Cardiomyocyte substructure reverts to an immature phenotype during heart failure

Abstract

Key points As reactivation of the fetal gene program has been implicated in pathological remodelling during heart failure (HF), we examined whether cardiomyocyte subcellular structure and function revert to an immature phenotype during this disease. Surface and internal membrane structures appeared gradually during development, and returned to a juvenile state during HF. Similarly, dyadic junctions between the cell membrane and sarcoplasmic reticulum were progressively ‘packed’ with L‐type Ca2+ channels and ryanodine receptors during development, and ‘unpacked’ during HF. Despite similarities in subcellular structure, dyads were observed to be functional from early developmental stages, but exhibited an impaired ability to release Ca2+ in failing cardiomyocytes. Thus, while immature and failing cardiomyocytes share similarities in subcellular structure, these do not fully account for the marked impairment of Ca2+ homeostasis observed in HF. Abstract Reactivation of the fetal gene programme has been implicated as a driver of pathological cardiac remodelling. Here we examined whether pathological remodelling of cardiomyocyte substructure and function during heart failure (HF) reflects a reversion to an immature phenotype. Using scanning electron microscopy, we observed that Z‐grooves and t‐tubule openings at the cell surface appeared gradually during cardiac development, and disappeared during HF. Confocal and super‐resolution imaging within the cell interior revealed similar structural parallels; disorganization of t‐tubules in failing cells was strikingly reminiscent of the late stages of postnatal development, with fewer transverse elements and a high proportion of longitudinal tubules. Ryanodine receptors (RyRs) were observed to be laid down in advance of developing t‐tubules and similarly ‘orphaned’ in HF, although RyR distribution along Z‐lines was relatively sparse. Indeed, nanoscale imaging revealed coordinated packing of L‐type Ca2+ channels and RyRs into dyadic junctions during development, and orderly unpacking during HF. These findings support a ‘last in, first out’ paradigm, as the latest stages of dyadic structural development are reversed during disease. Paired imaging of t‐tubules and Ca2+ showed that the disorganized arrangement of dyads in immature and failing cells promoted desynchronized and slowed Ca2+ release in these two states. However, while developing cells exhibited efficient triggering of Ca2+ release at newly formed dyads, dyadic function was impaired in failing cells despite similar organization of Ca2+ handling proteins. Thus, pathologically deficient Ca2+ homeostasis during HF is only partly linked to the re‐emergence of immature subcellular structure, and additionally reflects lost dyadic functionality.

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“…However, with the progression of heart disease, such as HF, the disorganization of cardiomyocyte structure reflects a reversion to an immature phenotype manifested at both the cell surface and interior. 12 Interestingly, T-tubules are present in sheep cardiomyocytes during the embryonic period, which contrasts with previous findings. 13 The distribution of T-tubules varies not only among species but also across chambers.…”

“…Next, the number of longitudinal T‐tubules approached peak levels between 17.5 and 30 days after birth before decreasing in density as the cell reached adulthood. However, with the progression of heart disease, such as HF, the disorganization of cardiomyocyte structure reflects a reversion to an immature phenotype manifested at both the cell surface and interior . Interestingly, T‐tubules are present in sheep cardiomyocytes during the embryonic period, which contrasts with previous findings …”

Reply from M. Frisk, D. B. Lipsett and W. E. Louch

“…We similarly examined only the early, pre‐contractile phase of Ca 2+ release (see Figs 8 and 9 in Lipsett et al . ). For similar reasons, we have not examined beat‐to‐beat stochasticity of local electrical or Ca 2+ fluorescence.…”

“…In their letter to the Editor, Crocini and colleagues comment on our recent article (Lipsett et al . ) published in The Journal of Physiology . In this article, we reported striking changes in cardiomyocyte substructure during heart failure, with reemergence of an immature phenotype.…”

Letter to the Editor

“…In their study recently published in The Journal of Physiology , Lipsett et al . (2019) attempted to explain t‐tubular defects observed in pathological cardiac remodelling during heart failure (HF) as the result of reactivation of the fetal gene programme in cardiomyocytes. In fact, fetal cardiomyocytes show rudimentary t‐tubular architecture, structurally similar to t‐tubules of HF cardiomyocytes.…”