Advances in Screening for Radiation-Associated Cardiotoxicity in Cancer Patients.

PURPOSE OF REVIEW: Radiation is foundational to the treatment of cancer and improves overall survival. Yet, it is important to recognize the potential cardiovascular effects of radiation therapy and how to best minimize or manage them. Screening-both through imaging and with biomarkers-can potentially identify cardiovascular effects early, allowing for prompt initiation of treatment to mitigate late effects. RECENT FINDINGS: Cardiac echocardiography, magnetic resonance imaging (MRI), computed tomography, and measurements of troponin and natriuretic peptides serve as the initial screening tests of choice for RICD. Novel imaging applications, including positron emission tomography and specific MRI parameters, and biomarker testing, including myeloperoxidase, growth differentiation factor 15, galectin 3, micro-RNA, and metabolomics, hold promise for earlier detection and more specific characterization of RICD. Advances in imaging and novel applications of biomarkers have potential to identify subclinical RICD and may reveal opportunities for early intervention. Further research is needed to elucidate optimal imaging screening modalities, biomarkers, and surveillance strategies.

Radiation-Induced Cardiovascular Toxicities.

OPINION STATEMENT: Several seminal papers over the last decade have furthered our recognition of radiation-induced heart disease (RIHD) as an important potential toxicity following radiation therapy (RT) to the chest. Investigators continue to evaluate the subacute and long-term effects of RT. In addition, studies are determining whether certain cardiac substructures are more sensitive to radiation, working to identify risk factors for the development of RIHD, and testing screening and mitigation strategies for RIHD. Multiple groups and expert consensus guidelines have published whole-heart and cardiac substructure dose constraints based on available data and cancer type. The authors recommend readers to familiarize themselves with the guidelines for screening and mitigating RIHD in adults and children, which advocate for cardiovascular risk assessment and reduction before and following RT, as well as cardiovascular imaging at appropriate follow-up intervals for early recognition of subclinical cardiovascular disease. Referrals to cardiology or cardio-oncology can also be helpful in prevention, screening, and mitigation strategies.

Radiation-induced cardiac dysfunction: Practical implications.

Radiation-induced cardiac dysfunction is a critical healthcare concern facing survivors of thoracic cancers treated with radiation therapy. Despite cardiac-sparing advances in radiation therapy delivery, many patients with thoracic cancers receiving modern radiation therapy will still have incidental radiation exposure to the heart. Therefore, it is imperative that cardiovascular healthcare providers take appropriate measures to prevent, screen, and manage radiation-induced cardiac dysfunction in patients with a history of thoracic radiation therapy. In this review, we aim to provide healthcare providers with foundational information about radiation-induced cardiac pathophysiology and a chronology of advances in radiation technology. Subsequently, we provide an up-to-date review of treatment- and host-related factors that can influence a patient's risk for radiation-induced cardiac dysfunction. Finally, we culminate our discussion by detailing current screening and management guidelines to aid healthcare providers in caring for their patients with a history of thoracic radiation therapy.

Echocardiographic and clinical predictors of cardiac amyloidosis: limitations of apical sparing.

AIMS: The accuracy of an apical-sparing strain pattern on transthoracic echocardiography (TTE) for predicting cardiac amyloidosis (CA) has varied in prior studies depending on the underlying cohort. We sought to evaluate the performance of apical sparing and other TTE strain findings to screen for CA in an unselected population and determine the frequency that patients with echocardiographic concern for CA undergo evaluation for amyloidosis in clinical practice. METHODS AND RESULTS: As strain is routinely performed at our institution on all clinical TTEs, we identified all TTEs performed from 2016 through 2019 with reported concern for CA or apical sparing. We determined the performance characteristics for echocardiographic strain findings in discriminating CA including apical sparing, the ejection fraction to global longitudinal strain ratio (EF/GLS), and the septal apical-septal basal ratio (SA/SB); other clinical predictors of confirmed CA; and predictors of patients who underwent complete evaluation for CA. CA was confirmed by endomyocardial biopsy or diagnostic cardiac imaging. A total of 547 TTEs, representing 451 patients, reported concern for CA and had adequate strain for analysis. A total of 111 patients underwent complete evaluation for amyloidosis with 100 patients undergoing complete cardiac evaluation for CA. In those 100 patients, multivariable predictors of confirmed CA were age [odds ratio (OR) 3.37 per 5 years], a visual apical-sparing pattern (OR 10.85), and left ventricular ejection fraction (LVEF)/GLS > 4.1 (OR 35.37). CA was less likely in those with coronary artery disease (OR 0.04), hypertension (OR 0.18), and increased systolic blood pressure (OR 0.60 per 5 mm Hg increase). SA/SB [area under the curve (AUC) 0.72, 95% confidence interval (CI) 0.60-0.84] and LVEF/GLS (AUC 0.72, 95% CI 0.60-0.84) both had improved discrimination for CA compared with the apical-sparing ratio (AUC 0.66, 95% CI 0.54-0.79). Many patients with suggestive TTE findings did not receive an evaluation for amyloidosis. Complete evaluation was more likely with Caucasian race (OR 2.1), increased septal thickness (OR 1.4), increased body mass index (OR 1.2), and if the report specifically stated 'amyloid' (OR 1.9). Evaluations were less likely in patients with comorbidities. While hypertension reduced the likelihood of evaluating for CA, 34% of patients with CA had hypertension (>130/80 mm Hg) at time of diagnosis. CONCLUSIONS: In a broad population of patients undergoing TTE, apical sparing on strain imaging increased the likelihood of CA diagnosis but with modest sensitivity and specificity. GLS/EF ratio may be a more reliable tool to screen for CA. The low rate of complete evaluation in patients with concerning TTE findings indicates a strong need for practice improvement and enhanced disease awareness.

