• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • Two other groups subsequently published


    Two other groups subsequently published further data on iPSCs models of ARVC that have improved our understanding of this disease. Kim et al. developed iPSC models using episomal methods from 2 ARVC patients, as well as with PKP2 mutations . Detailed electrophysiological characterization of mutant and control cardiomyocytes and alteration of the external pathogenic conditions using hormones and small molecules resulted in accelerated pathogenesis of the adult-onset phenotype. Important changes in intracellular calcium handling in mutant iPSC-derived cardiomyocytes were also observed, as well as the induction of adult-like metabolism and abnormal peroxisome proliferator-activated receptor gamma (PPAR-γ) activation, which were important in the pathogenesis of ARVC. To explain the predominant pathological characteristics of ARVC in the right ventricle, the investigators increased the number of Islet 1-positive cardiac progenitor order Forskolin by approximately 4-fold in mutant PKP2 iPSCs, simulating natural right ventricle formation of the secondary heart field. Caspi et al. also modeled ARVC from 2 patients with PKP2 mutations . Similarly, they found reduced PKP2 and plakoglobin expression as well as increased adipogenicity in ARVC cells, along with upregulation of PPAR-γ. Additionally, they found that the degree of adipogenicity was order Forskolin closely related to the extent of desmosomal abnormalities, suggesting “crosstalk” between desmosomal destruction and adipogenesis, and that ARVC cardiomyocytes were at an increased risk of apoptosis. Despite important advances in our understanding of inherited cardiovascular diseases based on patient-specific iPSC-models, the technology remains challenging and shows some limitations . The currently used models predominantly involve single cells; thus, it is unclear whether these cells replicate more complex processes involving synchronized groups of beating cardiomyocytes at the tissue or organ level, rather than just at the cardiomyocyte level. The currently used models do not fully assess the pathophysiological changes that may affect cell–cell interactions, which may play a role in diseases such as ARVC. Models must be refined to include layers of synchronized functional cardiomyocytes and explore the intercellular interactions in mutant and control cells. Furthermore, ARVC and other cardiomyopathies such as dilated cardiomyopathy are predominantly adult-onset diseases. Because iPSC-derived cardiomyocytes are relatively immature cells, it is unclear whether the changes observed in these cells truly reflect all pathophysiological changes in adult cells. Several novel methods have recently been reported, and they may improve the maturation of iPSC-derived cardiomyocytes and thus help overcome this limitation. These techniques include prolonged cell culture , bio-mimetic culturing using forced expression of Kir2.1 , and using a novel platform (consisting of biowires submitted to electrical stimulation) which combines 3-dimensional cell cultivation with electrical stimulation . Finally, although ARVC iPSC-models described to date show adipogenic changes in mutant cells , the precise mechanisms and external factors responsible for these changes in ARVC patients remain unknown.
    Introduction In patients with advanced heart failure (HF), recurrent spontaneous ventricular fibrillation (SVF)/electrical storm (ES) is a frequent complication requiring multiple defibrillation shocks within a short space of time. The mechanism underlying initiation of SVF/ES, spontaneously or immediately after defibrillation shocks, remains unclear. In 2009, Ogawa et al. developed a pacing-induced HF model, in which SVF occurred frequently in failing rabbit ventricles [1]. In that model, acute but reversible post-shock action potential duration (APD) shortening could induce recurrent SVF (Fig. 1, panel A) [1]. The induction of SVF was associated with persistent intracellular calcium (Cai) elevation during late phase 3 and/or phase 4 of the action potential (AP), indicating that APD shortening, in conjunction with persistent post-shock Cai elevation, is a novel mechanism of post-shock SVF/ES [1]. However, the mechanisms underlying acute APD shortening after fibrillation/defibrillation episodes in HF ventricles remains to be determined.