Myocarditis: Which Role for Genetics?

Myocarditis is a polymorphic disease characterized by a great variability both in its clinical presentation and evolution [1••].

Many efforts have been made to find useful tools for identifying patients with a high-risk and a poor prognosis. While there have been many advances in this field, there are still numerous unsolved issues. With the growing evidence of the role of genetics in other cardiovascular diseases, such as cardiomyopathies [2‐4], one recently raised and still unanswered question is if there could be a role for genetics also in myocarditis.

This review aimed at gathering the evidences available on this topic and examining the perspectives for the future, to yield insights for a better clinical management of those patients.

Myocardial inflammation can result from different infectious and non-infectious causes, including viral or bacterial agents, immunological disorders, and drug toxicity. Notably, the underlying cause of the myocardial inflammation can often remain unknown [5].

Viruses account for approximately 90% of myocarditis. Three stages of viral infection have been postulated: phase 1, viral entry into myocytes and activation of innate immunity; phase 2, viral replication and activation of acquired immune responses; and phase 3, evolution toward resolution with recovery or development of dilated cardiomyopathy (DCM) [6].

Although genome sequences of more than 27 viruses have been detected in hearts with myocarditis, only the pathogenic mechanism of enteroviruses has been well studied in animal models. This pathogenic mechanism implies the internalization through a transmembrane Coxsackievirus and adenovirus receptor and the induction of a rapid cytolysis with subsequent cardiac inflammation [6‐10]. Mechanisms of viral entry, replication, cellular injury, and death from other non-enteroviruses remain poorly understood and are still a matter of investigation [10].

In clinical practice, the question regarding why some patients develop myocarditis with different clinical severity and presentation, and other subjects exposed to the same interfering environmental factors (mostly viruses) do not, has been frequently raised. Data suggests that there may be a genetic predisposition toward the development of the disease [11•].

It is established that a key role in the pathophysiology of myocarditis is played by a maladaptive response of the immune system to specific environmental triggers [6, 12]. Since specific genetic loci have been discovered to determine different immune responses against infections, it has been postulated that genetic heterogeneity could help in understanding the diverse individual susceptibility to myocarditis. Thus helping in understanding why, despite the same environmental exposure, only specific individuals may develop myocarditis with different clinical manifestation. Available evidences regarding immune reactions and genetically defined host factors are conflicting as emerged from a recent study by Belkaya et al., where the authors failed to demonstrate a relationship between TLR3 and STAT1 deficiency and an increased susceptibility to viral myocarditis [13, 14]. Furthermore, single gene variants related to myocarditis are rare, and the available information is based on single case reports and small clinical series. More frequently, a genetic condition leading to immunodeficiency could act as a predisposition for the occurrence of myocarditis [15]. Therefore, more research is needed to identify constitutional gene variants which can influence the development of myocardial inflammation when exposed to environmental triggers.

Another debated issue is whether the genetic heterogeneity could also explain the different attitude toward a rapid viral clearance and resolution/chronic evolution of the myocardial inflammation. The attitude toward a rapid viral clearance or toward viral persistence may be determined also by the type of virus and the individual immune response. Furthermore, it is possible that a given insult (i.e., virus) produces an injury responsible of an inflammatory activation that in turn triggers the pathogenic mutant proteins further inciting injury and inflammation in a vicious circle. Therefore, inflammation may persist through a mechanism that is now independent of virus persistence. This may differentiate those subjects with and without genetic mutations. Finally, the viral clearance is only one of the components of the complex interplay between genetic background and environment that remains in general widely unexplored and represents the target of future research.

The heterogeneity of clinical presentation of myocarditis ranges from subclinical or benign forms that are generally characterized by chest pain as the main presenting symptom (i.e., low-risk forms) to major clinical syndromes, such as severe heart failure or life-threatening ventricular arrhythmias (i.e., high-risk forms) [16]. Whether genetics can play a role in determining the development of a definite clinical presentation over another is still unclear, and few evidences are known.