Association of early versus delayed normalisation of left ventricular ejection fraction with mortality in ischemic cardiomyopathy.

OBJECTIVE: In patients with non-ischaemic cardiomyopathy and reduced left ventricular ejection fraction (LVEF), normalisation of LVEF is associated with improved outcomes. However, data on patients with ischaemic cardiomyopathy and recovered LVEF are lacking. The goal of this study was to assess the prognostic significance of normalisation of the LVEF in patients with ischaemic cardiomyopathy. METHODS/RESULTS: We performed a non-prespecified post hoc analysis of the Surgical Treatment for Ischaemic Heart Failure (STICH) trial to determine the association between normalisation of LVEF (>50%) and mortality during follow-up. Of the 1212 patients with LVEF <35% enroled in the STICH trial, 932 underwent assessment of LVEF at 4 months and/or 2 years after enrolment. Among them, 18 patients experienced normalisation in LVEF at 4-month follow-up and 35 patients experienced recovery in LVEF at 2 years. Recovery of LVEF at 4 months and recovery of LVEF at 2 years were not correlated. Recovery of LVEF at 4 months was not associated with reduced all-cause mortality in unadjusted analysis (log-rank test p=0.54) or in Cox proportional hazards analysis (HR: 0.93; 95% CI: 0.48 to 1.80; p=0.82). Ejection fraction recovery at 2 years was associated with a reduction in all-cause mortality, both in unadjusted analysis (log-rank test p=0.004) and in the Cox proportional hazard model (HR: 0.41; 95% CI: 0.21 to 0.80; p=0.009). CONCLUSIONS: In patients with ischaemic cardiomyopathy, delayed normalisation of LVEF is associated with reduced mortality, whereas early recovery of LVEF is not. Further studies are needed to confirm these findings.

Coronary and aortic calcification are associated with cardiovascular events on immune checkpoint inhibitor therapy.

BACKGROUND: Although the incidence of immune checkpoint inhibitor (ICI)-related cardiovascular (CV) toxicity is low, the overall burden of CV events after ICI is unknown. Risk factors for CV events after ICI have yet to be identified. OBJECTIVES: We sought to evaluate the association between vascular calcification on routine baseline computed tomography (CT) imaging and CV events following ICI. METHOD: This was a single-center, retrospective cohort study of 76 patients referred to Cardio-Oncology with prior ICI treatment. Coronary and aortic calcification on non-gated chest and abdominal CT imaging were qualitatively assessed. The association of baseline clinical parameters and vascular calcification with symptomatic heart failure (HF), acute coronary syndrome, myocarditis, symptomatic arrhythmia, or pericardial effusion after ICI was evaluated. RESULTS: Over 11 months of follow-up, there were 80 CV events that occurred in 49 patients. Worse coronary and aortic calcification on pre-treatment CT imaging was seen in patients with a CV event (p = .018 and p = .014, respectively). There were no differences in traditional CV risk factors between those with and without a CV event. Eighteen patients (37%) were restarted on ICI therapy after a non- myocarditis or symptomatic systolic HF CV event without recurrent events or mortality over 13 months of follow-up. CONCLUSIONS: Symptomatic HF was the most common CV event seen after ICI therapy. Worse coronary and aortic calcification on baseline CT imaging was associated with CV events following ICI. With careful clinical evaluation, selected patients may be re-treated with ICI following a non- myocarditis or symptomatic systolic HF CV event.

Actionable Metabolic Pathways in Heart Failure and Cancer-Lessons From Cancer Cell Metabolism.

Recent advances in cancer cell metabolism provide unprecedented opportunities for a new understanding of heart metabolism and may offer new approaches for the treatment of heart failure. Key questions driving the cancer field to understand how tumor cells reprogram metabolism and to benefit tumorigenesis are also applicable to the heart. Recent experimental and conceptual advances in cancer cell metabolism provide the cardiovascular field with the unique opportunity to target metabolism. This review compares cancer cell metabolism and cardiac metabolism with an emphasis on strategies of cellular adaptation, and how to exploit metabolic changes for therapeutic benefit.

Therapeutic time window of multipotent adult progenitor therapy after traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability. TBI results in a prolonged secondary central neuro-inflammatory response. Previously, we have demonstrated that multiple doses (2 and 24 h after TBI) of multipotent adult progenitor cells (MAPC) delivered intravenously preserve the blood-brain barrier (BBB), improve spatial learning, and decrease activated microglia/macrophages in the dentate gyrus of the hippocampus. In order to determine if there is an optimum treatment window to preserve the BBB, improve cognitive behavior, and attenuate the activated microglia/macrophages, we administered MAPC at various clinically relevant intervals. METHODS: We administered two injections intravenously of MAPC treatment at hours 2 and 24 (2/24), 6 and 24 (6/24), 12 and 36 (12/36), or 36 and 72 (36/72) post cortical contusion injury (CCI) at a concentration of 10 million/kg. For BBB experiments, animals that received MAPC at 2/24, 6/24, and 12/36 were euthanized 72 h post injury. The 36/72 treated group was harvested at 96 h post injury. RESULTS: Administration of MAPC resulted in a significant decrease in BBB permeability when administered at 2/24 h after TBI only. For behavior experiments, animals were harvested post behavior paradigm. There was a significant improvement in spatial learning (120 days post injury) when compared to cortical contusion injury (CCI) in groups when MAPC was administered at or before 24 h. In addition, there was a significant decrease in activated microglia/macrophages in the dentate gyrus of hippocampus of the treated group (2/24) only when compared to CCI. CONCLUSIONS: Intravenous injections of MAPC at or before 24 h after CCI resulted in improvement of the BBB, improved cognitive behavior, and attenuated activated microglia/macrophages in the dentate gyrus.