AIMS:Ventricular tachycardia (VT) in patients with structural heart disease can be life-threatening and may persist despite anti-arrhythmic therapy and catheter ablation. When standard treatments are ineffective or contraindicated, stereotactic arrhythmia radioablation (STAR) has emerged as a non-invasive salvage option. METHODS AND RESULTS:This prospective, single-centre study included 19 patients with structural heart disease and recurrent VT unresponsive to conventional therapy and who were ineligible for ablation. Patients were selected by a multidisciplinary team and underwent cardiac CT and electroanatomic mapping for substrate characterization. STAR was delivered in a single 25 Gy fraction using volumetric modulated arc therapy. Primary endpoints included safety (adverse events within 12 months) and efficacy (reduction in VT burden, assessed by ICD-recorded anti-tachycardia pacing [ATP] and shocks). During a median follow-up of 14 months [IQR 9-15], STAR was associated with a significant reduction in ICD therapies, with an average decrease of 81%. Mean ATP interventions/month dropped from 4.5 ± 6.5 to 0.8 ± 2.3 (P = 0.029), and total ICD therapies/month decreased from 4.8 ± 7.0 to 0.9 ± 2.5 (P = 0.032). Mild pulmonary injury and pericardial effusion occurred in 22.2% of patients. Most cases were asymptomatic; one patient (5.5%) required non-urgent pericardiocentesis. No significant changes in left ventricular function, valvular status, or coronary artery disease progression (assessed by CAD-RADS and PCAT analysis) were observed. One-year mortality was 33.3%; no deaths were directly attributable to STAR. CONCLUSION:STAR shows promise as a safe, non-invasive option for patients with refractory VT and advanced cardiomyopathy. Larger multicentre studies are needed to confirm long-term outcomes and better define its clinical role.

Background:Sporadic cardiac myxoma (SCM) is the most common primary tumor of the heart; however, its molecular pathogenesis remains poorly understood. Unlike the familial forms associated with the Carney complex (CNC), SCM lacks well-defined genetic alterations. Recognizing the established role of pleomorphic adenoma gene 1 (PLAG1) rearrangements in developmental syndromes with cardiac anomalies and in neoplasms characterized by prominent myxoid stroma, we investigated whether similar genetic events occur in SCM. In parallel, we evaluated MYC amplification, considering its known association with the malignant transformation in the mesenchymal tumors. Methods:We retrospectively analyzed 14 SCM cases using fluorescence in situ hybridization (FISH) to assess PLAG1 rearrangement and MYC amplification. Histological and immunohistochemical analyses were performed. Fifteen normal salivary gland tissues were used as controls for the FISH-based cutoff definition. The statistical tests included the ROC curve with AUC and Youden index, t-test, Welch's test, F-test, along with corrections using the Bonferroni and Benjamini-Hochberg methods. Results:Classical PLAG1 break-apart signals were detected in 35.7% (5/14) of the SCMs. Atypical isolated 5' (red) and 3' (green) signals were frequently observed (64.3% and 85.7%, respectively), potentially reflecting unbalanced translocations or copy number variation. No MYC amplification was observed in any of the cases. Statistical analysis positively supported a >0.5% threshold for PLAG1 Break-Apart (PLAG1-BA). The histological features were consistent with typical SCM morphology, and there was no evidence of malignancy. Conclusion:This study reveals PLAG1 rearrangement in a subset of SCMs, suggesting potential molecular similarities with other tumors characterized by an abundant myxoid stroma. The absence of MYC amplification reinforces the benign nature of these neoplasms. These findings raise new hypotheses regarding the pathogenesis of SCM and warrant further investigation into cardiac myxoid tumors.

