Cardio-oncology imaging tools at the translational interface

https://doi.org/10.1016/j.yjmcc.2022.03.012Get rights and content

Highlights

  • ā€¢

    The role of imaging tools in diagnosis of cardiotoxicity.

  • ā€¢

    Limitations of current cardiovascular imaging technologies.

  • ā€¢

    Translational cardiovascular imaging technologies.

  • ā€¢

    Novel molecular targeted imaging strategies.

Abstract

Cardiovascular imaging is an evolving component in the care of cancer patients. With improved survival following prompt cancer treatment, patients are facing increased risks of cardiovascular complications. While currently established imaging modalities are providing useful structural mechanical information, they continue to develop towards increased specificity. New modalities, emerging from basic science and oncology, are being translated, targeting earlier stages of cardiovascular disease. Besides these technical advances, matching an imaging modality with the patients' individual risk level for a specific pathological change is part of a successful imaging strategy. The choice of suitable imaging modalities and time points for specific patients will impact the cardio-oncological risk stratification during surveillance and follow-up monitoring. In addition, future imaging tools are poised to give us important insights into the underlying cardiovascular molecular pathology associated with cancer and oncological therapies. This review aims at giving an overview of the novel imaging technologies that have the potential to change cardio-oncological science and clinical practice in the near future.

Introduction

Cardio-oncology is a growing field at the intersection of cardiovascular medicine, hematology and oncology [1]. Improved survival of cancer patients has led to an increased awareness of cardiac complications due to anticancer therapies [2]. Widely recognized, anthracyclines are associated with an acute or subacute cardiotoxic effect, typically detectable immediately or within the first year after treatment with conventional imaging methods [3], but also with chronic, progressive cardiotoxicity that can lead to impaired left ventricular function, many years after exposure [4,5] However, there are only limited tools to identify patients with late effects at an early stage, and most of them depend on elevated cardiac biomarker indicating myocardial injury or structural abnormalities. And more importantly, there are several novel anticancer therapies that are associated with cardiotoxic effects, such as transient cardiac dysfunction (e.g., kinase inhibitors, proteasome inhibitors, BRAF-inhibitors) [[6], [7], [8], [9]] or inflammation (e.g., immune checkpoint inhibitors) [10], but there are even less data available for detecting early molecular, immune or metabolic cardiotoxic effects of these breakthrough oncological interventions.

In addition to the cardiac risk, cancer survivors with cardiovascular side effects also have reduced progression free- and overall survival [6]. Therefore, early identification of patients at risk and early diagnosis of cardiotoxic events may allow to optimize the overall outcome after cancer treatment. Cardiovascular imaging can be implemented in a cardio-oncological surveillance strategy using established modalities (Table 1) and emerging more specific imaging techniques (Fig. 1, Table 2, Table 3) as a gatekeeper for suitable cardioprotective strategies.

This review is focused on novel imaging techniques that can visualize in new ways cardiovascular structures, biochemical processes and molecular targets and their possible implications for cardio-oncological patients. The literature is selected based on the translational potential and usefulness in preclinical and early clinical applications.

Section snippets

Structural and functional imaging in cardio-oncology

Cardiovascular changes evolve in cardio-oncological patients due to underlying diseases (e.g. cardiac hypertrophy, or accompanying amyloidosis) [11,12] and as a result of cardiotoxic therapies (e.g. cardiac atrophy in patients with anthracycline therapies) [13]. Specific tissue characteristics can be detected by established methods, such as echocardiography or conventional cMRI and PET-tracer based imaging, but all these changes can be understood as an end-stage situation of cancer or

Molecular imaging developments

Pathological cardiac remodeling is associated with fundamental metabolic changes [73]. Preclinical data suggest that such metabolic changes precede adverse cardiac remodeling and could be used as an early or predictive marker for patients at risk [74]. Simplified, pathological cardiac remodeling is based on a number of molecular events that are well accepted to be crucial for the development of left ventricular dysfunction. Many of the underlying molecular mechanisms were initially described in

Limitations of imaging in cardio-oncology

In case of echocardiography, image quality and expertise of the investigator is crucial to allow reliable diagnosis. Especially in case of 3D-echocardiography and strain analysis, investigators need a strong expertise to acquire and interpret novel findings. Semi-automated or AI-based algorithms may reduce this inter-observer problem of echocardiography. Still, in many cancer patients imaging quality and suitable depth of ultrasound is challenged by previous radiation of the chest or thoracic

