Circ J 2009; 73: 1595 -1596 unctional abnormalities of cardiac troponin caused by either mutations or auto-antibodies can induce dilated cardiomyopathy (DCM), 1,2 which is characterized by left ventricular enlargement and systolic dysfunction resulting from a reduction in the myocardial force of contraction. DCM causes congestive heart failure, which can be treated with diuretics, angiotensin-converting enzyme inhibitors (or angiotensin type-I receptor blockers), β-adrenergic blockers, and most aggressively in unresponsive patients with cardiac transplantation. However, the prognosis of DCM is still poor, so there is a need for new therapeutic approaches.
Article p 1691Approximately 20-50% of cases of idiopathic DCM may have a genetic basis. Screening first-degree relatives of a proband with idiopathic DCM by echocardiography and electrocardiography reveals that 20-48% of probands have affected relatives, consistent with a diagnosis of familial DCM. Numerous large kindreds with familial DCM have provided the foundation for establishing genetic causation, and mutations in multiple genes have been shown to cause as shown in the website of GENE Reviews. 3 Current estimates indicate that the 20-plus known familial DCMcausing genes account for only a minority of cases of this disease. To understand its pathology, and with the ultimate hope of finding a treatment, researchers have generated genetic rodent models of heart failure. 4,5 On page 1691 of this issue of the Journal, Ho et al 6 describe their attempt to established a transgenic model of idiopathic DCM in zebrafish using microinjection of tissue-specific and inducible RNA interference with cardiac troponin C (TnC).Myocardial contraction results from interaction of the myosin with the actin in the myocardial thin filament. The thin filament is comprised of actin, tropomyosin and troponin. Troponin is a complex of 3 subunits, troponin T (TnT), troponin I (TnI), and TnC, each of which has distinct roles in the thin filament. Elevated [Ca 2+ ] leads to a conformational change in TnC, increasing its affinity for TnI, while the affinity of TnI for actin decreases. The conformational change in the troponin subunits allows tropomyosin to move out of the way of the actin active sites, so that myosin can attach and produce movement. Thus, TnC plays an important role in the cardiac excitation-contraction coupling process. Interfering with TnC can produce contractile dysfunction. In contrast, the calcium sensitivity of TnC can be enhanced with pimobendan or levosimendan. 7 These calcium sensitizers are attractive therapeutic agents for improving contractile dysfunction in congestive heart failure without increasing oxygen demand or producing Ca 2+ overload. 8 The zebrafish has a highly conserved cardiac TnC amino acid sequence compared with mammals, with a 90% homology in the 4 calcium-binding domains. Since the generation of the first transgenic zebrafish in 1988 by microinjecting naked DNA, 9 numerous transgenic zebrafish models have been developed. Although other app...