ABSTRACT
Left ventricular noncompaction (LVNC) is a cardiomyopathy morphologically characterized by 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses communicating with the left ventricular cavity. The purpose of this study was to investigate patients with LVNC for possible disease causing mutations. We screened 4 genes (TAZ, LDB3, DTNA and TPM1) in 51 patients with LVNC for mutations by polymerase chain reaction and direct DNA sequencing. A novel missense substitution in exon 1 of TPM1 (c.109A>G: p.Lys37Glu) was identified in three affected members of a family with isolated LVNC. The substitution brings about a change in amino acid charge at a highly conserved residue and could result in aberrant mRNA splicing. This variant was not identified in 200 normal control samples. Pathologic analysis of a right ventricular myocardial specimen from the proband's maternal aunt revealed endocardial and subendocardial fibrosis with prominent elastin deposition, as well as the presence of adipose tissue between muscle layers, pathologic changes that are distinct from those seen in patients with HCM or DCM. Screening of the proband and her mother for variants in other sarcomeric protein-encoding candidate genes, MYH7, MYBPC3, TNNT2, TNNI3, ACTC, MYL2, and MYL3, did not identify any other non-synonymous variants or variants in splice donor-acceptor sequences that were potentially disease causing. We conclude TPM1 is a potential candidate disease-causing gene for isolated LVNC, especially in patients experiencing sudden death.
Subject(s)
Death, Sudden, Cardiac , Heart Ventricles/pathology , Isolated Noncompaction of the Ventricular Myocardium/genetics , Mutation , Tropomyosin/genetics , Adaptor Proteins, Signal Transducing/genetics , Adult , Asian People/genetics , Child , Dystrophin-Associated Proteins/genetics , Electrocardiography , Female , Genotype , Heart Ventricles/diagnostic imaging , Humans , Isolated Noncompaction of the Ventricular Myocardium/pathology , LIM Domain Proteins , Male , Middle Aged , Neuropeptides/genetics , Pedigree , Polymorphism, Single Nucleotide , Ultrasonography , Young AdultABSTRACT
AIMS: The aim of this study was to investigate long-term proportion and prognosis of healthy subjects with right precordial ST segment elevation without family history of sudden death. METHODS AND RESULTS: We followed up electrocardiograms (ECGs) of 3339 healthy subjects (male/female 2646/693) who underwent periodical medical examination form 1992 to 2001 to determine the relationship between year-to-year changes of ST segment morphology and the risk of fatal arrhythmias. Inclusion criterion was defined as presenting either coved or saddle back type ST segment elevation (>0.2 mV) in the right precordial leads. The cumulative total subjects who showed Brugada-like ECG changes at least once throughout the follow-up period were 69 (male/female 67/2; age 47.9+/-8.9 years, 2.1% of total subjects). During a follow-up period, annual mean proportion of coved or saddle back type ST elevation in the right precordial leads was 1.22+/-0.23% (0.88-1.88%). The morphological pattern of ST segment elevation was saddle-back in 77.3+/-7.9% and coved in 22.7+/-7.9% of subjects. Throughout the follow-up period, 39 subjects (56.5%) showed changes in ST segment elevation pattern. Twenty-nine subjects (42.0%) showed normalization of ST segment elevation at least once. Sixty-nine subjects were followed for a period of one to 10 years (median 4 years, interquartile range 4-8 years). Only one subject with persistent saddle-back type ST elevation had episodes of ventricular fibrillation (VF). CONCLUSIONS: The average proportion of healthy subject who had coved or saddle-back type of ST elevation in the right precordial leads without family history of sudden death was 1.22% and the risk of fatal arrhythmias was low (1/393.5 subject-years).