Patient and imaging method selection

From a clinical standpoint, it is increasingly important to select a suitable imaging modality, based on the patient's history and planned or ongoing oncological therapy. The choice for the imaging modality will have to take in account pathological processes, as well as statistical considerations of prevalence of abnormal results in the subgroup of patients. A certain imaging technology can be recommended only for a small number of oncological therapies. For example, in case of anthracyclines

Future directions

The development and systematic application of cardiovascular imaging tools has the potential to improve overall outcomes in cancer survivors. Observations from translational studies and proof of concept clinical trials open the opportunity to develop larger scale trials to establish the evidence necessary for the systematic application of cardiovascular imaging tools in cardio-oncology. Prospective studies will be required in multiple cancer types involving patients with different classes of

Conclusion

Paradigm-shifting scientific discoveries have driven major transitions in the therapeutic and diagnostic approaches in oncology towards molecular and immunologic targets. Considering the crosstalk between biological systems, new cardiovascular imaging methodologies are also poised to open a more granular understanding of the cardiovascular pathophysiology at the intersection with cancer. A systematic approach in this field may then result in bidirectional application of new knowledge with broad

Acknowledgements

This work was supported by awards from the German Center for Cardiovascular Research (DZHK), German Research Foundation (DFG LE3570/2-1, 3570/3-1) and the Federal Ministry for Education and Research (BMBF 01KC2006B) to LHL, and from the from the Cancer Prevention and Research Institute of Texas (CPRIT RP180404) to VGZ.

References (119)

  • F. Nudi et al.

    Diagnostic accuracy of myocardial perfusion imaging with CZT technology: systemic review and meta-analysis of comparison with invasive coronary angiography

    JACC Cardiovasc. Imaging

    (2017)
  • F. Nensa et al.

    Feasibility of FDG-PET in myocarditis: comparison to CMR using integrated PET/MRI

    J. Nucl. Cardiol.

    (2018)
  • K. Poels et al.

    Immune checkpoint inhibitor therapy aggravates T cell-driven plaque inflammation in atherosclerosis

    JACC CardioOncol.

    (2020)
  • L. Imbert et al.

    CZT cameras: a technological jump for myocardial perfusion SPECT

    J. Nucl. Cardiol.

    (2016)
  • S.S. Koenders et al.

    Value of SiPM PET in myocardial perfusion imaging using Rubidium-82

    J. Nucl. Cardiol.

    (2022)
  • A. Teresinska

    Iodine-123-metaiodobenzylguanidine cardiac SPECT imaging in the qualification of heart failure patients for ICD implantation

    J. Nucl. Cardiol.

    (2019)
  • D. Maresca et al.

    Noninvasive imaging of the coronary vasculature using ultrafast ultrasound

    JACC Cardiovasc. Imaging

    (2018)
  • J. Grondin et al.

    4D cardiac electromechanical activation imaging

    Comput. Biol. Med.

    (2019)
  • J.E. Salem et al.

    Cardiovascular toxicities associated with ibrutinib

    J. Am. Coll. Cardiol.

    (2019)
  • M.E. Grabowska et al.

    Computational model of cardiomyocyte apoptosis identifies mechanisms of tyrosine kinase inhibitor-induced cardiotoxicity

    J. Mol. Cell. Cardiol.

    (2021)
  • N.E. Boutagy et al.

    In vivo reactive oxygen species detection with a novel positron emission tomography tracer, (18)F-DHMT, allows for early detection of anthracycline-induced cardiotoxicity in rodents

    JACC Basic Transl. Sci.

    (2018)
  • J. Tillmanns et al.

    Fibroblast activation protein alpha expression identifies activated fibroblasts after myocardial infarction

    J. Mol. Cell. Cardiol.

    (2015)
  • C. Humeres et al.

    Fibroblasts in the infarcted, remodeling, and failing heart

    JACC Basic Transl. Sci.

    (2019)
  • T. Nakata et al.

    Cardiac death prediction and impaired cardiac sympathetic innervation assessed by MIBG in patients with failing and nonfailing hearts

    J. Nucl. Cardiol.

    (1998)
  • J. Moslehi et al.

