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Background Nonischaemic cardiomyopathy (NICM) represents a heterogenic disorder with a variable arrhythmogenic substrate. Its location is often epicardial and catheter ablation in this location proved to be an effective therapeutic modality in NICM patients with recurrent ventricular tachycardias (VTs). Purpose To determine the impact of the type of genetic mutation on the long-term outcome of endo-epicardial ablation in patients with NICM. Methods We investigated 82 patients (age 47±15 years, 10 women) with NICM who underwent endo-epicardial ablation for frequent VTs. Of them, 59% had a history of failed endocardial ablation. Patients had a left ventricular ejection fraction of 44±14% and all were implanted with cardioverter-defibrillator. One hundred candidate genes were examined using the new generation sequencing technique. Results Mutation in genes coding desmosomal complex (genes: PKP2, DSC, DSP, and DSG) was found in 30% of patients (“desmosomal” group). In 23% of patients, other gene mutations (genes: LMNA/C, MYH7, DES, TTN, RYR2, TPM1, MYPN, FLNC, and SCN5A) were detected (“non-desmosomal” group). In 46% of subjects no pathogenic mutation could be identified (“none” group). During a mean follow up of 34±33 months, patients in the “non-desmosomal” group were at significantly higher risk of VT recurrence and death/heart transplant compared to patients in the “desmosomal” group (Figure 1). Conclusion Potentially pathogenic mutation can be detected in about half of patients with NICM undergoing endo-epicardial VT ablation. Most commonly, mutations can be found in genes coding desmosomal complex and the endo-epicardial ablation is then associated with a satisfactory low VT recurrence rate and excellent survival in the long-term. On the other hand, patients with a mutation in non-desmosomal genes have poor outcomes despite endo-epicardial ablation. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Supported by Ministry of Health of the Czech Republic, grant nr. NV18-02-00237 Figure 1

Introduction Hereditary cardiomyopathy is associated with an increased risk of ventricular arrhythmia and sudden cardiac death (SCD). Genetic stratification substantiates risk assessment and enables the primary prevention of SCD in relatives at risk. We have analyzed the genetic aetiology of SCD in a representative Czech cohort with post mortem diagnosis of various forms of cardiomyopathy and compared it to living cases with these cardiac disorders. Patients and methods Between 2018 and 2019, altogether 47 victims of SCD with post mortem diagnosis of hypertrophic- (HCM; 18/47), arrhythmogenic- (ACM; 19/47) and dilated cardiomyopathy (DCM; 10/47) were identified. Concurrently, genetic testing was performed in 114 living patients (HCM 54/114, ACM 22/114, DCM 38/114). Genetic counselling and cardiologic examination had been carried out in first-degree relatives in all patients/SCD victims. Massively parallel sequencing (MiSeq platform; Illumina.com) was utilized for a custom-made panel comprising 100 candidate genes (Sophia Genetics, Switzerland). The presence of pathogenic variants was validated by Sanger DNA sequencing and through family segregation analyses. Results The causative detection rate (according to ACMG.net classes 4 or 5) in SCD victims with DCM was 60% (6/10) and in living patients with DCM 47.4% (18/38). Variants in TTN, RBM20, DES and FLNC (mainly truncating variants) prevailed in both groups. The detection rate in ACM was 5% (1/19 in SCN5A gene) in SCD victims and 31.8% (7/22) in living patients. Interestingly, the most prevalent mutated gene PKP2 in living patients was not detected in SCD victims. The detection rate in SCD victims with post mortem diagnosis of HCM was 16% (3/18) and in living patients 35% (19/54). The most prevalent gene was MYBPC3 in both groups, while PRKAG2 was detected in one SCD victim and in one living case who survived cardiac arrest. Conclusion Post-mortem genetic analysis in DCM yields a high detection rate and allows potentially effective primary prevention of SCD in relatives at risk. In contrast, the molecular autopsy of HCM and ACM renders a much lower yield which is below the mutation detection rate in living phenotype positive individuals. The results help to improve the genetic counselling in affected families in Czech Republic. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Ministry of Health of the Czech Republic