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that predisposes affected individuals, especially young patients, to malignant arrhythmias, sudden cardiac death, and heart failure. The disease is characterized by myocardial atrophy and fibro-fatty replacement, predominantly affecting the right ventricle. Current pharmacological treatments primarily aim to alleviate symptoms by addressing arrhythmias and heart failure. These approaches are often complemented by invasive interventions such as implantable cardioverter defibrillators (ICDs) and radiofrequency ablations. However, none of these strategies effectively halts disease progression, highlighting the urgent need for novel disease-modifying therapies. We recently demonstrated that elevated plasma levels of oxidized low-density lipoprotein (oxLDL) correlate with more advanced stages of ACM in patients. Moreover, treatment with atorvastatin, which reduces oxLDL levels, prevented disease manifestation in a mouse model of ACM. Based on these findings, we hypothesize that statins may attenuate disease progression in ACM patients not only through their lipid-lowering effects, but also via pleiotropic actions such as antioxidant, anti-inflammatory, and autonomic modulation. To test this hypothesis, we designed SEARCH (Statin Effect on ARrhythmogenic CardiomyopatHy), an investigator-initiated, multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial, aimed at evaluating the efficacy of atorvastatin in preventing ACM progression (NCT06922994). A total of 102 patients meeting ACM diagnostic criteria will be enrolled and randomized in a 1:1 ratio to receive either atorvastatin 80 mg/die or placebo for 18 months. The primary outcome will be the change in right ventricular global longitudinal strain, a sensitive echocardiographic measure of ventricular function, from baseline to 18 months. Secondary outcomes will include changes in arrhythmic burden, electrocardiography parameters, additional structural and functional cardiac indices, and circulating biomarkers. Tertiary and exploratory outcomes include the validation of risk scores for ACM progression and the identification of variables predicting the best responders to atorvastatin. Participants will undergo a comprehensive evaluation at baseline, 9 months, and 18 months, including cardiology visits, echocardiography, electrocardiography, blood testing, ICD or loop recorder interrogation, and cardiac magnetic resonance imaging (at enrollment and at 18 months only). Additional safety assessments and telephone follow-ups will be conducted throughout the study to monitor treatment adherence and potential adverse events. The SEARCH trial is expected to generate the first clinical evidence on the efficacy of atorvastatin in slowing ACM progression, thereby addressing a major unmet therapeutic need. The findings will shape the design of future large-scale studies and may pave the way for a novel, disease-modifying treatment strategy to improve outcomes and quality of life for patients with ACM.

BACKGROUND:Studies evaluating the systematic use of cardiac computed tomography (CCT) for the preprocedural assessment of myocardial fibrosis are limited. Their implementation in the electrophysiology workflow has not been extensively described. OBJECTIVE:This study aimed to explore the degree of concordance between CCT and electroanatomic mapping (EAM) for the evaluation of cardiac fibrosis in patients undergoing endo-epicardial ventricular tachycardia (VT) ablation. METHODS:From November 2017 to December 2021, patients undergoing endo-epicardial VT catheter ablation with CCT as the only source of preprocedural scar assessment were prospectively enrolled. After image integration, myocardial fibrosis detected with CCT was compared with low-voltage areas identified by endo-epicardial EAM. Postprocedural VT recurrences of this approach were evaluated after at least 1 year of follow-up. RESULTS:The study enrolled 35 patients (mean age, 60.7 ± 13.2 years; 94.2% male). The most common underlying arrhythmic substrate was dilated cardiomyopathy (48.6%). CCT was employed for contraindications to cardiac magnetic resonance, such as unstable VTs (31.4%) or nonconditional implantable cardioverter-defibrillators (28.6%), but also for patients' and operators' preferences (14.3%-25.7%). Myocardial fibrosis was correctly identified by CCT and EAM, with strong agreement between these techniques both overall (Cohen κ for agreement, 0.933) and in per-segment analysis (κ ranging from 0.796 to 1.0). Ischemic patients showed the best correlation (κ = 1.000), whereas myocarditis showed the worst (κ = 0.750). After a median follow-up of 14 (12-24) months, 1-year freedom from recurrences was achieved in 74.3% patients; overall freedom from recurrences was 60.0%. CONCLUSION:A CCT-based preprocedural assessment before VT ablation is feasible, showing high diagnostic concordance with EAM in detecting myocardial fibrosis.

