Jessica Chung

Centenary Institute, Camperdown, New South Wales, Australia

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Publications (5)28 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    International journal of cardiology 08/2007; 119(2):245-8. DOI:10.1016/j.ijcard.2006.09.001 · 6.18 Impact Factor
  • Journal of Molecular and Cellular Cardiology 10/2006; 41(4):747-747. DOI:10.1016/j.yjmcc.2006.06.055 · 5.22 Impact Factor
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    ABSTRACT: 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.
    Journal of Molecular and Cellular Cardiology 10/2006; 41(4):623-32. DOI:10.1016/j.yjmcc.2006.07.016 · 5.22 Impact Factor
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    ABSTRACT: 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. 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. 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. 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.
    Journal of Molecular and Cellular Cardiology 02/2005; 38(2):387-93. DOI:10.1016/j.yjmcc.2004.12.006 · 5.22 Impact Factor
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    ABSTRACT: Hypertrophic cardiomyopathy is an inherited primary disorder of the myocardium characterised by clinical heterogeneity. The severity and rate of progression of hypertrophy is an important factor in prognosis, and is likely to be dependent on factors including age, the disease-causing gene mutation, environmental influences and genetic modifiers. To study the influence of age on progression of hypertrophy, 62 patients with hypertrophic cardiomyopathy followed up for a minimum of 2 years were studied to determine the changes in left ventricular hypertrophy based on transthoracic M-mode and 2D echocardiography. DNA studies were performed to determine the role of the angiotensin-converting enzyme (ACE) gene deletion polymorphism in modulating progression of left ventricular hypertrophy. Sixty-two patients were followed-up over a period of 6.0 +/- 3.2 years (range 2-16 years). Patient data were analysed in two age groups: group 1 (patients aged < or = 30 years at first echocardiogram) had an increase in left ventricular septal wall thickness from 23.8 +/- 8.9 to 28.8 +/- 8.7 mm (p < 0.001), while group 2 (patients aged > 30 years) had a smaller but significant increase from 17.8 +/- 4.2 to 19.5 +/- 6.2 mm (p < 0.05). DNA analysis of the ACE gene deletion polymorphism showed those with the deletion/deletion (D/D) genotype had a greater progression of left ventricular hypertrophy compared to those carrying the other ACE genotypes (increase in hypertrophy: 6.2 +/- 3.3 vs. 1.7 +/- 4.2 mm; p < 0.01, D/D vs. I/D genotype; 2.8 +/- 5.8 mm; p = ns, D/D vs. I/I genotype). This association was independent of age, body mass and resting blood pressure. Progression of left ventricular hypertrophy is most evident in the first 3 decades of life, but is also observed in older age groups. Presence of the ACE gene D/D polymorphism may be an important marker to identify those individuals with hypertrophic cardiomyopathy who are likely to have more progressive disease, and therefore at higher risk of adverse clinical outcomes.
    International Journal of Cardiology 08/2004; 96(2):157-63. DOI:10.1016/j.ijcard.2004.05.003 · 6.18 Impact Factor