Manganese-Enhanced Magnetic Resonance Imaging of MyOcardial injuRY in COVID 19 (COVID-19)

COVID-19 Pandemic This is the first major pandemic the modern world has faced since the
Spanish Flu in 1918, with a profound impact on all aspects of society as we know it.
Governments worldwide have put in place emergency plans to help tackle and reduce the rapid
spread of the infection, with social isolation being implemented by most to varying degrees.
As expected, healthcare systems are facing unprecedented challenges and real-time
re-structuring. As well as focusing on the identification and management of critically unwell
COVID-19 patients, healthcare organisations have the responsibility of protecting the public
from infection and to continue the treatment of non COVID-19 related conditions. This has
resulted in a complete reorganisation in how we deliver care, prioritising safety and
infection control measures. In reality, this means cancelling routine clinics and procedures
and has the potential to have a great impact on patient care.

COVID-19 The pool of evidence regarding this novel strain of coronavirus and the associated
infection is growing as the condition unfolds. The current estimated case fatality rate
varies between 1.4%-2.3%, with higher rates in the elderly, certain ethnic groups and those
with co-morbidities. The largest case series from the Chinese Centre of Disease Control and
Prevention reported 72,314 case records from suspected and confirmed cases. The clinical
severity was reported as mild in 81.4%, severe in 13.9% and critical in 4.7%. Although
clinical presentation of COVID-19 can be variable, most commonly symptoms resemble those of
other viral respiratory tract infections: fever, cough, dyspnoea, myalgia and fatigue. In
severe cases, COVID-19 is associated with bilateral pneumonia, acute respiratory distress
syndrome (ARDS), and septic and cardiogenic shock, with higher mortality and morbidity seen
in elderly and comorbid patients.

Patients with known cardiovascular risk factors or established cardiac problems are at higher
risk of contracting severe acute respiratory syndrome- coronavirus-2 (SARS-CoV-2), and this
confers a worse prognosis in COVID- 19 infection. It is difficult to establish the true link
between COVID-19 and prevalence of cardiovascular complications due to the lack of testing in
community and the cohort of patients who are admitted to secondary care, who are likely to be
older and have co-morbidities and therefore are more likely to have pre-existing cardiac
conditions and develop new cardiovascular complications.

COVID-19: Myocardial Injury Myocardial injury with necrosis can occur with and without overt
ischaemia from acute myocardial infarction and is defined as an elevated plasma cardiac
troponin concentration above the 99th centile. There are different mechanisms underlying
acute myocardial injury; with ischaemia from an acute coronary syndrome and prolonged
myocardial oxygen demand/supply imbalance being the most familiar. It is well recognised that
an acute myocardial injury may occur in the absence of ischaemia due to a variety of cardiac
and non-cardiac causes. Furthermore, this can be seen in critically unwell patients of
varying aetiology and is a marker of poor prognosis.

Therefore determining the underlying mechanism is vital in guiding clinical care and
improving outcomes. Myocardial injury is increasingly recognised in COVID-19 patients and, as
anticipated, it correlates with severe cases and poor outcomes.5 In a cohort of 191 patients
with confirmed COVID-19, plasma cardiac troponin concentrations were elevated in non
survivors compared to survivors: 46% (23/50) compared to 1% (1/95) mortality.

Studies have demonstrated that rates of in-hospital death were 80 times higher in patients
with myocardial injury. Interestingly temporal change in cardiac troponin showed a marked
increase over time in those who did not survive, with no change on serial testing in
survivors, suggestive of a progressive process of evolving myocardial injury. The mechanism
of myocardial injury is not understood and it is likely that it has a similar non-direct
mechanism of injury similar to that of other severe respiratory illnesses. Other putative
mechanisms include direct myocardial injury due to endothelial dysfunction or cytokine
release, stress cardiomyopathy, or the results of a profound ongoing myocardial oxygen supply
or demand imbalance.

COVID-19: Myocardial Infarction Based on current disease patterns, COVID-19 will have a
significant impact directly and indirectly on cardiovascular health. Though myocardial injury
can affect those with and without cardiovascular risk factors, patients with underlying
cardiac conditions are predisposed to COVID-19 and have poorer prognosis. No published cases
of acute coronary syndromes have yet been described in the COVID-19 population. However,
previous studies have shown that the risk of an acute myocardial infarction was higher in
those with influenza and non-influenza (coronavirus) viruses. The management of acute
coronary syndrome is likely to be streamlined in the face of competing clinical demands. and
act upon these findings.

