Editors' ChoiceCardiovascular Disease

Modeling a Failing Heart Right in the Dish

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Science Translational Medicine  06 Feb 2013:
Vol. 5, Issue 171, pp. 171ec25
DOI: 10.1126/scitranslmed.3005802

In ARVD/C (arrhythmogenic right ventricular dysplasia/cardiomyopathy)—an inherited dysplasia of the heart—cardiac muscle in the right ventricle is progressively replaced by fatty tissue. The disease shows up in adults, who can then develop abnormal heart rhythms and pump failure. An implanted defibrillator prevents sudden death, but does not remedy the ensuing heart failure. Kim et al. have now used induced pluripotent stem cells (iPSs) from two patients with ARVD/C to recreate this problematic disease in a dish.

Fibroblasts from the ARVD/C patients were exposed to four retroviral vectors carrying the pluripotent factors Oct4, Sox2, Klf4, and cMyc, giving rise to several iPS lines that were then differentiated into cardiomyocytes. Like the donor patients, the resulting beating embryoid bodies harbored a typical ARVD/C mutation in the desmosome gene (PKP2). Lipogenesis and apoptosis, the hallmarks of ARVD/C in humans, did not develop during baseline culture, mimicking the adult-onset character of ARVD/C. The mutant PKP2 cardiomyocytes underwent apoptosis and stained positive for lipids only after exposure to adult-like metabolic signals (insulin, dexamethasone, and 3-isobutyl-1-methilxanthine) and abnormal activation of peroxisome proliferator–activated receptor– α (PPAR-α) and PPAR-γ pathways. Under these “adult” conditions, the cells also exhibited altered Ca2+ handling and electrical properties, as do patients’ hearts. Reintroduction of the wild-type PKP2 gene rescued the cells’ phenotype, and fatty apoptosis of the cardiomyocytes did not occur. Blockade of PPAR-α or PPAR-γ activation with small-molecule antagonists inhibited lipogenesis and apoptosis of mutant PKP2 cardiomyocytes, indicating that activation of both of these enzymes is necessary (but not sufficient) for ARVD/C pathology.

Thus, Kim and colleagues recreated the typical features of right-ventricle failure of ARVD/C in cells derived from patient fibroblasts. This approach will enable further studies of this enigmatic disease, including investigations of other causative mutations and drug screens to discover a dedicated therapeutic agent.

C. Kim et al., Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. Nature, published online 27 January 2013 (10.1038/nature11799). [Full Text]

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