Aims The pleomorphic clinical presentation makes the diagnosis of desminopathy difficult. This disease of intermediate filaments causes not only a contractile dysfunction in cardiomyopathy and skeletal myopathy, but also a secondary mitochondrial dysfunction. We aimed to describe prevalence, phenotypic expression and mitochondrial function in desmin mutation carriers identified in a large cohort of patients with unexplained cardiomyopathy. Methods and results A representative cohort of 327 Czech patients with unexplained cardiomyopathy underwent whole exome sequencing. The cohort consisted of cases with familial and sporadic dilated cardiomyopathy (81%), left ventricular noncompaction cardiomyopathy (LVNC) (13%), and less frequently of restrictive (3%) or arrhythmogenic cardiomyopathy (3%). Clinical and laboratory data of desmin mutation carriers were collected. Morphology, desmin expression and mitochondrial function were studied in available myocardial and skeletal muscle specimens. Rare, conserved and possibly pathogenic desmin variants were identified in 6 (1.8%) probands. Two desmin mutations previously classified as variants of uncertain significance (p.K43E, p.S57L), one novel desmin variant (p.A210D) and two known pathogenic desmin mutations (p.R406W, p.R454W) were in affected individuals associated with characteristic pathological desmin aggregates in myocardial and/or skeletal biopsy samples. The individual with the novel desmin variant p.Q364H had decreased myocardial expression of desmin with absent desmin aggregates in myocardial/skeletal biopsy and presented with familial left ventricular non-compaction cardiomyopathy, a novel phenotype of desminopathy. Assessment of mitochondrial function in four carriers of desmin mutations with fresh-frozen skeletal and/or myocardial muscle specimens confirmed decreased metabolic capacity of mitochondrial respiratory chain complexes, which was in case of myocardial succinate respiration more profound than in end-stage heart failure of other etiologies. Genetic testing corrected an inappropriate clinical diagnosis in two probands previously diagnosed with mitochondrial disease and inflammatory cardiomyopathy. During a median follow-up of 56 months, 5 (83%) probands developed end-stage heart failure. Conclusions Desminopathy is a rare cause of cardiomyopathy and/or skeletal muscle myopathy with a pleomorphic clinical presentation and poor prognosis. The presence of desminopathy should be considered also in individuals with left ventricular non-compaction cardiomyopathy, and in the differential diagnosis of mitochondrial diseases and inflammatory cardiomyopathy. Acknowledgement/Funding Research grant of the Ministry of Health, Czech Republic [MZ 15-27682A], No. 00023001 (IKEM, Prague, CZ), the Czech Science Foundation [14-36804G].

Background External aortic root support (PEARS) is a novel prophylactic aortic root surgery. Purpose The study aimed to determine the severity of inflammatory response after the personalized external aortic root support (PEARS) procedure in comparison to after the standard prophylactic aortic root surgery (SPARS). Materials and methods The study was a single-centre, retrospective, based on hospital record analysis of patients who underwent the PEARS procedure (PEARS group) or SPARS (SPARS group) during 1998–2017. C-reactive protein (CRP), white blood count (WBC), and echocardiography were routinely obtained. Fever was defined as body temperature ≥38°C. Diagnosis of pericarditis included a minimum of three signs from chest pain, pericardial effusion, ST elevation, elevated CRP, and body temperature. Results PEARS and SPARS groups consisted of 13 and 14 patients, respectively, scheduled for prophylactic aortic root surgery. A majority of patients in both groups had Marfan syndrome with causal mutation in the fibrillin 1 (FBN1) gene (62% vs 79%). Patient baseline characteristics were similar in the two groups, except aortic root was significantly larger in the SPARS group than in the PEARS group (60±12 mm vs 48±5 mm; P=0.003). All surgical procedures were successful and without major complications. The peak values of CRP and WBC were significantly higher in the PEARS group (264.5±84.4 mg/L vs 184.6±89.6 mg/L; P=0.034 and 15.2±3.8 109/L vs 11.9±3.3 109/L; P=0.029). Early and recurrent fever requiring hospital readmission was significantly more frequent in the PEARS group (77% vs 36%; P=0.032 and 46% vs 7%; P=0.020). Early and recurrent pericarditis requiring hospital readmission was also more frequent in the PEARS group (31% vs 0%; P=0.024 and 31% vs 0%; P=0.024). Inflammatory characteristics Postprocedural inflammatory characteristics PEARS group SPARS group P value (N=13) (N=14) Peak level of CRP (mg/L) 264.5±84.4 184.6±89.6 0.034 Peak WBC (109/L) 15.2±3.8 11.9±3.3 0.029 ST elevation (N) 11 (85) 6 (43) 0.024 Early fever (N) 10 (77) 5 (36) 0.032 Recurrent fever (N) 6 (46) 1 (7) 0.020 Early pericarditis (N) 4 (31) 0 (0) 0.024 Recurrent pericarditis (N) 4 (31) 0 (0) 0.024 CRP, C-reactive protein; WBC, white blood count. Echocardiography-signs of inflammation Conclusions The PEARS procedure is an extremely promising surgical technique, but the postoperative inflammatory response occurs frequently and more severely in comparison to SPARS. Clearly, these findings warrant further investigation.