Primary cardiac mesenchymal stromal cells (C-MSCs) can promote the aberrant remodeling of cardiac tissue that characterizes arrhythmogenic cardiomyopathy (ACM) by differentiating into adipocytes and myofibroblasts. These cells’ limitations, including restricted access to primary material and its manipulation have been overcome by the advancement of human induced pluripotent stem cells (hiPSCs), and their ability to differentiate towards the cardiac stromal population. C-MSCs derived from hiPSCs make it possible to work with virtually unlimited numbers of cells that are genetically identical to the cells of origin. We performed in vitro experiments on primary stromal cells (Primary) and hiPSC-derived stromal cells (hiPSC-D) to compare them as tools to model ACM. Both Primary and hiPSC-D cells expressed mesenchymal surface markers and possessed typical MSC differentiation potentials. hiPSC-D expressed desmosomal genes and proteins and shared a similar transcriptomic profile with Primary cells. Furthermore, ACM hiPSC-D exhibited higher propensity to accumulate lipid droplets and collagen compared to healthy control cells, similar to their primary counterparts. Therefore, both Primary and hiPSC-D cardiac stromal cells obtained from ACM patients can be used to model aspects of the disease. The choice of the most suitable model will depend on experimental needs and on the availability of human source samples.

Abstract Background Arrhythmogenic Cardiomyopathy (ACM) is an inherited heart disorder characterized by a high incidence of sudden death at young age. Mutations linked to ACM occur primarily in desmosomal genes (e.g. PKP2) [1]. Different cell types individually contribute to set the ACM phenotype with either functional abnormalities (cardiomyocytes; CM) [2]; or fibro-fatty substitution (cardiac mesenchymal stromal cells; CMSC) [3]; these two cell types interact and show a reciprocal influence [4]. The relative contribution of the different cell type derangements to determine disease evolution and electrical instability is still unclear. Purpose Based on this evidence, we hypothesize that the use of a multicellular cardiac system, modelling the functional interaction between CM and CMSC, will allow the understanding of the relative contribution of the different cell types to the ACM phenotypes. Methods Primary stromal cells (carrier of the PKP2 mutation c.2013delC) have been collected from a right ventricle biopsy sample; control stromal cells obtained from a biobank. iPSC reprogrammed from the same ACM patient and the isogenic line in which the PKP2 mutation c.2013delC was corrected [5] were used. Cardiac cocultures (cc) were assembled by combining 85% iPSC-CM and 15% primary CMSC, either mutated or control, in different combination (as in Table 1). Movies of contracting clusters have been collected and analysed by the MUSCLEMOTION tool [6]. Fibro-fatty accumulation have been evaluated by immunofluorescence analysis by confocal microscopy. Results Immunofluorescence analysis highlighted that ACM cc (cc 4) accumulate more lipids and collagen than healthy control (HC) ones (cc 3). Since intermediate fibro-fatty levels were observed in ‘mixed cc’ (cc 1 and 4), we conclude that ACM iPSC-CM are able to influence fibro-adipo-commitment of CMSC. Contraction studies showed a high propensity for cc monolayers which include ACM iPSC-CM (cc1 and cc2) to display arrhythmic events. An increase in the percentage of arrhythmic events was triggered when the ACM CMSC were replacing HC CMSC, indicating that ACM CMSC can affect iPSC-CM rhythm. Conclusion Overall, our data confirm the importance of the cardiomyocytes and stromal cells interplay during ACM pathogenesis. Furthermore, our novel advanced ACM cell model can recapitulate different phenotypes of ACM and offers a unique opportunity for validating pharmacological therapies to modulate ACM-related characteristics (e.g. fibro-adipose replacement, contractile defects and proarrhythmic events).

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare multisystem disorder; cardiac involvement may include eosinophilic myocarditis. A 67-year-old woman presented with 1-week history of dyspnoea and orthopnoea. She had a history of adult-onset asthma and peripheral eosinophilia. The investigations showed T-wave inversion on lateral leads, peripheral eosinophilia, elevated troponin and BNP values, and severe biventricular systolic dysfunction with diffuse hypokinesia and apical akinesia. Computed tomography excluded coronary disease and showed bilateral basal ground-glass opacities, air-space consolidation, and bilateral reticular-nodular pattern. Cardiac magnetic resonance findings were compatible with active myocardial inflammation. An endomyocardial biopsy (EMB) confirmed the diagnosis of eosinophilic myocarditis, and a therapy with oral corticosteroids and heart failure medications was started.