The background of cardiomyopathies is quite broad, and, in recent times, the complex interaction between genetic mutations and environmental factors helped unveil a wide range of conditions to better understand the pathophysiology of cardiomyopathies. In particular, Titin (TTN) is one of the most common mutation of DCM, and it is estimated that TTNtv may account for up to one-third of familial DCM cases [2]. In recent years, the idea that this gene possibly does not directly cause the cardiomyopathy but instead it acts as a modifier needing a second environmental hit to arise has emerged. On the other hand, increasing evidences point out that some of known secondary forms of cardiomyopathy, such as the alcohol-induced cardiomyopathy, the peripartum, the chemotherapy-induced, and in specific setting also the myocarditis, might have a genetic mutation on the background, which will predispose the development of the clinical phenotype. In particular, the peripartum cardiomyopathy shares a similar genetic background with the DCM, showing in approximately one-third of cases a genetic mutation, mostly TTNtv, leading to the phenotype [4]. Similarly, in patients with excess alcohol intake, having a TTNtv mutation predisposes to a more severe phenotype of the disease characterized by larger diameters and lower ejection fraction compared to those without the predisposing mutation [3]. In both conditions, the variants detected in the population were found with a frequency similar to that seen in DCM, suggesting a common pathophysiological background that can justify, or partially explain, the development of the disease. In addition, unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtv, have been shown to increase the risk for chemotherapy-induced cardiomyopathy in children and adults and adverse cardiac events in adults [28]. Curiously, it has recently been reported [19] that also in a cohort of adult patients with biopsy-proven lymphocytic myocarditis, the genetic yield was similar, especially for TTNtv prevalence, to a geographically comparable cohort of sporadic DCM [29]. This suggests that the inflammatory insult on the heart might uncover an increased genetic susceptibility to develop overt LV dysfunction or arrhythmogenic phenotypes.

While it seems reasonable to suspect a genetic basis both in the development and clinical course of myocarditis, there is still a lack of recommendation when performing genetic testing in this field. Similar to what it has just been reported for DCM [30‐32], genetic basis of myocarditis may be suspected in the presence of specific “red flags” either in personal or in family history. Indeed, family history of cardiomyopathy, sudden cardiac death, and pacemaker implantation in early age may suggest the transmission of pathogenic genetic variants. Also, the recurrence of acute myocarditis has been recognized as a clear risk factor for underling genetic mutation [15, 24]. Moreover, genetic predisposition to myocarditis is also supported by the presence of clinical traits at the physical examination (e.g., neurosensory disorders, skeletal muscle involvement, woolly hair, and keratoderma), at the laboratory analysis (e.g., creatine kinase elevation), at the ECG evaluation (e.g., persistent left bundle branch block, AV block, posterolateral pseudonecrosis, low voltage, epsilon wave), and at cardiac RMN (e.g., diffuse LGE).

Finally, it has to be clearly stated that a negative family history does not rule out a genetic predisposition to myocarditis, due to the presence of possible de novo mutations and of incomplete penetrance. In this context, persistent LV systolic dysfunction during follow-up may be an indicator of underlying genetic variant in cardiomyopathy-related genes. In fact, as recently reported by Artico et al. [19], a genetic analysis of patients with persistent LV dysfunction or arrhythmias after an episode of acute myocarditis revealed that a consistent proportion of them was a carrier of a pathogenic variant in sarcomeric or desmosomal genes.

To date there is no indication for performing routinely a genetic test in patients with a diagnosis of myocarditis. Genetic testing might be considered in the presence of clinical “red flags” that should be carefully and systematically evaluated (see Table 1), and in persistent LV dysfunction or malignant arrhythmias during follow-up. In all cases, when a pathogenic variant in non-immunity genes coding for structural proteins whose defects trigger heritable cardiomyopathies is identified, clinical and genetical family screening is mandatory [31].

In conclusion, there are growing evidences on the role of genetics both in the susceptibility and evolution of myocarditis, especially in patients presenting with severe LV dysfunction and evolution to DCM. However, these evidences need further future confirmation through multicenter focused studies based on larger populations, before being validated in daily clinical practice. Furthermore, many aspects in the genetics of myocarditis remain uncovered. In particular, data are lacking in patients with intermediate-low-risk syndromes, with chronic myocarditis and in patients with high arrhythmic burden. Therefore, future efforts should focus on filling these gaps, in order to better characterize all patients with myocarditis, paving the way to a more and more individualized and risk-tailored approach.