There has been an increasing recognition of the relationship between immune surveillance and
tumour proliferation over the last four decades. One of the most important therapeutic
advances as a result of this knowledge expansion has been the development of immunotherapies
such as Immune Checkpoints Inhibitors (ICI) for the treatment of a variety of malignancies.
ICI's stimulate an overproduction of cytotoxic T cells, which are capable of mounting an
attack on cancerous cells. There are currently seven different ICI's approved by the US Food
and Drug Administration (FDA) and used as commercially available therapeutics. With an
increased usage of ICI's, there has been increased reports of Immune Related Adverse Effects
(IRAE's) caused by autoreactive T cells, one of these being cardiac muscle inflammation, or
myocarditis. Acute fulminant myocarditis can result in heart failure, cardiogenic shock
and/or arrhythmias with a reported mortality rate of 25-56% within 3-10 years. Whilst ICI
induced fulminant myocarditis is rare, little is known about the rates of subclinical
myocardial injury and the cardiac functional and structural effects of ICI's over time.
Advanced cardiac imaging such as Cardiac Magnetic Resonance (CMR) and speckle tracking
echocardiography (Echo) facilitate the early diagnosis of myocardial injury. CMR is
non-invasive, free of ionizing radiation, highly sensitive and offers a variety of imaging
parameters such as LGE, T1 mapping, T2 mapping to aid in myocardial tissue characterisation.
Echo strain via speckle tracking echocardiography can depict early indications of cardiac
dysfunction prior to the onset of functional changes, therefore abnormal strain measurements
such as abnormal global longitudinal strain (GLS) and right ventricular free wall strain (RV
FWS) occur prior to changes in left ventricular ejection fraction (LVEF). Cardiac biomarkers
such as cardiac Troponin I (cTn I) and N-Terminal-Pro-hormone-B- type Natriuretic Peptide
(NT-pro BNP) assess for myocardial injury and hemodynamic stress respectively within the
myocardium. As the frequency of ICI's use increases as a cancer therapy, the concerns
regarding cardiotoxicity are ever present and there is a lack of prospective data regarding
this. The likelihood of pericardial and skeletal muscle inflammation resulting in cTn
elevation has been raised as a distinct possibility. Hence, there is current clinical
uncertainty in (a) the prevalence and severity of cTn elevation in the setting of ICI, (b)
the functional and structural changes (if any) associated with the cTn elevation, and (c) the
long-term cardiac clinical outcomes associated with the cTn elevation in patients receiving
ICI therapy.
Hypotheses and Aims Our primary hypothesis was that patients receiving ICI therapy will
demonstrate subclinical myocardial injury in the absence of cardiac symptoms as detected by
elevations of cardiac troponin. Our secondary hypothesis was that patients demonstrating
elevated CTnI would also demonstrate myocardial oedema and/or necrosis on CMR and impairments
in Echo strain as detected by TTE. The primary outcome measure was the percentage of study
patients who demonstrated cTnI above normal range at 6 weeks post treatment. Secondary
outcome measures were to assess LV and RV global and regional dysfunction post ICI therapy
via echocardiography, changes in NT-pro BNP, myocardial injury assessed by CMR 6 weeks post
treatment and the MACE rate at 3 months. Patients were screened for participation in the
study according to the inclusion/exclusion criteria.
Methodology Prior to treatment with ICI, patients have blood investigations and
echocardiography at baseline. This was repeated at 6 weeks (+/- 1 week) with the inclusion of
a possible CMR. Any cardiac event was noted within 3 months of treatment. A data record was
stored and password protected. This information was shared with the attending oncologist and
any adverse reaction/cardiac event was noted.