BACKGROUND Recurrent ventricular tachycardia (VT) due to dilated cardiomyopathy (DCM) is difficult to treat, and long-term outcome data are limited. OBJECTIVES The aim of this study was to identify predictors of mortality or heart transplantation (HTx) and VT recurrence. METHODS Consecutive patients with DCM accepted for radiofrequency catheter ablation (RFCA) of VT at 9 centers were prospectively enrolled and followed. RESULTS Of 281 consecutive patients (mean age 60 +/- 13 years, 85% men, mean left ventricular ejection fraction [LVEF] 36% +/- 12%), 35% had VT storm, 20% had incessant VT, and amiodarone was unsuccessful in 68%. During follow-up of 21 months (IQR: 6-30 months), 67 patients (24%) died or underwent HTx, and 138 (49%) had VT recurrence (45 within 30 days, defined as early); the 4-year rate of VT recurrence or mortality or HTx was 70%. Independent predictors of mortality or HTx were early VT recurrence (HR: 2.92; 95% CI: 1.37-6.21; P < 0.01), amiodarone at discharge (HR: 3.23; 95% CI: 1.43-7.33; P < 0.01), renal dysfunction (HR: 1.92; 95% CI: 1.01-3.64; P = 0.046), and LVEF (HR: 1.36; 95% CI: 1.0-1.84; P = 0.052). LVEF <= 32% identified patients at risk for mortality or HTx (area under the curve: 0.75). Mortality or HTx per 100 person-years was 40.4 events after early, compared with 14.2 events after later VT recurrence and 8.5 events with no VT recurrence after RFCA (P < 0.01 for both). Patients with early recurrence and LVEFs <= 32% had a 1 -year rate of mortality or HTx of 55%. VT recurrence was predicted by prior implantable cardioverter-defibrillator shocks, basal anteroseptal VT origin, and procedural failure but not LVEF. CONCLUSIONS Patients with DCM needing RFCA for VT are a high-risk group. Following RFCA, approximately one-half remain free of VT recurrence. Early VT recurrence with LVEF <= 32% identifies those at very high risk for mortality or HTx, and screening for mechanical support or HTx should be considered. Late VT recurrence after RFCA does not predict worse outcome. (J Am Coll Cardiol 2022;80:1045 & ndash;1056) (c) 2022 by the American College of Cardiology Foundation.

Background: Aim of the present study was to verify the feasibility and accuracy of live integration of myocardial fibrosis evaluated at CCT with EAM (electro-anatomical mapping). Methods: We prospectively enrolled a consecutive cohort of patients with clinical indication to EAM before radiofrequency catheter ablation (RFCA) of refractory ventricular tachycardia (VT) and an absolute contraindication to cardiac magnetic resonance. All patients underwent per protocol CCT for myocardial fibrosis and coronary anatomy evaluation. Diagnostic performance was assessed for myocardial fibrosis evaluation with CCT vs EAM. Live integration feasibility of CCT vs EAM was evaluated for every patients. Results: A total of 19 patients were included in the present study with 323 myocardial segments analyzed for myocardial fibrosis at CCT. In all patients CCT data were successfully integrated with EAM during RFCA procedure. All patients had myocardial fibrosis correctly identified at CCT vs EAM on a per-patients basis. A diagnostic accuracy on a per-segment basis of 94.1% for detection of any type of myocardial fibrosis at CCT vs EAM was recorded. Conclusions: CCT identification of myocardial fibrosis is feasible and accurate vs EAM in a very selected high risk patients with clinical indication to RFCA of VT and contraindication to CMR.

