To evaluate the efficacy of immunosuppression in virus-negative inflammatory cardiomyopathy. This randomized, double-blind, placebo-controlled study included 85 patients with myocarditis and chronic (>6 months) heart failure unresponsive to conventional therapy, with no evidence of myocardial viral genomes. Patients received either prednisone 1 mg kg^–1 day^–1 for 4 weeks followed by 0.33 mg kg^–1 day^–1 for 5 months and azathioprine 2 mg kg^–1 day^–1 for 6 months (43 patients, Group 1) or placebo (42 patients, Group 2) in addition to conventional therapy for heart failure. Primary outcome was the 6 month improvement in left-ventricular function. Group 1 showed a significant improvement of left-ventricular ejection fraction and a significant decrease in left-ventricular dimensions and volumes compared with baseline. None of Group 2 patients showed improvement of ejection fraction, that significantly worsened compared with baseline. No major adverse reaction was registered as a result of immunosuppression. These data confirm the efficacy of immunosuppression in virus-negative inflammatory cardiomyopathy. Lack of response in 12% of cases suggests the presence of not screened viruses or mechanisms of damage and inflammation not susceptible to immunosuppression.

Long-term results of the Tailored IMmunosuppression in virus-negative Inflammatory Cardiomyopathy (TIMIC) trial protocol have been evaluated. Eighty-five patients with endomyocardial biopsy-proven virus-negative chronic inflammatory cardiomyopathy were enrolled in the randomized, double-blind, placebo-controlled TIMIC trial and received prednisone and azathioprine (n = 43) vs. placebo (n = 42) for 6 months. Immunosuppressive treatment promoted an improvement in cardiac function in 88% of the cases compared with none of the patients in the placebo group, which were switched to a 6-month immunosuppressive therapy at the end of the 6-month study period. Long-term (up to 20 years) clinical outcomes of the whole cohort of 85 patients originally enrolled in the TIMIC trial (Group A) were compared with those of a 1:2 propensity score-matched control cohort of patients untreated with the TIMIC protocol (Group B) and followed for a comparable period of time. The primary outcome was a composite of cardiovascular death and heart transplantation. At long-term follow-up, the risk of cardiovascular death [hazard ratio (HR) 6.77; 95% confidence interval (CI) 2.36–19.45] and heart transplantation (HR 7.92; 95% CI 1.80–34.88) was significantly higher in Group B patients. Group A showed a persistent improvement in the left ventricular ejection fraction compared with Group B (HR 7.24; 95% CI 3.05–17.18). A higher number of Group B patients underwent implantable cardioverter defibrillator implantation. The incidence of recurrent myocarditis was similar between groups, and patients with evidence of a recurrent cardiac inflammatory process promptly responded to a TIMIC protocol application. Virus-negative inflammatory cardiomyopathy benefits from immunosuppressive therapy even after long-term follow-up. Recurrence appears to respond to a new TIMIC protocol application. Box plots of the distribution of left ventricular ejection fraction and left ventricular end-diastolic volume at baseline, short-term (6 months), and long-term follow-up in patients on TIMIC protocol (blue) and control patients (green) are presented in the left upper panel. The composite endpoint of cardiovascular death and heart transplantation (primary outcome) during follow-up in patients on TIMIC protocol (blue line) and control patients (red line) is shown in the left lower panel. The incidence of cardiovascular death (right upper panel) and heart transplantation (right lower panel) during follow-up in patients on TIMIC protocol (blue line) and controls (red line) is also presented.

Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the partial or total deficit of the lysosomal enzyme α-galactosidase A (α-Gal A). It is an X-linked, lysosomal enzymopathy due to mutations in the galactosidase alpha gene (GLA), encoding the α-Gal A. To date, more than 900 mutations in this gene have been described. In our laboratories, the study of genetic and enzymatic alterations related to FD was performed in about 17,000 subjects with a symptomatology referable to this disorder. The accumulation of globotriaosylsphingosine (LysoGb3) was determined in blood of positives. Exonic mutations in the GLA gene were detected in 471 patients (207 Probands and 264 relatives): 71.6% of mutations were associated with the classic phenotype, 19.8% were associated with the late-onset phenotype, and 8.6% of genetic variants were of unknown significance (GVUS). The accumulation of LysoGb3 was found in all male patients with a mutation responsible for classic or late-onset FD. LysoGb3 levels were consistent with the type of mutations and the symptomatology of patients. α-Gal A activity in these patients is absent or dramatically reduced. In recent years, confusion about the pathogenicity of some mutations led to an association between non-causative mutations and FD. Our study shows that the identification of FD patients is possible by associating clinical history, GLA gene analysis, α-Gal A assay, and blood accumulation of LysoGB3. In our experience, LysoGB3 can be considered a reliable marker, which is very useful to confirm the diagnosis of Fabry disease.

Background— Chest pain is frequently reported in Fabry disease (FD). However, its mechanism and clinical relevance are unclear.

Aim We sought to determine whether myocarditis can be a major cause of acute electrical instability or clinical deterioration in HCM patients.