The p.Ala2430Val mutation in filamin C causes a "hypertrophic myofibrillar cardiomyopathy".

Hypertrophic cardiomyopathy (HCM) often leads to heart failure. Mutations in sarcomeric proteins are most frequently the cause of HCM but in many patients the gene defect is not known. Here we report on a young man who was diagnosed with HCM shortly after birth. Whole exome sequencing revealed a mutation in the FLNC gene (c.7289C > T; p.Ala2430Val) that was previously shown to cause aggregation of the mutant protein in transfected cells. Myocardial tissue from patients with this mutation has not been analyzed before and thus, the underlying etiology is not well understood. Myocardial tissue of our patient obtained during myectomy at the age of 23 years was analyzed in detail by histochemistry, immunofluorescence staining, electron microscopy and western blot analysis. Cardiac histology showed a pathology typical for myofibrillar myopathy with myofibril disarray and abnormal protein aggregates containing BAG3, desmin, HSPB5 and filamin C. Analysis of sarcomeric and intercalated disc proteins showed focally reduced expression of the gap junction protein connexin43 and Xin-positive sarcomeric lesions in the cardiomyocytes of our patient. In addition, autophagy pathways were altered with upregulation of LC3-II, WIPI1 and HSPB5, 6, 7 and 8. We conclude that the p.Ala2430Val mutation in FLNC most probably is associated with HCM characterized by abnormal intercalated discs, disarray of myofibrils and aggregates containing Z-disc proteins similar to myofibrillar myopathy, which supports the pathological effect of the mutation.

Isolated aortic valve replacement in patients with small aortic annulus-a high-risk group on long-term follow-up.

BACKGROUND: Patients with small aortic annulus undergoing isolated aortic valve replacement face an often underestimated surgical risk. We describe initial clinical results and long-term follow-up of this particular high-risk group. METHODS: Between January 1998 and December 2004, 148 consecutive patients with small aortic annulus underwent isolated aortic valve replacement by implantation of a Mitroflow Aortic Pericardial Heart Valve (Sorin S.p.A., Milano, Italy) 19 or 21 mm bioprostheses. Mean age was 75.4 ± 6.2 years. Female gender, obesity, and multiple comorbidities were predominant. Mean logistic euroSCORE for mortality was 18.5 ± 2.3%. Follow-up time was 7.2 ± 2.0 years, with a total of 1,066 patient years. RESULTS: Postoperative course and outcome during follow-up were strongly influenced by extracardiac morbidities. Hospital mortality was 6.1%, 5-year survival 71.9%, and 10-year survival 40.9%. Most patients (70.0%) died because of extracardiac reasons. Significant reasons for death were age, pre-existing atrial fibrillation, diabetes mellitus type 2, chronic renal failure, extracardiac vascular disease, history of stroke, and preoperative presentation at Canadian Cardiovascular Society class III and IV (p < 0.05). Freedom from valve-related reoperation was 99.1% at 5 years and 93.4% at 10 years. Prosthesis-patient mismatch occurred in 12.2% and was not affected with any adverse outcome (p = nonsignificant). Echocardiographic data demonstrated a significant reduction of mean transvalvular gradients in all patients (61.2 ± 19.7 mm Hg preoperatively; 18.0 ± 8.0 mm Hg during follow-up; p < 0.05). All patients reported a significant improvement in New York Heart Association functional class (p < 0.05). CONCLUSION: Patients with small aortic annulus are predominantly small, obese, and old-aged females with multiple comorbidities. Mitroflow valve avoids prosthesis-patient mismatch and provides excellent hemodynamics. Observed long-term results were disappointing, but they were mainly limited by extracardiac comorbidities and advanced age.