The rate of post-vaccine myocarditis is being studied from the beginning of the massive vaccination campaign against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although a direct cause-effect relationship has been described, in most cases, the vaccine pathophysiological role is doubtful. Moreover, it is not quite as clear as having had a previous myocarditis could be a risk factor for a post-vaccine disease relapse. A 27-year-old man presented to the emergency department for palpitations and pericardial chest pain radiated to the upper left limb, on the 4th day after the third dose of BNT162b2 vaccine. He experienced a previous myocarditis 3 years before, with full recovery and no other comorbidities. Electrocardiogram showed normal atrioventricular conduction, incomplete right bundle branch block, and diffuse ST-segment elevation. A cardiac echo showed lateral wall hypokinesis with preserved ejection fraction. Troponin-T was elevated (160 ng/L), chest X-ray was normal, and the SARS-CoV-2 molecular buffer was negative. High-dose anti-inflammatory therapy with ibuprofen and colchicine was started; in the 3rd day high-sensitivity Troponin I reached a peak of 23000 ng/L. No heart failure or arrhythmias were observed. A cardiac magnetic resonance was performed showing normal biventricular systolic function and abnormal tissue characterization suggestive for acute non-ischaemic myocardial injury (increased native T1 and T2 values, increased signal intensity at T2-weighted images and late gadolinium enhancement, all findings with matched subepicardial distribution) at the level of mid to apical septal, anterior, and anterolateral walls. A left ventricular electroanatomic voltage mapping was negative (both unipolar and bipolar), while the endomyocardial biopsy showed a picture consistent with active myocarditis. The patient was discharged in good clinical condition, on bisoprolol 1.25 mg, ramipril 2.5 mg, ibuprofen 600 mg three times a day, colchicine 0.5 mg twice a day. We presented the case of a young man with history of previous myocarditis, admitted with a non-complicated acute myopericarditis relapse occurred 4 days after SARS-CoV-2 vaccination (3rd dose). Despite the observed very low incidence of cardiac complications following BNT162b2 administration, and the lack of a clear proof of a direct cause-effect relationship, we think that in our patient this link can be more than likely. In the probable need for additional SARS-CoV-2 vaccine doses in the next future, studies addressing the risk-benefit balance of this subset of patient are warranted. We described a multidisciplinary management of a case of myocarditis recurrence after the third dose of SARS-CoV-2 BNT162b2 vaccine.

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): The study was partially supported by an investigator initiated grant from Biosense Webster (a Johnson & Johnson company) Background Recurrent sustained ventricular tachycardia (VT) due to nonischemic dilated cardiomyopathy (DCM) is difficult to treat and long-term outcome data are limited. Objective We aimed to identify predictors for mortality or heart transplantation (MHT) and VT recurrence. Methods Consecutive DCM patients accepted for VT catheter ablation (RFCA) in 9 centers were prospectively enrolled and followed. Results Of 281 consecutive patients (age 60±13yrs, 85% men, LVEF 36±12%) 35% had VT storm, 20% incessant VT, and 68% failed amiodarone. During a median follow-up of 21 (IQR 6-30) months after RFCA (epicardial in 58%, no RFCA due to inaccessible target in 6.4%), 67(24%) patients died/underwent HT and 138(49%) had VT recurrence (45 within 30 days defined as early); the cumulative 4-year rate of VT or MHT was 70% and of MHT 38%. In multivariable analysis predictors of MHT were early VT recurrence (HR 2.92 (CI1.37-6.21), p<0.01), amiodarone at discharge (HR 3.23 (CI1.43-7.33, p<0.01), renal dysfunction (HR 1.92 (CI1.01-3.64), p=0.046), and LVEF (HR 1.36 (CI 1.0-1.84), p=0.052). A LVEF ≤32% was the optimal threshold to identify patients at risk for MHT (AUC 0.75). MHT per 100 person-years was 40.4 after early VT recurrence and significantly higher, compared to 14.2 after later VT recurrence and to 8.5 after RFCA with no VT recurrence (both p<0.01). Mortality rates for patients with VT recurrence after 30 days were not significantly higher than for patients with no VT recurrences Patients with early recurrence and LVEF≤32% had a 1-year MHT rate of 55% (figure). VT recurrence was predicted by prior ICD shocks, basal antero-septal VT origin, and procedural failure but not LVEF. Conclusion DCM patients needing RFCA for VT are a high-risk group. Following RFCA half remain free of VT recurrences. Early VT recurrence with LVEF<0.32 identifies those with a very high risk and screening for mechanical support/ HT should be considered. Late VT recurrence after RFCA does not predict worse outcome.

