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Lien Lam

Publications and source records attributed to Lien Lam.

6 recordsLinked to original sources
PubMed2006

Abnormal cardiac response to exercise in a murine model of familial hypertrophic cardiomyopathy.

Clinical outcome in familial hypertrophic cardiomyopathy (FHC) may be influenced by modifying factors such as exercise. Transgenic mice which overexpress the human disease-causing cTnI gene mutation, Gly203Ser (designated cTnI-G203S), develop all the characteristic phenotypic features of FHC. To study the modifying effect of exercise in early disease, mice underwent swimming exercise at an early age prior to the development of the FHC phenotype. In non-transgenic and cTnI-wt mice, swimming resulted in a significant increase in left ventricular wall thickness and contractility on echocardiography, consistent with a physiological hypertrophic response to exercise. In contrast, cTnI-G203S mice showed no increase in these parameters, indicating an abnormal response to exercise. The lack of a physiological response to exercise may indicate an important novel mechanistic insight into the role of exercise in triggering adverse events in FHC.

Animals↗
PubMed2006

Molecular insights from a novel cardiac troponin I mouse model of familial hypertrophic cardiomyopathy.

Gene mutations in cardiac troponin I (cTnI) account for up to 5% of genotyped families with familial hypertrophic cardiomyopathy (FHC). Little is known about how cTnI mutations cause disease. Five lines of transgenic mice were generated which overexpress the human disease-causing cTnI gene mutation, Gly203Ser (designated cTnI-G203S), in a cardiac-specific manner. Mice were compared to transgenic mice that overexpress normal cTnI (cTnI-wt) and non-transgenic littermates (NTG). cTnI-G203S mice developed all the characteristic features of FHC by age 21 weeks. Left ventricular hypertrophy was observed on echocardiography (1.25+/-0.05 mm vs. 0.86+/-0.02 mm in cTnI-wt, P<0.01), associated with a significant 4-fold increase in RNA markers of hypertrophy, ANF and BNP. Myocyte hypertrophy, myofiber disarray and interstitial fibrosis were observed in cTnI-G203S mice. Expression of the cTnI-G203S mutation in neonatal cardiomyocytes resulted in a significant increase in myocyte volume, and reduced interactions with both troponins T and C. Ca2+ cycling was abnormal in adult cardiomyocytes extracted from cTnI-G203S mice, with a prolonged decay constant in Ca2+ transients and a reduced decay constant in response to caffeine treatment. Mice with the cTnI-G203S gene mutation develop all the phenotypic features of human FHC. The cTnI-G203S mutation disrupts interactions with partner proteins, and results in intracellular Ca2+ dysregulation early in life, suggesting a pathogenic role in development of FHC.

Animals↗
PubMed2006

Application of proteomics in cardiovascular medicine.

Proteomics is an emerging field that has the potential to uncover new therapeutic targets for the treatment and prevention of cardiovascular disease, as well as new diagnostic biomarkers for early disease detection. The basic strategy when carrying out proteomic analysis of cardiovascular disease is to compare the protein complements of diseased hearts or sera with controls. Any proteins that have altered expression between the two groups can be studied further for their involvement in disease pathogenesis. A number of steps need to be taken to identify changes in protein expression, including sample preparation, protein separation, imaging, and protein identification. Such studies are already underway in some cardiovascular conditions including dilated cardiomyopathy and atrial fibrillation. This review provides a summary of the techniques used in proteomic analysis and their application to cardiovascular research.

Cardiovascular Diseases↗
PubMed2005

Cardiac troponin I mutations in Australian families with hypertrophic cardiomyopathy: clinical, genetic and functional consequences.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder caused by mutations in sarcomeric proteins. Cardiac troponin I (cTnI) is a key switch molecule in the sarcomere. Mutations in cTnI have been identified in <1% of genotyped HCM families. METHODS: To study the prevalence, clinical significance and functional consequences of cTnI mutations, genetic testing was performed in 120 consecutive Australian families with HCM referred to a tertiary referral centre, and results correlated with clinical phenotype. Each cTnI mutation identified was tested in a mammalian two-hybrid system to evaluate the functional effects of these mutations on troponin complex interactions. RESULTS: Disease-causing missense mutations were identified in four families (3.3%). Two mutations were located at the same codon in exon 7 (R162G, R162P), and two in exon 8 (L198P, R204H). All four mutations change amino acid residues which are highly conserved and were not found in normal populations. Follow-up family screening has identified a total of seven clinically affected members in these four families, with a further four members who carry the gene mutation but have no clinical evidence of disease. Age at clinical presentation was variable (range 15-68 years) and the mean septal wall thickness was 19.3 +/- 4.6 mm (range 7-33 mm) in clinically affected individuals, including children. In all four families, at least one member had a sudden cardiac death event, including previous cardiac arrest, indicating a more malignant form of HCM. All four mutations disrupted functional interactions with troponin C and T and this may account for the increased severity of disease in these families. CONCLUSIONS: Gene mutations in cTnI occur in Australian families with HCM with a prevalence higher than previously reported and may be associated with a clinically more malignant course, reflecting significant disruptions to troponin complex interactions.

Adolescent↗
PubMedDate not supplied

Genes, calcium and modifying factors in hypertrophic cardiomyopathy.

1. Familial hypertrophic cardiomyopathy (FHC) is a primary disorder of the myocardium characterized by remarkable diversity in clinical presentations, ranging from no symptoms to severe heart failure and sudden cardiac death. 2. Over the past 15 years, at least 11 genes have been identified, defects of which cause FHC. Most of these genes encode proteins that comprise the basic contractile unit of the heart (i.e. the sarcomere). 3. Genetic studies are now beginning to have a major impact on the diagnosis in FHC, as well as in guiding treatment and preventative strategies. Although much is known about which genes cause disease, relatively little is known about the molecular steps leading from the gene defect to the clinical phenotype and what factors modify the expression of the mutant genes. 4. Concurrent studies in cell culture and animal models of FHC are now beginning to shed light on the signalling pathways involved in FHC and the role of both environmental and genetic modifying factors. Calcium dysregulation appears to be important in the pathogenesis of FHC. 5. Understanding these basic molecular mechanisms will ultimately improve our knowledge of the basic biology of heart muscle function and will therefore provide new avenues for diagnosis and treatment not only for FHC, but also for a range of human cardiovascular diseases.

Animals↗