were right-sided and 47 left-sided. Thirty-one patients received doxorubicin, 16 right-sided and 15 left-sided. Mean heart dose was 1.10 Gy and 3.63 Gy for right- and left-sided patients, respectively (P < .001). In the entire cohort, a significant LVEF decrease of 3.0% was observed pre- and post-treatment. There was a significant effect of doxorubicin (P = .013) and a nonsignificant effect of RT laterality (P = .088) on LVEF change. The test of interaction between doxorubicin and laterality was not significant (P = .90). No significant association was found between LVEF change and heart dosimetric parameters, including percent volume of heart receiving 5 Gy (V5), 10 Gy (V10), 20 Gy (V20), and 45 Gy (V45), and maximum dose. Similar results were found when baseline LVEF was compared with the lowest post-treatment LVEF. CONCLUSION: With cardiac doses < 4 Gy, declines in LVEF were not related to tumor laterality or heart dosimetric parameters. Statistically significant LVEF decreases were mainly attributed to doxorubicin.

Cardio-oncology: the Nuclear Option.

PURPOSE OF REVIEW: Cardio-oncology focuses increased effort to decrease cancer treatment-related cardiotoxicity while continuing to improve outcomes. We sought to synthesize the latest in nuclear cardiology as it pertains to the assessment of left ventricular function in preventative guidelines and comparison to other modalities, novel molecular markers of pre-clinical cardiotoxicity, and its role in cardiac amyloid diagnosis. RECENT FINDINGS: Planar ERNA (equilibrium radionuclide angiocardiography) provides a reliable and proven means of monitoring and preventing anthracycline cardiotoxicity, and SPECT ERNA using solid-state gamma cameras may provide reproducible assessments of left ventricular function with reduced radiation exposure. While certain chemotherapeutics have vascular side effects, the use of stress perfusion imaging has still not been adequately studied for routine use. Similarly, markers of apoptosis, inflammation, and sympathetic nerve dysfunction are promising, but are still not ready for uniform usage. SPECT tracers can assist in nonbiopsy diagnosis of cardiac amyloid. Nuclear cardiology is a significant contributor to the multimodality approach to cardio-oncology.

Advanced Heart Failure Therapies for Cancer Therapeutics-Related Cardiac Dysfunction.

End-stage heart failure in cancer survivors may result from cardiotoxic chemotherapy and/or chest radiation and require advanced therapies, including left ventricular assist devices (LVADs) and transplantation. Traditionally, such therapies have been underutilized in cancer survivors owing to lack of experience and perceived risk of cancer recurrence. Recent data from large registries, however, have shown excellent outcomes of LVADs and transplantation in cancer survivors, albeit subject to careful selection and special considerations. This article summarizes all aspects of advanced heart failure therapies in patients with cancer therapy-related cardiac dysfunction and underscores the need for careful selection of these candidates.

Radiotherapy-induced right ventricular remodelling: The missing piece of the puzzle.

The number of studies demonstrating that right ventricular structure, function and mechanics are valuable predictors of cardiovascular and total morbidity and mortality in patients with a wide range of cardiovascular conditions is constantly increasing. Most studies that evaluated the influence of radiotherapy on the heart focused on left ventricular remodelling, which is why current guidelines only recommend detailed assessment of the left ventricle. Data regarding right ventricular changes in cancer patients treated with radiotherapy are scarce. Given that radiotherapy more often induces late cardiac impairment - unlike chemotherapy-induced cardiotoxicity, which is usually acute - it is quite reasonable to follow these patients echocardiographically for a long time (even for 20years after initiation of radiotherapy). Investigations that have followed cancer survivors for at least 10years after radiotherapy agree that right ventricular structure, systolic/diastolic function and mechanics are significantly impaired. The mechanisms of radiation-induced right ventricular remodelling are still unclear, but it is thought that fibrosis is the dominant factor in myocardial remodelling and vascular changes. Many factors may contribute to right ventricular impairment during and after radiotherapy: cumulative radiation dose; dose per treatment; delivery technique; radiation target (chest and mediastinum); and co-morbidities. In this review, we aim to provide a comprehensive overview of the potential mechanisms of radiation-induced right ventricular remodelling, and to summarize clinical studies involving radiotherapy-treated cancer patients.