BACKGROUND:Endomyocardial biopsy (EMB) is required to make a definite diagnosis of lymphocytic myocarditis (LM), to identify its etiology, and to classify LM into different phases. OBJECTIVES:This study aims to characterize and compare clinical and electrophysiological characteristics of different biopsy-proven LM phases, namely acute myocarditis (AM), chronic active myocarditis (CAM), and healed myocarditis (HM). METHODS:All patients with a diagnosis of LM at 3 Italian referral centers were prospectively enrolled. According to EMB findings, LM was classified as AM, CAM, or HM; per-group comparisons of clinical presentations, noninvasive, and invasive findings are reported. RESULTS:Among the 122 enrolled patients (AM, n = 44; CAM, n = 42; HM, n = 36), complex ventricular arrhythmias were very common overall (n = 109, 89%), but ventricular fibrillation was slightly more prevalent in AM (P = 0.028). Cardiac magnetic resonance imaging showed late gadolinium enhancement in more patients with HM and CAM than AM (94.4% vs 92.9% vs 50%; P < 0.001), whereas edema was more common in AM than in CAM, being absent in HM (90.9% vs 50% vs 0%; P < 0.001). Accordingly, edema was the strongest independent clinical predictor of EMB-proven active inflammation. Electroanatomical mapping revealed a lower prevalence of low-voltage areas in AM than in CAM or HM. We observed a strong association between edema at a specific myocardial segment and normal voltages at that site (odds ratio: 0.24; 95% CI: 0.10-0.54; P < 0.01), as well as between late gadolinium enhancement and low-voltage areas (odds ratio: 2.86; 95% CI: 1.19-6.97; P = 0.019). CONCLUSIONS:LM is a highly heterogeneous disease, and its different phases are characterized by diverse clinical, morphological, and electrophysiological features. Further research is required to identify electroanatomical markers of inflammation.

Aim The purpose of this study is to collect available evidence on the feasibility and efficacy of stereotactic arrhythmia radio ablation (STAR), including both photon radiotherapy (XRT) and particle beam therapy (PBT), in the treatment of atrial fibrillation (AF), and to provide cardiologists and radiation oncologists with a practical overview on this topic. Methods Three hundred and thirty-five articles were identified up to November 2021 according to preferred reporting items for systematic reviews and meta-analyses criteria; preclinical and clinical studies were included without data restrictions or language limitations. Selected works were analyzed for comparing target selection, treatment plan details, and the accelerator employed, addressing workup modalities, acute and long-term side-effects, and efficacy, defined either by the presence of scar or by the absence of AF recurrence. Results Twenty-one works published between 2010 and 2021 were included. Seventeen studies concerned XRT, three PBT, and one involved both. Nine studies (1 in silico and 8 in vivo; doses ranging from 15 to 40 Gy) comprised a total of 59 animals, 12 (8 in silico, 4 in vivo; doses ranging from 16 to 50 Gy) focused on humans, with 9 patients undergoing STAR: average follow-up duration was 5 and 6 months, respectively. Data analysis supported efficacy of the treatment in the preclinical setting, whereas in the context of clinical studies the main favorable finding consisted in the detection of electrical scar in 4/4 patients undergoing specific evaluation; the minimum dose for efficacy was 25 Gy in both humans and animals. No acute complication was recorded; severe side-effects related to the long-term were observed only for very high STAR doses in 2 animals. Significant variability was evidenced among studies in the definition of target volume and doses, and in the management of respiratory and cardiac target motion. Conclusion STAR is an innovative non-invasive procedure already applied for experimental treatment of ventricular arrhythmias. Particular attention must be paid to safety, rather than efficacy of STAR, given the benign nature of AF. Uncertainties persist, mainly regarding the definition of the treatment plan and the role of the target motion. In this setting, more information about the toxicity profile of this new approach is compulsory before applying STAR to AF in clinical practice.