    Cardio-oncology: a novel platform for basic and translational cardiovascular investigation driven by clinical need

    Cardiovasc. Res.

    (2019)
  • K.C. Stoltzfus et al.

    Fatal heart disease among cancer patients

    Nat. Commun.

    (2020)
  • D. Cardinale et al.

    Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy

    Circulation

    (2015)
  • S.E. Lipshultz et al.

    Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood

    N. Engl. J. Med.

    (1991)
  • S.E. Lipshultz et al.

    Doxorubicin-induced cardiomyopathy

    N. Engl. J. Med.

    (1999)
  • R.F. Cornell et al.

    Prospective study of cardiac events during proteasome inhibitor therapy for relapsed multiple myeloma

    J. Clin. Oncol.

    (2019)
  • A.Y. Khakoo et al.

    Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor

    Cancer

    (2008)
  • M.S. Ewer et al.

    Sunitinib-related cardiotoxicity: an interdisciplinary issue

    Nat. Clin. Pract. Cardiovasc. Med.

    (2008)
  • V.S. Hahn et al.

    Cancer therapy-induced cardiotoxicity: basic mechanisms and potential cardioprotective therapies

    J. Am. Heart Assoc.

    (2014)
  • D.B. Johnson et al.

    Fulminant myocarditis with combination immune checkpoint blockade

    N. Engl. J. Med.

    (2016)
  • K.T. Murphy

    The pathogenesis and treatment of cardiac atrophy in cancer cachexia

    Am. J. Physiol. Heart Circ. Physiol.

    (2016)
  • M.S. Willis et al.

    Doxorubicin exposure causes subacute cardiac atrophy dependent on the striated muscle-specific ubiquitin ligase MuRF1

    Circ. Heart Fail.

    (2019)
  • J.C. Plana et al.

    Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging

    Eur. Heart J. Cardiovasc. Imaging

    (2014)
  • J.L. Zamorano et al.

    2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC)

    Eur. Heart J.

    (2016)
  • S.H. Armenian et al.

    Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline

    J. Clin. Oncol.

    (2017)
  • L.D. Jacobs et al.

    Rapid online quantification of left ventricular volume from real-time three-dimensional echocardiographic data

    Eur. Heart J.

    (2006)
  • C. Santoro et al.

    2D and 3D strain for detection of subclinical anthracycline cardiotoxicity in breast cancer patients: a balance with feasibility

    Eur. Heart J. Cardiovasc. Imaging

    (2017)
  • K.E. Farsalinos et al.

    Head-to-head comparison of global longitudinal strain measurements among nine different vendors: the EACVI/ASE inter-vendor comparison study

    J. Am. Soc. Echocardiogr.

    (2015)
  • M.T. Ali et al.

    Myocardial strain is associated with adverse clinical cardiac events in patients treated with anthracyclines

    J. Am. Soc. Echocardiogr.

    (2016)
  • A. Calleja et al.

    Right ventricular dysfunction in patients experiencing cardiotoxicity during breast cancer therapy

    J. Oncol.

    (2015)
  • K. Keramida et al.

    Longitudinal changes of right ventricular deformation mechanics during trastuzumab therapy in breast cancer patients

    Eur. J. Heart Fail.

    (2019)
  • M.I.C. Planek et al.

    Prediction of doxorubicin cardiotoxicity by early detection of subclinical right ventricular dysfunction

    Cardiooncology

    (2020)
  • J.R. Christiansen et al.

    Right ventricular function in long-term adult survivors of childhood lymphoma and acute lymphoblastic leukaemia

    Eur. Heart J. Cardiovasc. Imaging

    (2016)
  • H. Park et al.

    Left atrial longitudinal strain as a predictor of cancer therapeutics-related cardiac dysfunction in patients with breast cancer

    Cardiovasc. Ultrasound

    (2020)
  • A. Singh et al.

    Utilizing left atrial strain to identify patients at risk for atrial fibrillation on ibrutinib

    Echocardiography

    (2021)
  • V.M. Ferreira et al.

    Myocardial tissue characterization by magnetic resonance imaging: novel applications of T1 and T2 mapping

    J. Thorac. Imaging

    (2014)
  • Cited by (0)

    1

    Authors contributed equally

    View full text