COVID-19: Myocarditis, stress cardiomyopathy and heart failure Previous studies demonstrated
cases of acute myocarditis in Middle East Respiratory Syndrome with the use of cardiac
magnetic resonance imaging. A small number of case reports have suggested fulminant
myocarditis may occur in patients with COVID-19 in the setting of high viral load with
autopsy findings of inflammatory mononuclear infiltrate in myocardial tissue. Among 68 deaths
in a case series of 150 patients with COVID- 19, 7% were attributed to myocarditis with
circulatory failure and in 33% of cases myocarditis may have played a contributing role to
the patient's demise. There have been reports of COVID-19 mimicking an ST elevation
myocardial infarction (STEMI), with normal coronaries and left ventricular systolic
dysfunction suggesting a pattern of insult similar to that of stress cardiomyopathy. Zhou and
colleagues reported that heart failure was observed in 23.0% of patients with COVID-19
presentations. Notably, heart failure was more commonly observed than acute kidney injury in
this cohort and was more common in patients who did not survive the hospitalisation compared
to those who did survive (51.9% vs. 11.7%). Whether heart failure is most commonly due to
exacerbation of pre-existing left ventricular dysfunction versus new cardiomyopathy (either
due to myocarditis or stress cardiomyopathy) remains unclear.

As this situation evolves, so will our strategies for assessment and treatment, with the use
of focused bedside echocardiography and the consideration of systemic thrombolysis therapy.
It is certainly possible that this will have an impact on clinical outcomes. There will be
many lessons learned from this global emergency, lessons which have the potential to improve
the efficiency of healthcare delivery in the future.

However, there is also a risk of worsening outcomes in conditions where there is a strong
evidence base for treatment improving outcomes.

Magnetic Resonance Imaging with Late gadolinium enahancement Cardiac imaging using magnetic
resonance imaging with late gadolinium enhancement is the gold-standard method for
non-invasive characterisation of myocardial function and scar formation. It has been used to
determine the presence of scar formation following myocardial infarction and
cardiomyopathies, and has been an invaluable tool for precisely defining cardiac performance
and disease.

Manganese - enhanced magnetic resonance imagining Manganese, one of the first magnetic
resonance imaging contrast agents, is a calcium analogue that is taken up actively by
voltage-gated calcium channels in viable myocardium. This unique property allows direct
quantification of viable cardiomyocytes. The investigators have recently demonstrated that
the manganese-based contrast medium, mangafodipir, is taken up by normal viable myocardium
but is absent in infarcted non-functional myocardium in patients with acute myocardial
infarction. In separate studies, the investigators have also shown that patients with dilated
cardiomyopathy have reduced and impaired manganese uptake and this correlates with the
severity of left ventricular dysfunction. Thus manganese-enhanced magnetic resonance imaging
is a unique method of assessing myocardial calcium handling to detect overt or subclinical
evidence of myocardial dysfunction.

Computed tomography coronary angiography. CTCA has excellent sensitivity for detecting
coronary artery disease and plaque burden, both of which are associated with adverse coronary
events. Furthermore, with the vast choice of cardiac imaging available, major guidelines
advocate the use of CT coronary angiography as the investigation of choice for the assessment
of the presence of coronary artery disease.

Rationale for Study The investigators wish to explore the cardiac consequences of severe
COVID-19 infection using cardiac magnetic resonance imaging (both gadolinium and manganese
enhancement) to characterise the early injury and subsequent recovery of the heart.

Furthermore, the investigators will use CT coronary angiography to determine the extent of
concomitant coronary artery disease since this is likely to be the single biggest modifier of
the extent of myocardial injury consequent on severe COVID-19 infection.

Study Aims There is growing evidence that myocardial injury is seen in a large number of
patients with COVID-19 infections. Although there have been cases of patients infected by
COVID-19 presenting with heart failure, it remains unknown whether this is a result of
myocarditis, stress cardiomyopathy, acute coronary syndrome, coronary heart disease or
myocardial injury related to multi-organ failure. As a result, the underlying mechanism,
immediate treatment and long-term impact remains unknown. This study will improve our
understanding of the underlying mechanisms which lead to myocardial injury seen in patients
infected with COVID-19. This will change the way patients are treated both during the acute
COVID-19 infection and in the longer term.