BACKGROUND:Cardiac mesenchymal stromal cells (C-MSC) were recently shown to differentiate into adipocytes and myofibroblasts to promote the aberrant remodeling of cardiac tissue that characterizes arrhythmogenic cardiomyopathy (ACM). A calcium (Ca2+) signaling dysfunction, mainly demonstrated in mouse models, is recognized as a mechanism impacting arrhythmic risk in ACM cardiomyocytes. Whether similar mechanisms influence ACM C-MSC fate is still unknown. Thus, we aim to ascertain whether intracellular Ca2+ oscillations and the Ca2+ toolkit are altered in human C-MSC obtained from ACM patients, and to assess their link with C-MSC-specific ACM phenotypes. METHODS AND RESULTS:ACM C-MSC show enhanced spontaneous Ca2+ oscillations and concomitant increased Ca2+/Calmodulin dependent kinase II (CaMKII) activation compared to control cells. This is manly linked to a constitutive activation of Store-Operated Ca2+ Entry (SOCE), which leads to enhanced Ca2+ release from the endoplasmic reticulum through inositol-1,4,5-trisphosphate receptors. By targeting the Ca2+ handling machinery or CaMKII activity, we demonstrated a causative link between Ca2+ oscillations and fibro-adipogenic differentiation of ACM C-MSC. Genetic silencing of the desmosomal gene PKP2 mimics the remodelling of the Ca2+ signalling machinery occurring in ACM C-MSC. The anti-arrhythmic drug flecainide inhibits intracellular Ca2+ oscillations and fibro-adipogenic differentiation by selectively targeting SOCE. CONCLUSIONS:Altogether, our results extend the knowledge of Ca2+ dysregulation in ACM to the stromal compartment, as an etiologic mechanism of C-MSC-related ACM phenotypes. A new mode of action of flecainide on a novel mechanistic target is unveiled against the fibro-adipose accumulation in ACM.

Acute myocarditis (AM) is a heart inflammatory disease that may also rarely occur as a complication of COVID-19 vaccines. Inflammation is involved in arrhythmogenic cardiomyopathy (ACM) pathogenesis. Little is known regarding the COVID-19 vaccines influence on ACM relapses. We present two cases of vaccine related AM revealing a pre-existent (silent) ACM. Table shows a summary of the patients’ main clinical characteristics. We presented 2 cases of arrhythmic myocarditis-like clinical presentation in patients without previous cardiovascular history, whose timing was temporally related to a dose of vaccine against COVID-19. Subsequent diagnostic workup suggested the possible presence of an underlying silent ACM. In our case series, tissue characterization provided by CMR played a fundamental role as a diagnostic tool, showing in all cases a prominent left ventricle involvement and identifying both the underlying ACM disease and the superimposed myocardial inflammation. We hypothesize that a vaccine-induced AM could have revealed the presence of a pre-existent ACM, on which an inflammatory acute phase triggered the arrhythmic manifestation. Vaccine-induced AM could reveal the presence of a pre-existent ACM. Our report suggests that a high index of suspicion and a multidisciplinary approach is required, in order to continue the diagnostic process once the acute event has been resolved, as it may have fundamental implication in the patient management. Further studies are required to verify if some of the vaccine-triggered AM represent the ACM first manifestation.

Purpose: Within the STRA-MI-VT phase Ib/II trial (NCT04066517), the aim of this phantom study was to explore the feasibility of Cyberknife treatments on cardiac lesions by tracking as a single marker the lead tip of an implantable cardioverter defibrillator. The residual displacement of the lesion during the tracking was studied, planning margins were found and the dosimetric accuracy of the treatment was checked. Materials and methods: A lead was inserted into a phantom (EasyCube phantom, Sun Nuclear Co, USA) and then placed on the translating ExacTrac Gating System (BrainLAB AG, Germany). The phantom was rotated, a virtual lesion was identified and its displacement during the tracking was studied. Two plans were compared, calculated on the unrotated volume and on the envelope of the unrotated and the rotated volumes. The plans were delivered using the Cyberknife System (Accuray Inc, USA) and their dosimetric accuracy verified by gamma analysis with gafchromic films. Results: The residual margin increases enhancing the distance between the lead and the lesion. It is 4 mm for distance 0 cm and 5 mm for distance 5 cm. The coverage is reduced by 3.8% (interquartile range 2.5%-4.7%) when the dose is prescribed on the unrotated volume. All treatment plans are accurate and 3% 3 mm gamma analysis results are greater than 94%. Conclusions: Results showed that tracking with a single marker is feasible considering adequate residual planning margins. The volumes could be further reduced by using additional markers, for example by placing them on the patient's skin.

