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Meet the Expert: Myocarditis

Sanjay Prasad MD has been a consultant in cardiology and cardiovascular magnetic resonance at the Royal Brompton Hospital since 2003 and is also Professor of Cardiomyopathy at Imperial College, London. His clinical and research interests focus on myocarditis and cardiomyopathy, the causes of these conditions, and treatment and risk stratification using cardiac MRI, using both a phenomic and genomic approach.

He spoke to us about his work and a recent study looking at the genetic architecture of myocarditis and cardiomyopathy.

What is myocarditis and what are the most common causes?
Dr Prasad defined myocarditis as inflammation of the heart muscle, describing how ‘we’re still learning lots about what causes it, but typically it results from a viral infection, and this is something we’ve seen lots of during the COVID pandemic.’ Other recognised causes or insults he mentioned include certain drugs, e.g., some of those used in chemotherapy, as well as both bacterial and fungal infections. Dr Prasad also stressed that ‘it is important to emphasise that ‘most patients [with myocarditis] will do well but a small percentage of patients will do badly.’

He described how myocarditis can arise in at least three different ways. Firstly, the heart can receive a ‘direct hit from the virus or the insult that attacks the heart cells directly and their function becomes impaired.’ In such cases, patients would normally present with shortness of breath. In contrast, where the insult gave rise to scarring, rhythm disturbances, leading to palpitations, were a more likely outcome. Second, Dr Prasad described how a causative insult could, ‘send the immune system into overdrive with a resultant and direct attack on the heart cells.’ Finally, myocarditis may occur because of systemic infections such as sepsis.

Although more severe myocarditis gives rise to a higher symptom burden, Dr Prasad described that ‘the scarring can be variable and doesn’t necessarily reflect the level of heart dysfunction.’ In fact, he noted how ‘we will often see scarring in patients with very mild levels of LV [left ventricular] dysfunction but because of a genetic predisposition or because of the way a virus has affected the heart, they can actually have a lot of scarring as well.’ As he put it, ‘scarring can occur independently of the level of heart dysfunction.’

How common is myocarditis?
Fortunately, as Dr Prasad said, myocarditis is rare and occurs at a rate of ‘about 5 per 1000’ or 5 per 10,000 in another series.’ Nevertheless, researchers are continually learning about the precise incidence, and current estimates are based on hospitalised patients. Dr Prasad feels that, in reality, there are likely to be many patients in the community who probably develop a mild form of myocarditis following a viral infection, but which spontaneously resolves without the need for medical intervention. However, he added that ‘we did see some increase during the COVID pandemic and numbers there increased to something like 300 per million, through COVID natively’.

Interestingly, Dr Prasad described that the most common demographic affected by myocarditis and who also required hospitalisation, were those aged between 20 and 30, particularly in cases with an underlying viral cause. In contrast, in drug-related causes, especially chemotherapy, patients were generally aged 50–60 years. He also described how males were twice as likely to suffer than females in the younger demographic. While the reason behind this disparity remains to be determined, Dr Prasad thinks it might be due to either differences in immune function or genetics. He said, ‘a key question is, is this a predisposition, i.e., are men more predisposed or are women somehow or other more protected?

How is myocarditis managed?
Dr Prasad described how the first step in managing myocarditis is to identify the most likely causative agent. For example, if drug-related, then the medication would be stopped. The next step depended to some extent on whether a patient has existing heart problems. As he said, where ‘a patient has heart dysfunction with chest pain, they are treated with drugs like colchicine to try and reduce the inflammation and then put on heart failure therapy, so drugs like beta-blockers, ACE inhibitors, SGLT2 inhibitors to try and improve heart function.’ In patients with a normal heart function, a more conservative approach is adopted. Nevertheless, there are several lifestyle changes that are recommended. For example, patients without cardiac dysfunction are advised to avoid moderate to vigorous exercising for 3 months, due to excessive strain on the heart muscle as well as a pro-arrhythmic effect. In addition, patients should avoid any exercise which makes them either tired, dehydrated or if they develop a fever. Abstinence from alcohol is also recommended. Fortunately, even among those who are prescribed heart failure treatment, therapy can be discontinued after 6 months, provided that cardiac function improves, as is the case in approximately a third of patients.

