Electroanatomical Voltage Mapping Endomyocardial Biopsy-Guided Diagnosis and Therapy of Erythroparvovirus Myocarditis Presenting with Ventricular Arrhythmias: Case Series and Review of the Literature

Voltage Mapping Endomyocardial Bi-opsy-Guided Diagnosis and Therapy of Erythroparvovirus Myocarditis Presenting with Ventricular Arrhythmias: Case Series and Review of the Literature. Biomed Background: Myocarditis of viral origin can be frequently missed due to its various manifestations and possible false negative results after a classical fluoroscopy-guided endomyocardial biopsy. The 3D-electroanatomic mapping (3D-EAM) -guided endomyocardial biopsy reduces the false negative results by targeting the tissue areas with abnormal electrical voltage while also reducing the radiation exposure for patients and operators. Results: we report on two clinical cases of acute/subacute myocarditis with a first arrhythmic presentation, in which the endomyocardial biopsy guided by 3D-EAM system was fundamental in achieving the diagnosis and guiding the optimal medical therapy. As far as we know these are the two first published cases that show a documented link between Erythroparvovirus and sustained ventricular tachycardia and which moreover show the use of a developing technology such as 3DEAM-guided myocardial biopsy. Conclusion: 3D-EAM-guided endomyocardial biopsy is promising not only in reducing radiation exposure for patients and operators during such procedures, but also in identifying the tissue areas that must be targeted in order to reduce the false negatives. We also demonstrated how the first manifestation of a myocarditis due to Erythroparvovirus can be a ventricular arrhythmia.


Introduction
Myocarditis is an inflammation of the cardiac muscle caused by infiltration of immunogenic cells following different kinds of cardiac injury. It most commonly results from a viral illness; however, it can also be due to non-infectious etiologies. Given its variable clinical presentation, the diagnosis is frequently missed, making it difficult to quantify the true incidence of acute myocarditis. Infectious causes include a large number of viruses, as well as bacteria, protozoa and fungi; among these pathogens viruses are the most frequent cause of the myocardial inflammatory process. The most common forms of cardiotropic viruses found in endomyocardial biopsies (EMB) are erythroparvovirus B19 (B19V) and human herpes virus 6 (HHV6) and most recently Coronavirus (COVID19) [1][2][3][4]. We present two cases of 3 Dimensional electroanatomical mapping (3D-EAM) guided endomyocardial biopsy for the diagnosis and therapy of B19V myocarditis presenting with ventricular arrhythmias.

Case 1
A 54-year-old woman presented to our emergency department with sustained monomorphic ventricular tachycardias (VTs) (inferior axis, RBBB, Figure 1), which, due to evolving haemodynamic instability, had to be cardioverted externally. She had no other known diseases except for a MTHFR mutation without clinical relevance and did not take any medications. On her arrival and after the external cardioversion she had no complaints. She had a normal blood work with no signs of an active infection and only a slightly elevated Troponin without elevation of CK as well as CKMB. Her ECG in sinus rhythm showed a minimal diffuse STelevation and relatively low voltages in the praecordial leads.
The patient underwent a coronary-angiography, with no signs of coronary disease, an echocardiography which showed a normal left ventricular function with a slightly enlarged and dyskinetic right ventricle and finally a cardiac MRI (c-MRI) with evidence of preserved LV function and a RV dyskinesia as well as multiple RV aneurysms and areas of edema and multisegmental transmural late gadolinium enhancement on both ventricles, setting a differential diagnosis between sarcoidosis and myocarditis. The patient underwent a PET-CT which ruled out the sarcoidosis.
We performed a 3D-EAM-guided EMB to target areas of edema and fibrosis on the interventricular septum and avoid false negative results, which showed signs of an inflammatory cardiomyopathy with B19V with active replication ( Table 1). The patient started on a therapy with interferon Beta which is a well-tolerated and safe treatment option, leading to effective virus clearance or reduction of the virus load in patients with chronic viral cardiomyopathy [5].
After two months of therapy, we repeated a c-MRI which showed an almost complete resolution of the edema with persistence of late enhancement and scarred myocardial tissue. The patient underwent a secondary prophylactic implantation of an ICD and is stable ever since, without having experienced any new arrhythmias.

Case 2
A 66-year-old woman was sent to our cardiology department after a secondary prophylactic implantation of an ICD, due to

Discussion
Even though for many years the medical research has failed to show a causative role of B19V in the genesis of heart failure confirming only an association [5][6][7], some more recent works have reported that chronic viral infections of the heart can be one antecedent event leading to progressive dysfunction of the myocardium, often with an impaired prognosis due to a virus-or immune-mediated myocardial injury [6]. Moreover, even if it is known that myocarditis can lead to cardiac dysfunction and to ventricular arrhythmias through the development of scars and therefore reentry circuits [8] no direct association between B19V persistence and those clinical pictures has been described.
As the diagnosis of viral myocarditis can be problematic and the presentation can mimic other diseases such as sarcoidosis, arrhythmogenic cardiomyopathy as well as an evolution in dilated cardyomyopathy, the gold standard for the diagnosis and guide of the therapy is the EMB, an invasive but safe diagnostic tool that allows the quantification and identification of immune cell infiltrates, the quantification of viral loads and confirmation of virus subtypes via sequencing [9][10][11][12][13][14]. Hystorically, the EMB was performed under fluoroscopy guidance and was associated with potentially critical complications such as a cardiac tamponade. In the last years, there has been an evolving and promising use of EMB guided by 3D-electroanatomic voltage mapping, which could confere a higher specificity and sensitivity in targeting the involved tissue and in reducing false negative result. Moreover,it could reduce the radiation exposure of patients and operators in such procedures and present a higher safety profile compared with the mono-dimensional fluoroscopy images [15].

Conclusion
To our knowledge this is the first case series described in the literature of B19V presenting with ventricular arrhythmias.
Even if we will need a greater number of patients to confirm our observations, we hypothesize that B19V active replication could have a pivotal role in some forms of myocarditis which show an arrhythmogenic clinical presentation and that diagnosing and treating B19V in patients with a subacute myocarditis and ventricular arrhythmias could be determinant in solving the arrhythmias as well as the myocardial inflammation, although is not curative of the areas where the myocarditis has already produced a myocardial scar. We also described the emerging role of 3DEAMguided endomyocardial biopsy targeting the involved myocardial tissue and reducing complications and false negative results.