Abstract Background Eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg–Strauss, is a rare multisystem disorder characterized by chronic rhinosinusitis, asthma, and prominent peripheral blood eosinophilia (PE). Cardiac involvement may include eosinophilic myocarditis and it is a serious manifestation of EGPA. Case Presentation A 67–year–old woman presented to the emergency department with 2–weeks history of dyspnea, orthopnea and asthenia. She had history of asthma, PE, adjuvant radiotherapy after right mastectomy (July 2021). The patient was diagnosed with new onset atrial fibrillation in the previous month. At admission, the patient was hemodynamically stable and with signs of congestion. Complementary exams showed sinus rhythm and T–wave inversion on lateral leads; PE (2010/uL), elevated troponin and BNP values; and severe biventricular systolic dysfunction with diffuse hypokinesia and apical akinesia. The patient was admitted to the ICU and was treated with intravenous diuretics and levosimendan. Optimal HF therapy was introduced. Serial echocardiography revealed partial recovery of LVEF and blood analysis showed a decrease in troponin levels, with persistent eosinophilia (6330/uL). Computed tomography (CT) excluded significant coronary disease, and showed bilateral basal ground–glass opacities, areas of air–space consolidation and bilateral reticular–nodular pattern. Cardiac magnetic resonance revealed increased T2 values/signs of myocardial edema in anterior wall, interventricular septum and apex and no late gadolinium enhancement, compatible with myocarditis. An endomyocardial biopsy (EMB) was performed and confirmed the diagnosis of eosinophilic myocarditis. Oral corticosteroids were started. Paranasal CT scan showed signs of chronic sinusitis, without polyposis, and antineutrophil cytoplasmic antibodies were positive, making the diagnosis of EGPA, according to ACR criteria. Discussion In a patient presenting with new onset heart failure and with history of asthma and eosinophilia, it is important to suspect eosinophilic myocarditis, as this is a rare but reversible life–threatening condition. EMB plays an important role in the diagnosis and should be done promptly. Conclusion We described a multidisciplinary management of a case of a patient with eosinophilic myocarditis and EGPA, presenting with severe acute biventricular dysfunction.

Background: Peripartum cardiomyopathy (PPCM) is a rare cardiomyopathy with systolic dysfunction that presents in late pregnancy. A number of coronavirus disease 19 (COVID-19)-related myocarditis cases have been reported. In a pandemic situation, the coexistence of COVID-19 and PPCM can be relatively frequent, making it difficult to assess the weight of the individual components on the heart condition. Case Presentation: A 34-year-old girl develops COVID-19 at the 31st week of pregnancy. In the following 2 weeks she recovered and, after 4 days from the disappearance of symptoms, she gave birth without complications. Three weeks after delivery she presented to the ED with worsening dyspnea and elevated troponine and BNP values. Echocardiogram showed severe biventricular systolic dysfunction, mitral regurgitation, pulmonary hypertension and biventricular thrombosis. She was treated with oxygen, diuretics, heparin and transferred to our center. Cardiac MRI showed dilation and severe biventricular dysfunction with positive LGE and T1 mapping values diffusely increased. A treatment with betablockers, Sacubitril/valsartan, anti-aldosterone drugs, ivabradine and bromocriptine was started. An Endomyocardial biopsy (EMB) was performed showing a picture consistent with dilated cardiomyopathy and a final diagnosis of peripartum cardiomyopathy was made. However, after a few days the molecular biology report arrived showing EMB positivity for Sars-Cov-2 and Parvovirus B19. The patient was discharged and after 6 months she is well and a control MRI showed complete recovery of biventricular systolic function. Discussion: Cardiovascular complications of COVID-19 are well known and cases of related myocarditis have been reported. Anatomopathological and biopsy studies show the presence of Sars-Cov-2 in the heart of a significant number of patients with COVID-19, however the virus is often found at the interstitial level, suggesting in most cases more an endothelial localization than a real invasiveness of cardiomyocytes. It is not impossible that a patient with PPCM could be simultaneously affected by Sars-Cov-2. Only a multidisciplinary clinical, imaging, histological, functional evaluation and a congruent follow-up can help to understand the weight of the single etiological components on cardiac dysfunction. Conclusions: We described a case of a patient with PPCM and concomitant cardiac localization of COVID-19 with severe acute biventricular dysfunction. (Figure Presented).