Is there a genetic predisposition to myocarditis?
While cases of acute myocarditis might appear to be both sporadic and random, Dr Prasad notes that upon closer inspection, it becomes apparent that often more than one family member is also affected. Indeed, his own research (see below) revealed that in about ‘8 to 10 per cent of patients there is a genetic predisposition’ and which somehow increases the vulnerability of heart cells to myocarditis.

How is myocarditis related to cardiomyopathy?
Although most patients with myocarditis make a successful recovery, in a subset where the cardiac impairment persists, this can lead to dilated cardiomyopathy, characterised by an enlarged and weakened heart. Interestingly, Dr Prasad described how roughly a third of patients with dilated cardiomyopathy will have an antecedent history of severe viral infection such as myocarditis and while around 60% of patients with dilated cardiomyopathy show significant recovery and do well, the remainder have persistent LV dysfunction requiring life-long therapy.

What was the rationale for your genetic study of acute myocarditis?
With some evidence of a possible familial predisposition with both myocarditis and dilated cardiomyopathy, Dr Prasad’s team wanted to better understand if this was in fact due to a genetic aberration and, perhaps equally important, what were the potential triggers. As he explained, in relation to dilated cardiomyopathy, a key question, was if myocarditis served as a potential trigger. As part of the research, his team contacted hospitals across the country to identify patients hospitalised with myocarditis. These individuals underwent a series of genetic tests and scans within two weeks of their presentation and clinically followed-up. The study was therefore looking at cardiomyopathy from slightly different perspectives: ‘one was for every patient with myocarditis, was there a genetic predisposition; and; from the second perspective, in patients presenting with myocarditis, do they go on to develop dilated cardiomyopathy?’

What were the key findings from the study?
After all the testing, Dr Prasad’s team was able to identify that ‘around 8% of patients had a genetic mutation that is associated with cardiomyopathy’. But as Dr Prasad explained, there two distinct genotypes. ‘We identified two different gene categories depending on the presentation; the heart failure side, the weak heart, was more of a titin gene predisposition and the ones with preserved heart function, but more electrical issues, was enriched for desmosomal genes.’ Furthermore, collaborating with Dutch colleagues, Dr Prasad’s team was able to confirm these findings in a second patient cohort.

What the next steps based on these research findings?
Dr Prasad defined how ‘the immediate next steps are to better understand why it is that these gene abnormalities predispose patients.’ His research group is currently pursuing several lines of work. One area involves growing artificial heart cells with the identified gene defects in an effort understand the changes induced by viruses which lead to cellular dysfunction. A second line of enquiry involves genetic screening of other family members to determine if these gene abnormalities are present and to try and untangle the effect of monogenic and polygenic (i.e., genetic) and environmental risk factors involved in the development of acute myocarditis.

Finally, there is what he described as the ‘so-what?’ research. In other words, ‘if patients have these gene abnormalities, are they going to do better or worse than those patients that have myocarditis but don’t have a gene predisposition.

He is hopeful that in the medium term, it will be possible to identify medications to mitigate the effects of the gene abnormalities. But his ultimate end goal is that once patients with the genetic abnormality predisposing them to cardiomyopathy have been identified, such patients can undergo gene editing to replace or remove the aberrant gene. While this may take several years, as he said, ‘a genetic disease requires a genetic solution’. Nonetheless, he feels that this approach represents the ultimate disease prevention strategy.

Details of the study mentioned in the interview can be seen below.

Reference
Lota As et al. Genetic Architecture of Acute Myocarditis and the Overlap With Inherited Cardiomyopathy. Circulation 2022






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